Download phosphoinositides: tiny lipids with giant impact on cell regulation

Physiol Rev 93: 1019 –1137, 2013
doi:10.1152/physrev.00028.2012
PHOSPHOINOSITIDES: TINY LIPIDS WITH GIANT
IMPACT ON CELL REGULATION
Tamas Balla
Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver
National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
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INTRODUCTION
THE BASICS: PHOSPHOINOSITIDE...
HISTORICAL OVERVIEW
PHOSPHATIDYLINOSITOL SYNTHESIS
PHOSPHOINOSITIDE KINASES
PHOSPHOINOSITIDE PHOSPHATASES
PHOSPHOLIPASE C ENZYMES
PHOSPHATIDYLINOSITOL TRANSFER...
PHOSPHOINOSITIDES AT THE...
PHOSPHOINOSITIDES IN INTERNAL...
PHOSPHOINOSITIDES IN DISEASE
CONCLUDING REMARKS
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I. INTRODUCTION
It is hard to define the research interest of people who study
polyphosphoinositides (PPIs). Naturally, PPIs are lipid molecules, yet many researchers who study PPIs did not initially
have a primary interest in lipids. Many of us have gotten
interested in PPIs when these lipids became known as the
source of second messengers in transducing signals from cell
surface receptors. The spectacular progress in the 1980s in
defining the pathways by which G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) activated phospholipase C (PLC) enzymes had a major impact
on many scientists who showed interest in transmembrane
signaling. However, cell biologists also developed immense
interest in PPIs because of the importance of PPIs in shaping
the membranes and controlling vesicular trafficking and
organelle physiology. The attention of scientists who
study ion channels also turned toward PPIs as it became
obvious that many channels or transporters require PPIs
for their activity or control. The discovery of phosphatidylinositol 3-kinases (PI3Ks) has set the stage to widen
research interest in PPIs: association of PI3K with oncogenic as well as RTKs and their strong ties with cancer
biology has won over cancer researchers, while the importance of PPIs in immune cell functions, chemotaxis,
and secretion brought immunologists to the field. If this
had not been enough, researchers working with infectious diseases noted that many pathogenic organisms
possess enzymes essential for their pathogenic nature that
act upon PPIs to invade cells or use the host cells’ PPI
machinery to evade natural defense mechanisms or reprogram cells to produce the pathogen. Neuroscientists
also discovered that synaptic vesicle exocytosis and recycling requires phosphoinositides at multiple steps and
that brain development, including neurite outgrowth and
axon guidance, is highly dependent on PPIs. Even the invertebrate photo-sensing and signal transduction is dependent on
PPIs, further extending the group of scientists showing interest
in PPIs. This selected and probably incomplete list increases
every day as more and more cellular processes are linked to
these universal lipid regulators.
0031-9333/13 Copyright © 2013 the American Physiological Society
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Balla, T. Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation. Physiol Rev
93: 1019 –1137, 2013; doi:10.1152/physrev.00028.2012.—Phosphoinositides (PIs)
make up only a small fraction of cellular phospholipids, yet they control almost all aspects
of a cell’s life and death. These lipids gained tremendous research interest as plasma
membrane signaling molecules when discovered in the 1970s and 1980s. Research in
the last 15 years has added a wide range of biological processes regulated by PIs, turning these lipids
into one of the most universal signaling entities in eukaryotic cells. PIs control organelle biology by
regulating vesicular trafficking, but they also modulate lipid distribution and metabolism via their close
relationship with lipid transfer proteins. PIs regulate ion channels, pumps, and transporters and control
both endocytic and exocytic processes. The nuclear phosphoinositides have grown from being an
epiphenomenon to a research area of its own. As expected from such pleiotropic regulators, derangements of phosphoinositide metabolism are responsible for a number of human diseases ranging from
rare genetic disorders to the most common ones such as cancer, obesity, and diabetes. Moreover, it
is increasingly evident that a number of infectious agents hijack the PI regulatory systems of host cells
for their intracellular movements, replication, and assembly. As a result, PI converting enzymes began
to be noticed by pharmaceutical companies as potential therapeutic targets. This review is an attempt
to give an overview of this enormous research field focusing on major developments in diverse areas of
basic science linked to cellular physiology and disease.
TAMAS BALLA
With the spectacular expansion of the PI field, it has become
impossible to cover all aspects of PPI regulation at great
depth in a comprehensive review. In the following overview
I will attempt to describe the most basic features of the
enzymes that synthesize and degrade PPIs and focus on
aspects of this diverse research field that highlight general
principles that govern PI-mediated regulation of the many
different processes. For a more comprehensive analysis and
deeper understanding of the details of the individual processes and their PPI regulation, the reader is referred to the
many excellent reviews that have been published over the
years and ones that are likely still in preparation. Soluble
inositol phosphates partly liberated from inositol lipids and
further phosphorylated to highly charged inositol polyphosphates also represent a research topic of great interest but will
not be discussed here. The interested reader will find excellent
reviews on that topic (29, 1079, 1390). Another aspect of
PtdIns function not covered here is related to PtdIns serving
as an anchor for a selected group of proteins found on the
cell surface linked to the 6-position of the inositol ring
through glycan linkages. More about the biology of these
GPI-anchored proteins can be found in several comprehensive reviews (473, 1200).
II. THE BASICS: PHOSPHOINOSITIDE
STRUCTURES AND ENZYMOLOGY
Polyphosphoinositides are phosphorylated derivatives of PtdIns
generated by a number of kinases and phosphatases that act upon
their membrane-bound lipid substrates (FIGURE 1). Phosphorylation occurs in one of the -OH groups of the inositol ring of
PtdIns that is linked to the diacylglycerol (DG) backbone
via a phosphodiester linkage utilizing the -OH group of the
ring at the D1 position. PtdIns contains myo-inositol that
assumes a “chair” conformation with five of its six -OH
groups being equatorial and the one at position 2 being
axial. The best visual representation of the myo-inositol
structure and ring numbering was introduced by Bernard
William Agranoff in 1978, who likened the “chair” structure of myo-inositol to a turtle whose body represents the
inositol ring and the numbering starts at the right front
flipper and proceeds counterclockwise through the head
and the other appendages (9) (FIGURE 1A). Since the turtle is
taken through its right flipper by the DG backbone, it leaves
five hydroxyls for phosphorylation, but only three of these
(positions -3, -4, and -5) are actually phosphorylated in
naturally occurring PPIs according to current knowledge.
The combination of these phosphorylations gives rise to the
seven known PPIs (FIGURE 1B). A distinctive feature of PPIs
is their enrichment in arachidonic acid at the sn-2 position
of their glycerol backbone. The majority of the PPIs is the
1-stearoyl-2 arachidonyl form, and it has been a puzzling
question where this enrichment takes place and what role
deacylation-reacylation cycles play in determining this
composition. It has been suggested that enzymes responsible for PtdIns synthesis and phosphorylation may show
preference to the form(s) of lipids esterified with arachidonic acid at the sn-2 position (405). Arachidonate-rich
phosphoinositides are also believed to be the source of
PLA2-mediated arachidonate release for the synthesis of
prostaglandins and leukotrienes.
The amounts of PPIs within cells have been estimated in
different cells and tissues (1121, 1703). These estimates and
measurements show significant variations. PtdIns represents ⬃10 –20% (mol%) of total cellular phospholipids,
whereas PtdIns4P and PtdIns(4,5)P2 constitute ⬃0.2–1%.
Based on long-term [3H]inositol labeling, PtdIns4P and
PtdIns(4,5)P2 have about 2–5% of the labeling relative to
PtdIns (e.g., Ref. 87). Recent estimates of PtdIns(4,5)P2
density in the plasma membrane (PM) ranged between
5,000 –20,000 molecules/␮m2 (421). The other PPIs contribute even smaller amounts, PtdIns(3,4,5)P3 being about
2–5% of PtdIns(4,5)P2 and PtdIns3P about 20 –30% of
PtdIns4P. It is noteworthy that these ratios show great tis-
FIGURE 1. Phosphoinositide basics. A: Agranoff’s turtle demonstrating the orientation of the hydroxyl groups in myo-inositol. B: interconversions between various phosphoinositides and the enzymes catalyzing these reactions. The yeast enzymes are listed in parentheses. Where there
is some ambiguity it is indicated by “??”. *It is worth pointing out that contrary to their designation, PIP5K2s are 4-kinases that act on PtdIns5P.
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Such an ever-expanding list of processes regulated by PPIs
begs an answer to the fundamental question of how and
why these lipids gained such a pivotal role in eukaryotic cell
regulation during evolution? What structural and functional features make these molecules so widely used and so
adaptable to support the functions of a variety of signaling
complexes? We have only begun to ask, let alone answer
these questions for which evolution may give us some clues.
Although PIs have been detected in mycobacteria, their appearance in evolution coincides with the development of
internal membranes and organelles. Remarkably, PI kinases
surfaced earlier in evolution than tyrosine kinases (190,
986) with common ancestors being a group of serine-threonine kinases, called the PI-kinase related kinases (190, 669).
The latter enzymes are all functionally linked to DNA damage
control and repair (190, 1350, 1422). PtdIns is unique
among phospholipids in that it is a rich phosphorylation
target at the cytoplasmic surface of any cellular membrane. In their phosphorylated forms, PPIs can serve as
critical reference points for a great variety of proteins to
find their docking destinations and/or change their conformation. This is true for cytosolic proteins that are
recruited to the membrane by PPIs, as well as for peripheral or integral membrane proteins whose membrane adjacent regions or cytoplasmic “tails” show interaction
with PPIs.
PHOSPHOINOSITIDES
A
Stearoyl
Arachidonyl
1
2
HO
6
2
O
OH
HO
5
O
6
1
OH
4
3
HO P
OH
5
O
O
2
OH
6
1
HO
3
4
OH
OH
5
OH
3
4
Agranoff’s turtle
myo-inositol
PtdIns
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PtdIns
B
1
8
2
8
8
3
11
PtdIns4P
4
9
10
PtdIns(4,5)P2
7
14
PtdIns3P
PtdIns5P
5
11
PtdIns(3,4)P2
12
6
13
PtdIns(3,5)P2
15
PtdIns(3,4,5)P3
Kinases
Phosphatases
1. PI4KA, PI4KB,PI4K2A, PI4K2B
(Stt4, Pik1, Lsb6)
2. PIP5K3/PIKfyve ??
3. PI3KC3,(Vps34), PI3KC2A
4. PIP5K1A, PIP5K1B, PIP5K1C (Mss4)
5. PIP5K2A*, PIP5K2B*, PIP5K2C*
6. PIP5K3/PIKfyve (Fab1)
7. PI3KCA, PI3KCB, PI3KCG, PI3KCD
8. SAC1M1L, (Sac1), SYNJ1/2 ??
9. SYNJ1, SYNJ2, OCRL, INPP5B, INPP5E,
INPP5F, (Inp51, Inp52, Inp53)
10. TMEM55 ??
11. MTMs, MTMRs
12. INPP4A, INPP4B
13. SAC3 (Fig4)
14. PTEN
15. SHIP1, SHIP2, INPP5E, INPP5J, INPP5K
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TAMAS BALLA
sue variations and they are also very different in yeast and plants.
Yeast do not have detectable amounts of PtdIns(3,4,5)P3 and
some plants have a lot more PtdIns4P relative to a smaller
pool of PtdIns(4,5)P2, and it is not clear if PtdIns(3,4,5)P3 is
at all present in plants (1093, 1469). Remarkably, yeast and
plant orthologs of the mammalian PTEN enzyme that has a
critical role in PtdIns(3,4,5)P3 dephosphorylation have
been found in spite of the apparent lack of detectable
PtdIns(3,4,5)P3 in these organisms (611).
The two main routes of PPI elimination are through dephosphorylation by PPI phosphatases and hydrolysis by phosphoinositide-specific phospholipase C enzymes (PLCs).
Some of the PPI phosphatases are quite specific for the position of the phosphate group that they remove, while others, mainly the ones that dephosphorylate monophosphorylated PPIs, are more promiscuous and their functional
specificity lies in their localization. The diversity of the PPI
phosphatases parallels, in fact, exceeds that of the kinases
(FIGURE 1B), and several human diseases have been traced
to the dysfunction of PPI phosphatases (see sect. VI). The
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Although individual groups of PPI metabolizing enzymes
will be featured in more details below, a few important
general questions are worth highlighting here. The first is
related to their substrate recognition. Most, if not all, of the
PPI kinase and phosphatase enzymes are loosely membrane-associated peripheral membrane proteins that utilize
a substrate that is part of the membrane with the inositol
headgroup facing the cytoplasmic leaflet of the membrane.
When enzyme activities of these proteins are measured in
vitro, the assay usually contains the lipid substrate in some
form of lipid micelle, and the type and amount of detergent
yielding optimal activity greatly differ for each of these
enzymes. For example, the in vitro activity of PI 4-kinases
depends on the presence of detergents such as Triton X-100,
while those of the class I PI 3-kinases are inhibited by detergents and the activity of class III PI 3-kinases are usually
assayed in the presence of Mn2⫹ instead of the usual Mg2⫹.
Overexpression in cells of some of the PI kinases (such as
the type III PI 4-kinases) hardly yields an increase in the
phosphorylation of their endogenous lipid substrates. This
indicates that the mechanism(s) that ensure recruitment of
the enzymes to the membrane and their access to the membrane-bound PtdIns substrate are major determinants of
their in situ activities. Few studies have been designed to
understand the exact nature of the lipid substrate PI kinase
interactions, and most of the solved structures of the kinase
enzymes do not resolve the activation loop (a mobile part of
the molecule that is critical for substrate presentation)
within their catalytic center. Similarly, the lipid substrate in
these structures is either missing or, if present, was provided
in the form of a soluble inositol-phosphate headgroup.
Therefore, there is a major gap in our understanding of how
these enzymes work in their natural membrane environment.
Phosphoinositides affect cellular functions by interacting with
molecules that either reside in the membrane, such as ion channels and transporters, or get recruited to the membrane by
reversible mechanisms. Several signaling molecules are recruited to the membrane through interaction with PPIs via
inositide-binding protein modules (see TABLE 1). The first
such protein module was identified in pleckstrin (574), and
ever since, the homologous modules have been termed
pleckstrin homology (PH) domains. PH domains are present in a large number of regulatory molecules (296). It is
important to note, however, that not all PH domains bind
lipids and probably all PH domains also bind proteins
(880). Often simultaneous protein and lipid binding are
required for the membrane recruitment or conformational
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PtdIns is synthesized in the endoplasmic reticulum from
CDP-DAG and myo-inositol by a PtdIns synthase (PIS) enzyme (11) (see sect. IV) and is then distributed throughout
the cell presumably by several PI transfer proteins (PITPs)
(277, 689) and possibly via vesicular trafficking. Our recent
studies identified the PIS enzyme in an ER-derived highly
mobile “organelle” that may serve as a dynamic PtdIns
distribution device (796). Early studies already detected the
phosphorylation reaction generating two “polyphosphoinositides” that had been previously described in the brain
and determined to be PtdIns4P and PtdIns(4,5)P2 (186),
thereby postulating PtdIns kinase (PI-kinase) and PtdInsP
kinase (PIP kinase) activities associated with membranes
(1044). Although these enzymatic activities were associated
with various membrane fractions in fractionated tissues,
and they showed even some unique features (like sensitivity
to different detergents), the general consensus that emerged
from these studies was that PI- and PIP-kinase activities
were primarily present in the PM, serving what has become
known as the signaling pool of PPIs (see sect. III). However,
by now it is apparent that multiple isoforms of almost all of
the kinase and phosphatase enzymes act upon PPIs, and
they do so in different cellular compartments. This explains
why in most cases these enzymes are not functionally redundant even if they catalyze the same biochemical reaction.
The mechanism(s) that determine the intracellular localization and regulation of the PI kinase and phosphatase enzymes became a central question for each family of these
proteins. Generally speaking, most PtdIns mono-phosphorylations (by the PI4Ks and Class III PI3K) occur in endomembranes,
such as the endosomes and the Golgi/trans-Golgi network,
whereas the phosphorylation of PtdIns4P to PtdIns(4,5)P2 by PIP
5-kinases and further to PtdIns(3,4,5)P3 by class I PI3Ks occurs
primarily at the PM.
diversity of phosphoinositide-specific PLCs is also remarkable (see sect. VII). The preferred in vivo substrate of the
mammalian PLC enzymes is believed to be PtdIns(4,5)P2,
although this question has not been satisfactorily answered
in whole cell studies and purified PLC enzymes can also
hydrolyze PtdIns4P and PtdIns in vitro.
PHOSPHOINOSITIDES
Table 1. Inositide binding domains
Name of Domain
Pleckstrin homology (PH) domains
change of PH domains; hence, these (and other PI binding
modules) are called coincidence detectors (214). Most frequently the protein input for PH domains come from interaction with small GTP binding proteins. Other domains,
such as the FERM domains link the actin cytoskeleton to
the PM (255). Both FERM and GLUE-domains contain a
structural fold similar to that of PTB (phosphotyrosine
binding) or PH domains (1062, 1416). EHD domains
(1120) and BAR domains also bind anionic lipids including
inositol lipids and also sense and/or generate membrane
curvatures (466). This list is ever expanding and now also
includes PDZ domains (1825) and the KA1 domain, a novel
fold found at the COOH terminus of a range of proteins and
which binds PtdIns(4,5)P2 but also other anionic phospholipids such as PS (1083). A recently described PtdIns(3,4,5)P3
binding domain found at the COOH termini of some IQ
domain containing GAP proteins has a structure reminiscent of the integral fold of C2 domains (363). In addition,
several proteins contain polybasic stretches that do not
amount to a characteristic domain, but also interact with
acidic phospholipids with electrostatic interaction. Good
examples are the MARCKS proteins (1670) and the K-Ras
COOH terminus (601), but many other proteins show
membrane association using this mechanism. Importantly,
many of these targeting sequences can use PtdIns4P as well
as PtdIns(4,5)P2 as their membrane anchor lipid (559).
III. HISTORICAL OVERVIEW
Although one can argue that a newcomer to a field can
benefit from not being biased by existing dogmas, ignorance
PtdIns(4,5)P2
PtdIns4P
PtdIns(3,4,5)P3
Reference Nos.
574, 882
381, 895
PtdIns(3,4)P2
PtdIns3P
478, 1252, 1627
381, 460
1457
PtdIns3P
PtdIns(4,5)P2
PtdIns(4,5)P2
PtdIns(4,5)P2
1721
877
877
255
PtdIns(4,5)P2
PtdIns(3,4,5)P3
PtdIns(4,5)P2, PtdIns4P
PtdIns(4,5)P2, other lipids
PtdIns(4,5)P2
Acidic phospholipids, PS
1062
1416
1120
1211, 1607
1825
1083
of the history of a research field and lack of understanding
of the milestones and breakthroughs are making it difficult,
if not impossible, to put any new research findings into
perspective. One also has to know and respect the contribution of the scientists whose findings serve as the foundation upon which new knowledge can be built. Therefore, I
give a short overview of the field that is certainly biased by
my experiences, but can still give some ideas about the
major milestones as this research field has evolved. Several
reviews and recollections have been published on the historical aspects of this huge research field, and they are
highly recommended for interested readers (10, 634, 701,
1039).
Inositol had already been discovered as a component of
muscle by the end of the 19th century and its structure
established as a hexa-hydroxyl-cyclohexane (990). Nine
different stereoisomers of inositol were described in the
1940s, and myo-inositol was found to be the main eukaryotic isomer (1234). The importance of inositol was
recognized in the era of vitamins when it was realized
that inositol was an important dietary ingredient for rodents, especially when animals were kept in germ-free
conditions. Animals kept on inositol-free diets developed
alopecia and “fatty liver” (reviewed in Ref. 642). Subsequently, it was found that mammalian cells required
myo-inositol to grow properly in culture (394). In the
fungus neurospora, lack of inositol caused a defect in lysosomal membrane integrity and autolysis (1006). The notion
that inositol was a component of lipid membranes was first
recognized in mycobacteria [the lipid was phosphatidylinosi-
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FYVE domains
(named after the four proteins in which they were first identified:
Fab1,YOTB/ZK632, Vac1p, and EEA1)
Phox homology (PX) domains
ENTH (epsin NH2-terminal homology)
ANTH (AP180 NH2-terminal homology)
FERM domains
(named after the first proteins in which they were found:
4.1-ezrin-radexin-moiesin)
PTB domain
GLUE domain
Eps15 homology (EHD) domains
BAR (Bin–Amphiphysin–Rvs)
PDZ domain
KA1 (kinase-associated 1) domain
Lipid Species
TAMAS BALLA
tol mannoside (96)] and a phosphoinositide was also described in soybean (803).
A. Identification of Phosphoinositides and
Their Metabolic Fate
To understand the meaning of their 32P labeling, it was
essential to understand the synthetic and degradation pathways of PPIs. From the pioneering work of Eugene Kennedy
and his colleagues on the synthesis of glycerolipids, it had
been understood that cytidine nucleotide intermediates
(such as CDP-choline and CDP-ethanolamine) donate the
headgroups to the sn-1,2-DG backbone during phosphatidylcholine and -ethanolamine synthesis. However, Bernard
Agranoff and his colleagues found that this was not the case
for PtdIns. Here, the lipid backbone itself was “activated”
by the cytidine nucleotide in the form of CDP-DG (11).
Since the precursor of this intermediate is phosphatidic acid
(PtdOH), which is produced by phosphorylation of sn1,2-DG by a DG kinase using the terminal phosphate of
ATP, described by Hokin and Hokin (640), an alternative
name of CMP-PtdOH was suggested, to indicate that the
phosphate was carried over to PtdIns not from CTP but
ATP. PtdIns synthesis was found primarily associated with
“microsomal” fractions and hence attributed to the ER, but
CDP-DG is also a precursor of the mitochondrial lipids
phosphatidylglycerol and cardiolipin (324), suggesting an
important compartmentalization of these metabolic pathways.
Several studies then indicated that DPI was a phosphorylation product by PtdIns kinase activities associated with various membrane fractions (283, 636, 1044), including the
1024
The very rapid labeling kinetics of PtdIns(4,5)P2 and
PtdIns4P in erythrocyte membrane and in intact cells relative to the much slower labeling kinetics of PtdIns and other
phospholipids suggested high turnovers of the phosphomonoester groups due to rapid “futile” phosphorylationdephosphorylation cycles (reviewed in Ref. 385). This also
indicated that dephosphorylation of the monophosphate
groups and rephosphorylation can all take place in the PM.
PLC activities were then found in several tissues both in
soluble and membrane fractions (464, 775), and association of PLC activity with the PM was also described (852,
1047). The distribution of PLC activities between soluble
and membrane fractions and the enzymatic characteristics
of the activities associated with different fractions showed
significant variations between various laboratories (e.g., see
Ref. 702). These discrepancies are now better understood
knowing how many PLC enzymes and membrane-recruitment mechanisms exist (see sect. VII).
B. Agonists Stimulate Phosphoinositide
Metabolism
In 1953 Mabel and Lowell Hokin (638) reported that
[32P]phosphate incorporation into a phospholipid fraction
was strikingly increased in the exocrine pancreas when the
tissue was stimulated with secretagogues that induced protein secretion. In a series of subsequent work (635), the
Hokins found that the increased 32P-labeling was limited to
the two lipids, “DPI” and PtdOH that were identified by
Dawson as acutely 32P-labeled in the brain slices (328). The
Hokins also found that this increase was a general phenomenon observed in various cells associated with a stimulated
secretion response (635). They suggested that the primary
response was an increased phosphoinositide-specific PLC-catalyzed hydrolysis of PtdIns with production of DG, which was
then converted to PtdOH (a step where the 32P incorporation
took place) and then back to PtdIns to complete a cycle that
was dubbed the “PI cycle” (639) (FIGURE 2A). These studies
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The real beginning of the “modern” era of PI research
was marked by a series of ground-breaking studies in the
1940s by Jordi Folch who identified inositol in the ethanol-insoluble phospholipid fraction of bovine brain and
determined that it contained phosphates and inositol in a
molar ratio of 2:1 (450). This lipid, termed diphosphoinositide or DPI, was found primarily in myelin in tight
association with proteins (“neurokeratin”) (449) and showed
rapid metabolic labeling when guinea pigs were injected
with [32P-⶿]phosphate (328, 329). Subsequent work mainly
by three groups (led by Clinton Ballou, Rex Dawson, and
Tim Hawthorne) identified the structures of mono-, di-, and
tri-phosphoinositides (abbreviated at the time as MPI, DPI,
and TPI, respectively) as glycerophospholipids with an inositol ring linked to an sn-1,2-DG backbone via the D1-OH
group of myo-inositol, and containing a phosphate at the 4and both the 4- and 5-positions, in DPI and TPI, respectively (359, 581, 1563). Although these lipids had been
isolated and identified primarily from brain, where they are
most abundant, it had become evident by the early 1960s
that they were present in small amounts in all eukaryotic
tissues (1651).
PM (1043) and, importantly, similar activities were also
present in red blood cell membranes where it was possible
to show generation of PtdIns4P and PtdIns(4,5)P2 by presumed sequential phosphorylations of PtdIns (636). These
observations, together with the notion that PPIs were highly
enriched in myelin sheets that are essentially rolled up
plasma membranes, gave strong support to the idea that
PPIs were primarily associated with the PM. The metabolism of DPI and TPI was also explored in early studies.
Sloane-Stanley identified a phospholipase C (PLC) activity
(although not called it PLC yet) capable of hydrolyzing
brain phosphoinositides (1420), and Rodnight found this
activity increased by Ca2⫹ (1276). These early observations
were followed by the realization that TPI is metabolized in
two different ways: one route with dephosphorylation to
DPI and PtdIns and another, via hydrolysis to InsP3 and
diacylglycerol (what is now known as PLC) (1554).
PHOSPHOINOSITIDES
A
PtdIns
PLC
DG
ATP
DGK
PtdIns
PtdOH
PIS
CDS
CTP
inositol
CDP-DG
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B
Plasma membrane
PtdIns
PtdIns(4,5)P2
PtdIns4P
PI4K
PIP5K
DG
PLC
PtdOH
DGK
Ins(1,4,5)P3
PITPs?
?
Li+
Inositol
PtdIns
PIS
CDP-DG
CDS
PtdOH
ER membrane
FIGURE 2. The phosphoinositide cycle as originally perceived (A) and the updated version also showing the
polyphosphoinositides, PtdIns4P and PtdIns(4,5)P2 (B). The primary event in triggering the cycle is the agonistinduced PLC activation. Note that all of the products of PtdIns(4,5)P2 hydrolysis are recycled. Diacylglycerol (DG) is
converted to phosphatidic acid (PtdOH) by one of many DG-kinase enzymes (DGK). PtdOH then has to be transferred
from the PM to the endoplasmic reticulum by a mechanism that has not been identified. In the ER, one of two
CDP-DG synthase (CDS) enzymes conjugates PtdOH with CTP, and the CDP-DG is then conjugated with myo-inositol
to phosphatdylinositol (PtdIns). PtdIns synthesis takes place mainly in a highly dynamic subcompartment of the ER.
Much of the inositol used for PtdIns synthesis is derived from the sequential dephosphorylation of inositol 1,4,5trisphosphate [Ins(1,4,5)P3], the other product of PLC-mediated PtdIns(4,5)P2 hydrolysis. Several of the dephosphorylation steps are inhibited by Li⫹, including the final dephosphorylation of inositol monophosphates by the
enzyme inositol monophosphatase (IMP). The newly synthesized PtdIns has to reach the PM by a still obscure
mechanism, perhaps mediated by PtdIns/PtdCho transfer proteins (PITPs).
implicated PIs in secretion, but how increased inositide labeling was linked to any specific biochemical process in
secretion remained elusive. In fact, more and more studies
indicated that the increased PI turnover could be dissociated
from secretion: it was observed in cells and with stimuli that
did not evoke secretion, such as in postganglionic neurons
(632) or lymphocytes (441). Also, the increased PI turnover
was preserved in Ca2⫹-free medium, whereas secretion was
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TAMAS BALLA
These studies prepared the field for the notion that the PI
turnover was somehow related to receptor action, although
the link was not clearly defined (338, 392). This prompted
Michell and Lapetina to consider that the PI response was a
critical intermediate during stimulation of cell surface receptors that did not act via cAMP. They suggested that a
product of PLC action on PtdIns, such as 1,2-cyclic inositol
monophosphate, perhaps acted as a second messenger (852,
853). In parallel developments, cytoplasmic Ca2⫹ increase
and, in many instances, cGMP elevations were increasingly
recognized as possible triggering signals not only in excitable tissues, such as muscle cells, but in secretory cells as
well. Intriguingly, the kind of receptors and agonists that
evoked the Ca2⫹ responses were almost always identical to
those that elicited a PI response. A theory was then introduced by Bob Michell in his seminal 1975 review (1040),
where he proposed that the increased PI turnover was an
early receptor-triggered event initiated by PLC activation
characteristic of receptors that used Ca2⫹ or cGMP as second messengers. There were, however, some cracks in this
picture that hampered its immediate endorsement and
prompted further research. One of these points was related
to the “speed” of the response relative to that of Ca2⫹
elevations, and the other was due to a few reports that
found the enhanced PI labeling dependent on the presence
of Ca2⫹ (21, 276) or perhaps Ca2⫹-controlled (32). This
latter, together with the Ca2⫹ sensitivity of PLC activity
appeared to support the views that the PI response was
secondary or parallel to Ca2⫹ elevations (1174). Most studies, however, found the response independent of Ca2⫹, arguing against this idea (1041). Finally, Fain and Berridge
(417) presented clear evidence that inositol lipid turnover
was upstream of calcium fluxes during stimulation with
5-hydroxytryptamine in the blowfly salivary gland.
Another question raised was whether PtdIns or its phosphorylated derivatives (“DPI or TPI”) were the primary
subject of PLC-mediated hydrolysis. Durrell (393) noted
first that inositol-bisphosphate was one of the products that
1026
accumulated during stimulation, which can be derived only
from hydrolysis of PtdInsP or PtdInsP2. Other reports described earlier that radiolabeled PtdInsP and PtdInsP2 were
rapidly decreased upon stimulation with acetylcholine in
avian salt gland (1339) and in iris smooth muscle (1), but
the latter response was found Ca2⫹ sensitive and its connection to the increased PI labeling was not all that clear. The
time must have been right for clarifying this question in the
early 1980s when three groups reported that PtdIns(4,5)P2
was the initial target of PLC-mediated hydrolysis yielding
Ins(1,4,5)P3 as the primary water-soluble hydrolytic product (131, 132, 299, 800, 1046). This was almost instantly
followed by the recognition that Ins(1,4,5)P3 released Ca2⫹
from nonmitochondrial Ca2⫹ stores, finally unequivocally
linking inositol lipid hydrolysis and Ca2⫹ signaling (1481).
The other product of PtdIns(4,5)P2 hydrolysis, sn-1,2-DG,
also found its targets when a DG-regulated phospholipiddependent kinase family, named protein kinase C (PKC)
was identified by Nishizuka. These findings opened a whole
new research direction for the characterization and functional analysis of the PKC enzymes (1141, 1142). An extended view of the “PI cycle” has then been established by
the mid 1980s (FIGURE 2B).
C. Expansion of Phosphoinositides
With these developments, the phosphoinositide-Ca2⫹ signaling paradigm became consolidated, and the efforts were
concentrated on isolating and characterizing the enzymes
that catalyzed these reactions. Particularly important was
to identify the PLC enzymes that were activated by the Ca2⫹
mobilizing receptors. A significant achievement of this time
was the purification (763, 1319, 1521) and subsequent molecular cloning (402, 762, 1493) of several forms of PLC
pursued in the laboratories of Sue Goo Rhee, Matilda Katan, and Tadaomi Takenawa. It was also an important revelation that two major routes of PLC activation exist: one
via the ␣ and ␤␥ subunits of heterotrimeric G proteins, in
the case of PLC␤ enzymes (207, 866, 1194, 1195), and the
other via association and activation by RTKs, in the case of
PLC␥ (786, 995). Similar developments occurred in the inositide kinase (167, 362) and phosphatase (801, 1065,
1775) fields, and the former also produced some unanticipated and surprising results that were forerunners of an
entirely new research field. These began with the discovery
that several transforming oncogenes such as the Rous sarcoma virus, polyoma middle T antigen, or avian src were
associated with PtdIns kinase activities (963, 1486, 1713),
and it was simultaneously noted that more than one kind of
PtdIns kinase was present in mammalian cells (403, 1712).
Since all previous studies assumed that PtdInsP was a
4-phosphorylated PtdIns and hence PtdIns kinases were, by
default, believed to be 4-kinases, it came as a surprise when
the lipid product of the so-called type I PtdIns kinase was
identified as a 3-phosphorylated PtdIns (1462, 1711). Soon
it was also shown that growth factor or GPCR stimulation
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eliminated under those conditions (633). Moreover, increased PI labeling needed higher concentrations of agonists
than those for secretion (637), and it was not evoked by
some agonists that increased secretion via cAMP (1337). In
the meantime, a series of important experiments linked the
PI turnover to cell proliferation. Fisher and Muller (442)
found that lymphocytes stimulated with the mitogen phytohemagglutinin increased 32P- or [3H]inositol labeling of
PtdIns and a rapid appearance of PtdOH, consistent with
increased turnover of PI. A close correlation between cell
proliferation and specifically inositol lipid turnover was
found in cells subjected to various stimuli, including transformation with viruses, such as Rous sarcoma or SV40
(358). A dramatic drop in PtdIns turnover was shown to
correlate with the transition from proliferation to differentiation during lens development in chicken embryos (1791).
PHOSPHOINOSITIDES
evoked the production of novel phosphoinositides PtdIns(3,4)P2
and PtdIns(3,4,5)P3 (66, 1572), while PtdIns3P was constitutively
present in cells and did not respond to similar stimuli (1462).
D. Soluble Inositol Phosphates
Another direction to which the expansion took place was
marked by the discovery that eukaryotic cells contained
water-soluble inositol phosphates other than those generated by PLC-mediated hydrolysis of the PPIs and their dephosphorylated metabolites. This started when Robin Irvine’s group discovered that the majority of the InsP3 increase after stimulation was not due to the active
Ins(1,4,5)P3 isomer but another form, Ins(1,3,4)P3 (707)
that was inactive as a Ca2⫹ mobilizing agent (706). The
source of this isomer was soon clarified with the discovery
of the “inositol tris/tetrakisphosphate pathway” whereby
Ins(1,4,5)P3 was phosphorylated by a 3-kinase yielding
Ins(1,3,4,5)P3, which was then converted to Ins(1,3,4)P3
(705). A long quest has followed to find a messenger func-
IV. PHOSPHATIDYLINOSITOL SYNTHESIS
PtdIns synthesis takes place in the ER and, as recently suggested, in an ER-derived highly mobile subcompartment
that may serve as a means to supply the lipid to other membranes (796). Since the increased PI synthesis after agonist
stimulation is believed to be secondary to PPI breakdown
that occurs in the PM, there have been speculations that
PtdIns synthesizing activities might have separate ER and
PM components and perhaps more than one phosphatidylinositol synthase (PIS) enzymes were responsible for them.
Indeed, the whole PI synthesizing machinery was found in
turkey erythrocyte membranes (1021, 1622), and PIS activities were found associated with PM as well as ER membranes after cell fractionation (694, 695, 1407). Molecular
identification of the PIS enzyme was first achieved in yeast
(1133, 1134) as a result of complementation cloning using
a yeast strain that had been previously found defective in
PIS enzyme activity (1135). Mammalian PIS was then
cloned and characterized (957, 1528), showing that the
same enzyme was responsible for both PtdIns synthase and
myo-inositol exchange activities, two reactions that had
been formerly attributed to distinct molecular entities
(1522). There appears to be no other gene for PtdIns synthesis, so the association of the enzyme activity with PM
fractions may be related to their contamination with ER or
with the lighter mobile PIS membrane compartment (796).
Two studies reported defects in PIS activity in zebrafish, one
describing ER stress and hepatic steatosis (1547), while the
other observed lens structural defects and reduced number
of photoreceptors (1098).
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Interest in PI 3-kinases was rapidly propelled by the association of PI 3-kinase activities with growth factor and oncogenic signaling, ultimately unraveling the various subclasses
and primary structures of these enzymes and their adaptors
(192, 614, 1178, 1367, 1465, 1476, 1638). Moreover, PI
3-kinase research was greatly aided by the discovery that
the fungal drug wortmannin (Wm) was a potent PI 3-kinase
inhibitor (52, 1761) and was further motivated by the revelation, with the help of large-scale genomic sequencing,
that oncogenic mutations within the catalytic subunit of PI
3-kinase class I␣ are found in a large number of human
cancers (1334). However, PI 3-kinase research had a large
impact on the overall PI field even beyond its close association with cancer. The fact that PtdIns(3,4,5)P3 was a poor
substrate of PLC enzymes (1384) has directed research toward the notion that the lipid itself within the membrane
must function as a signaling entity and that molecules must
exist that respond to these lipid changes (1467). This concept has been proven with the discovery of the Akt kinase
(also known as protein kinase B, PKB) as a major signaling
route downstream of PI 3-kinases and PtdIns(3,4,5)P3 (202,
461). This, together with the identification of pleckstrin
homology domains (1014, 1584) as protein modules that
directly bind phosphoinositides (768, 881, 882), exposed
the side of phosphoinositides as membrane-bound regulatory molecules as opposed to just being precursors of the
two messengers Ins(1,4,5)P3 and DG. This has been a monumental paradigm shift that hugely expanded the functional versatility of PPIs and gave new meaning to the diversity of the PI kinases and phosphatases. These enzymes
turned out to be regulators of a whole range of cellular
functions with a still poorly understood contribution to the
increased metabolic labeling of inositides described in early
studies. More detailed description of how the PI3K field was
established and expanded can be found in (1559, 1612).
tion for Ins(1,3,4,5)P4 with suggestions that it would link
Ins(1,4,5)P3-sensitive Ca2⫹ pools with sustained Ca2⫹ entry (235), and led to the isolation of an Ins(1,3,4,5)P4-binding
protein identified as a Ras-GAP1 protein family member (306).
However, the biological functions (if any) of Ins(1,3,4,5)P4 still
remain elusive. In the meantime, additional, highly phosphorylated inositols, such as InsP5 and InsP6 have been described
by HPLC analysis of myo-[3H]inositol-labeled cells (610)
and a new pathway was identified by which Ins(1,3,4)P3
could be converted to Ins(1,3,4,6)P4 and then to InsP5 (91,
92, 1391). Although there were significant agonist-induced
changes observed in the newly discovered InsP4 isomers,
InsP5, and even InsP6 (86, 93, 1032), the significance and
functions of these inositol phosphates remained unknown
for a period of time until the discovery of a pathway in yeast
that took Ins(1,4,5)P3 all the way to InsP6 with a functional
link to messenger RNA export (1777). This was the beginning of a new era in inositol polyphosphate research with
the discovery of pyro-phosphorylated inositol polyphosphates (954, 1031) and possible roles of several of these
compounds (1068) in cell regulation. These new developments will not be detailed further in this review as they
deviated from the PPI lipids themselves. However, these
exciting findings deserve attention and have been reviewed
recently elsewhere (1375, 1389, 1390).
TAMAS BALLA
The other substrate of PtdIns synthesis is myo-inositol, and
cells have three ways of providing this substrate for the PIS
enzyme. Some organisms and cells can synthesize myo-inositol de novo from glucose-6-phosphate via Ins3P. [Many
studies use Ins1P to designate this product. This refers to the
L-enantiomer, whereas we use the D-designation for all inositol phosphates. Accordingly, L-Ins1P corresponds to
D-Ins3P (1376)]. Otherwise, cells can take up myo-inositol
from their surroundings or, importantly, they can recycle
the myo-inositol from the inositol phosphates liberated during PLC activation (FIGURE 2B). Inositol uptake in mammalian cells is mediated by three different proteins: SMIT1
(841), SMIT2 (274), and HMIT (1589). SMIT1 and -2 are
Na⫹/myo-inositol cotransporters that use the Na⫹ electrochemical gradient to transport myo-inositol into the cells.
SMIT1 has a Km of ⬃30 ␮M for myo-inositol, and it shows
highest expression in kidney medulla and MDCK cells
where it responds to osmotic challenge with increased expression (841). This already suggests that the protein functions in osmoregulation since myo-inositol serves as an important osmolyte in both neurons and the kidney. SMIT-2
has higher Km (⬃150 ␮M) (274), and it shows wider tissue
distribution (1292). HMIT is a H⫹/myo-inositol cotransporter that has a lower affinity (Km of ⬃ 100 ␮M) but high
capacity. It shows highest expression in the brain (1589).
Interestingly, HMIT is mostly intracellular due to internalization and ER-retention signals within its sequence (1589),
1028
and its membrane insertion is regulated by activity in neurons (1590).
The question of how cells supply myo-inositol for PtdIns
synthesis has attracted a lot of attention when it was discovered that treatment of rats with Li⫹ at doses that are
used in the treatment of manic-depressive disorders caused
brain inositol levels to drop with accumulation of inositol
monophosphate (34, 35). Subsequent studies showed that
Li⫹ inhibited the dephosphorylation of inositol monophosphates and that it was D-Ins1P that accumulates in the rat
brains after prolonged Li⫹ treatment (1396). This latter
finding was important because it showed that the accumulating inositol phosphate was not the isomer synthesized de
novo by the cells (which is Ins3P or L-Ins1P) but it was
originated from the PLC-liberated Ins-phosphates that yield
Ins1P and Ins4P (87, 88). Indeed, Li⫹ was shown to enhance the accumulation of several inositol phosphate isomers upon stimulation by agonists that activate PLC enzymes (88, 133). Based on these findings it was suggested
that the beneficial effects of Li⫹ treatment in manic-depressive disease are related to a deficient recycling of the inositol
phosphates liberated by PLC activity, and this would affect
neurons that display the highest activity (134). These observations and the proposed theory draw attention to the question of why brain cells are unable to supply inositol from the
CSF and brought the inositol uptake pathways into the
focus of intense research. Many studies have since been
devoted to study the effects of mood-stabilizing drugs on
myo-inositol uptake and inositol phosphate generation and
recycling (60, 350, 351, 1258).
In light of these observations, it was a remarkable finding
that SMIT1 knockout mice develop normally but die from
congenital central apnea due to abnormal respiratory
rhythmogenesis (138, 195). These mice have more than
90% reduction in brain and more than 80% in whole body
myo-inositol content. Yet, their brain PtdIns levels are completely normal (137, 195). These findings cast some doubts
about the “inositol-depletion hypothesis” of Li⫹ action and
suggested that myo-inositol uptake by SMIT1 serves a different purpose, perhaps contributing to osmotic control.
These findings also showed that PtdIns synthesis could go
on undisturbed even at greatly reduced myo-inositol levels.
However, Li⫹ treatment combined with strong PLC activation can drive down PtdIns levels in cultured cells (87, 727),
suggesting that without sufficient external inositol it is possible to deplete cellular myo-inositol levels to the point
where PtdIns synthesis will suffer. Concerning Li⫹ effects, it
has also been hypothesized that some of the accumulating
metabolites, such as CDP-DG or PtdOH, exert an inhibitory effect on signaling from PLC-coupled receptors (87,
90, 727). There are a number of other effects of Li⫹ unrelated to PtdIns synthesis, such as the inhibition of the
GSK3␤ enzyme (739), but those are not subject to this review.
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The two substrates of PtdIns synthesis are myo-inositol and
CDP-DG (FIGURE 2B). The latter is synthesized from CTP
and PtdOH by CDP-DG synthase (CTP:phosphatidate cytidylyltransferase, or CDS for short) enzymes (11, 119).
Early studies described two CDS activities: one associated
with the outer surface of the ER (95) and another located in
the matrix of mitochondria that was responsible for feeding
into cardiolipin synthesis (1360). Mammalian CDS enzymes have been cloned (589, 1325, 1688), and two, highly
similar but different genes, cds1 and cds2 are found in the
human and other mammalian genomes (552, 1645). Both
CDS proteins localize to the ER, but they do not enter the
PIS positive mobile compartment (796). Importantly, none
of the cloned CDS enzymes is found in the mitochondria
(796) or showed the unique characteristics of the mitochondrial activity (1522). Therefore, the mitochondrial enzyme
still remains elusive. A photoreceptor-specific isoform of
Drosophila CDS was shown to be necessary for the maintenance of PtdIns(4,5)P2 levels and hence for a sustained
light response, and CDS mutant flies developed light-dependent retinal degeneration (1736). Recent studies also identified mutations in one of the CDS genes in zebrafish causing
specific defects in blood vessel formation and angiogenesis,
and these effects were attributed to the rundown of
PtdIns(4,5)P2 levels in the VEGF-stimulated endothelial
cells (1188). These studies also concluded that CDS enzyme
activities are necessary for maintaining the signaling pool of
PtdIns(4,5)P2.
PHOSPHOINOSITIDES
V. PHOSPHOINOSITIDE KINASES
As mentioned above in the historical overview, PI kinases
were described as early as the 1960s, and it was already
understood that separate activities converted PtdIns to
PtdIns4P and PtdIns4P to PtdIns(4,5)P2, defining these two
activities as “PI-kinases” and “PIP kinases.” This historical
fact determines the terminology of these enzymes and their
classification. Some of the enzymes can phosphorylate both
PtdIns and phosphorylated PPIs in vitro, but in the following sections they will be discussed according to what is (or
was) believed to be their primary enzymatic function within
the intact cells. This may be a deviation from other reviews
that discussed the enzymes only according to the position of
the inositol ring that they can phosphorylate.
1. PtdIns 4-kinases
PtdIns 4-kinases (PI4Ks) were initially believed to be the
only PtdIns kinases. Only after discovering that type I PI
kinases were actually PI 3-kinases, had the PI4Ks been so
named. That is why PI4Ks were left with the type II and type
III PI4K designations. Initial reports on PI4K activities suggested that the enzymes were associated with the PM
(1043), and consistent with this notion, they were also present in red blood cell membranes (636). However, distinct
activities present in ER membranes showing differential
sensitivities to detergents such as cutscum were already
noted by early studies (280, 283, 577, 1043). Purification of
these activities from a variety of membranes was then carried out (525, 651, 1233, 1658, 1705). This required solubilization of the membranes with detergents yielding an
activity of ⬃55 kDa termed type II PI4K. This tightly membrane-bound activity could be reactivated after separation
and extraction from SDS gels and showed high affinity for
ATP (Km ⬃10 –50 ␮M), potent inhibition by adenosine (Ki
⬃10 –70 ␮M), stimulation by detergents, and inhibition by
Ca2⫹. Another PI4K activity was described in cholate extracts of bovine brain with larger size, lower ATP affinity,
and lower adenosine sensitivity, and it was termed type III
PI4K (403). A soluble, PI4K activity was also identified
based on its sensitivity to PI 3-kinase inhibitors (1112),
which showed the enzymatic properties of type III PI4Ks
(386) and was then separable to a larger (210 –230 kDa)
and smaller (110 kDa) entity (89). The first PI4Ks were
cloned from Saccharomyces cerevisiae and were designated
as Pik1p and Stt4p (444, 1778). The mammalian homologs
of these enzymes cloned from various species (89, 504,
1036, 1106, 1107, 1725) were then identified as PI4K type
III␤ and -␣, respectively. Although the type II PI4Ks were
known first with several attempts for isolation, their successful purification and cloning happened only later when
two groups independently cloned PI4K type II␣ (108, 1058)
followed by the identification of another closely related
2. PI4KIII␣/PI4KA
Most of what we know about this enzyme was derived from
studies in S. cerevisiae (1479). The yeast ortholog STT4 was
initially identified in a screen that sought staurosporinesensitive mutants (1778). Deletion of STT4 results in an
osmo-remediable phenotype with defects in cell wall integrity (64, 1778). The connection to PKC1 has been revealed
in that Stt4p was found to be essential to supply the Mss4p
PIP 5-kinase with its substrate, PtdIns4P, to synthesize the
PM pool of PtdIns(4,5)P2 (63, 64). The PM pool of
PtdIns(4,5)P2 anchors Rom2p, an exchange factor that activates the Rho1p GTPase, which, in turn, is an activator of
Pkc1p (63). Pkc1p kinase is a well-documented hub for
several signaling pathways that are essential for cell wall
integrity (892). Synthetic genetic array analysis of Stt4p
revealed a strong connection to sphingolipid metabolism,
again via the control of PM PtdIns(4,5)P2 pools and recruitment of Slm1p and Slm2p proteins (1510). Further defect
related to an insufficient supply of the PM with PtdIns4P in
temperature-sensitive Stt4 alleles was the failure of the actin
cytoskeleton to properly organize (64). Such cells are also
unable to recruit the p21-activated kinase, Cla4p, a direct
downstream effector of Cdc42, to the sites of polarized
growth (1717) and to assemble septin at the bud neck (140).
However, in addition to the roles of Stt4p in supplying the
PM with PtdIns4P, several observations suggest that the
kinase also affects processes linked to internal membranes.
First, Stt4p generates a pool of PtdIns4P that is degraded by
the ER resident Sac1p phosphatase (455). Although recent
elegant studies showed that Sac1 in the ER still can access
the PM PtdIns4P pool in trans (1454), it is likely that Stt4p
is also involved in the synthesis of additional PtdIns4P pools
found in the ER membranes. This possibility is supported
by studies in which Stt4p could rescue defects in aminophospholipid transfer between the Golgi and the ER (1580)
and that temperature-sensitive Stt4p mutants also display
lysosomal defects (64). Moreover, Stt4p function was genetically linked to some of the Sec14 homologs (SFHs),
which are lipid transfer proteins (1303), some of them connected to aminophospholipid transport (1737). Interestingly, Stt4p is also the major target of Wm in yeast, since
neither the yeast PI 3-kinase, Vps34p, nor the other PI 4-kinase, Pik1p is particularly sensitive to this inhibitor (311).
As far as regulators of Stt4p are concerned, temperaturesensitive alleles of Stt4p can be rescued by overexpression of
Sfk1 (suppressor of four kinase 1), a multispanning membrane protein with yet unidentified functions (63). Intriguingly, two other proteins, Ypp1p (79, 1792) and Efr3p,
were described as regulators of Stt4p and organizers of the
kinase into special signaling domains at contact zones between the ER and the PM (79, 980). Ypp1 also targets the
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A. PtdIns Kinases
form, PI4KII␤ (83, 1058). The structural features of PI4K
enzymes are shown in FIGURE 3.
TAMAS BALLA
NS5A
interaction
PR
NLS?
LKU
PH
Kinase
PI4KA
2,102 aa
LKU
PH
Kinase
Stt4p
1,900 aa
PR
LKU
Fq
Rab-binding
Kinase
PI4KB
816 aa
LKU
Fq
Rab-binding
Kinase
1,066 aa
PR
Kinase CR
Kinase
PI4K2A
479 aa
acidic
Kinase CR
Kinase
PI4K2B
481 aa
Kinase
Kinase
Lsb6p
607 aa
FIGURE 3. The family of PI 4-kinase enzymes. PI 4-kinases (PI4Ks) have two major types, the type III and type
II enzymes [the type I enzyme(s) turned out to be the PI 3-kinases]. The type III enzymes are comprised of two
proteins: the larger (⬃210 –230 kDa) PI4KA (Stt4p in yeast) and the smaller (⬃92–110 kDa) PI4KB (Pik1p in
yeast). These enzymes are relatives of PI 3-kinases and the PIK-related protein kinases, with a highly conserved
COOH-terminal catalytic domain. They also have lipid-kinase unique (LKU) domains also found in PI 3-kinases.
Other domains include proline-rich sequences (PR) and a frequennin-binding (Fq) domain in the PI4KB form. The
smaller sized (⬃56 kDa) type II PI4Ks exist in two forms in vertebrates: PI4K2A and PI4K2B that are highly
homologous except at their very NH2 termini. [Only one form is found in S. cerevisiae (Lsb6) and in D.
melanogaster]. The signature feature of these enzymes is a cysteine-rich (CR) sequence that is palmitoylated
in the vertebrate enzymes providing stronger membrane association.
Parkinson-related protein, A30P ␣-synuclein to the vacuole
for degradation in yeast, again pointing out the possible
role of Stt4p at internal membranes.
The biology of Stt4p orthologs (PI4KA or PI4KCA) in
higher eukaryotes is much less understood. This enzyme
also seems to be primarily responsible for the generation of
the PM pool of PtdIns4P in cultured cells (82, 84), even
though its primary location was originally described at the
ER/Golgi interface (1107, 1726). Recent studies, however,
showed that PI4KA was localized to the PM with the aid of
the TTC7 and EFR3 proteins, which are homologs of the
yeast Ypp1 and Efr3 proteins (1114). Importantly, this feature was linked to the presence of an NH2-terminal short
sequence in PI4KA that has been missed in previous studies.
Morpholino-induced downregulation of PI4KA in zebrafish
embryos caused massive and complex developmental de-
1030
fects especially affecting the brain and were characterized
by lack of pectoral fins. This latter defect could be traced to
impaired Fgf signaling and was phenocopied by PI 3-kinase
inhibitors consistent with a decreased supply of PtdIns(4,5)P2 at
the PM (959). It is notable that PI4KA shows the highest
expression in the brain both during development and in
adult rodents (1107, 1828). At the cellular level, the enzyme
was also found associated with nucleoli, but the biological
significance of this finding is not known (748). A series of
recent studies using RNAi screens to search for cellular host
factors required for the infection cycle of hepatitic C virus
(HCV), identified PI4KA as a critical protein for HCV replication in the liver (122, 166, 1513, 1577, 1597). Since
HCV-infected cells develop a special replication organelle,
the “membranous web,” it is possible that the PI4KA is
needed for the formation of this organelle (1082). This is
supported by the finding that PI4KA interacts with the HCV
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Pik1p
PHOSPHOINOSITIDES
viral protein NS5A (13), which by itself can generate membrane structures resembling the “membranous web” (1082).
Since PI4KA has also been linked to COPII positive ER exit
sites (154, 425), it is a possibility that the “membranous
web” originates from the ER. Studies are underway in several
laboratories to untangle this process and to test whether inhibition of the kinase is a viable strategy to combat HCV infections.
3. PI4KIII␤/PI4KB
Recent studies reported that PI4KB is a key host enzyme in
the replication cycle of small RNA viruses that reorganize
the host cell ER-Golgi membrane structure to establish a
replication platform (656). Intriguingly, some HCV strains
also require this enzyme for replication and inhibitors of
PI4KB potently slow down viral replication (656). This
identifies PI4KB as a potential therapeutic target in antiviral
strategies.
No studies have been published with targeted deletion of
PI4KB in mammalian organisms. Disruption of the gene
Fwd encoding PI4KB in Drosophila results in male infertility due to a cytokinesis defect during spermatogenesis
(182). Since PtdIns(4,5)P2 is important in the formation of
the cleavage furrow during cytokinesis (436, 1728), it seems
that fwd is the only PI4K that can supply the PtdIns4P for
cytokinesis during spermatogensis in Drosophila. Gene disruption of both PI4KB (AtPI4K␤1 and its sister, AtPI4K␤2)
in Arabidopsis thaliana manifests in a defect in root hair
growth (1237). These enzymes facilitate budding of vesicles
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The yeast homolog of PI4KB, called Pik1p, was the first
PI4K purified and cloned in the Thorner laboratory (444,
445). Interestingly, the same gene was cloned using a monoclonal antibody that was raised against NUO135, a protein
part of the nuclear pore complex (493). The PIK1 gene is
essential, which clearly demonstrates that Stt4p and Pik1p
assume nonredundant functions in yeast. Pik1p inactivation by temperature-sensitive alleles causes ⬃50% decrease
in cellular PtdIns4P and PtdIns(4,5)P2 levels (64, 1655).
Pik1ts strains show greatly distorted and exaggerated Golgi
membranes, vacuole fragmentation, and defective actin polarization at the budding pole (64, 1655). Certain Pik1ts
alleles also show cytokinesis defects (493, 1655). Pik1p localizes to the Golgi and the nucleus (493, 1478, 1655) and
regulates trafficking in the late secretory pathway (64, 555,
1655). Pik1p is localized to the Golgi in the yeast by interaction with Frq1p, the yeast ortholog of the small Ca2⫹
binding protein frequenin (also called NCS-1 in mammalian cells) (reviewed in Ref. 615) (599). Frq1p is essential for
Pik1p Golgi localization (1478), and the Frq1p binding site
was mapped between residues 125–169 of Pik1p, a region
adjacent and downstream of the lipid kinase unique (LKU)
domain characteristic of PI3Ks and type III PI4Ks (672).
The Golgi recruitment of Pik1p is also controlled by Arf1,
and the enzyme also interacts with the Arf1 exchange factor
Sec7 (512). Pik1p shuttles between the nucleus and the cytoplasm, and both the nuclear and Golgi localizations of the
enzyme are required for viability (1478). Phosphorylated
Pik1p interacts with 14-3-3 proteins, and this interaction
keeps Pik1p out of the nucleus (343). It is not clear why
PtdIns(4,5)P2 levels are decreased in Pik1ts strains at the
permissive temperature, since the yeast PIP 5-kinase Mss4p
does not show Golgi localization and the only place where
the two enzymes are found together is the nucleus. This may
suggest that the Pik1p-dependent PtdIns(4,5)P2 has a nuclear function. A synthetic lethality screen identified the
Golgi-associated Rab-GTPase Ypt31p (a Rab11 homologue) as a downstream target of Pik1p (1369) and Drs2, an
aminophospholipid translocase that is also important for
post-Golgi trafficking (240 ). Recent studies also showed
that Ypt31p interacts with the Sec2/Sec4 complex in a
Pik1p-dependnent manner and is replaced by the Sec4p effector Sec15p (a component of the exocyst) as PtdIns4P
levels decrease, thereby establishing a link between Pik1pmediated PtdIns4P generation and vesicular secretion
(1072).
Mammalian PI4KB is also primarily Golgi-localized (514,
1726) and shuttles between the cytoplasm and the nucleus
(332). In Madin-Darby canine kidney (MDCK) cells, PI4KB
regulates Golgi to PM trafficking, both intra-Golgi (for influenza hemagglutinin) and for basolateral delivery (for vesicular stomatitis virus VSV-G protein) (193). Kinase-inactive forms of PI4KB also inhibit the Golgi-to-PM delivery of
the VSV-G protein in nonpolarized cells (513). Recruitment
of PI4KB to the Golgi is regulated by the small GTP binding
protein Arf1 (514). The enzyme also interacts with NCS-1
(586, 1695), but unlike yeast Frq1, NCS-1 does not primarily localize to the Golgi, and it is not known to what extent
(if any) NCS-1 contributes to the recruitment of PI4KB to
the Golgi in mammalian cells (615). The GTP-bound form
of Rab11 also binds mammalian PI4KB (at residues 401–
516), but this interaction does not seem to regulate PI4KB
activity or to recruit the enzyme to the Golgi. Conversely,
PI4KB appears to be required to recruit Rab11 (333), and
similar interactions between these proteins were demonstrated in the plant Arabidopsis thaliana (1237) and in Drosophila (1231). Notably, this latter study suggested that this
function of PI4KB [called four wheel drive (Fwd) in the fly]
is partially independent of the enzyme’s catalytic activity.
PI4KB is phosphorylated at multiple sites (1485), and phosphorylation of Ser258 and Ser266 affects the Golgi recruitment of the protein during recovery from brefeldin A treatment(590). A PKD-mediated phosphorylation of PI4KB at
Ser268 regulates PI 4-kinase activity and is critical for the
post-Golgi transport of the VSV-G protein, but not for
Golgi recruitment of the enzyme (579). PKD phosphorylation of PI4KB also promotes interaction with 14-3-3 proteins, and this interaction stabilizes the protein in its active
conformation (578). Mammalian PI4KB also shuttles between the cytoplasm and the nucleus, but the nuclear function(s) of the enzyme remains to be determined (332).
TAMAS BALLA
from the TGN and associate with the TGN-localized
RabA4b protein (a Rab11 homolog of the plant) at the
region corresponding to the Rab11 interaction site in
PI4KIII␤. This process seems to be essential for polarized
secretion and hence for root hair extension. Similarly to
yeast and mammalian cells, the Arabidopsis homolog of
frequenin interacts with the NH2-terminal domain of
AtPI4K␤1 to add Ca2⫹ regulation to the enzyme (1237).
4. Type II PI 4-kinases/PI4K2s
Type II PI4Ks are tightly membrane-bound proteins, due to
the palmitoylation of a conserved stretch of cysteines within
their catalytic domains (108, 109). In spite of a similar
palmitoylation sequence within the two isoforms, a larger
fraction of PI4K2B than PI4K2A is found in the cytosol (83,
1690) and the cytoplasmic fraction of PI4K2B is not palmitoylated (743). Based on early studies in which the type II
PI4K activity was found in PM fractions, and in red blood
cell membranes, it was logically assumed that the type II PI
4-kinase produces PtdIns4P in the PM. Therefore, it was
surprising to find the majority of PI4K2A and PI4K2B enzymes in intracellular membranes, mostly associated with
the TGN and endosomes by immunocytochemical analysis
(83, 1060, 1680). It has been shown that PtdIns4P in the
Golgi/TGN is critical to the membrane recruitment of various clathrin adaptors, such as the heterotetrameric AP-1
(1680) and monomeric GGAs (1509, 1671) and that
PI4K2A, rather than the type III PI4KB, was the important
enzyme in this process (1671, 1680). PI4K2A also shows
association with a vesicular pool rich in the adaptor protein
AP-3 (1330), and it directly interacts with AP-3 via a sorting
motif found in the enzyme, which then acts both as a regulator and a cargo (298). Both the catalytic activity of the
kinase and the direct interaction with AP-3 are important in
supporting AP-3-mediated trafficking (298). An additional
role of PI4K2A in EGF receptor trafficking was indicated by
studies showing that EGFR targeting and degradation in
lysosomes were found to be impaired after RNAi-mediated
knock-down of the enzyme (1060). Similarly, PI4K2A was
found important for the lysosomal trafficking of the glucorebrosidase enzyme (741). Undoubtedly, type II enzymes
are also present in the PM, either under unstimulated conditions (PI4K2A) or after stimulation with PDGF (PI4K2B)
(1690). Based on mass measurements, ⬃50% of the total
cellular PtdIns(4,5)P2 pool is synthesized via Wm-sensitive
1032
Regulation of the type II PI4Ks is poorly understood. An
important feature of the type II PI4Ks is their association
with cholesterol and sphingolipid-rich membrane domains
(1685). The cholesterol content of these membranes has a
big impact on both enzyme activity and interaction of the
protein with regulatory factors (1059, 1686). Recent studies found that the palmitoylation of the PI4K2A enzyme in
the Golgi is regulated by cholesterol (949). Calcium inhibits
both type II PI4Ks, and membrane association increases
PI4K2B activity (1690). Remarkably, the activity of type II
PI4Ks varies between the isoforms, the PI4K2A enzyme
being most active, while the PI4K2B form has much lower
activity (83). The enzyme activity shows good correlation
with palmitoylation and membrane association. In addition
to palmitoylation, membrane attachment of these enzymes
is also determined by the COOH-terminal part of the catalytic domain (109). The yeast ortholog LSB6 (also termed
PIK2) (562, 1392) shows only very moderate PI4K activity
and makes minor contribution to the overall PtdIns4P production of yeast cells under normal growth conditions. It
also lacks most of the cysteines that are palmitoylated in the
mammalian enzymes (562, 1392). Importantly, inactivation of LSB6 causes only a mild alteration in the trafficking
of the endocytosed mating factor receptor. This defect is
rescued by a construct that does not contain the catalytic
domain but requires regions that interact with Las17p, the
yeast homolog of WASP, a protein that is important for
regulation of actin polymerization (230). It is possible that
LSB6 acts as a scaffold and regulates the movements of
vesicles; the lipid kinase activity of LSB6 may not be crucial
for normal functions in the yeast.
A gene-trapped mouse with a truncated PI4K2A has been
thoroughly investigated. The homozygous mice develop
and are born normal in spite of the lack of detectable
PI4K2A protein, but they succumb to late-onset spinocerebellar degeneration (1408). These animals develop severe
lipofuscin-like depositions in the cerebellum associated
with gliosis, and lose most of their Purkinje cells. They also
show massive axonal degeneration in the spinal cord and
die prematurely (1408). However, a screening study on patients suffering from autosomal recessive hereditary paraplegia, a human disease highly similar to the pathologies of
PI4K2A-deficient mice, failed to identify pathogenic changes
in the PI4K2A gene (270). Little is known about type II
PI4Ks in other organisms. Zebrafish already contain both
isoforms of the type II enzymes (959), while there is only
one gene found in Drosophila (110). Arabidopsis contains
eight genes encoding proteins with homology to the type II
PI4Ks, six of which contain ubiquitin within their coding
sequences (1092). Since ubiquitination is an important
means of tagging proteins, including EGF receptors destined for endocytosis and degradation (547), this observa-
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Early biochemical studies using mammalian tissues characterized what has become known as the type II PI 4-kinases.
However, cloning of the genes for this group of proteins had
to wait for a while (108, 1058). Two forms of the enzymes
exist in vertebrates, the type II␣ (PI4K2A) and type II␤
(PI4K2B) enzymes, with very similar features. Little information unique to PI4K2B is available as of to date; therefore, the two isoforms will be discussed together. Yeast and
other lower organisms only have one form of the protein.
PI4Ks (1615), but what fraction of this is found in the
different membranes has yet to be determined.
PHOSPHOINOSITIDES
tion is a further hint that type II PI4Ks are regulators of
endocytosis and they may direct endocytosed proteins for
degradation.
5. Class III PI 3-kinase/PI3KC3
The mammalian ortholog of Vps34p, called hVps34, PtdInsspecific PI 3-kinase or class III PI3K and its adaptor protein
p150 have been also cloned (1189, 1642). The mammalian
class III PI3K also has a role in endocytic sorting, and the
hVps34/p150 complex is recruited to Rab5 positive endosomes (254, 1100) where it produces PtdIns3P, which attracts proteins that contain FYVE domains and PX domains
(509, 752, 1409, 1750). hVps34 is also central to autophagy in mammalian cells (1532, 1631), but there is less
distinction between the roles of complex I and complex II in
this process. This is due to multiple interactions of the
hVps34-associated Beclin-1 (the homolog of yeast Vps30p)
with distinct protein complexes that regulate endocytosis as
well as different steps of autophagy (709, 1011, 1818). One
of these proteins is UVRAG (functionally related to Vps38)
(709), which promotes autophagy either by recruiting curvature-sensing BAR-domain containing proteins (317, 1517) or
by enhancing fusion of autophagosomes with lysosomes
(908). An additional Beclin 1-interacting protein, Rubicon,
is a negative regulator of autophagy that competes with
Atg14L (the mammalian Atg14p) for binding Beclin 1
(1011, 1818). In addition, hVps34 is also involved in mediating mTOR activation during amino acid starvation
(203). The mammalian enzyme is also less sensitive to Wm
than the ClassI PI3Ks (1464). The structural basis of this
difference as well as the potential for isoform specific inhibition of the enzyme has been highlighted in the recently
published structure of the protein (1054).
B. PtdInsP Kinases
As mentioned above, PtdInsP kinase (PIPK) activities associated with membranes including the red blood cell membrane
have been detected by early studies. These activities were
thought to produce PtdIns(4,5)P2 from PtdIns4P in the PM as
part of the PI signaling cycle, but comprised of two clearly
distinguishable activities (type I and type II) with unique immunological and catalytic properties (114, 361, 1504). One of
the distinctive features of the type I PtdInsP 5-kinase activity
was its strong stimulation by PtdOH (726). It was also a curious early observation that type II PtdInsP kinase was ineffective against native membrane PPIs even though it was active
against PtdIns4P substrates presented as micelles (although
with higher Km for the lipid)(114). The first PtdInsP kinase
cloned was the type II form (167, 362) (called C-isoform in
Ref. 362) followed by the type I enzymes with a high degree of
sequence similarity between the two forms (933). Only later
was it discovered that the type II enzymes actually use
PtdIns5P as substrate adding a phosphate to the 4-position to
yield PtdIns(4,5)P2 and that their “5-kinase activity” was due
to contamination of the commercial PtdIns4P preparations
with PtdIns5P (1254). This explains why the type II enzymes
were unable to make PtdIns(4,5)P2 from PtdInsPs of natural
membranes.
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These enzymes are usually discussed with the PI 3-kinases,
but because of their substrate restriction they are, in fact,
PtdIns kinases and, therefore, will be discussed in this paragraph. The yeast enzyme, VPS34 was the first cloned PtdIns
3-kinase (1367). As indicated by its name, this protein had
been initially identified in screens for S. cerevisiae mutants
that develop vesicular sorting defects (Vps) (101, 1300).
Only after the realization that the COOH-terminal half of
Vps34p shows very high sequence homology with the mammalian type I PI 3-kinase 110 kDa catalytic subunit (614)
was it understood that Vps34p is a PI 3-kinase (1367).
Yeast cells with deleted Vps34p lack PtdIns 3-kinase activity and the lipid PtdIns3P, indicating that this enzyme is the
sole source of this lipid in yeast (1367, 1446). The enzyme is
unique among PI 3-kinases in that it can only phosphorylate
PtdIns but not further phosphorylated PPIs (1446). Cells
with Vps34 mutations or deletions have morphologically
intact vacuoles and a normal secretory pathway, but fail to
sort certain cargoes, such as the enzyme carboxypeptidase
Y (CPY), to the vacuole (604). Vps34p tightly associates
with a serine/threonine kinase, Vps15p, that greatly stimulates its kinase activity (1445), and Vps15 mutants display
vacuolar sorting defects very similar to those described in
Vps34p mutants (605). The production of PtdIns3P by
Vps34p is important for transport from the Golgi to a
prevacuolar compartment and subsequently to the vacuole (1445). Vps34p is also important for the membrane
invaginations in multivesicular bodies (MVB) (70, 71, 765)
and for various forms of autophagy (779). In each of these
functions, different proteins are associated with the
Vps34p-Vps15 complex (779). Accordingly, PtdIns3P exerts its effects by recruiting a variety of proteins that contain
PI binding domains that are attracted to the membrane by
this particular PPI species. These include FYVE domains
(584, 766, 836), PX domains (239), and perhaps others that
are less characterized (486, 1739). The specificity of these
interactions is not solely determined by the interaction with
PtdIns3P but also by the protein-protein interactions that
are unique for the functionally distinct signaling complexes.
It is noteworthy that Vps34p is less sensitive to the PI 3-kinase inhibitor Wm (IC50: ⬃3 ␮M) than the mammalian PI
3-kinases (⬃2–5 nM), especially the class I enzymes (1446).
Vps34p not only regulates the trafficking of proteins to the
vacuole but is also important for autophagy (74, 751), a
starvation-induced protein-degradation process targeting
cytosol and organelles to the lysosome (1073). Vps34p
serves the secretory and autophagy pathways in two different protein complexes: both complexes I and II contain
Vps34p, Vps15, and Vps30p, but complex I also has
Atg14p and complex II has Vps38p. Complexes I and II
regulate autophagy and CPY sorting to vacuoles, respectively (779).
TAMAS BALLA
PIP kinases are soluble peripherally membrane-bound proteins that show a highly conserved catalytic core and differ
only in their COOH termini (FIGURE 4). The substrate specificity of the enzymes is determined by the activation loop
within their catalytic domains and can be reversed by swapping activation loops between the type I and type II forms
(832). The first reports on the cloning of the mammalian
type II enzymes also identified two homologous sequences
in the S. cerevisiae genome, Mss4 and Fab1 (167, 362).
Mss4p is important for actin organization and membrane
morphogenesis (348, 644) while Fab1p is essential for normal vacuolar morphology and functions (498, 1757). Since
Fab1, as well as its mammalian homolog PIKfyve (1404),
turned out to phosphorylate PtdIns3P to PtdIns(3,5)P2,
these enzymes were classified as type III PIP kinases.
1. Type I PIP-kinases
These enzymes are the true PtdIns4P 5-kinases, and several
forms have been described in mammalian tissues encoded
by three genes (PIPKI␣, -␤, and -␥) and a number of splice
forms within PIPKI␥. Although all three major forms are
widely expressed, the relative tissue distribution and the
cellular localization of the various isoforms are unique, and
Kinase
539 aa
PIPKIβ
546 aa
PIPKIγ
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PIPKIα
PIPKIγ–v1 (PIPKIγ87)
PIPKIγ–v2 (PIPKIγ90)
PIPKIγ–v3 (PIPKIγ93)
PIPKIγ–v4
PIPKIγ–v5
PIPKIγ–v6
Kinase
PIPKIIα
406 aa
PIPKIIβ
416 aa
PIPKIIγ
421 aa
Kinase
Mss4p
779 aa
FYVE
DEP
TCP-1
Kinase
PIPKIII/
PIKfyve
2,052 aa
FYVE
TCP-1
CR
Kinase
Fab1p
2,278 aa
FIGURE 4. The family of PIP kinase enzymes. Type I PIP kinases phosphorylate PtdIns4P to PtdIns(4,5)P2.
They have three forms: ␣, ␤, and ␥; the latter has five splice variants in humans that differ in their very COOH
termini (alternative but still commonly used names are shown in parentheses). The type II PIP kinases
phosphorylate PtdIns5P to PtdIns(4,5)P2 and also exist in three forms, of which the ␥ form has very low
catalytic activity. Yeast only has one enzyme, Mss4p, that makes PtdIns(4,5)P2 from PtdIns4P. A third group
of PIP kinases are called type III PIPkins, and they phosphorylate PtdIns3P to PtdIns(3,5)P2. The mammalian
enzyme is called PIKfyve, while the yeast ortholog is Fab1p. The typical feature of these enzymes is the
presence of a FYVE domain close to their NH2 termini that binds PtdIns3P and a Cpn60/TCP-1 chaperonin
family domain (TCP-1).
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PHOSPHOINOSITIDES
it is generally agreed that they generate functionally distinct
and specialized pools of PtdIns(4,5)P2 (375). However, the
plasticity and redundancy of the PIP5Ks is really enormous,
and a single copy of the PIP5KI␥ gene is able to support
normal mouse development and life to adulthood (1644) in
spite of clearly distinguishable roles of these enzymes in
specific cellular functions (see below).
From this description it is clear that Mss4 controls
PtdIns(4,5)P2 synthesis in the context of a number of diverse biological functions, all of which are interfaced with
unique regulatory molecular complexes. These functionally
distinct roles have been diversified during evolution and are
assumed by the various isoforms of the mammalian PIP
5-kinases.
PIPKI␥ is the most versatile PIP 5-kinase, as it comes in
several splice forms: PIPKI␥87, -␥90 (708), and a neuronalspecific -␥93 (510, 1741) (FIGURE 4). Aditional forms of
700 and 707 amino acid forms have been found in human
(1359) and another 90-kDa form in the rat (1741). Since the
exon structure differs between the rodent and human genes,
and different splice forms have similar apparent molecular
weights, the designation of these splice forms becomes
somewhat complicated (1359, 1741). The various PIPKI␥
forms are now named PIPKI␥-v1– 6 in human and PIPKI␥v1,2,3,6 in the rat (1359, 1741) (it is not clear if the I␥-4,5
forms exist in rodents). In most tissues the 87-kDa form
(PIPKI␥-v1) is prevalent, but brain expresses mostly the
90-kDa (PIPKI␥-v2) variant. Both the 87- and 90-kDa
forms localize to the PM, but the 90-kDa form also localizes
to focal adhesions via interaction with talin (353, 913). The
interaction with talin is controlled by a balance of Tyr and
Ser phosphorylations at the COOH terminus of the 90-kDa
form of the kinase (875, 914). PIPKI␥93 (PIPKI␥-v3) is also
localized to the PM, but the 707 amino acid human splice
form (PIPKI␥-v5) shows both PM and intracellular vesicular localization (511, 1359), and the 700 amino acid form
(PIPKI␥-v4) is found in nuclear speckles (1359). These localization patterns cover all the compartments where the ␣
and ␤ forms of type I PIPKs are found. Substrate (PtdIns4P)
binding is a major factor in the PM localization of PIPKI␥
(as well as I␣ and -I␤) (832), although there are other protein-protein interactions that are suspected to contribute to
membrane localization (511). For example, Rac binding
makes a significant contribution to the PM binding of the
PIPKI␤ (553). Functionally, PIPKI␥ has been linked to endocytosis via interaction with the AP-2 adaptor and clathrin
(80, 1550) and by promoting actin polymerization at the
PM (398). A similarly important role of the enzyme was
found in establishing adherent junctions via regulation of
E-cadherin trafficking (912) and for EGF-driven directional
migration (1498). Both the invasion and proliferation of
breast cancer cells was found highly dependent on PIPKI␥
(1499). PIPKI␥ is the major PtdIns(4,5)P2 synthesizing activity in the brain and the synapse in particular (1704), and
it plays critical roles at several steps in the synaptic vesicle
exocytosis-retrieval cycle (352). Outside the brain, expression of PIPKI␥90 increases the pool of rapidly releasable
dense core vesicles in chromaffin cells (1056), while elimination of the enzyme decreases the same pool and causes a
defect in vesicle priming (520). Finally, PIPKI␥87 was
found uniquely responsible for the generation of the
PtdIns(4,5)P2 pools for agonist-stimulated Ins(1,4,5)P3 increases and Ca2⫹ signaling in HeLa cells (1679), and mast
cells lacking PIPKI␥ (both the 87- and 90-kDa forms)
showed greatly reduced response to IgE receptor cross-linking (1621).
The activity of PIPKI␥ is regulated by the small GTP-binding protein Arf6 (824) and by binding to AP-2 adaptor
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Yeast possesses only one type I PtdInsP kinase, Mss4, that
was first isolated as a multicopy suppressor of the stt4 –1ts
growth defect (1779), and subsequently shown to be a
PtdIns4P 5-kinase (348, 644). Cells lacking Mss4 are not
viable, and inactivation of the enzyme results in enlarged
cells with rounded shape. This phenotype is very reminiscent of the defects seen in mutants of actin binding proteins
(40, 546). Indeed, actin organization is severely impaired in
mss4ts mutants at nonpermissive temperature (40, 65, 546).
Interestingly, mss4ts and stt4ts mutants have overlapping
but not identical phenotypes, suggesting that not all Mss4
functions are mediated by Pkc1 (1779). Remarkably, some
(but not all) temperature-sensitive calmodulin (Cmd1) alleles confer defects in actin organization that can be rescued
by Mss4 (347). In addition, Mss4 also has a role in endocytosis (347) and is linked to TOR2 (594), which is a Ser/
Thr kinase with a role in cell cycle-dependent polarized actin
distribution (1363). Further effectors of the PtdIns(4,5)P2 generated by Mss4 are the Slm1/2 proteins that are not only
implicated in actin polarization (65, 415) but also are
linked to sphingolipid metabolism (321, 486, 1510). Inhibition of sphingolipid synthesis also interferes with the signaling function of Mss4 and releases the protein from the PM
(806), further supporting a connection between PtdIns(4,5)P2
synthesis and sphingolipid metabolism. The yeast phosphatidylcholine-specific PLD, Spo14 is also regulated by the
PtdIns(4,5)P2 generated by Mss4 (284), and Mss4 was also
found to have a role in late stages of secretion probably at
the fusion step. In this capacity, Mss4 is tied to the components of the exocyst, the PM t-SNARE, Sec9, and the syntaxin-binding protein Sec1 (1303). Finally, a fraction of
Mss4 also localizes to the nucleus, and temperature-sensitive mutants of Mss4 have been isolated that either accumulate in the nucleus or remain PM-associated (62). The
functional significance of the nuclear Mss4 is not clear at
this point, but it is worth noting that Mss4 can be phosphorylated by the yeast casein kinase I orthologs, and phosphorylation is required for PM binding and optimal functions (62).
2. PIPKI␥/PIP5K1C
TAMAS BALLA
complexes (80, 1113). Stimulation of the enzyme by PtdOH
has also been well documented, but it needs further studies
to clarify if this regulation occurs in a physiological setting.
PIPKI␥ knockout mice develop normally but die soon after
birth probably because of lack of suckling due to generalized neuronal defects (352). Interestingly, in another study,
in which PIPKI␥ was inactivated by a gene-trap method, the
mouse exhibited embryonic lethality at E11.5 and showed
cardiovascular and neural tube closure defects (1677). The
lack of this enzyme also impairs anchoring the membrane to
the cytoskeleton in megakaryocytes and platelets (1678). A
mutation abrogating the kinase activity of PIPKI␥ (PIP5K1C)
has been identified as the cause of Lethal Contractual Syndrome 3, a severe developmental defect with early perinatal
lethality (1119).
The terminology of the -␣ and -␤ forms of the type I PIP
kinases is rather confusing as the human ␣ form corresponds to the mouse ␤, and conversely, the homolog of
human ␤ is the mouse ␣. As most reviews do, I will also
follow the human nomenclature. There are only few functions that are specifically assigned to the ␣ and ␤ isoforms.
In fact, overexpression of any of the type I PIP kinases
affects actin dynamics and increases membrane activity, but
the effects depend on the enzyme, the expression level, and
the cell type. For example, PIPKI␤ expression manifests in
actin comet formation (1305), increased number of stress
fibers (1759), increased membrane ruffling (646) and forced
the appearance of internal vesicles that are coated with actin
and unable to recycle to the PM (189). There have been
reports, however, on changes specific to particular isoforms. For example, PIPKI␤, but not PIPKI␣ or PIPKI␥, was
shown to localize at the trailing appendage of differentiated
HL60 cells and knockdown of PIPKI␤ interfered with polarization and movement of these cells during chemotaxis
(845). Another special case of highly coordinated membrane activity where specific PIP5Ks are important is Fc␥Rmediated phagocytosis (172, 289). Here, PIPKI␣ is recruited to the phagocytic cup, and a kinase dead version of
the enzyme blocks the process as well as the PtdIns(4,5)P2
accumulation associated with it (172, 289). It has been
suggested that PtdIns(4,5)P2 is required for the actin polymerization during the pedestal formation to engulf and initiate
ingestion of the phagocytic particle (172), but PtdIns(4,5)P2
needs to be eliminated for closure of the phagocytic cup
(1370, 1766). However, recent studies suggest a more complicated mechanism, where PIPKI␥-deficient bone marrowderived macrophages (BMM) showed the presence of
highly polymerized actin and impaired attachment of the
opsonized particles. In contrast, BMMs from PIPKI␣-deficient mice showed no attachment defect, but instead a problem with particle ingestion (989). Remarkably, PIPKI␥-deficient cells showed increased RhoA and decreased Rac1
activation, and correction of the distorted activated RhoA/
Rac1 ratio remedied the attachment defect (989). PIPKI␣-
1036
Not all of the effects of type I PIPKs are linked to actin
polymerization. PIP5KI␤ promotes transferrin receptor endocytosis in HeLa cells unrelated to its effects on actin polymerization by increasing the membrane association of
AP-2 adaptor protein complexes (1185). Conversely,
PIP5KI␤ knockdown by RNAi (but not the other forms)
inhibits the same process (1185). In another study, PIPKI␣
was found to regulate EGF receptor endocytosis (106) and
an N-terminally truncated PIPKI␣ was described as a potent
inhibitor of the removal of colony stimulating factor-1 receptors from the cell surface (326). As mentioned above, it
is the PIPKI␥ isoform that regulates clathrin-mediated endocytosis in neurons (80, 824).
In most of these actions, PIP5Ks are working tightly coupled with small GTP binding proteins, which can act both
upstream and downstream of the PIP5K. RhoA was found
to mediate the effects of PIP5K on stress fibers (1759) but
was also found to act via a PIP5K (1010). Similarly, both
PIPKI␣ and -␤ were found to associate with Rac1 regardless
of the GTP-GDP status of the latter, but only PIPKI␤ association regulated actin assembly (1560). On the other hand,
the effects of PIP5K on ezrin membrane localization were
found to be Rac1 dependent (68). Arf6 was also found to
recruit both PIPKI␣ and -␤ to the PM and stimulate PIPKI␤
activity (646), and constitutively active Arf6 mimicked
many of the effects of overexpressed PIP5K (189). Arf6 also
can indirectly regulate PIP5K by recruiting PLD2 to membrane ruffles where production of PtdOH by PLD can further activate PIP5K activity (1415). Type I␤ PIP kinases are
also regulated by phosphorylation. Oxidative stress decreased PtdIns(4,5)P2 levels by releasing PIPKI␤ from the
PM (244, 554). This effect was due to Tyr phosphorylation
of PIPKI␤ by a Src family kinase (554) that was later identified as Syk and the phosphorylated residue as Y105 (244).
Syk also phosphorylates PIPKI␥87 (but not the ␣ form)
during phagocytosis (989). In another paradigm, hypertonic osmotic stress increases PIPKI␤ activity by Ser/Thr
dephosphorylation (1758).
In addition to being associated with membrane dynamics,
an exciting role of PIPKI␣ in the nucleus has recently been
revealed. The existence of a nuclear PI system has been
appreciated and studied for quite some time (see sect. X),
but the exact processes that are regulated by the PI lipids
and their modifying enzymes have been elusive. The presence of endogenous PIPKI␣ in nuclear speckles at the sites
of pre-mRNA processing has been described earlier (168).
Recent studies described the association of a noncanoni-
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3. PIPKI␣ and -␤/PIP5K1A and -B
deficient BMMs, on the other hand, had problems extending their pseudopods due to impaired WASP and Arp 2/3dependent actin polymerization. These studies clearly showed
that distinct PtdIns(4,5)P2 pools delivered by distinct kinases had functionally unique roles in a highly orchestrated
process of membrane remodeling.
PHOSPHOINOSITIDES
cal poly(A) polymerase, named Star-PAP with the PIPKI␣
enzyme in nuclear speckles (1029). Star-PAP was found
strongly stimulated by PtdIns(4,5)P2 and responsible for
the control of the expression of selected group of genes
(1029).
4. Type II PIP kinases PIP5K2s
Although the type II form was the first member cloned from
the PIP kinase family (167, 362), the role(s) of these enzymes has remained largely elusive. Structurally, they are
highly homologous to the type I enzymes (FIGURE 4) but, as
pointed out above, they use PtdIns5P as substrate and convert it to PtdIns(4,5)P2 (1254). Understanding the function
of the kinases is closely coupled to understanding the distribution, the pathway of production, and function(s) of the
minor PI species PtdIns5P. There is much to be learned in
this area, but the picture emerging from recent studies indicates that type II PIPKs (also called PI5P 4-kinases) may be
more important in controlling PtdIns5P levels than to contributing to PtdIns(4,5)P2 production (267, 737). Mammalian type II PIP kinases also exist in three forms: -␣, -␤, and
-␥ (710, 934). Functional data suggest that PIPKII␣ is enzymatically the most active, while -␤ has moderate and -␥ very
low catalytic activity using the standard in vitro assay conditions (197, 266). This is relevant as PIPKII enzymes form
dimers, and it has been speculated that the less active forms
may just serve as targeting devices to localize the active
PIPKII␣ enzyme to specific cellular locations (197, 263,
1672). The X-ray analysis of PIPKII␤ crystals also shows
the protein in a dimeric form (1257). In fact, PIPKII␤ is
localized both in the cytosol and to nuclear speckles, and it
can bring PIPKII␣ into the same nuclear location (197,
1672). PIPKII␥, on the other hand, shows special tissue
distribution being highly enriched in the kidney (266, 710)
where it is mostly found in the epithelial cells of the thick
ascending limb associated with intracellular vesicles (266).
Notably, in other reports, the expressed enzyme was found
Functionally speaking, there are very few studies addressing
the cellular role(s) of PIPKII enzymes. RNAi-mediated knockdown and overexpression studies showed that PIPKII␣-mediated PtdIns(4,5)P2 formation was important for secretion in
platelets (1307, 1308) and that the enzyme was also involved in platelet formation during development of the demarcation membranes in megakaryocytes (1368). Membrane recruitment of PIPKII␣ could be mediated by interaction of the kinase with type I PIP kinases (620). A cytosolic
and membrane-related role of PIPKII␤ was suggested by
association of the protein with the TNF (223) and EGF
(222) receptors. Deletion of PIPKII␤ in mice increases insulin sensitivity by enhancing Akt activation in muscle (848),
and overexpression studies suggest that the enzyme attenuates insulin signaling (218). In agreement with these data,
generation of PtdIns5P in the PM by the bacterial phosphatase IpgD enhances Akt activity (1206) presumably by altering EGF receptor trafficking and signaling (1255). The
nuclear functions of PIPKII␤ have also been emerging. Ultraviolet irradiation increased nuclear PtdIns5P levels by a
cascade of events that included p38 MAP-kinase mediated
phosphorylation of PIPKII␤ at Ser236 leading to decreased
activity. Decreased activity of the kinase led to the elevation
of PtdIns5P, which, in turn, interacts with the ING2 protein
via a PHD domain. PHD2, a nuclear adaptor protein controls p53 and histone acetylation, and PtdIns5P binding to
PHD2 changes its association with the chromatin (737). In
light of the recent discovery that the majority of the kinase
activity associated with PIPKII␤ can be attributed to the -␣
enzyme as part of a heterodimer (197, 1672), it was important to show that Ser236 phosphorylation of -␤ does not
affect its association with -␣, and it is likely that the decreased activity of the complex is due to an allosteric regulatory mechanism (197).
5. Type III PIP kinases/PIP5K3
Type III PIP kinases phosphorylate PtdIns3P to PtdIns(3,5)P2.
The yeast ortholog, named Fab1, was first described based
on a genetic screen for defects in nuclear segregation (1757).
The cloning of the 257-kDa protein revealed a strong sequence similarity with the first cloned type II PIPK within its
putative catalytic region (1757). Fab1 contains a PtdIns3P
binding FYVE domain close to its NH2 terminus (FIGURE
4). Although FAB1 is not an essential gene, fab1 null or
temperature-sensitive mutant cells grow slowly and show
defective spindle orientation resulting in haploid and binucleated daughter cells (1757). Fab1 null cells also develop
huge vacuoles and display a block in the transport of certain
hydrolyses (such as CPY) to the vacuole (498). It is specu-
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PIPKI␣ knockout mice (lacking the mouse PIPKI␤) appear
normal and develop to adulthood, although the number of
offspring is lower than expected by the Mendelian ratio
(1676). Interestingly, the platelets of these mice showed a
defect in thrombin-induced InsP3 increases and aggregation
that could be overcome at high agonist concentrations
(1676). Because of the lack of any major abnormalities, it is
likely that the other type I PIPK can assume the membraneassociated functions normally performed by PIPKI␣, and as
for nuclear functions, the recently described PIPKI␥ 700
amino acid form found in nuclear speckles (1359) may be
able to substitute for the PIPKI␣ enzyme. PIPKI␤ knockout
mice (lacking mouse PIPKI␣) are also born and develop
normally but show highly enhanced degranulation response of their mast cells after FceR-I crosslinking and
enhanced cutaneous and systemic anaphylaxis (1344).
This effect is explained by a defect in the stability of the
actin cytoskeleton.
ER-associated (710). The enzyme is also expressed in nervous tissues in neurons, again associated with endomembranes (265). Given the very low enzymatic activity of this
form, it has been speculated that PIPKII␥ is a scaffold that
brings the active -␣ enzyme to special membrane compartments (267).
TAMAS BALLA
The mammalian type III PIP kinase is an ortholog of Fab1
and is named PIKfyve (1404). PIKfyve shows many similarities to Fab1 both structurally and functionally. It also has a
PtdIns3P recognizing FYVE domain and interacts with several proteins that are homologues of the yeast proteins
found in complex with Fab1. The mammalian version of the
Vac14 scaffold is called ArPIKfyve that holds PIKfyve and
Sac3 in one complex (734, 1351). Sac3 is the homolog of
Fig4, the 5-phosphatase that converts PtdIns(3,5)P2 back to
PtdIns3P (685). Intriguingly, the presence of Sac3 in the complex not only ensures that the kinase is balanced, but curiously, it
also keeps PIKfyve in a highly active conformation (683). The
biological advantage of this unique phenomenon that maintains a
high turnover rate of PtdIns(3,5)P2 is not fully understood.
Nevertheless, inhibition of PIKfyve function either by
RNAi-mediated depletion (1316), expression of a dominant negative version (684), or pharmacological inhibition
(with a selective PIKfyve inhibitor, YM2016636; Ref. 723)
leads to massive vacuolization. These vacuoles represent
swollen endocytic compartments and are associated with
defects in fluid phase endocytosis (684) and in retrograde
transport from the endosomes to the TGN (1316). Importantly, while the trafficking and degradation of transferrin
and EGF receptors were found unaffected by knockdown
studies (684, 1316), acute pharmacological blockade of
1038
PIKfyve did affect the degradation of EGF receptors with
their accumulation in the membrane of the enlarged vesicles
(336, 723). PIKfyve was also found functionally coupled to
insulin-induced GLUT4 translocation and glucose uptake
(618, 686), and PIKfyve inhibitors led to the accumulation
of the autophagy marker LC3-II in endocytic structures
(336). This latter finding also indicates a defect in the fusion
of prelysosomal compartments and MVB with lysosomes.
PIKfyve-depleted or -inhibited cells also fail to properly
acidify their endocytic compartments (723), but it is not
clear whether PtdIns(3,5)P2 directly or indirectly affects the
activity of the V-ATPases. This latter effect may be related
to the recently described PtdIns(3,5)P2 dependence of the
lysosomal cation channel, TRPML1 or mucolipin (371).
Most recently, PtdIns3P and PtdIns(3,5)P2 generation were
found to control the activation and localization of the
mTORC1 complex via a direct association between Raptor
and PtdIns(3,5)P2 (180). Other recent studies indicated that
PIKfyve, together with some of the myotubularin phosphatases that remove the 3-phosphate from PtdIns(3,5)P2 (see
sect. VI), are important for PtdIns5P generation in mammalian cells (1173, 1352, 1827). One of these studies also
found that PtdIns5P generated via this pathway is a regulator of cell migration (1173).
PIKfyve inactivation in Caenorhabditis elegans (1129) and
Drosophila (1315) also leads to swollen endocytic compartments. Germline deletion of PIKfyve in mice is embryonic
lethal in the preimplantation stage, and MEF cells from
heterozygotes show an increased sensitivity to the PIKfyve
inhibitor YM201636 (682). A debilitating mutation in one
allele of PIKfyve causes Francois-Neetens mouchetée corneal fleck dystrophy in humans characterized by multiple
focal vacuolization in the cornea (901). The evolutionary
conservation of the tripartite PIKfyve/Fig4/Vac14 complex
that is required for proper PIKfyve function is also underscored by mouse and human genetics. The genetic aberration responsible for the “pale-tremor mouse” phenotype
has been identified as an early transposon insertion into the
mouse Fig4/Sac3 gene. This also resulted in a decrease
rather than an increase in PtdIns(3,5)P2 levels and caused a
prominent defect at the late-endosome to lysosome transition (and probably in many other trafficking steps) responsible for the pigmentation defect and a progressive neurodegeneration (253). Pathogenic mutations in the human
FIG4 gene have also been identified in a novel form of
autosomal recessive Charcot-Marie-Tooth disorder, CMT4J,
characterized by motor and sensory neuropathy (253) and
in a small percentage of patients with amyotrophic lateral
sclerosis (ALS) (252). Similarly, a Vac14 gene-trap mouse
showed early newborn lethality associated with rapid neurodegeneration with massive vacuolization and cell death in
certain brain areas. Since the development of these animals
appears to be normal and their other organs are not as
severely affected, the lack of Vac14 only compromises but
does not completely eliminate PIKfyve function (1810). It is
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lated that the chromosomal segregation defect is secondary
to the vacuolar defect possibly because of steric interference
from the enlarged vacuoles (1757). That Fab1 is a PtdIns3P
5-kinase was revealed when it was found that osmotic stress led to
a rapid increase in the level of a novel phospholipid,
PtdIns(3,5)P2, in yeast (376), and it was shown that this increase was dependent on functional Fab1 (287). Simultaneously, it was demonstrated that Fab1 deletion or Fab1 mutant cells lacked PtdIns(3,5)P2 (498). Finally, in vitro Fab1
was shown to phosphorylate PtdIns3P to PtdIns(3,5)P2
(287, 1017), and consistent with its roles in vacuole physiology, Fab1 was localized to the vacuolar membrane (162,
378, 498). Interestingly, deletion of two other genes, Vac7
and Vac14, also eliminates detectable PtdIns3P 5-kinase
activity (162, 378, 498), suggesting that they are upstream
regulators of Fab1. Counterintuitively, deletion of Fig4, the
phosphatase that converts PtdIns(3,5)P2 back to PtdIns3P
(390, 497, 1311), does not increase the level of
PtdIns(3,5)P2. Quite to the contrary, it decreases both the
basal and osmotic stress-induced increase in the level of this
lipid (389, 1311). This curious finding is due to the fact that
Vac14 acts as a scaffold that holds Fig4 and Fab1 in a
signaling complex (that also contains Vac7 and Atg18)
(734), and removal of Fig4 leads to the destabilization of
this complex with impaired Fab1 activity (170). Functionally speaking, all these proteins via the control of
PtdIns(3,5)P2 have an important role in the multivesicular
body (MVB) sorting pathway (378, 1159). This pathway is
also important in autophagy via connection to the Atg18
protein (379) (see more on this in sect. X).
PHOSPHOINOSITIDES
a fascinating question why only certain neurons mainly after birth are so dependent on PtdIns(3,5)P2 function.
PtdIns (1711) and that the PI 3-kinase activity associated
with oncogenes and stimulated growth factor receptors primarily produced PtdIns(3,4,5)P3 and, in fact, was a
PtdIns(4,5)P2 3-kinase (66). These early reports have
marked the beginning of the explosion of the PI 3-kinase
field that unraveled the existence of several classes of PI
3-kinase enzymes and their regulatory adaptor proteins
(FIGURE 5). The 110-kDa catalytic domains of class I PI
3-kinases are encoded by four distinct but highly related
genes in mammals (-␣, -␤, -␥, and -␦). In addition, five
C. PtdIns(4,5)P2 Kinases
The first indication that PtdIns(4,5)P2 can be further phosphorylated was the detection of novel lipids, PtdIns(3,4,5)P3 and
PtdIns(3,4)P2, in 1989 by Taynor-Kaplan in human neutrophil cells (1572). In parallel studies it was discovered that
type I PtdIns kinases could phosphorylate the 3-position of
p85BR
Ras-BD
SH3
C2
Rho-GAP
LKU
nSH2
Kinase
1,068 aa
1,070 aa
1,044 aa
cSH2
PIK3r1/P85α
PIK3r2/P85β
PR
PR
PIK3r1/P55α
PIK3r1/P50α
PIK3r2/P55β
PIK3r3/P55γ
iSH2
nSH2
PR
AdBR Ras-binding
cSH2
iSH2
C2
LKU
Kinase
PIK3CG/PI3Klγ
1,102 aa
p100γ-BR
Gβγ-BR
PIK3r5/p101
PIK3r6p/p84/p87
PIK3C2A/PI3KC2α
PR
Ras-binding
C2
LKU
Kinase
PX
C2
PIK3C2B/PI3KC2β
PIK3C2G/PI3KC2γ
1,686 aa
1,634 aa
1,444 aa
C2
LKU
Kinase
PI3KC3/Vps34
887/875 aa
FIGURE 5. The family of PI 3-kinase enzymes. Class I PI 3-kinases phosphorylate PtdIns(4,5)P2 to
PtdIns(3,4,5)P3. There are four different genes coding for the catalytic subunits of PI3Ks, called p110␣, -␤, -␥,
and -␦. They all have a conserved COOH-terminal catalytic domain preceded by lipid kinase unique (LKU, also
called “helical”), C2 and Ras binding domains (Ras-BD). These enzymes have tightly associated regulatory
subunits: p110␣, -␤, and -␦ associate with p85 and p55/50 regulatory subunits encoded by three different
genes. Their association is mediated by an interaction between the very NH2-terminal p85-binding region
(p85BR) of the catalytic chains with the inter-SH2 (iSH2) region of the regulatory subunits. These enzymes are
also called class IA enzymes. The catalytic p110␥ differs from the previous forms (hence it is called class IB)
in that it associates with either of two adaptors, p101 and p84/p87. These different adaptors interact with
NH2-terminal adaptor binding region (AdBR) of p110␥ and lend regulation by G protein ␤␥ subunits (p101) and
perhaps by Ras (p84/p87) to the enzyme. Class II PI3Ks also come in three forms (␣, ␤, and ␥) and contain
phox-homology (PX) and C2 domains placed COOH terminally to their catalytic domains. These enzymes can
phosphorylate PtdIns and PtdIns4P in vitro, but their in vivo substrate preference is still debated. The enzymes
most likely form PtdIns3P in the cell. The single class III PI3K and its yeast ortholog, Vps34p, phosphorylates
PtdIns to PtdIns3P. These enzymes associate with a larger regulatory protein Vps15p in yeast and p150 in
mammalian cells (not shown).
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PIK3CA/PI3Klα
PIK3CB/PI3Klβ
PIK3CD/PI3Klδ
TAMAS BALLA
Class I PI 3-kinase activation leads to the production of
PtdIns(3,4,5)P3 in the PM, and this molecule is the ultimate
initiator of a great variety of cellular signaling responses
and cascades of molecular events. A chief mediator of
PtdIns(3,4,5)P3 actions is the protein kinase Akt (also called
PKB) that is recruited to the PM by PtdIns(3,4,5)P3 via its
PH domain where it gets phosphorylated on Thr308 and
Ser473 by PDK1 (1081) and mTORC2 (1830), respectively, leading to its increased kinase activity. Interestingly,
PDK1 also has a PH domain, and its recruitment to the
membrane is also aided by PtdIns(3,4,5)P3 (816). Recent
data suggest that mTORC2 may also be regulated by
PtdIns(3,4,5)P3 (489, 1430). Activated Akt phosphorylates
a whole range of substrates to regulate energy metabolism,
survival, cell cycle progression, or differentiation depending
on the tissue and the signaling context under which it is
activated. These pathways will be detailed in section IX.
Additional molecules regulated by PtdIns(3,4,5)P3 are guanine exchange factors (GEFs) for a range of small GTP
binding proteins, such as Arfs (1627) and Rac/Rho/Cdc42
(608, 1699) or the Tec family tyrosine kinases such as Bruton’s tyrosine kinase (Btk) (1261) or Itk (44), key components of B- and T-cell activation, respectively. PtdIns(3,4,5)P3
gradients have a major role in the migrational response of
cells to chemotactic stimuli (459), a response not only serving phagocytic cells, but also being critical for morphogenic
patterning, axon extension, blood vessel formation, and for
invasion and metastasis by cancer cells. The contribution of
the individual isoforms and their regulatory subunits to
these processes during development and to the functions of
various cells and tissues is only beginning to unfold with the
help of genetic deletion of the individual enzymes in whole
animals or in selected tissues and with the availability of
subtype-specific PI 3-kinase inhibitors.
Class I PI 3-kinases control several cellular processes such as
cell energetics and metabolism or immune cell functions,
and they are also key players in cancer development, prop-
1040
agation, and metastasis. These important roles have propelled PI 3-kinase research into ever-increasing heights. In
light of the incredible progress made in this research area, it
seems ironic that PI 3-kinases were initially deemed nondruggable targets because of their fundamental roles in supporting almost every aspect of a cell’s life. Contrast this
with the fact that several subtype-specific PI 3-kinase inhibitors are now in development and some are being tested in
clinical trials. Due to the enormity of the PI 3-kinase literature, its coverage in this review will be inevitably limited
and focused only on fundamentals. Several excellent reviews have summarized various aspects of this topic in
greater details in recent years (75, 221, 467, 814, 996,
1609, 1612, 1613, 1640, 1727, 1785).
1. Class I PI 3-kinases
PI3K␣/PI3KCA is a widely expressed and most studied
member of the class I PI3K family. The 110-kDa protein
contains a COOH-terminal catalytic domain that is highly
homologous to those found in other PI 3-kinases, in type III
PI 4-kinases (190, 505), and in PI kinase-related kinases
(669). This group of catalytic domains is also highly conserved from yeast to human, although yeast has only a class
III PI 3-kinase, Vps34. The domain architecture of these
enzymes is shown in FIGURE 5. PI3K␣ is tightly associated
with a regulatory subunit encoded by the p85␣ gene with
three splice forms: p85␣, p55␣, and p50␣ (468, 699, 1178).
p85␣ has an NH2-terminal SH3 domain, a BH (BCR homology) domain, proline-rich regions, and two SH2 domains linked with a coiled-coil iSH2 (inter-SH2) region,
which is one of the major sites of interaction with the NH2
terminus (1053) and C2 domains (660) of the catalytic
p110␣ subunit. The shorter variants, p55␣ and p50␣, lack
the NH2 terminus of p85␣ including the SH3 and BH domains. The classical activation sequence of PI3K␣ occurs
during receptor tyrosine kinase activation, with recruitment
of the p85/p110␣ complex via direct binding of the SH2
domains of p85 to the tyrosine phosphorylated motifs of the
receptors (1435) such as the PDGF receptor (770) or the
immunoglobulin family tyrosine-based activation motif
(ITAM) of T- and B-cell receptors (943, 1078). In some
cases, the recruitment is indirect, involving docking proteins, such as Grb2 and Gab1 for EGF receptors (1277,
1669) or IRS-1/2, in the case of insulin or IGF1 receptors
(76, 1102). During this process, the p85 subunit also gets
tyrosine phosphorylated and renders the catalytic subunit
active via molecular rearrangements, the details of which
are just beginning to unfold thanks to elegant structural
studies (1053, 1807). Early reports showed that the iSH2
domain of p85 fused to the NH2 terminus of p110␣ yielded
a constitutively active PI 3-kinase (657), but p85 interaction
actually stabilizes the catalytic domain and keeps it in an
inactive state (1781) as indicated by more recent structural
studies (660, 978, 1807). As with all class I PI 3-kinases, the
p110␣ subunit also has a Ras binding domain, and GTPbound form of Ras is capable of directly activating PI3K␣
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distinct genes encode tightly associated PI 3-kinase regulatory proteins, p85␣ (with several splice variants), p85␤,
p55␥, p101 and p84/p87, the latter two serving as adaptors
for the p110␥ enzyme. Class II PI 3-kinases also exist in
three forms (-␣, -␤, -␥). These are larger proteins (150 –180
kDa) with relatively little known about their cellular regulation and functions. These enzymes were believed to phosphorylate PtdIns4P to PtdIns(3,4)P2 until recently, when
increasing evidence suggests that their primary product in
vivo is PtdIns3P (418, 1700) and, hence, they function as
PtdIns 3-kinases rather than PtdIns4P or PtdIns(4,5)P2 kinases. However, because of the still lingering uncertainty
about their in vivo substrate preference, these enzymes will
be discussed here. The only class III PI 3-kinase, hVps34, is
usually discussed with the PI 3-kinases, but because of its
only substrate being PtdIns, it was already covered with the
PtdIns kinases.
PHOSPHOINOSITIDES
(221, 657, 809, 1280). Several oncogenes like Src and polyoma middle T or the avian Rous sarcoma virus associate
with the p85/p110␣ complex also leading to its strong activation (228, 292, 479, 760).
Several studies reported on the knockout of the p85␣ regulatory subunit, either eliminating all three splice forms (469,
470, 1585) or either the long (85 kDa) (1503, 1543) or
short (p55 and p50) (241) forms. These studies surprisingly
found that all these mice showed increased insulin sensitivity and hypoglycemia. Moreover, the MEF cells isolated
from these animals showed enhanced rather than decreased
PtdIns(3,4,5)P3 response after stimulation. Since p85␣ is
the major adaptor protein that is needed to recruit PI3K␣ to
the insulin receptor, these paradoxical changes suggested
that either upregulation of p85␤, or more likely the presence of “free” p110␣ catalytic subunits that are more active
because of the lack of their inhibition by the associated p85.
More recently, it was also found that the p85␣ regulatory
subunit also interacts and activates PTEN (226), the phosphatase that counters PI 3-kinase action, and this negative
regulation is lost in p85␣ knockout mice. Therefore, the
abundance or shortage of p85 relative to p110␣ could be an
important factor in determining the extent of PI 3-kinase
activation and hence is also a factor in tumorigenesis
(1530). However, a detailed recent study casts doubt on the
role of “free” p85␣ or p110␣ subunits in normal cells as
they appear to exist as obligate heterodimers (503). Interestingly, elimination of p85␣ causes a severe defect in B-cell
development and decreased B-cell proliferation in response
Mutations within the human PI3KCA (coding for PI3K␣) as
well as in the PIK3r1 (coding for p85␣) genes have been
identified in a variety of cancers, at especially high percentage in colorectal cancers and glioblastomas, but also in
other cancer forms (247, 716, 1198, 1219, 1334). It was
also demonstrated that oncogenic mutants of PI3K␣ are
sufficient to promote cell proliferation and dissemination of
cancer cells when injected into nude mice (541, 1190,
1333). It has been noted that the mutations cluster mostly in
two regions that code for the helical and kinase domains of
PI3K␣ and some other ones within the NH2-terminal and
C2 domains (1334). The X-ray structures of the p110␣
complexed with the iSH2 domain (660, 978) and the
p110␤/p85␤ complex (1807) has shed light on the possible
mechanism of how these mutations lead to constitutive activation of the kinase. Most of these mutations are located
in regions where the catalytic domain interacts with the
iSH2 domain. These mutations probably weaken the interaction between the p85 and p110 subunits, therefore releasing the catalytic domain from the inhibitory effect exerted
by the iSH2 domain. A unique role of the p85 regulatory
subunits in stabilization of the PTEN phosphatase has been
reported recently as well as mutations within these subunits
causing destabilization and loss of PTEN in endometrial
cancers (247).
2. PI3K␤
The roles of PI3K␤ appear to be more restricted or specialized than those of PI3K␣, but this isoform has also been less
studied. PI3K␤ forms a heterodimer with p85␤ and was
expected to function in a similar manner as PI3K␣ and
thought to be functionally redundant with the latter. However, this idea was quickly repudiated when the embryonic
lethality of the PI3K␣ deleted homozygous animals was
reported. An initial study reported early embryonic lethality
in mice after deletion of PI3K␤ (142). Later studies using
different strategies, either replacing the enzyme with a catalytically inactive (K805R) form (261) or deleting exons
critical for catalytic activity (534), unexpectedly showed
that these animals were viable and developed to adulthood.
However, heterozygous mice in either case were born at a
sub-Mendelian ratio, and some of the early embryos were
small and moribund. Remarkably, the severity of the developmental defect of the embryos in one study correlated with
the low expression levels of the kinase-dead PI3K␤ alleles
and not with compensation from other forms of PI3K or
regulatory subunits (261). This suggested a noncatalytic
function of the protein that was attributed to a scaffolding
role supporting clathrin-mediated endocytosis (261). Analysis of MEF cells from these animals revealed unexpected
enzymatic roles of the kinase in mediating signals from
certain GPCRs such as the sphingosine 1-phosphate receptor (261) or the LPA receptor (534). In contrast, PI3K␤
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Homozygous deletion of PI3K␣ in mouse is embryonic lethal (143) and so is the homozygous replacement (“knock-in”) of
the kinase with a catalytically inactive mutant, D933A
(457). Mice heterozygous for this mutation showed reduced growth, hyperinsulinemia with glucose intolerance, hyperphagia, and adiposity, all signs of reduced
insulin sensitivity, demonstrating that IRS-mediated recruitment and activation of PI3K␣ is a major pathway in
insulin/IGF1-mediated regulation of growth and metabolism (457). Targeted deletion of PI3K␣ in endothelial
cells showed that this isoform has a cell-autonomous
function critical for angiogenesis, and the embryonic lethality of PI3K␣ deficiency is likely caused by defects in
vascular remodeling (524). The complete deletion of
PI3K␣ also changes the balance between the p85 and
p110 subunits resulting in excess free p85 subunits that
can associate with other proteins affecting their functions
(899). The best example for this is the association of the
free p85␣ subunit with IRS-1 after insulin stimulation,
which competes with the recruitment of the p85/p110
heterodimer, therefore limiting insulin signaling (955).
These findings also highlight the complex changes that
can indirectly result from a complete deletion of a protein
in a knockout animal.
to mitogens and in this case PI 3-kinase signaling is decreased rather than increased (470, 1503).
TAMAS BALLA
was not a major contributor to growth factor-induced
signaling (534) but made some contribution to insulinmediated signals (261). Similar conclusions were reached
when using PI3K␤-specific inhibitors (534, 804). These
studies were consistent with early observations that
PI3K␤ can be activated by both RTKs and G␤␥ subunits
(835).
Deletion of the p85␤ regulatory subunit enhanced T-cell
proliferation and decreased cell death (342). On the other
hand, p85␤ showed redundant functions with p85␣ in early
embryonic development and either one was necessary and
sufficient to support membrane-ruffling responses to PDGF
(176). The two p85 regulatory subunits were also found to
be required but redundant in B-cell development (1156).
Curiously, PI3K␤ mutations are not commonly found in
human cancers even though this isoform also has oncogenic
potential (346, 758, 1813). There are, however, conditions
under which PI3K␤ can also be a factor in tumorigenesis
especially under PTEN loss (731, 1687). The transforming
ability of PI3K␤ was dependent on G␤␥ interaction (331).
PI3K␤ appears to be more “constitutively active” than the
wild-type PI3K␣ behaving similarly to one of the oncogenic
mutants of PI3K␣ (N345K) (330). Comparison of the
solved structures of the PI3K␣ (660, 978, 1733) and PI3K␤
(1807) complexed with their respective regulatory subunits
(or pieces of it) may explain some of these differences, although the conclusions of the different studies differ as to
whether the catalytic domain of PI3K␤ is restrained more or
less by interactions from p85␤ (nSH2, iSH2, and cSH2).
Also interesting is the question of why the discrepancy between these highly homologous enzymes in their responses
to tyrosine-phosphorylated peptides or G␤␥ subunits liberated during stimulation of a restricted group of GPCRs.
Recent identification of the G␤␥ subunit interaction region
1042
3. PI3K␥/PI3KCG
The earliest indications that there was an alternative way of
PI3K activation via GPCRs and heterotrimeric G proteins
were the PtdIns(3,4,5)P3 increases found in neutrophils after stimulation with GPCR ligands (1461, 1572). It was also
observed that PI3K inhibition blocked chemotaxis and oxidative burst in neutrophils, and the GPCR-stimulated degranulation in basophilic leukemia cells (52, 1484, 1761).
This was followed by the detection of a G␤␥-regulated distinct PI3K activity in myeloid cells (1468) and the subsequent cloning of the 110-kDa catalytic (1465, 1476) and
101-kDa regulatory subunits (1465) of what was named
PI3K␥. More recently, another regulatory subunit of
PI3K␥, called p84 or p87PIKAP, has been identified (1496,
1641). The tissue distribution of PI3K␥ and its adaptors is
more restricted than those of other PI3K isoforms, showing
highest expression in cells of myeloid origin, such as macrophages, neutrophils, eosinophils, and mast cells (128).
However, these enzymes are also found in lower levels in
other tissues such as the heart or the exocrine pancreas
(128, 1476). The p84/87 regulatory subunit is especially
enriched in mast cells, macrophages, and heart (157, 1641),
whereas the p101 subunit is more abundant in neutrophils
(1497).
PI3K␥ can be activated by both Ras and G␤␥ subunits, and
both pathways are important for the full repertoire of neutrophil responses, such as chemotaxis and respiratory burst
in response to chemotactic stimuli (1497). The relative roles
of the two regulatory adaptors p101 and p84 in mediating
G␤␥ and Ras stimulation were uncovered relatively recently. Early studies showed that the isolated p110␥ catalytic domain of PI3K␥ can be directly stimulated by G␤␥
subunits (887, 1476) as well as by Ras (1184, 1309). The
direct stimulation of p110␥ lipid kinase activity by Ras was
found only modest in one study (1309), but oncogenic Ras
mutants potently stimulated p110␥ both in vitro and in
transfected cells in another (1184). Importantly, the G␤␥
sensitivity of PI3K␥ stimulation is greatly enhanced by the
p101 regulatory subunit in vitro or in cells (833, 1465), yet
p101 does not change the Ras sensitivity of the kinase.
Accordingly, a mutant p110␥ with impaired Ras binding
still responds to G␤␥, and this response is still enhanced by
p101 (1184, 1497). In contrast, p84/p110␥ complexes are
not sensitized to G␤␥ stimulation. Instead, the p84/p110␥
complex requires Ras binding for membrane recruitment
and activation by GPCRs (833). Therefore, it appears that
p110␥ complexed to the two distinct adaptors is regulated
in a clearly distinct manner and participates in distinct cellular responses. In support of this idea, recent studies
showed that mast cell degranulation that depends on simultaneous engagement of Fc⑀RI and the GPCR adenosine receptors relied on the p84/p110␥, while chemotaxis or Akt
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PI3K␤ was also found essential in male fertility (262), and
in platelet functions, especially related to platelet integrinmediated signaling (209, 1003). Recent studies reported
that a majority of PI3K␤ was nuclear where it contributed
to the control of DNA replication (998) and also to doublestranded break DNA repair (831), but it is doubtful that the
functions of the enzyme would be only nuclear. PI3K␤deficient MEF cells showed impaired autophagy, and expression of the enzyme enhanced autophagy. Surprisingly,
PI3K␤ was not acting via the Akt-mTOR pathway but was
associated with the Vps34-Vps15-Beclin-1-Atg14L complex and promoted PtdIns3P synthesis (374). Reactive oxygen species production by neutrophil cells in response to
fungal antigens mediated by integrins was also found to
require either the PI3K␤ or the PI3K␦ isoforms (175). These
studies suggest a clear specialization of PI3K␤ for certain
tissues and processes, but more studies are needed to define
the exact role(s) of this isoform under more acute inhibitory
conditions and not only by genetic manipulations.
in PI3K␤ is a major step toward understanding the unique
regulation of this PI3K isoform (331).
PHOSPHOINOSITIDES
activation were also supported by the p101/p110␥ complex. Moreover, the fate of the PtdIns(3,4,5)P3 made by the
distinct complexes also differed; the one made by p101/
p110␥ quickly internalized while those made by p84/p110␥
remained in the PM (157).
In addition to its lipid kinase function, PI3K␥ can also phosphorylate proteins such as MEK and activate the MAP kinase pathway through its protein kinase activity (1477). In
elegant studies using activation loop swapping, PI3K␥ enzymes defective in either lipid or protein kinase activities
were created to test the relative importance of lipid vs. protein kinase activities of the enzymes in initiating downstream responses (163).
Even if the role of PI3K␥ in myeloid cell functions, chemokine responses, and inflammation are dominating themes,
PI3K␥ has also been identified in other tissues and biological processes. These include a specific role of the kinase in
platelet aggregation in response to Gi-coupled receptors,
such as the ADP-receptor P2Y12 (623, 907), or in T-cell
signaling (1346) and T-cell development resulting in a decreased CD4⫹/CD8⫹ T-cell differentiation ratio in PI3K␥deficient mice (1279, 1346). Moreover, PI3K␥ function is
also important in the heart, especially under pathological
conditions, as PI3K␥ deficiency protected mice from hypetrophy, fibrosis, and related dysfunctions caused by prolonged ␤-adrenergic exposure (1182). Strangely, PI3K␥-de-
4. PI3K␦/PI3KCD
The last member of the class I PI 3-kinase family, named
PI3K␦, was cloned from a U937 monocyte cDNA library
and showed an expression pattern restricted to white blood
cells. The 110-kDa protein was able to associate with the
SH2-domain-containing adaptors, p85␣ (as well as its
smaller forms), p85␤, and also with the Ras proteins
(1614). Recruitment of this enzyme to the membranes of
cytokine-stimulated leukocytes was similar to those of
p110␣, but a distinctive feature of the PI3K␦ enzyme was its
ability to autophosphorylate (1611, 1614). Distinctive
functions of this kinase were revealed by genetic ablation
of the protein or “knock-in” studies that replaced the
wild-type allele with a kinase-dead version (D910A) of
the protein. More recently, the development and testing of
subtype-specific PI 3-kinase inhibitors also shed light on the
unique functions of this kinase in physiology and disease.
These studies showed a nonredundant role of PI3K␦ in Bcell development and an abrogated proliferative response of
B cells to B-cell receptor stimulation (268, 740, 1165). Accordingly, both T-cell-dependent and -independent humoral responses were strongly impaired in both the PI3K␦
deleted and the kinase-dead “knock-in” animals (268, 740,
1165).
Importantly, PI3K␦ often works together with PI3K␥ to
support immune cell functions. One of the best examples of
the complementary roles of the two enzymes is mast cells.
Here the activation requires triggering of both the tyrosine
kinase pathways (via either the KIT receptor or FcR⑀I engagement) with PI3K␦ participation and sensitization via
adenosine receptors that activate PI3K␥ (157, 847). This
explains why inactivation of either enzyme impairs mast
cell-mediated allergic responses and attenuates passive anaphylaxis (30, 847). Similarly, neutrophil cells also showed
complementary roles of PI3K␥ and -␦ isoforms in their ROS
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The phenotypes observed after PI3K␥ deletion in mouse
also supported the pivotal role of this enzyme in host defense and inflammation, consistent with the roles of this
enzyme in chemotaxis of neutrophils and macrophages
(624, 906, 1346). Analysis of PI3K␥-deficient animals also
revealed that the enzyme was critical in amplifying degranulation responses in mast cell and, accordingly, the knockout animals were protected from systemic anaphylaxis
(847). Several other pathological conditions in which recruitment of neutrophils and macrophages by inflammatory chemokines is an aggravating factor have been alleviated by genetic or pharmacological inactivation of PI3K␥.
For example, atherosclerotic lesions are attenuated in apoEdeficient mice by inhibitors of PI3K␥, or by replacing the
macrophages of the apoE mice with ones originated from
PI3K␥-deficient animals (231, 456). Sepsis-induced multiorgan damage was also significantly reduced in mice with
genetic or pharmacological inactivation of PI3K␥ (1002),
and PI3K␥ deleted mice were largely protected in mouse
models of rheumatoid arthritis (208). PI3K␥ inhibition also
alleviated the severity of glomerulonephritis in a mouse
model of systemic lupus (104). These studies and many
others reviewed in more details (996, 1294) have identified
PI3K␥ as a very desirable drug target for the control of a
variety of inflammatory conditions, and several companies
are developing subtype-specific PI3K␥ inhibitors (1294,
1310).
ficient and “knock-in” mice expressing the kinase-dead version showed opposite responses to pressure overload
following aortic constriction: knockout mice developed
myocardial damage and heart failure while the knock-in
mice were protected from all of these effects and even
showed protection from fibrosis (1199). This striking difference revealed a kinase-independent function of PI3K␥ in
the heart through its association with the phosphodiesterase PDE3B and stimulation of its PDE activity (1199). A
PI3K␥-mediated effect of angiotensin II (ANG II) on L-type
Ca2⫹ channels in vascular smooth muscle cells has also been
described (1244), and PI3K␥-deficient mice were protected
from the vascular damage and hypertensive effects of ANG
II administration (1623). An initial report found an increased incidence of colorectal cancer in PI3K␥-deficient
mice (1345), but this phenotype was not reproduced in
other studies using independently developed PI3K␥-deficient mice and has been attributed to some unrelated and
yet unclear genetic constellations (105).
TAMAS BALLA
generation response under certain conditions (175, 285).
These studies identified the PI3K␥ and -␦ isoforms as potential targets to treat allergic diseases and also some autoimmune diseases including rheumatoid arthritis (1294, 1295,
1549). Moreover, PI3K␦-specific inhibitors have shown
some promise in the treatment of chronic lymphocytic leukemia (606) and multiple myeloma (681), and they were
found potentially beneficial in reversing the glucocorticoid
resistance in chronic obstructive pulmonary disease (1005,
1558). The recently solved structure of PI3K␦ (125) will
certainly aid the development of PI3K␦-specific inhibitors
(41) that can be tested in a variety of immunological disease
models.
Class II PI 3-kinases were discovered based on their sequence homology with class I PI 3-kinases (192, 369, 965,
1638). These enzymes also exist in three forms in mammalian cells: PI3KC2␣, PI3KC2␤, and PI3KC2␥ (1347, 1610).
Class II PI 3-kinases are larger proteins (170 –200 kDa) that
have highly homologous domains with other PI 3-kinases,
such as the Ras binding domain, the helical and catalytic
domains, but also have some distinctive features, such as a
PX and C2 domains at their COOH termini. They are most
dissimilar at their NH2 termini that differ in lengths but all
contain proline-rich segments (FIGURE 5). Class II PI 3-kinases can phosphorylate PtdIns as well as PtdIns4P but not
PtdIns(4,5)P2 in vitro, and based on this feature, it was
initially believed that these enzymes produce primarily
PtdIns(3,4)P2 from PtdIns4P in cells (369). However, increasing evidence suggests that class II PI 3-kinases also
make PtdIns3P for specific processes (420). Since relatively
little is known about the physiology of these enzymes, the
three isoforms will be discussed together.
PI3KC2␣ and PI3KC2␤ are ubiquitously expressed, whereas
PI3KC2␥ shows more restricted expression mainly in liver
and some other tissues depending on the species (627, 1061,
1171). PI3KC2␣ is found primarily in the trans-Golgi and
in clathrin-coated vesicles (367) but was also localized to
nuclear speckles (356). PI3KC2␤, on the other hand, was
found in the cytoplasm and in perinuclear puncta (1706),
while PI3KC2␥ was described in the Golgi (1171). Both
PI3KC2␣ (484) and PI3KC2␤ (1706) were shown to bind
clathrin, and clathrin stimulated the kinase activity of
PI3KC2␣ (484, 485, 1583). These studies suggested a role
of these kinases in clathrin-mediated endocytosis and trafficking. Although class II PI 3-kinases do not have any
known adaptor proteins, several studies have indicated that
PI3KC2␣ can respond to EGF (53), insulin (191), chemokine (1583), or TNF and leptin (829) receptor stimulation.
Similarly, PI3KC2␤ associates with the activated PDGF and
EGF receptors (53) and is stimulated by stem cell factor (51)
and integrin engagement (1796).
1044
Genetic ablation of PI3KC2␤ in mice has been reported, but
the mice are viable and fertile with no obvious specific phenotype reported (569). Inactivation of the enzyme’s ortholog in C. elegans causes fat accumulation mimicking the
effects of inactivation of the insulin receptor homolog (57).
Ectopic expression of the PI3KC2 ortholog or its kinasedead version in fly epithelium caused pattern formation
defects (966).
VI. PHOSPHOINOSITIDE PHOSPHATASES
Initial interest toward the inositol lipid phosphatases in the
early 1980s paled compared with the excitement for lipid
kinases and PLC enzymes, and only a few groups pursued
research in this direction. PI phosphatase research was motivated primarily by the interest in the metabolism of the
second messenger Ins(1,4,5)P3 (286, 1474) by 5-dephosphorylation and by the prominent effect of lithium on inositol phosphate metabolism causing an accumulation of Ins
monophosphates and depletion of myo-inositol (34), with a
possible link to the effectiveness of Li⫹ in manic-depressive
disease (134) (see sect. III). Therefore, identification of the
Ins(1,4,5)P3 5-phosphatase (that showed no lithium sensitivity) and the lithium sensitive inositol monophosphatase(s) were top priorities in the mid 1980s. However, Phil
Majerus’ group had already focused on every form of inositol phosphate or -lipid phosphatases from early on and
identified several enzymes that acted upon various inositol
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5. Class II PI 3-kinases/PI3KC2s
As to the roles of these enzymes in cellular processes, several
studies suggested that PI3KC2␣ is involved at multiple levels in the secretion and actions of insulin (418). PI3KC2␣
was found to regulate exocytosis of insulin in pancreatic
beta cells (370), but was also activated by insulin via the
small GTP binding protein TC10 (970) and played a role in
insulin-induced Glut4 translocation (370). A role of PI3KC2␣ was also suggested in neurosecretion (1034), and in
this context, it is notable that TC10 was recently found to
regulate axon cone specification by inducing translocation
of the exo70 exocyst complex to membranes (391). PI3KC2␤, on the other hand, was found to regulate cell migration (368, 764, 971) via a Rac-dependent signaling pathway
also involving PtdIns3P production. PI3KC2␥ was claimed
to play a role in regenerating liver (1171), but there is little
knowledge concerning the involvement of this enzyme in
any biological process. As pointed out above, it is increasingly evident that class II PI 3-kinases make PtdIns3P as
their signaling molecule (370, 970, 1700). If the enzyme
indeed makes primarily PtdIns3P, it is likely that it does so
in very specific molecular contexts that differ from those
regulated by the class III Vps34 enzymes. This has initiated
a discussion as to what extent class II enzymes contribute to
the bulk amount of PtdIns3P found in cells (418, 1034). It is
worth pointing out that classII PI3Ks are less sensitive to the
PI3K inhibitor Wm (369), and some of the PtdIns3P in cells
is more resistant to inhibition by Wm (1464).
PHOSPHOINOSITIDES
A. 5-Phosphatases
This group of enzymes can remove the phosphate from the 5-position from PtdIns(3,4,5)P3, PtdIns(4,5)P2, and PtdIns(3,5)P2.
They are divided into four types (I-IV), but the 43-kDa type
I enzyme (INPP5A), which was the first 5-phosphatase isolated and cloned, does not act on lipids but dephosphorylates Ins(1,4,5)P3 and Ins(1,3,4,5)P4 (340, 862, 863). The
type II 5-phosphatases include the synaptojanins, OCRL,
INPP5B, INPP5J, and SKIP, while the two type III enzymes
are SHIP-1 and -2. The only type IV enzyme is INPP5E. All
of these enzymes belong to the AP family of endonucleases
and have two signature motifs (F/Y)WXGDXN(F/Y)R and
P(A/S)(W/Y)(C/T)DR(I/V)L(W/Y) separated by ⬃60 –75 resi-
dues (973). The structure of the 5-phosphatase domain of
one of the S. pombe 5-phosphatases has been solved, and it
revealed the positions of His/Asp active site pairs within the
core of the catalytic domain (1581). In addition to their
catalytic domain, 5-phosphatases contain several additional protein motifs that determine their cellular localization and interactions with other proteins (FIGURE 6).
1. Type II 5-phosphatases
SYNAPTOJANINS. As described above, synaptojanin-1
(Synj1) was discovered by the De Camilli group as a 5-phosphatase that functions in synaptic vesicle exocytosis and
recycling (1022). SYNJ1 has multiple splice forms that differ in their COOH termini. SYNJ1–145 shows very high
expression in the brain while SYNJ1–170 shows wider tissue distribution. A highly homologous sister enzyme, synaptojanin-2 (SYNJ2), is more widely expressed and also
exists in three splice forms differing in their COOH termini
(1123). Two of the SYNJ2 isoforms (SYNJ2B1 and -2) are
highly expressed in nerve terminals and in the testes (1126).
The hallmark of all SYNJs is a Sac1-like phosphatase domain located in the NH2 termini of the proteins. The isolated Sac1 domain of SYNJs can also dephosphorylate
PtdIns3P and PtdIns(3,5)P2 in vitro (538, 1126). On the
basis of these findings, it is believed that the Sac1-domain
takes the 5-phosphatase product (mainly PtdIns4P) and further dephosphorylates it to PtdIns. Indeed, it has been
shown that the activities of both the 5-phosphatase domain
and the Sac1 domain of SYNJ1 were required to support
synaptic vesicle recycling (981).
A)
Both SYNJs were found to be critical in determining the fate
of the endocytosed clathrin-coated vesicles (CCVs). SYNJ1
knockout mice develop and are born seemingly normally
but die shortly after birth. These newborns show accumulation of CCVs in their nerve termini due to a defect in
“uncoating” of the vesicles (301). This also causes poor
recycling of vesicles into a fusion competent synaptic vesicle
pool (794). SYNJ1 associates via its COOH-terminal domain with several proteins enriched in the nerve terminal
such as amphyphysin (335) and with proteins that play
important roles in the endocytic pathways, such as endophilin, intersectin, syndapin, and Eps15 (1418). SYNJ1 is
constitutively phosphorylated and undergoes activity-dependent dephosphorylation by calcineurin, which, in turn,
affects both its catalytic activity and interactions with other
proteins (876, 1023, 1419). Both SYNJs interact with the
SH3-domain containing adaptor protein, Grb2 and SYNJ2,
but not SYNJ1, participates in clathrin-mediated EGF receptor and transferrin receptor endocytosis (974, 1314).
These results suggest nonredundant functions of the SYNJ
phosphatases in controlling PtdIns(4,5)P2 levels in the
membranes of vesicles along the endocytic pathway. Interestingly, one isoform of SYNJ2, SYNJ2A, is targeted to the
mitochondria via binding to the outer mitochondrial membrane protein OMP25 (1124). It is an intriguing possibility
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phosphate isomers and some on the lipids themselves (see
Ref. 972 for a review on these early studies). The interest
level was significantly raised when the gene causing the
X-linked human disease Oculo-Cerebro-Renal Syndrome
of Lowe (OCRL) was mapped and found to have significant
homology to an already known 75-kDa inositol polyphosphate 5-phosphatase (61). Subsequent research showed
that OCRL was a PtdIns(4,5)P2 rather than an inositol
polyphosphate 5-phosphatase (1166, 1805). Further momentum was gained when a PtdIns(4,5)P2 5-phosphatase
associated with presynaptic membranes and named synaptojanin (Snj) was described and cloned (1022). In parallel
studies, the same enzyme was purified and cloned as a PLD
inhibitor (259), a feature that was due to its PtdIns(4,5)P2
phosphatase activity since PLD requires PtdIns(4,5)P2 for
optimal activity (918). These studies helped disseminate the
notion that inositol lipid dephosphorylation was an important regulator of inositol lipid signaling and that it was
essential to determine whether a phosphatase acted on lipids or on soluble inositol phosphates in its natural cellular
location. The next huge development of the phosphatase
field was marked by the realization that the tumor suppressor gene PTEN (phosphatase and tensin homolog located
on chromosome 10) was actually a PtdIns(3,4,5)P3 3-phosphatase (and not only a protein tyrosine phosphatase as
previously believed) and that it countered the actions of PI
3-kinases (968, 969, 1104). Fortuitously, another group of
enzymes initially thought to be phosphotyrosine phosphatases, called the myotubularins, were also discovered by identification of a gene mutated in human X-linked centromyotubular myopathy (858). This enzyme, called MTMR1, turned out
to be a PtdIns3P 3-phosphatase (152, 1536) and so did its
sister protein, named MTMR2, that was mutated in the
neurodegenerative disorder Charcot-Marie-Tooth disease
type 4B (792). So, in the case of the phosphatases, human
genetics played a pivotal role in unearthing several of the
enzymes, and the usually pioneering yeast studies can be
credited with the first identification of only one of the phosphatases, namely Sac1, with connection to actin polymerization (273), inositol lipids (1714) and which was later
proven to be a phosphoinositide monophosphatase (538).
TAMAS BALLA
Type II
Sac1-domain
5-ptase
PR
SYNJ1-145
1,292 aa
Sac1-domain
5-ptase
PR
NPF
SYNJ1-170
1,558 aa
Sac1-domain
5-ptase
SYNJ2A
1,288 aa
PR
Sac1-domain
5-ptase
PR
PR
SYNJ2B1/2
1,451/1,496 aa
5-ptase
ASH Rho-GAP
901 aa
CB
PH
CB
5-ptase
ASH Rho-GAP
INPP5B
CAAX
PR
5-ptase
SKICH
993 aa
PR
INPP5J/PIPP
1,006 aa
5-ptase
SKICH
INPP5K/SKIP
448 aa
Type III
SH2
5-ptase
C2
PR
SHIP1
1,189 aa
SH2
5-ptase
C2
PR
SAM
SHIP2
1,258 aa
Type IV
PR
INPP5E/Pharbin
5-ptase
CAAX
644 aa
FIGURE 6. The inositol lipid 5-phosphatase family. These enzymes dephosphorylate PtdIns(4,5)P2 and/or
PtdIns(3,4,5)P3 in the 5-position. There are three major subgroups called type II, III, and IV. [The type I enzyme
is a smaller, 43-kDa protein that hydrolyzes the water-soluble Ins(1,4,5)P3 molecule but not the membranebound lipids.] The type II 5-phosphatase enzymes are encoded by six genes. Two of these, synaptojanin-1 and
synaptojanin-2, exist in multiple splice forms differing in their respective COOH termini (only the two main forms
are shown). The characteristic feature of these enzymes is the presence of a Sac1 homology domain upstream
of their conserved 5-phosphatase domains. The NPF repeats of the longer form of SYNJ1 binds to the
endocytic protein Eps15. OCRL and INPP5B are also very similar to one another, with a whole set of domains
providing multiple interactions in addition to the catalytic 5-ptase domain. These include an NH2-terminal PH
domain and COOH-terminal ASH and Rho-GAP domains. The ASH domain binds Rab5 and the adaptor protein
APPL1, while Rho-GAP domain binds the small GTP binding proteins, Rac1 and Cdc42. OCRL1a contains two
clathrin binding (CB) domains, the second of which is not present in OCRL1b. INPP5B has very similar
structure, but it lacks the clathrin-binding domains and has a COOH-terminal CAAX domain. INPP5J and
INPP5K are smaller proteins that have a SKICH domain downstream of their 5-phosphatase domain. This core
structure is surrounded by proline-rich sequences in INPP5J. The type III 5-phosphatases are represented by
the SH2-domain-containing enzymes SHIP1 and SHIP2. They have an NH2-terminal SH2 domain and C2 and
proline-rich sequences downstream of the 5-phosphatase domain. SHIP2 also has a sterile alpha motif (SAM)
at its very COOH terminus. The single type IV enzyme, INPP5E has a proline-rich sequence and a COOH-terminal
CAAX box in addition to the 5-phosphatase domain.
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PH
OCRL1a/b
PHOSPHOINOSITIDES
S. cerevisiae cells also express three phosphatases that show
homology to mammalian SYNJs and contain both a Sac1like and 5-phosphatase domains (1440, 1473). These enzymes, named Inp51, Inp52, and Inp53 (or “synaptojaninlike,” Sjl1, -2, and -3, respectively) can be individually deleted, suggesting their significant functional redundancy,
but triple deleted cells are nonviable (1440, 1473). Interestingly, a mammalian type II 5-phosphatase (75-kDa phosphatase, or Inpp5B) that does not contain a Sac1 domain
still can restore viability in triple Sjl inactivated cells or
alleviate the phenotypic changes observed in double-deleted
strains (1155). The significance of this finding is that a functional Sac1 domain may not be necessary for the functions
of the yeast Sjl proteins. This conclusion was supported by
further reports that Inp52 (1453) or Inp53 (545) enzymes
with mutated, inactive Sac1 but not inactive 5-phosphatase
domains were able to restore the viability of triple Sjl inactivated strains. Nevertheless, the isolated Sac1 domains of
Inp52 and Inp53 are able to hydrolyze PtdIns4P and
PtdIns3P (538) and rescue defects caused by inactivation of
the yeast Sac1 protein (667). Mutations in key residues
within the Sac1 domain already render this domain of the
Inp51 protein inactive. Individual or double mutant Sjl
strains display functional defects that still suggest some specialization among the three Sjl proteins. The general conclusion reached based on a number of studies analyzing
these mutants is that Inp51/Sjl1 and Inp52/Sjl2 have partially overlapping functions and that Slj1, in particular, is
involved in the cell-wall integrity pathways and actin organization both of which requires PM PtdIns(4,5)P2 produced
by the Stt4 PI4K and the Mss4 PIP 5-kinase (see Ref. 1479
for a detailed review). In contrast, Inp53/Sjl3 deleted strains
display defects that suggest unique functions linked to
clathrin-mediated trafficking both at the PM, such as endocytosis, or at the Golgi and TGN (544, 545, 1473) (and see
Ref. 1479 for more details). The complicated phenotypes of
the inactivation of the three Inp51–53 proteins in various
combinations are due to several factors. First, the 5-phosphatase domains of the three enzymes control specific but
perhaps overlapping pools of PtdIns(4,5)P2 and because of
this the severity of the functional defects do not always
correlate with overall PtdIns(4,5)P2 elevations. Second, the
Sac1 phosphatase activity of Inp52 and Inp53 also contributes to
the control of specific PtdIns4P and PtdIns3P pools and in most of
these locations the Sac1 phosphatase has a redundant function
with the Sjl enzymes (1479).
B) OCRL.
As mentioned before, mutations in the OCRL gene
were found responsible for the X-linked human disease
OCRL (61). OCRL patients present with congenital cataract, renal tubular acidosis, aminoaciduria, and mental retardation (944). However, some patients with mutations of
the same gene can also present with Dent’s disease with
milder symptoms that are mostly confined to the kidney
(647). The similarity of the OCRL protein to the 75-kDa
inositol lipid 5-phosphatase (INPP5B) gave a clue that this
protein was a 5-phosphatase, and subsequent studies
showed that PtdIns(4,5)P2 was the preferred substrate for
OCRL over the soluble Ins(1,4,5)P3 or Ins(1,3,4,5)P4, establishing OCRL as an inositol lipid 5-phosphatase (1805).
OCRL prefers PtdIns(4,5)P2 over PtdIns(3,4,5)P3 and was
also shown to hydrolyze PtdIns(3,5)P2 (1361), but it remains to be seen whether this lipid is indeed regulated by
OCRL within the cells. The OCRL protein shows wide
tissue expression, and its localization to the Golgi and TGN
originally suggested that the OCRL disease is a result of a
Golgi-originated trafficking defect (388, 1166, 1483). An
attempt to make a mouse model of OCRL was complicated
by the fact that OCRL deletion in mice does not reproduce
the phenotypes associated with the human disease, apparently because of the overlapping function(s) of the homologous 75-kDa 5-phosphatase Inpp5b (722). Combined inactivation of both genes, on the other hand, manifests in
early embryonic lethality (722). The difference between humans and mice in the ability of the 75 kDa phosphatase to
compensate for OCRL functions must lie within the 75 kDa
phosphatase itself, which differs between the two species in
expression level and splicing. Indeed, replacement of the
mouse Inpp5b with the human INPP5B version in an Ocrl
(⫺/⫺) background created mice that show some of the
symptoms found in the human disease (173). This mouse
model should greatly facilitate the progress in understanding the molecular pathology of OCRL and Dent’s disease.
Since OCRL is only one of numerous 5-phosphatases
within the cell, it is likely that it affects localized pool(s) of
PtdIns(4,5)P2. Not surprisingly, it has been difficult to show
increased levels of total PtdIns(4,5)P2 in cells obtained from
OCRL patients, although in some cases such increases have
been reported (1804). Other studies showed only indirect
signs of aberrant PtdIns(4,5)P2 levels, such as altered F-actin distribution and dynamics in fibroblasts obtained from
OCRL patients (1482). Although the bulk of the OCRL
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that membrane deformations during mitochondrial fission
and fusion are regulated by this enzyme in a manner similar
to what occurs during endocytosis. An extra copy of SYNJ1
due to a trisomic arrangement found in the Ts65Dn mice, a
model for Down’s syndrome, is associated with neurological defects and PtdIns(4,5)P2 dysregulation, and these aberrations are corrected by restoring SYNJ1 to disomy (1647).
Since SYNJ1 is located on human Chr21 that is trisomic in
Down’s syndrome patients, it is an attractive possibility that
SYNJ1 is a major factor in the neurological dysfunctions
found in these patients (1647). Recent studies also linked
SYNJ2 to hearing and cochlear function. In a mouse strain,
called Mozart, which exhibits progressive hearing loss, the
causative mutation was mapped to a critical region within
the phosphatase domain of the Synj2 gene (N539K) (983).
Whether this gene is affected in human hereditary hearing
disorders has yet to be investigated. SYNJ2 deleted mice
have not been reported yet in the literature.
TAMAS BALLA
C) INPP5B. This enzyme is highly similar to the OCRL protein
The OCRL protein associates with clathrin-coated transport intermediates and regulates trafficking between endosomes and the TGN (250). However, somewhat surprisingly, a prominent role of OCRL in the early steps of the
endocytic pathway has been also described (407, 1634).
Membrane recruitment and activation of the OCRL protein
occurs via interaction with multiple Rab proteins (674) and
the Rab5 effector APPL1 (adaptor protein containing PH
domain, PTB domain and leucine zipper motif 1) protein
(407). Interaction of OCRL with another Rab protein,
Rab35, connects the phosphatase with abscission, the last
step in cytokinesis (318). The structural details of the various domains of OCRL and their possible roles in activating
and orienting of the phosphatase domain have begun to
emerge based on the crystal structures of these domains
with possible associated proteins (407, 652, 988, 1223,
1224). Taking all these data into consideration, the OCRL
protein plays multiple roles in endocytic trafficking by its
interaction with clathrin and Rab proteins (1223). It has
been more difficult to connect the molecular details and
cellular functions of OCRL to the defects underlying the
pathophysiology of the disease. The similarity of the kidney
symptoms of OCRL patients to those of Fanconi syndrome
(236) led to the suggestion that the large LDL receptor
family protein megalin, which recycles between the apical
membrane and the TGN in proximal tubule cells, displays
aberrant trafficking in OCRL patients (945, 1146). However, one study found no signs of aberrant megalin trafficking in human and canine renal epithelial cells after siRNAmediated knockdown of OCRL, even though there was
increased secretion of lysosomal hydrolyses (303). Recent
studies also suggested that OCRL is important for the assembly and functions of the primary cilium, and this may be
an important clue to understand the renal pathology of the
disease (288, 956, 1263).
Homozygous mice deficient in Inpp5B are viable and appear normal, but do have testicular degeneration and defective sperm functions that manifest after sexual maturation
(722). The sperm of these mice show reduced motility and
reduced ability to fertilize eggs (722, 992). These defects can
be the consequence of the impaired proteolytic processing
of a sperm cell surface protein, fertilin-␤, which is important for egg binding (596). In addition, there is a defect in
the apical endocytosis in Sertoli cells causing swollen vacuoles (595).
1048
(45% identical at the amino acid level) and has a similar
domain organization. In fact, INPP5B was identified before
OCRL (1065). The enzyme, also called 75-kDa type II
5-phosphatase, is widely expressed, especially enriched in
the kidney, lung, and testes (1438). Although initial studies
claimed mitochondrial localization (1438), subsequent
studies found the enzyme to be associated with the Golgi
and ER exit sites (1718), and Rab proteins also affect the
localization of the enzyme (1401, 1718). While INPP5B
shows a similar domain structure to the OCRL 5-phosphatase, there are notable differences between the two enzymes.
Unlike OCRL, INPP5B does not contain clathrin binding
sites, and it has a COOH-terminal CAAX prenylation sequence (724) (FIGURE 6). The mouse has three splice variants of Inpp5B as 87-, 104-, and 115-kDa proteins, the
expression of which are tissue and developmental stage specific (1013). INPP5B hydrolyzes equally PtdIns(4,5)P2 and
PtdIns(3,4,5)P2 [and Ins(1,4,5)P3 and Ins(1,3,4,5)P4], but
not PtdIns(3,5)P2 (724, 1361).
D) INPP5J. This 5-phosphatase, also called proline-rich inositol polyphosphate 5-phosphatase (PIPP), was identified due
to the presence of consensus 5-phosphatase sequences
(1076). The enzyme is widely expressed and contains proline-rich regions both at the NH2 and COOH terminus and
several 14-3-3 protein-binding motifs (1076). The enzyme also
contains a SKICH (SKIP COOH-terminal homolgy) domain
(540) that mediates PM association (1172) (FIGURE 6). In
vitro, the 108-kDa enzyme can hydrolyze PtdIns(4,5)P2 and
PtdIns(3,4,5)P3 as well as Ins(1,4,5)P3 and Ins(1,3,4,5)P4
(1076), but it is believed to regulate PtdIns(3,4,5)P3 levels in
cells (1172). Overexpression of the enzyme in PC12 cells
decreased PtdIns(3,4,5)P3 levels, Akt activation, and neurite outgrowth (1172). Recent studies identified collapsing
response mediator protein 2 (CRMP2) as an INPP5J interacting partner and showed that the two proteins have opposing roles in regulation of nerve cell polarization, axon
selection, and neurite elongation (59). Importantly, higher
INPP5J expression levels have been correlated with better
prognosis and disease outcome in breast cancer (1515,
1600).
D) SKIP/INPP5K. This enzyme is enriched in skeletal muscle
and kidney (hence the name skeletal muscle and kidney
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protein is associated with the Golgi/TGN (388, 1166,
1483), an increasing body of evidence suggests that its functions are more widespread. Localized functions of OCRL
rely on the recruitment and regulation of the protein to
different membranes and, therefore, the domain structure
and multiple interactions of the protein with various regulatory proteins have attracted significant attention. In addition
to its conserved 5-phosphatase domain, OCRL contains an
NH2-terminal PH domain (988), an ASH (ASPM-SPD2-Hydin) domain (1232), and a COOH-terminal Rho-GAP-like
domain that is catalytically inactive (407). OCRL has two
clathrin binding domains: one located within the NH2-terminal PH domain (251, 988), while the other is found
within the COOH-terminal Rho-GAP domain (250, 1594).
None of the clathrin binding sites is present in the otherwise
similarly built INPP5B protein (988). OCRL has two spliceoforms that only differ in a small eight-amino acid stretch
within the Rho-GAP-like domain close to the clathrin binding site; the longer form binds clathrin with higher affinity
(251) (FIGURE 6).
PHOSPHOINOSITIDES
enriched inositol polyphosphate phosphatase) and was
identified also because of the presence of the two conserved regions found in 5-phosphatases (540). SKIP also
contains a COOH-terminal SKICH domain that mediates its translocation from the Golgi/ER region to the PM
after insulin stimulation (540) (FIGURE 6). It was shown
that SKIP limits the insulin-mediated PtdIns(3,4,5)P3 accumulation at the PM, decreasing Akt activation, GLUT4
translocation, and glucose uptake (679). The notion that
SKIP might control the insulin sensitivity of skeletal muscles is supported by studies on SKIP ⫹/⫺ mice that show
increased insulin sensitivity associated with increased
Akt activation and glucose uptake in skeletal muscles of
the mice (680). Homozygous SKIP ⫺/⫺ mice exhibit embryonic lethality (680).
A) SHIP1 AND
-2. These 5-phosphatases were named because
of their NH2-terminal SH2-domains. SHIP1 (also called
INPP5D) was initially identified as an inositol lipid phosphatase associated with a number of adaptor proteins, such
as Shc, Grb, and DOK (924), as well as with immunoreceptor tyrosine-based inhibitory (ITIM) or activation (ITAM)
motifs of immune receptors (798, 1175). SHIP1 has several
splice variants, a full-length (SHIP1␣) and three shorter
forms (SHIP1␤, SHIP1␦ and s-SHIP1) (not shown in FIGURE 6) (1290). Structurally, SHIP1 and -2 contain a central
5-phosphatase domain followed by a C2 domain and two
NPXY sequences in which the Tyr can be phosphorylated to
interact with PTB domains. All SHIP variants except
SHIP1␦ contain a COOH-terminal proline-rich sequence,
and SHIP2 also has a COOH-terminal SAM (sterile alpha
motif) sequence, whereas s-SHIP1 lacks the NH2-terminal
SH2 domain. The mechanism of SHIP1/2 activation is
based on recruitment of the phosphatase from the cytosol to
the membrane via the various protein-protein interaction
domains present in the molecule. These proteins function as
part of multi-protein complexes, and their cell- and tissuespecific functions are probably dictated by their binding
partners. Initially, the SHIP proteins were believed to have a
restricted substrate recognition only able to dephosphorylate the 5-position in PtdIns(3,4,5)P3 [and Ins(1,3,4,5)P4
and perhaps other soluble higher inositol phosphates] (248,
1722). Recent studies, however, suggested that they can
also hydrolyze PtdIns(4,5)P2 and control clathrin-mediated
endocytosis (1115). Nevertheless, SHIP proteins are still
considered as key enzymes in the control of the PI 3-kinase
products PtdIns(3,4)P2 and PtdIns(3,4,5)P3 (112). It is important to note that the reaction product PtdIns(3,4)P2 can
also activate certain downstream targets, such as Akt (460);
hence, SHIP1/2 can selectively inactivate signaling pathways initiated by PI 3-kinases (1290). The enzymatic activity of SHIP1 does not appear to be regulated by Tyr phosphorylation or protein-protein interaction (1213), but it is
enhanced by binding of the product PtdIns(3,4)P2 to the C2
domain (1170). Recent studies suggested that PLC␤3 and
SHIP1 and its splice variants are expressed exclusively in
hematopoietic and spermatogenic cells (928), while SHIP2
(also called INPP5L1) shows ubiquitous expression (1095).
Recent studies showed that SHIP1 expression is repressed
by the human MIR155 microRNA (1154). Consistent with
its expression pattern and enzymatic functions, SHIP1 deficiency results in enhanced PI 3-kinase signaling affecting
cells and organs with hematopoietic cell involvement (B and
T cells, macrophages, osteoclasts, mast cells, neutrophil
cells, and platelets). Ship1 knockout mice develop a chronic
myelogenic leukemia (CML)-like disease with myeloid proliferation, splenomegaly, and vast myeloid infiltration of
the lungs causing premature death (593, 927). The significantly elevated PtdIns(3,4,5)P3 levels induce a hyperproliferative response of hematopoietic progenitors to a variety
of growth factors (593) and increased Akt activation in mature
neutrophils and mast cells (927). Since PtdIns(3,4,5)P3 has a
pivotal role in amplifying polarization during chemotaxis both in phagocytic cells (1385, 1463) and lower
organisms, such as Dictyostelium (976), there is a massive dysregulation of neutrophil polarization in Ship1
null mice (1140). The severe osteoporosis reported in
Ship1 ⫺/⫺ mice is due to the hyperactivation of osteoclasts that are more numerous, enlarged, and hypernucleated (1523), resembling those in patients with Paget
disease. Ship1 ⫺/⫺ mice also show deficient platelet aggregation (1386), an increased number of splenic dendritic cells that are hyperresponsive to GMCSF in vitro
but have an immature phenotype (47).
The more ubiquitously expressed SHIP2 enzyme serves as
a negative regulator of insulin signaling. Overexpression
of SHIP2 antagonizes the PI3K angle of insulin signaling
in 3T3-L1 adipocytes (1650) and cerebellar granule cells
(1429). Additionally, transgenic mouse, overexpressing
SHIP2, showed signs of mild insulin resistance (744).
Higher levels of SHIP2 expression were found in the
cerebral cortex of the db/db obese mice (1429), and
SHIP2 gene polymorphisms have been linked to metabolic syndrome (746, 991). A mouse strain lacking Ship2
(and the neighboring Phox2a gene) shows insulin hypersensitivity and severe hypoglycemia and has early neonatal mortality (271). Curiously, another study reported no
such problems with a SHIP2 knockout strain and, to the
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2. Type III 5-phosphatases
Lyn controls SHIP1 activity via phosphorylation of Tyr536
and Tyr564 (1742). Other studies identified a PKA phosphorylation site (Ser440) in SHIP1, which, when phosphorylated, significantly enhances the activity of the enzyme.
This could contribute to the well-documented negative effects of cAMP-mobilizing signals on PI 3-kinase signaling in
immune cells (1798). Some meroterpenoid compounds are
also able to activate SHIP1 and exert strong anti-inflammatory effects that could represent a means of controlling PI
3-kinase downstream effectors in hematopoietic cells
(1170, 1459, 1460).
TAMAS BALLA
contrary, reported a resistance of these mice to weight
gain in a high-fat diet (1417). A recent study identified
Ser132 phosphorylation of SHIP2 that regulates its nuclear localization in nuclear speckles in a cell cycle-dependent manner. This study also found SHIP2 interaction with nuclear lamin A/C and that Ser132-phosphorylated SHIP2 also hydrolyzed PtdIns(4,5)P2 (400).
Understanding the relationship between these novel features of SHIP2 and the phenotypic changes listed above
will require further investigations. More details about
SHIP2 can be found in Reference 401.
3. Type IV 5-phosphatase
1050
B. 3-Phosphatases
The phosphoinositide 3-phosphatases are comprised of two
major groups. The first group contains PTEN (phosphatase
and tensin homolog located on chromosome TEN), the voltage-sensitive phosphatases (VSPs) first isolated from the ascidia, Ciona intestinales (1096) but also found in zebrafish
(650) and Xenopus (1259), and the mammalian VSP homolgs,
the TPIP proteins (␣, ␤ and ␥) (1163). These enzymes all share
similar catalytic phosphatase domains (FIGURE 7), but differ in
their substrate preference and what phosphates they remove.
PTEN is one of the key enzymes that antagonizes PI 3-kinase
action by removing the 3-phosphate from PtdIns(3,4,5)P3. In
contrast, the nonmammalian VSPs are 5-phosphatases that act
on PtdIns(4,5)P2 and PtdIns(3,4,5)P3 (550, 713). The mammalian TPIP proteins can dephosphorylate 3-phosphorylated inositides (1662), but it is not clear whether they can
also act on PtdIns(4,5)P2. It is also questionable whether
any of the mammalian VSP homologs are also voltage regulated (1163). In spite of the differences in their catalytic
targets, these enzymes will be discussed in this section because of their close structural relationship to PTEN, an
enzyme that has risen to prominence as a PtdIns(3,4,5)P3
3-phosphatase and a tumor suppressor gene. The second
group of the 3-phosphatases are made up by the myotubularins (MTMs) with 15 structurally related members, 9 of
which have phosphatase activity removing the 3-phosphate
from PtdIns(3,5)P2 and PtdIns3P. The other six members
are catalytically inactive proteins (1273) (FIGURE 7).
1. PTEN
This enzyme (also known as MMAC1 and TEP1) was first
identified as a tumor suppressor gene after mapping its homozygous deletions in several human advanced cancers on
chromosome 10 (897, 898, 1452). Due to its similarity to
phosphatases and weak homology to tensin (there lies the
origin of its name), PTEN was initially believed to be a
dual-specificity protein phosphatase (1104). However, the
enzyme shows low activity against protein and peptide substrates, and subsequent studies revealed that it was a
PtdIns(3,4,5)P3 3-phosphatase (968, 969). Although able to
dephosphorylate PtdIns(3,4)P2, PTEN is a lot more active
against PtdIns(3,4,5)P3 (1015) and, therefore, is a functional antagonist of the class I PI 3-kinases. The protein and
lipid phosphatase activities of PTEN can be dissociated, and
a G129E mutation identified in a family with Cowden disease eliminates lipid but spares the protein phosphatase
activity of the enzyme (481, 1103). Since Cowden disease is
one of the cancer predisposition syndromes (641), these
studies showed that the tumor suppressive function of
PTEN is primarily associated with its lipid phosphatase
activity. A mutant form of PTEN impairing protein but not
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The only type IV 5-phosphatase, also called INPP5E, 72kDa polyphosphate 5-phosphatase, and Pharbin (801,
818), contains an NH2-terminal proline-rich segment, a
central 5-phosphatase domain, and a COOH-terminal
farnesylation CAAX motif (FIGURE 6). This enzyme can remove the 5-phosphate from PtdIns(4,5)P2, PtdIns(3,4,5)P3, and
PtdIns(3,5)P2 and has about a 10 times higher affinity against
PtdIns(3,4,5)P3 than SHIP1 (801, 818). INPP5E is located
mostly in the Golgi and partially in the PM (818), but its
distribution could be more specialized in specific cell types.
Notably, INPP5E does not seem to be a general antagonist
of PtdIns(3,4,5)P3 signaling. In macrophages, INPP5E is
recruited to the phagocytic cup where it controls the conversion of PtdIns(3,4,5)P3 to PtdIns(3,4)P2, but unlike
SHIP1 (294, 750), it only affects the Fc␥R- and not the
complement receptor 3 (CR3)-mediated phagocytosis (649).
Interestingly, overexpression of INPP5E in adipocytes does
not antagonize insulin signaling but instead hydrolyzes
PtdIns(3,5)P2 to PtdIns3P, which in turn increases GLUT4
translocation (817). Two recent studies linked INPP5E to
the primary cilium. In one of these studies, mutations clustering within the 5-phosphatase domain of INPP5E were
identified in patients with Joubert syndrome (145). These
patients present with specific midbrain-hindbrain malformation, and variably with retinodystrophy, nephronophthisis, liver cirrhosis, and polydactyly and are considered as
an emerging group of ciliopathies (1599). In this study,
INPP5E was found to localize to the primary cilium in cells
of the affected organs and the mutations caused destabilization of the cilia during stimulation (145). The other study
found that disruption of the Inpp5e gene in mice caused
multiorgan failure associated with defects in primary cilia
(714). This latter study (714) also found destabilization of
cilia in response to growth factor stimulation and identified
a mutation in the human INPP5E gene that affected cilia
localization in a family with MORM syndrome. The physical targeting of INPP5E to the cilia was recently shown to
be dependent on a protein complex that included phosphodiesterase 6D, the Arf-like protein, ARL13B, and the centrosomal protein, CEP164, all of which had been linked to
ciliopathies (668). These interesting discoveries should facilitate further studies to better understand the role of phos-
phoinositides in ciliary function and how INPP5E controls
this process.
PHOSPHOINOSITIDES
A
PBM
Ptase
C2
PDZb
PTEN
403 aa
TM
Ptase
C2
TPIPα/γ
445/522 aa
Ptase
C2
TPIPβ
326 aa
TM
Ptase(intact)
C2
TPTE
533 aa
PBM
Ptase
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VSD
C2
ci-VSP
576 aa
B
MTM1
MTMR1
MTMR2
PHG
Ptase
CC PDZb
603 aa
665 aa
643 aa
SID
PHG
Ptase
CC
FYVE
MTMR3
MTMR4
1,198 aa
1,195 aa
SID
MTMR6
MTMR7
MTMR8
PHG
Ptase
CC
621 aa
660 aa
704 aa
SID
Ptase
MTMR14
650 aa
FIGURE 7. The inositol lipid 3-phosphatases. A: the PTEN family of enzymes dephosphorylate PtdIns(3,4,5)P3 at the
3-position and hence “antagonize” the class I PI3Ks. The conserved phosphatase domain is followed by a C2
domain and a PDZ binding sequence in PTEN. The PBM is a phospholipid binding domain present in PTEN and
also in the voltage-dependent phosphatases (these latter enzymes are actually 5-phosphatases). The TPIP␣
and -␥ enzymes have an NH2-terminal putative transmembrane domain (TM) that is lacking in the ␤ form. The
TPTE enzyme is catalytically inactive. B: the myotubularin family of 3-phosphatases dephosphorylate PtdIns3P
and PtdIns(3,5)P2. They fall into three subgroups. All of these enzymes (except for MTMR14) have a PHG (PH
and GRAM) domain and coil-coil (CC) regions in addition to their phosphatase domain. The phosphatase domain
also contains a SET interaction domain (SID). MTMR3 and -4 also has a FYVE domain in their COOH termini.
No specific domains beyond the phosphatase domain have been described in MTMR14. There are additional
MTM-related proteins that lack catalytic activity. They are not shown in this figure.
lipid phosphatase activity was recently identified showing
that together with the lipid phosphatase activity, the protein
phosphatase activity of PTEN was also necessary to maintain proper migration of glioblastoma cells (325).
PTEN has a catalytic phosphatase domain, with a conserved C-(X)5-R signature motif, an NH2-terminal phosphoinositide binding segment (PBM), a C2 domain toward
the COOH terminus followed by two PEST (proline, glu-
tamic acid, serine, threonine) sequences, and a COOH-terminal PDZ binding motif (FIGURE 7). The structure of the
catalytic domain of PTEN has been solved showing similarities to those of phosphotyrosine and dual-specificity phosphatases (870). However, PTEN has a deeper substrate
binding pocket that allows the bulkier PtdIns(3,4,5)P3
headgroup to be used as a substrate. The C2 domain is
important for membrane targeting and regulation of the
enzyme. Unlike many other C2 domains, the C2 domain of
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TAMAS BALLA
The most important known function of PTEN is to serve as
a negative regulator of PtdIns(3,4,5)P3 and hence serving as
a tumor suppressor. As detailed under class I PI 3-kinases,
PtdIns(3,4,5)P3 promotes carcinogenesis in a number of
ways, both in a tumor cell autonomous manner, and also
within the tumor cell environment. In the former, it stimulates
proliferation, and protects cells from apoptosis, and it also increases the tumor cells’ ability to migrate and break down tissue
1052
barriers including those of capillaries, thereby promoting metastasis. In the tumor environment, PtdIns(3,4,5)P3-dependent signaling has a crucial role in angiogenesis, stromal cell function, or immune surveillance. It has been very clear that
germline mutations of PTEN cause increased incidence of
multiple hamartomas and high risk of tumorigenesis observed in a number of human syndromes such as Cowden
disease, Bannayan-Riley-Ruvalcaba syndrome, LhermitteDuclos disease, and Proteus- and Proteus-like syndrome
(349, 1434). PTEN mutations have been detected in a variety of human cancers such as glioblastoma, breast, lung,
colon, kidney, and uterine carcinomas or melanomas. Very
often monoallelic mutations of PTEN are present in cancer
tissues, but late-stage aggressive metastatic cancers show
biallelic loss of PTEN (210, 349, 1434).
Most PTEN mutations cluster within the phosphatase domain making the enzyme catalytically inactive, but many
mutations are found in other regions that affect the cellular
localization or stability of the enzyme (999). It is also of
great interest that PTEN is very sensitive to oxidative damage, and hydrogen peroxide rapidly inactivates its enzymatic activity (384, 842, 874, 888, 1297). One interesting
and poorly understood aspect of PTEN tumor suppressor
function is linked to its nuclear localization where a noncatalytic role has been recently proposed (1433). Clearly,
there is more to PTEN function than PtdIns(3,4,5)P3 signaling, and its link to nuclear proteins, chromosomal instability, DNA repair, and kinetochore assembly (1394) suggests
a complexity that has yet to be fully understood.
Mouse models of PTEN inactivation have been providing
more detailed information on the tumor suppressor as well
as the developmental and tissue-specific roles of PTEN. Homozygous PTEN deficiency causes early embryonic lethality, and heterozygote mice also develop tumors (838, 1450,
1500). Remarkably, a dose-dependent reduction in PTEN
even above monozygocity is associated with increased tumor formation (31, 1578). In addition, conditional and
tissue specific PTEN knockout mice revealed a plethora of
PTEN-associated functions in virtually all tissues and organ
systems. This is not unexpected based on the multitude of
processes regulated by PtdIns(3,4,5)P3. More on the variety
of the PTEN-related defects can be found in excellent reviews focusing on PTEN (805, 1434, 1501).
2. PTEN-related phosphatases
A) TPTE/TPIP PROTEINS. Humans express one TPTE (transmembrane phosphatase with tensin homology) (242, 1662) and
several splice variants of TPIP (TPTE and PTEN homologous inositol lipid phosphatase) (␣, -␤ and ␥) (1662) (FIGURE 7A). Of these, TPTE is specifically expressed in the
testis and lacks phosphatase activity, while TPIPs are expressed in the testis, brain, and stomach and are enzymatically active against 3-phosphorylated inositides (1531,
1662). Mice also have a similar testis-specific protein called
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PTEN does not bind Ca2⫹, but it contributes to membrane
binding through electrostatic interactions (323). However,
membrane binding is not the sole function of the PTEN C2
domain (507), which also makes several contacts with the
catalytic domain via hydrogen bonds (870). Truncation or
mutations within the C2 domain of PTEN make the protein
unstable (323, 506, 507). The NH2-terminal phosphoinositide binding domain (PBM) of PTEN also contributes to
membrane binding and localization. This domain in isolation can bind PtdIns(4,5)P2, and mutation of its key basic
residues (such as K13E) abrogates its lipid binding (1266).
Basic residue mutations within the PBM in the full PTEN
molecule or PtdIns(4,5)P2 depletion prevent PTEN from
efficiently localizing to the membrane (1249). Interestingly,
PtdIns(4,5)P2 binding to the PBM domain, is also present in
the Ciona VSP, and seems to be important for the coupling
of the voltage sensor to the phosphatase domain (846). A
phosphorylation-dependent autoinhibitory role of the PBM
has also been suggested for the mammalian PTEN enzyme(1249). The COOH-terminal tail contains a stretch of
⬃60 amino acids that can be phosphorylated by several
protein kinases (22, 905) and phosphorylation renders
PTEN inactive (1160, 1249) through interaction of the
phosphorylated COOH terminus with the membrane interaction site of the C2 domain (1160). Since this COOHterminal segment of PTEN is quite acidic and the protein
phosphatase activity of PTEN is strongest against acidic
peptides (1104), it was suggested that PTEN autocatalytically can activate itself through dephosphorylation of its
COOH terminus (1247). The role of the PEST sequence
within PTEN is not clear, but it may be related to the degradation of PTEN by proteosomes. Phosphorylation also
affects the stability of PTEN (1562), and polyubiquitylation
has been proposed to mark PTEN for proteosomal degradation (1561). The identity of the E3 ubiquitin ligase responsible for polyubiquitylation of PTEN has been controversial (458, 1674), but most recent studies suggest that
WWP2 that belongs to the NEDD4-like family of E3 ligases
is the elusive PTEN E3 ubiquitin ligase (967). Monoubiquitylation of PTEN, on the other hand, was found important for nuclear localization and tumor suppression (1579),
at the same time mono- or poly-ubiquitylation was shown
to inhibit PTEN phosphatase activity (964). A recent study
found that PTEN gets sumoylated at residues K254 and
K266 and that sumoylation is essential for the tumor suppressor function of the protein, presumably because of its
contribution to membrane recruitment (521, 663).
PHOSPHOINOSITIDES
PTEN2, but it does not seem to be the ortholog of the
human TPTE or TPIP enzymes (535, 1738). TPIP␣ and -␥
have NH2-terminal sequences suggestive of three to four
transmembrane domains. Expressed TPIP␣ localizes to the
ER, but TPIP␤, which lacks transmembrane segments, is cytosolic and has no significant phosphatase activity (1662). The
transmembrane domains of TPIP␥ show weak similarity to the
voltage sensor of the ci-VSP (713, 1096). The functions of
these proteins are presently unknown.
The voltage-sensing domain of VSPs shows significant homology to those of voltage-gated ion channels, and its voltage sensing is manifested as a “sensing current” even in
isolation (650, 1096). Mutations within the sensor module
can shift the voltage dependence of the molecule (813). The
exact mechanism of how the voltage-sensing unit couples to
increased enzymatic activity is not yet understood. However, there is a close correlation between the conformational change of the voltage sensor and the activity of the
enzyme (846, 1096, 1097). Also, the enzymatic activity of
the phosphatase module has a retrograde effect on the voltage-sensing unit and phosphatase inhibitors and catalytically inactive Cys mutant catalytic modules alter the speed
of the “sensing current” (650, 812). Recent studies found
that the PBM domain of VSP has a critical role in coupling
the voltage sensor to increased phosphatase activity (812,
846, 1637). This domain, which is homologous to the
similar domain found at the NH2 terminus of PTEN, is a
phosphoinositide binding module, and its deletion or
mutations as well as PtdIns(4,5)P2 depletion affects the
coupling between the two functional modules (812, 846,
1637).
C) PLIP/PTPMT1.
A PTEN-like phosphatase (PLIP) has been
described with unique preference to PtdIns5P as a substrate
in vitro (1187). However, subsequent studies identified the
same enzyme as a mitochondrion-localized protein tyrosine
phosphatase (PTPMT1) that dephosphorylates phosphatidylglycerol-phosphate, an essential intermediate of cardiolipin synthesis (1797). Therefore, it is quite unlikely that
this enzyme works on any phosphorylated inositide and its
deletion does not affect PtdIns5P levels (1186).
3. Myotubularins
The myotubularin (MTM) family includes 15 members that
share a distinctive phosphatase domain (FIGURE 7B) (776,
855, 856, 1536). Nine of these proteins possess 3-phosphatase activity against PtdIns3P and PtdIns(3,5)P2 and share a
CXXGWDR sequence motif within their catalytic core. The
other six homologs are catalytically inactive proteins often
referred to as “pseudophosphatases” that associate mostly
with and regulate the active MTM enzymes. The phosphatase active forms can be divided into four subgroups: the
MTM1 group contains MTM1, MTMR1, and MTMR2;
the MTMR3 group includes MTMR3 and MTMR4; and
the MTMR6 subgroup has MTMR6, -7, and -8. MTMR14
stands alone in a separate group. The pseudophosphatases
consist of MTMR5, -9, -10, -11, -12, and -13. In addition to
their catalytic domains, these proteins contain several protein- and lipid-interacting modules, such as PH-GRAM domains (364), FYVE domains, coiled-coil domains, and
COOH-terminal PDZ binding sequences (see FIGURE 7B for
details). Most of the family members show expression in a
wide range of tissues except MTMR5 and MTMR7 that are
expressed exclusively in the testes and brain, respectively
(440, 855, 856).
A) MTM1.
This was the first MTM described as the gene
mutated in X-linked myotubular myopathy (XLMTM)
(858). MTM1 was originally believed to be a dual specific-
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B) VOLTAGE-SENSITIVE PHOSPHATASES. Voltage-sensitive phosphatases (VSPs) were first identified in Ciona intestinales
based on their sequence similarity to PTEN and the presence of a voltage sensing domain within their transmembrane segments (1096). These enzymes are remarkable in
that they hydrolyze phosphoinositides and increase their
catalytic activity in response to depolarization. Similar enzymes have been found in other species, notably in Xenopus
laevis (1259) and in zebrafish (650) with slightly different
voltage characteristics, and the human TPIPs are likely to be
their mammalian homologs (1163). The catalytic domains
of VSPs are similar to that of PTEN, but they lack the
COOH-terminal PEST sequences and the PDZ binding motif. However, in spite of their sequence homology to PTEN,
these enzymes function as 5-phosphatases (as opposed to
3-phosphatases) acting on PtdIns(3,4,5)P3 and PtdIns(4,5)P2
(550, 713, 1097). The substrate specificity of VSP at least
partially depends on a single Gly residue within the conserved C-(X)5-R sequence, and an Ala substitution at this
position (G365A) abolishes the activity against PtdIns(4,5)P2
(713). Comparison of the structures of the catalytic domains
of PTEN and ciVSP showed a reduced size of the catalytic
pocket of ciVSP due to a protruding Glu411 residue (1009).
The biological functions of VSP or its orthologs are not
known, but their primary expression in the testes and its
localization in the sperm tail in Ciona intestinales (1096)
suggests a role in fertilization. In spite of the limited understanding of its physiology, VSPs have become invaluable
experimental tools. To study the multiple roles of PM
PtdIns(4,5)P2, our ability to rapidly manipulate the level of
this lipid in intact cells has been a highly desirable methodological invention. A major breakthrough in this area was
the introduction of the rapamycin-induced translocation of
5-phosphatase enzymes to rapidly deplete PtdIns(4,5)P2
(1489, 1617). However, the VSP enzymes offer several further advantages over the rapamycin-inducible changes: they
allow induction of extremely rapid, quantitatively precise,
and reversible changes in PM PtdIns(4,5)P2. Therefore, VSP
is becoming an important experimental tool in phosphoinositide research for the controlled manipulation of PM phosphoinositides(422, 609, 953).
TAMAS BALLA
B) MTMR1 AND -2. MTMR (R stands for -related) proteins are
close homologs of MTM1. MTMR1 is in fact located next
to MTM1 on the X-chromosome both in humans and mice
as a result of gene duplication (799). Accordingly, the structure and enzyme activity of MTMR1 is very close to those
of MTM1 (1576). The function(s) of MTMR1 is not
known, but it is likely that the restricted phenotype of
MTM1 mutations are due to the fact that MTMR1 can
substitute for MTM1 functions in all but a few tissues.
MTMR2, on the other hand, was discovered as the gene,
whose mutations cause the hereditary recessive disorder
Charcot-Marie-Tooth disease type 4B1 (CMT4B1), which
is characterized by peripheral neuropathy due to demyelination (124, 159, 653, 792). Disease-causing mutations severely affect the ability of MTMR2 to dephosphorylate
1054
PtdIns3P and PtdIns(3,5)P2 (123, 792). The structure of
MTMR2 has been solved and found to have a larger phosphatase domain than other PtdIns3P phosphatases (117,
118). This is because of the presence of a “SID” [SET interaction domain (36)] domain within the phosphatase domain of MTMR2 (118). These studies also found that the
NH2-terminal GRAM domain of MTMR2 has a similar
architecture to PH domains, and it also binds phosphoinositides, primarily PtdIns(3,5)P2 (118). Expressed MTMR2 has
been reported to be cytosolic or associated with perinuclear
membranes or the nucleus (793, 1274). However, endogenous MTMR2 localizes to late endosomes (211). Recent
studies showed that dephosphorylation of the NH2 terminus of MTMR2 facilitates its binding to early endosomes
(462). MTMR2-deficient mice develop symptoms very reminiscent of those found in CMTB4B1 patients with peripheral neuropathy and impaired spermatogenesis (158, 164).
The myelin unfolding seen in these mice can be reproduced
by selective deletion of the gene in Schwann cells (160, 161),
confirming the primary defect in myelination. MTMR2 interacts with the catalytically inactive pseudophosphatases
MTMR5 (also named Set binding factor 1 or SBF1) (793)
and MTMR13 (also called SBF2), and these interactions
greatly enhance the phosphatase activity of MTMR2, as
well as determine its cellular localization (123, 1274). Mutations in MTMR13 cause Charcot-Marie-Tooth disease
type 4B2 (CMT4B2) with similar defects to CMT4B1 (69,
1381), and these deficiencies can be replicated in mice with
MTMR13 gene disruption (1275, 1545). In contrast,
MTMR5 deletion in mice causes defective spermatogenesis
without any peripheral neuropathy (440). Therefore, it appears that the MTMR2-MTMR5 complex functions in
spermatogenesis, whereas the MTMR2-MTMR13 complex is essential for myelination in Schwann cells (1273).
C) MTMR3 AND
-4. These widely distributed phosphatases are
characterized by the presence of a FYVE domain in their
extended COOH termini (1659, 1814). Interestingly, however, the FYVE domain of MTMR3 does not bind
PtdIns3P, nor is it responsible for the endosomal localization of MTMR3 (941). MTMR3, on the other hand, binds
PtdIns5P at its GRAM domain (941), which may be important for allosteric activation of the enzyme by this rare lipid
species (1355). Only few data are available on the functions
of these phosphatases. Expression of human MTMR3 in
yeast induces enlargement of vacuoles and increases yeast
PtdIns5P levels (1659) consistent with its ability to dephospharylate PtdIns3P and PtdIns(3,5)P2 (1659). Recent genome-wide association studies identified MTMR3 as a susceptibility gene in lung cancer in a large Chinese population
(659) and also in early-onset inflammatory bowel disease in
another study (598). It is not clear yet how the functions of
these genes contribute to the respective pathologies. Nevertheless, evidence is accumulating that these phosphatases
also regulate endocytic sorting (1122), routing, and inacti-
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ity phosphotyrosine phosphatase (858), but its lipid phosphatase activity against PtdIns3P (152, 1536, 1814) was
later demonstrated both as a GST-fusion protein and in cell
expression studies. Many of the disease-causing mutations
as well as mutation of the conserved Cys (C375S) residue
render the enzyme catalytically inactive, and expression of
such phosphatase inactive enzymes has dominant negative
effects elevating PtdIns3P levels (1536). However, MTM1
can also dephosphorylate PtdIns(3,5)P2 and, therefore, increase PtdIns5P levels (1576). MTM1 knockout mice show
perinatal mortality, and the pups that are born alive quickly
succumb into muscle weakness and develop centronuclear
myopathy with histological findings reminiscent of those
seen in human XLMTM disease (196). Conditional and
tissue-specific MTM1 knockout mice showed that MTM1
deficiency in skeletal muscle is the underlying cause of the
disease, and it is not the development, but the maintenance
of the skeletal muscle that requires this enzyme (196).
MTM1 mutations were also identified in dogs suffering
from X-linked myotubular myopathies (116). The intracellular localization of MTM1 has been controversial. Overexpressed MTM1 is mostly cytoplasmic with some perinuclear association, and it also shows up in membrane ruffles
generated by overactive Rac (857). In other studies, endogenous MTM1 was found in early endosomes in association
with the class III PI 3-kinase complex (212). It is likely that
interaction with other proteins perhaps via phosphorylation-dephosphorylation cycles determine the location and
therefore the localized regulatory function of the MTM1
protein. In support of this idea, MTMR12, a phosphataseinactive MTM family protein, originally identified as an
MTM1 adaptor protein (3-PAP), tightly associates with
MTM1 (1117) and determines its localization (1118). MTM1
also associates with the intermediate filament desmin, and
XLMTM-causing mutations in MTM1 disrupt this association leading to altered intermediate filaments, and abnormal
mitochondrial positioning and functions (626). Recent data
also suggest that MTM homologs in lower organisms control
discrete pools of PtdIns3P specifically involved in endocytosis
(1127, 1625).
PHOSPHOINOSITIDES
vation of receptors (1780) and also can be ubiquitylated
(1227).
D) MTMR6,
E) MTMR14.
This member of the MTMR family was identified in silico (1566) based on its homology to MTMRs and
its high sequence homology to a Drosophila protein named
“egg-derived tyrosine phosphatase” (EDTP) (1756). Disruption of the gene in flies produced the “JUMPY” phenotype characterized by progressive loss of muscle control and
shaky movements (1382). Importantly, the human Jumpy/
MTMR14, which displayed PtdIns3P and PtdIns(3,5)P3
3-phosphatase activity, harbored catalytically compromising mutations in two patients suffering from centronuclear
myopathy (1566). The same phosphatase was also identified as an inositol lipid phosphatase showing highest activity against PtdIns(3,5)P2 with prominent expression in skeletal muscle and heart and hence also named muscle-specific
inositol phosphatase (MIP) (1393). MTMR14-deficient
mice show muscle weakness and fatigue that develops with
aging, due to a Ca2⫹ leakage from the SR-cisternae apparently because of increased PtdIns(3,5)P2 levels (1393). The
progressive muscle weakness is attributed to an increased
activity of ryanodine receptors by the PtdIns(3,5)P2 (1570),
altered t-tubule morphology observed in MTMR14-deficient mouse (625), and impaired excitation-contraction
coupling in MTMR14-depleted zebrafish embryos (382).
MTMR14 levels are also decreasing with age in parallel to
weakened muscle function, and deletion of the gene in
mouse significantly speeds up this process (1293). Since
MTMR14 was also shown recently as a negative regulator
of autophagy (1631, 1632), the rapid aging of muscles
might be also related to an altered process of autophagy in
MTMR14-deficient animals (625).
C. 4-Phosphatases
Phosphoinositide 4-phosphatases can remove the phosphate from the 4-position of PtdIns(3,4)P2 or PtdIns(4,5)P2.
1. INPP4s
Two enzymes belong here, INPP4A and INPP4B. INPP4A,
first isolated and cloned from rat brains, is ⬃100 kDa in size
and dephosphorylates the 4-position in PtdIns(3,4)P2 and
to a much lesser extent Ins(3,4)P2 and Ins(1,3,4)P3 (1149,
1150). Another form of the enzyme, INPP4B, was cloned
subsequently showing highest expression in the heart and
skeletal muscle (originally termed type II inositol polyphosphate 4-phosphatase) (1147). In addition to their conserved
phosphatase domains, both enzymes have a C2 domain at
their NH2 termini that show distinct lipid binding specificities. While the C2 domain of INPP4A prefers binding
PtdIns(3,4)P2, PtdIns3P and PtdSer (712), that of INPP4B
binds PtdOH and PtdIns(3,4,5)P3 (434). In addition, there
is a PEST sequence in INPP4A (but not INPP4B) that is
cleaved by calpain, thereby inactivating the enzyme, as
shown in stimulated platelets (1148). Expressed INPP4A is
localized to early and recycling endosomes and is activated
by Rab5 (1401). Consistent with an endosomal function,
knockdown of INPP4A decreases transferrin uptake (1401).
Conversely, overexpression of the enzyme restores the morphology of enlarged endosomes caused by PtdIns3P deficiency (712), suggesting that INPP4A can produce
PtdIns3P. INPP4A acts as a negative signal via decreasing
the levels of PtdIns(3,4)P2 and attenuates Akt activation
and also exerts an antiproliferative effect (712, 1649). Decreased levels of INPP4A and loss of heterozygocity of
the enzyme are observed in a variety of cancers, suggesting that the enzyme acts as a tumor suppressor (428). No
such functions have been attributed to INPP4B. A frameshift mutation that eliminates a functional Inpp4a in
mice was found to cause the weeble phenotype (1153).
These mice develop early onset ataxia due to the loss of
Purkinje cells from the cerebellum. Interestingly, islands
of Purkinje cells remain normal, and these express Eaat4,
a glutamate transporter, suggesting that the lack of Inpp4a
is associated with glutamate toxicity that is remedied by
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-7, AND -8. MTMR6 and MTMR7 are both capable of hydrolyzing PtdIns3P and PtdIns(3,5)P2 (1355),
but MTMR7, which is mainly expressed in the brain, also
acts on water-soluble Ins3P (1075). MTMR6 has been
shown to inhibit the Ca2⫹-activated potassium channel
KCa3.1 (1444), which requires PtdIns3P for its optimal activity (1442). Through this action, MTMR6 expression depolarizes T cells, thereby decreasing the driving force for the
ICRAC channels, and hence, inhibiting T-cell activation
(1443). This action of MTMR6 is not mimicked by
MTMR8 and, conversely, MTMR6 does not regulate
other, highly related KCa channels (1442). Recent studies
reported that the right balance between PI3K and MTMR8
was important for muscle (1024) and vascular development
(1025) in zebrafish. Of the pseudophosphatases, MTMR9
interacts with both MTMR6 and MTMR7 and activates
the phosphatase activity of the respective enzymes (942,
1075, 1832).
The enzymes that hydrolyze PtdIns(3,4)P2 are called
INPP4A and INPP4B, while those that use PtdIns(4,5)P2 are
TMEM55A and -B (the A and B forms of both groups are
also called types I and II, respectively) (FIGURE 8A). The
mammalian Rac guanine nucleotide exchange factors PRex1 and -2 also contain a domain homologous to the
phosphatase domains of INPP4s, but these proteins do not
have phosphatase activity (1317, 1698). There are two bacterial virulence toxins, IpgD from Shigella flexneri and
SigD/SopB from Salmonella, that possess a wide range of
phosphoinositide phosphatase activity in vitro but appear
to act on PtdIns(4,5)P2 as a 4-phosphatase when expressed
in cells, yielding the rare lipid PtdIns5P. Therefore, they are
often used to study the functions and metabolism of
PtdIns5P (1130, 1255, 1544). The Sac1 phosphatase dephosphorylates PtdIns4P, but it can also dephosphorylate PtdIns3P
and will be discussed separately. No PtdIns(3,4,5)P3-directed
4-phosphatase activity has been reported.
TAMAS BALLA
A
C2
PEST
Ptase
INPP4A
978 aa
C2
Ptase
INPP4B
924 aa
Ptase
TM
TMEM55A/B
257/277 aa
B
Sac1-Ptase
TM
587 aa
Sac1-Ptase
hSac3/Fig4
907 aa
Sac1-Ptase
hSac2
1,132 aa
FIGURE 8. The inositol lipid 4-phosphatases. INPP4A and -B dephosphorylate PtdIns(3,4)P2 at the 4-position. They have a C2 domain in their NH2 termini and a phosphatase domain at their COOH termini. INPP4A
also has a PEST sequence. The TMEM proteins have lower activity, and they act on PtdIns(4,5)P2 to generate
PtdIns5P. These enzymes have putative transmembrane domains (TM) at their COOH termini. B: the Sac1
phosphatases can dephosphorylate any monophosphorylated PtdIns, but in the cell they primarily function as
PtdIns4P 4-phosphatases. The yeast and human Sac1 are tail-anchored proteins with a COOH-terminal TM
domain. Human Sac3 and yeast Fig4p work as PtdIns(3,5)P2 5-phosphatases. hSac2 is a 5-phosphatase
acting on PtdIns(4,5)P2 and PtdIns(3,4,5)P3 yet, structurally is a homolog of the Sac1 family.
glutamate removal by the Eaat4 transporter (1321). Recently, an Inpp4a knockout mouse was generated and
showed rapid neurodegeneration in the striatum and basal
ganglia, causing a phenotype similar to involuntary movement disorders such as Parkinson disease. The neurons of
these mice undergo NMDA receptor-mediated cell death
due to the increased levels of NMDA receptors at the postsynaptic density (1343). There is little known about the
connection between Inpp4s and human disease. A polymorphism in INPP4A has been associated with severe asthma
(1388), and a loss of INPP4A and -B has been reported in
various human malignancies (107, 1317).
2. TMEM55
The two forms of these enzymes, A and B, originally called
type I and type II PtdIns(4,5)P2 4-phosphatases, were cloned
based on the presence of a conserved CX5R motif also found
in the Burkholderia pseudomallei virulence factor Bop, a putative phosphatase (1593). Both enzymes are expressed ubiquitously and act exclusively on PtdIns(4,5)P2. The TMEM55
name refers to the two putative transmembrane domains
found in the COOH termini of these proteins following their
catalytic domains (1317). Overexpression of TMEM55A increases EGF receptor degradation (1593). TMEM55B, on the
other hand, was shown to control nuclear PtdIns5P levels and
1056
respond to DNA damage by nuclear translocation, activating
the ING2 protein (522) and promoting p53-mediated cell
death (1833).
D. The SAC1 Family of Phosphatases
The prototypical Sac1 phosphatase was discovered independently in two laboratories as a mutant allele that rescued
defects associated with temperature-sensitive actin mutants
(1152) or secretion defects caused by sec14ts mutations in
yeast (273). The connection between SAC1 being linked to
actin dynamics on the one hand, and to the secretion process on the other, had not been fully realized for a long
period, nor was it known what the Sac1p protein did in
yeast cells. Eight years had passed from these original discoveries before it was realized that Sac1 is a phosphoinositide phosphatase (538, 667). On the basis of sequence
similarities within their phosphatase domains, additional
members of the SAC1 phosphatase family include the yeast
PtdIns(3,5)P2 5-phosphatase Fig4 (497) and its mammalian
homolog Sac3, as well as the mammalian Sac2 protein,
which does not have a yeast counterpart. In addition, a Sac1
homology domain is found in the synaptojanin family of
5-phosphatases that were discussed above. These enzymes
all have a conserved signature C(X)5R(T/S) motif within
their catalytic domains (FIGURE 8B).
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hSac1/Sac1
PHOSPHOINOSITIDES
1. Sac1/SAC1M1L
The mammalian Sac1 enzyme is a ubiquitously expressed
protein, first isolated from rat brain and showing the same
substrate specificity profile as the yeast ortholog, capable of
hydrolyzing all PtdIns monophosphates and PtdIns(3,5)P2
but not PtdIns(4,5)P2 (1125). Curiously, human Sac1 expressed as a GST fusion protein only acts on PtdIns3P and
PtdIns4P in spite of 95% homology with the rat enzyme
(1289). Mammalian Sac1 is mostly ER localized in steady
state, but it cycles between the Golgi and the ER. A basic
stretch of amino acids found at the Sac1 COOH terminus
mediates its interaction with the coatomer COPI complex
that mediates its retrieval to the ER (147). Under starvation,
2. Fig4/SAC3
Yeast Fig4 was first identified in a screen looking for genes
that are activated by pheromone-induced mating pathway
(406). FIG4 was found as a nonessential gene that was
required for cell and actin polarization and notably had a
Sac1 homologous region (406). It took several years again
before it was discovered that Fig4p is a phosphoinositide
phosphatase that dephosphorylates PtdIns(3,5)P2 at the
5-position (497, 1045). As already discussed in the Fab1p
PtdIns3P 5-kinase section (sect. 5), Fig4p forms and stabilizes a trimeric complex with Fab1p and the scaffold protein, Vac14p located on the vacuolar membrane (390,
1042). This explains why deletion of Fig4 paradoxically
decreases, rather than increases, PtdIns(3,5)P2 levels (389,
390, 1311) as it is needed to keep Fab1p in a functional
form. Therefore, Fig4 deletions cause vacuolar fission defects with enlarged vacuoles and defective retrograde transport (1311).
The mammalian homolog of Fig4 is called Sac3, and it
should not be confused with the yeast Sac3 protein that is a
member of the nuclear pore complex involved in mRNA
export (878). The first mammalian Sac3 was identified as a
human KIAA 00274 clone (1057) and characterized as the
mammalian homolog of Fig4 (1353). Human Sac3 displayed features similar to its yeast counterpart: it hydrolyzed PtdIns(3,5)P2, formed a complex with the mammalian
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The yeast Sac1p is capable of removing a phosphate from phosphoinositide monophosphates, such as PtdIns4P, PtdIns3P, and
PtdIns5P, and also from bisphosphorylated PtdIns if the
phosphates are not in vicinal positions [such as in
PtdIns(3,5)P2, but not PtdIns(3,4)P2 or PtdIns(4,5)P2] in
vitro (538, 667). Sac1-deleted yeast strains are viable, but
show defects in actin dynamics, vacuolar sorting, and secretion and have cell wall abnormalities (273). They also show
large (8- to 10-fold) accumulation of PtdIns4P with moderate increases in PtdIns3P and PtdIns(3,5)P2 (455, 538, 667).
Paradoxically, PtdIns4P increases are not associated with
increased PtdIns(4,5)P2; in fact, the latter shows moderate
to substantial decreases depending on the study (455, 538,
667). The large increase in PtdIns4P in Sac1-deleted yeast
requires a functional Stt4 but not Pik1, suggesting that Sac1
controls primarily the PtdIns4P pools generated by the
Stt4p PI4K (455). This finding raised important questions
since Sac1 is primarily found in the ER while Stt4 is in the
PM, enriched in ER-PM junctional zones (79). Recent studies solved this apparent conundrum showing that ERtethered Sac1 can act in trans to control PM PtdIns4P
that is generated by Stt4 at ER-PM junctional zones
(1454). However, it is still puzzling why the increased
PM PtdIns4P is not reflected in increased PtdIns(4,5)P2
levels. Sac1 is tethered to the ER by its COOH-terminal
hydrophobic motif that binds to the ER dolicholphosphate-mannose synthase enzyme Dpm1 (427). However,
Sac1 cycles between the Golgi and the ER, and under
nutrition deprivation, it is mostly localized to the Golgi
and it is suggested that this relocalization limits PtdIns4P
levels in the Golgi and, hence, inhibits secretion (427).
Sac1 also associates with Orm proteins at the ER that are
negative regulators of serine palmitoyltransferase, the
rate-limiting enzyme in sphingolipid synthesis (178).
Sac1 is also linked to the synthesis of complex sphingolipids in additional ways as it was found to be important
for the synthesis of inositol phosphoceramide (IPC)
(179). Accordingly, Sac1 deletions increase the sensitivity of yeast cells to Aerobasidin, an inhibitor of IPC synthesis (1529). All of these studies suggest that Sac1 performs multiple functions as part of numerous distinct
protein complexes linked to different pathways.
Sac1 interacts with COPII and undergoes oligomerization
mediated by its NH2-terminal leucine-zipper motif, and a
significant fraction of Sac1 is then found in the Golgi (147).
This process is reversed by growth factor stimulation via
activation of p38 MAPK (147). Mammalian Sac1 is an
essential protein, and deletion of the gene in mouse causes
preimplantation lethality, and even in cells, knockdown of
Sac1 leads to cell death, making it difficult to study the
functions of the protein (929). Sac1-deficient cells show a
major disorganization of their Golgi morphology without a
gross defect in secretion. Importantly, using PtdIns4P-recognizing PH domains, no sign of PtdIns4P accumulation in
any cellular compartment could be detected, although an
increased level of [3H]PtdIns4P was demonstrable in metabolically labeled cells (929). Sac1 knockdown also caused a
high level of spindle defects, creating aberrant chromosomal segregation and a block in exit from mitosis (929).
All of these defects can be rescued by overexpression of
Sac1, and both its catalytic activity and ability to cycle
between the ER and the Golgi were required for complementation (929). Sac1 mutant flies also die in embryonic
stage and develop dorsal closure defects (1689). The structure of yeast Sac1 has been recently solved at 2 Å resolution.
The enzyme consists of an NH2-terminal lobe of yet unknown function and a COOH-terminal catalytic lobe
showing both similarities and notable differences with
other phosphoinositide phosphatases, such as PTEN and
MTMR2 (979).
TAMAS BALLA
3. hSac2/INPP5F
There is no yeast homolog of human Sac2. The human Sac2
enzyme was identified as a phosphatase showing significant
homology to the yeast Sac1 and Fig4 proteins (1057). Strikingly, this enzyme is a PtdIns(4,5)P2 5-phosphatase capable
of acting also on PtdIns(3,4,5)P3 but not on any of the other
phosphoinositides or soluble inositol phosphates (1057). A
genetrap mouse lacking a functional Sac2 shows no major
abnormalities but is more susceptible to isoproterenol-induced cardiac hypertrophy, whereas overexpression of
Sac2 in hearts protects animals from developing cardiac
hypertrophy (1823). These studies suggested that Sac2 reduces PtdIns(3,4,5)P3 levels in mouse heart and hence antagonizes the activation of the fetal gene programs that
underlie cardiac hypertrophy.
1058
VII. PHOSPHOLIPASE C ENZYMES
PLC enzymes hydrolyze the phosphodiester at the sn-3 position of phosphoinositides, yielding inositol phosphates
and DAG. Other PLC enzymes (e.g., ones that hydrolyze
PC) also exist justifying the term “phosphoinositide-specific” or PI-PLC to designate the substrate specificity of
these proteins. Several bacteria also use PLC enzymes as
virulence factors (528, 1646), and the bacterial PLCs do not
hydrolyze phosphorylated PtdIns and act primarily on GPI
linkages at the outer surface of cells. However, bacterial
PLCs can also act on PtdIns itself. Because of this substrate
restriction, the bacterial PLCs are also referred to as PtdIns
(or PI) specific PLCs, which can cause some confusion. The
eukaryotic PI-PLCs can use PtdIns, PtdIns4P, and PtdIns(4,5)P2
but not 3-phosphorylated inositides as substrates in vitro,
but they are believed to act primarily on PtdIns(4,5)P2 in
their native cellular environment. Only a few studies addressed this question rigorously, and a few reports suggested that PLCs act on PtdIns (1066) and that they are
present in intracellular locations (149, 354), where they
could act on PtdIns or PtdIns4P.
Initially, PLC enzymes were studied as activities responsible
for phospholipid catabolism in the lysosome (703, 1272).
After discovering that PLC was a key component of receptor-regulated signal transduction (1040) (see sect. III on the
history of phosphoinositides), these enzymes were sought
after as important receptor-regulated signal transducers.
Having membrane-bound substrates, PLCs were studied in
membranes, the red blood cell membrane being the purest
case (383), but they were also detected and characterized in
soluble fractions obtained from sheep seminal vesicle (630)
or from rat and bovine brain (704, 1319, 1555). It was an
important question to understand how PLCs were regulated by receptors. The Ca2⫹ requirement of PLC enzymatic
activity and its strong stimulation by Ca2⫹ supported views
that Ca2⫹ elevations might be the primary signals linking
receptors to PLCs. These claims were later settled as PLC
activation clearly precedes the cytoplasmic Ca2⫹ increases
(see sect. III for more details). Also, several studies showed
that the physicochemical state of the membrane determines
the access of PLC to phosphoinositide substrates, raising
the possibility that substrate presentation would be an effective way to regulate the enzyme (e.g., Refs. 631, 704).
Soon it became clear that PLC enzymes are regulated by
GPCRs via heterotrimeric G protein subunits (174, 571,
602, 1539). It was an important discovery in the late 1980s
that GPCRs and RTKs generate Ins(1,4,5)P3 and evoke cytosolic Ca2⫹ increases with notably different kinetics (939,
1116), suggesting that the two kinds of receptors activate
PLC enzymes with different mechanisms and possibly they
act upon distinct PLC isoforms (67, 603, 1236). By that
time two or three major forms of PLCs have been purified
from various sources including the sheep seminal vesicle
(630), liver (1521), and bovine brain (763, 1265, 1318,
1319). These activities differed in molecular size and immu-
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homologs of Fab1 (PIKfyve) and Vac14 (ArPIKfyve), and
localized to endosomes (1353). Interestingly, in a parallel
study, Sac3 was characterized in rats as a ubiquitously expressed protein that localized to the ER, Golgi, and recycling endosomes and played a role in neurite extension in
response to NGF (1786). This latter report found Sac3 displaying a wider substrate profile of phosphatase activity
acting on PtdIns4P, PtdIns3P, and PtdIns(3,5)P2. Genetic
inactivation of Sac3 by an early transposon insertion into
the mouse Fig4/Sac3 gene is responsible for the “paletremor mouse.” This Fig4⫺/⫺ mouse is characterized with
pigmentation defects and progressive spongiform neurodegeneration. Fibroblasts obtained from Fig4⫺/⫺ mice show a
decrease rather than an increase in PtdIns(3,5)P2 levels with
prominent defects at the late-endosome to lysosome transition (and probably in many other trafficking steps). These
are probably the underlying causes for the pigmentation
defect and neurodegeneration (253). Pathogenic mutations
in the human FIG4 gene have also been linked to a special
form of autosomal recessive Charcot-Marie-Tooth disorder, CMT4J, characterized by motor and sensory neuropathy (253) and in a small percentage of patients with amyotrophic lateral sclerosis (ALS) (252). The most common
mutation of Sac3 in CMT4J patients is I41T, which decreases Sac3 association with the PIKfyve-ArPIKfyve
(Fab1-Vac14) complex and enhances its proteosomal degradation (683, 884). However, the Fig4I41T transgene overexpressed in Fig4⫺/⫺ mice rescues the most severe phenotypes showing that this mutant protein still retains most of
its functions (884). FIG4⫺/⫺ mice also develop severe myelination defects that are especially pronounced in smaller
caliber axons, and the number of myelinating oligodendrocytic progenitors are greatly reduced (1720). Remarkably,
this defect can be corrected with neuron-targeted expression of Sac3/Fig4, suggesting that the defective oligodendrocytic progenitors are secondary to a neuronal defect. In
this study, again the Fig4I41T mutant enzyme was able to
rescue the hypomyelination (1720).
PHOSPHOINOSITIDES
noreactivity. These advances were rapidly followed by the
molecular cloning of the first mammalian PLC enzymes
(1493, 1494) that later became known as PLC␤, PLC␥, and
PLC␦ (1271). The protein initially designated as PLC␣
turned out to be an ER resident Cys-protease (1179, 1595),
so there is no PLC␣ enzyme. The genomic era has led to the
subsequent identification of several forms of each of the
three classes and revealed additional families such as PLC␧,
PLC␨, and PLC␩ with a total of 13 isoforms belonging to
six PLC families (572) (FIGURE 9).
Each PLC contains common basic building blocks, such
as a PH domain, four EF-hands, a triose phosphate
isomerase (TIM) barrel-like catalytic domain formed
from X and Y conserved regions, and a C2 domain
(found in this order from NH2 to COOH terminus). In
addition, most PLC families feature additional unique
regulatory regions (FIGURE 9). PLC enzymes work mostly
PH
EF
EF
X
Y
C2
1,216 aa
1,181 aa
1,234 aa
1,194 aa
CTR
PLCβ1-4
PH
EF
EF
X
N-SH2 C-SH2
SH3
Y
C2
1,290 aa
1,265 aa
PLCγ1,2
1/2PH
PH
EF
EF
X
PH
EF
EF
X
1/2PH
Y
C2
756 aa
789 aa
762 aa
PLCδ1,3,4
Y
C2
S/P
1,693 aa
1,416 aa
PLCη1,2
EF
EF
X
Y
C2
PLCζ
608 aa
CR
Ras-GEF
PH
EF
EF
X
Y
C2
RA RA
PLCε
2,302 aa
FIGURE 9. The phospholipase C family. These enzymes hydrolyze PtdIns(4,5)P2 to Ins(1,4,5)P3 and diacylglycerol, hence are called phosphoinositide-specific (PI)-PLCs. They should not be mistaken for the bacterial
PLCs that are specific to PtdIns, unable to hydrolyze phosphorylated PtdIns, and hence called PI-specific PLC
(unfortunately similarly abbreviated to PI-PLC). Mammalian PLCs have a core structure consisting of a PH
domain, followed by EF hands, a catalytic domain formed from X and Y conserved regions and a C2 domain.
PLC␦ enzymes show this minimal domain organization. The only exemption is PLC␨ that lacks the PH domain.
This basic core is then extended in the various PLCs: the ␤ enzymes have a characteristic COOH-terminal
extension (CTR) that lends regulation by heterotrimeric G protein alpha subunits. The X and Y domains are
separated with a long insert in the PLC␥ enzymes consisting of two SH2 domains, an SH3 domain, and this
whole insert is sandwiched in between two half PH domains. The PLC␩ enzymes have a long serine-proline-rich
(S/P) segment in their COOH termini. The largest PLC enzyme is PLC␧, which has a cysteine-reach region (CR)
and a RAS-GEF domain at the NH2 terminus and two Ras association domains (RA) at the COOH terminus.
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at the PM, and they are recruited to the membrane via
multiple interactions with proteins and lipids mediated
by the PH domain, the C2 domain, and a polybasic
stretch within the CT-sequence found in PLC␤ forms
(419, 1214, 1673, 1760). The exact mechanism of membrane recruitment, however, is mostly obscure. The first
mammalian PLC structure was that of PLC␦1 (408) followed by those of PLC␤2 (729), PLC␤3 (1657), and an
invertebrate PLC␤ (958). These structural studies revealed the molecular anatomy of the catalytic core and its
relationship to the substrate PtdIns(4,5)P2 (408). They
also showed the mode of interaction of PLC enzymes
with regulators such as Rac1 (729) and the G␣q subunit
(958, 1657). These structural studies also helped identify
an acidic autoinhibitory loop located between the X and
Y conserved domains, which may act as a pseudosubstrate to occlude the catalytic active site of the enzymes
(612).
TAMAS BALLA
PLC enzymes have also been identified in lower eukaryotes
such as the PLC␦-like Plc1 in S. cerevisiae (447, 1771) and
Dictyostelium (387). A PLC␤-like protein called NorpA
was found in Drosophila (153), and a homologous G protein-regulated PLC is present in the squid eye (1067). The
latter two play a critical role in invertebrate photo-signal
transduction. Deletion of Plc1 in yeast causes several abnormalities with severe growth defects, impaired cell wall integrity, decreased osmotic resistance, and an inability to use
carbon sources other than glucose (447). Hyposmotic stress
activates Plc1 in yeast, and the produced Ins(1,4,5)P3 is
rapidly converted to InsP6 (1208). Intriguingly, PLC deletion in Dictyostelium does not cause any major abnormalities, but PLC null cells fail to properly respond to chemorepellents while they do respond to chemoattractants, suggesting a modulatory role of PLC in chemosensing (771).
NorpA mutant flies are viable, but they have defective light
response in the retina and develop retinal degeneration
(153). NorpA also serves as a downstream effector of the fly
rhodopsin (ninaE) in temperature discrimination (1395).
A. PLC␤
There are four members of the PLC␤ family designated as
PLC␤1– 4. All PLC␤ enzymes are activated by G␣ subunits
of the Gq/11 class (1425, 1538, 1656) and PLC␤2 and
PLC␤3 also by ␤␥ subunits (174, 207). Therefore, PLC␤ is
a major downstream effector of GPCRs. It is now understood that GPCR activation of PLC that is resistant to pertussis toxin is mediated by the G␣ subunits of Gq/11 (mostly
PLC␤1, -␤3, and -␤4), while pertussis toxin-sensitive PLC
activation by GPCRs occurs via ␤␥ subunits liberated from
Gi and Go proteins (mostly PLC␤2 and -␤3) (183). PLC␤1
(and probably all other ␤ isoforms) also acts as GTPase
activating proteins (139). For a time it was believed that the
characteristic COOH-terminal conserved coiled-coil (CT)
domain found in all PLC␤ is the site of activation by G
protein ␣-subunits and is also the region that confers GAP
1060
activity (690, 1196, 1201, 1410). Structural studies allowed
a more precise insight into the molecular details of Gq activation. They identified a unique, highly conserved helical
extension of the C2 domain not found in any other PLC
forms as the major site of Gq interaction (958, 1657). Most
recent studies using expressed GFP-tagged enzymes in intact cells found that only PLC␤1 and PLC␤4 were enriched
in the PM while PLC␤2 and PLC␤3 were mostly cytosolic
and that the isolated CT domains of all but PLC␤2 were
also localized to the PM (7). The importance of the CT
domain was also highlighted in this study by the ability of
the expressed isolated CT domains to inhibit Gq-mediated
PLC activation and Ca2⫹ signaling apparently by interacting with the Gq alpha protein (7).
1. PLC␤1
This enzyme is broadly expressed but especially enriched in
brain cortex and hippocampus. In fixed cells, the endogenous enzyme is found in the cytoplasm presumably associated with a variety of membranes (844), but an overexpressed PLC␤1 tagged with GFP associates with the PM (7,
8, 380). Two splice variants of PLC␤1 (PLC␤1a and -b),
first described in heart, differ in their COOH termini and
show different membrane localization (532). Both isoforms
of PLC␤1 were also found in the nucleus (451, 987) and
have a role in cell cycle control, lamin B1 phosphorylation,
and G2/M progression (416, 443). PLC␤1 was also linked
to myelodysplastic syndrome and its progression to acute
myeloid leukemia (452). PLC␤1 ⫺/⫺ mice show growth
retardation, and although viable at birth, they start to die at
the third week after severe generalized seizures without any
sign of gross brain structural abnormality. The similarity of
these seizures to those developing after GABAA receptor
inhibition suggested that PLC␤1 deletion affects the function of inhibitory neurons (784). Interestingly, impairment
of receptor-mediated increase in PLC activity showed remarkable selectivity in brain slices from PLC␤1 ⫺/⫺ mice in
that the response to muscarinic stimuli was greatly reduced,
while that to mGluR agonist was enhanced and the response to serotonin receptor stimulation was unchanged
(784). However, in another report, the cortical layering of
neurons in the somatosensory cortex of PLC␤1 ⫺/⫺ mice
was found impaired and the InsP response to mGluR stimulation significantly reduced (565). Other studies found
these mice still reaching normal age but showing memory
deficits, hyperactivity, reduced acustic startle response, attributed to an imbalance between muscarinic and dopaminergic or serotoninergic systems, reminiscent of animal
models of schizophrenia (1020).
2. PLC␤2
This isoform is mostly expressed in hematopoetic cells
(1194), but it is also found in other tissues such as in taste
buds (787, 1070, 1299). PLC␤2 is primarily regulated by
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A thiol-reactive alkylating compound, U73122, has been
widely used as an inhibitor of PLC (150). However, how
this compound works is quite puzzling. It does behave as a
PLC inhibitor in many cellular systems with a very narrow
concentration range (2–5 ␮M) between effective and toxic
doses (1423, 1552, 1732). However, it either has no effect
on purified PLC enzymes or stimulates PLC activity in vitro
at somewhat higher concentrations (⬃10 ␮M) (802).
U73122 also inhibits a number of Ca2⫹-regulated processes
independent of its putative effects on PLC (169, 1240,
1660, 1817). The fact that its nonreactive control compound U-73343 does not reproduce the effects of the active
compound, by no means is a satisfying criterion to indicate
specificity on PLC. Newly developed PLC inhibitors will be
extremely helpful to better understand the role of PLC enzymes in various cellular settings and also to understand the
mode of action of U73122 (664).
PHOSPHOINOSITIDES
3. PLC␤3
This broadly expressed isoform can be activated by G␣q/11
as well as G␤␥ subunits (1215). The recent structure of
PLC␤3 in complex with activated G␣q defined the interface
between the two proteins (1657). This enzyme has also been
claimed to have an intracellular role to mediate the G␤␥/
PKC␩/PKD-mediated regulation of TGN to PM transport
(354). PLC␤3 ⫺/⫺ mice have a shorter life span and succumb to myeloproliferative diseases, lymphomas, and other
forms of cancer (1742, 1743). These animals do not respond to stimuli that evoke an itching response apparently
due to impaired signaling from H1 histamine receptors in
C-fiber nociceptive neurons (563). Smooth muscle cells obtained from PLC␤3 ⫺/⫺ mice failed to show Ca2⫹ elevations in response to opiate receptor stimulation. However,
these mice showed high sensitivity to morphine and increased voltage-gated Ca2⫹ channel activity in response to
opiates in their dorsal root ganglion neurons arguing
against impaired opioid receptor signaling (1746). In zebrafish, PLC␤3 was found critical for endothelin-1-driven
regulation of pharyngeal arch patterning (1661) and a negative regulator of VEGF-mediated vascular permeability
(629).
4. PLC␤4
This enzyme is mostly expressed in specific areas in the
brain, especially in the cerebellum (789, 868, 1526). A
shorter splice variant of the enzyme has also been described
showing high expression in the rat retina (5) but not responding to G␣q stimulation (790). PLC␤4 is regulated exclusively through G␣q and not via G␤␥ or Rac proteins
(570, 867). Because of the closest homology of PLC␤4 to
the Drosphila NorpA protein that has key roles in photosignal transduction, and the presence of the enzyme in retina, it was assumed that this isoform had important roles in
visual processing in mammals. PLC␤4 ⫺/⫺ mice do, indeed, have impaired visual processing, but it is not related
to defective photoreceptor light responses or structural aberrations of the retina but probably due to impaired signal
processing (733). PLC␤4 ⫺/⫺ mice develop normally but
show ataxia with slower cerebellar development (784). The
InsP3 responses to mGluR or muscarinic receptor stimulation were reduced in cerebellar slices obtained from
PLC␤4 ⫺/⫺ mice (784), and the process of climbing fiber
synapse elimination in the developing cerebellum was
also found impaired (759).
B. PLC␦
There are three different PLC␦ enzymes, named PLC␦1,
PLC␦3, and PLC␦4 (570) (PLC␦2 turned out to be the bovine version of human PLC␦4; Ref. 700). These enzymes all
show broad tissue distribution but differ in cellular localization. PLC␦ enzymes possess the minimal PLC building
blocks: the NH2-terminal PH domain, the EF hands, the
conserved X and Y domains, and the C2 domain at the
COOH terminus (FIGURE 9). The PLC enzymes of lower
organisms (yeast and Dictyostelium) are orthologs of PLC␦.
The regulation of this isoform is the least understood. The
activity of the enzyme is increased with Ca2⫹ elevations in
the physiological range (33) but not by the G proteins that
activate other PLCs (neither the heterotrimeric, nor the
small forms). However, it was suggested that PLC␦1 is activated by the atypical G protein, transglutaminase II, or
G␣H (429) or the small GTP binding protein RalA (515,
1406). According to current views, PLC␦1 is regulated via
its PH domain that recruits the enzyme to the PM. The
isolated PH domain of PLC␦1 was one of the first PH domains to be structurally characterized showing binding to
both PtdIns(4,5)P2 and the soluble Ins(1,4,5)P3 (431, 882).
Because of its binding to PtdIns(4,5)P2, the PH domain of
PLC␦1 is widely used as a PtdIns(4,5)P2 reporter in live cells
(1451, 1615). Therefore, the enzyme is recruited to the PM
via binding to its own substrate, PtdIns(4,5)P2, and the
production of Ins(1,4,5)P3 would displace the enzyme from
the membrane providing with a self-limiting regulatory
mechanism (936). However, PM recruitment may not be
the sole regulation of the enzyme by PtdIns(4,5)P2, since the
enzyme was strongly stimulated by the lipid even in cell free
systems (936). Elimination of the PH domain, or single
residue mutations within, strongly influence the activity of
the enzyme but not its catalytic site suggesting an allosteric
regulation (187, 1754). The C2 domain of PLC␦ enzymes
has also been implicated in Ca2⫹ regulation and membrane
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␤␥ subunits released from pertussis toxin-sensitive Gi/Go
proteins (174, 207, 1426). PLC␤2 is also activated by small
GTP binding proteins of the Rho family (691, 692), and this
regulation requires the PH domain (693, 1428). The structure of PLC␤2 with a bound Rac1 showed a direct interaction between the PH domain of PLC␤2 and the switch region of Rac1 (729), but no major confromational change in
the catalytic site compared with the PLC␤2 structure alone.
Rac1 was also shown to recruit the enzyme into more specialized membrane compartments relative to the more general membrane recruitment by G␤␥ subunits (542, 693).
PLC␤2 ⫺/⫺ mice are viable but, contrary to expectations
(being enriched in hematopoetic cells), their immune responses to bacterial and viral pathogens are not impaired, if
anything they are enhanced. At the same time, neutrophil
cells of these animals showed a greatly reduced InsP3, Ca2⫹,
and superoxide responses, but a variety of bone marrowderived cells (including neutrophils) showed enhanced chemotaxis, suggesting that PLC␤2 may exert a negative rather
than positive influence on chemotactic signaling (732, 906).
This may be due to more PtdIns(4,5)P2 being available for
PI 3-kinases. Interestingly and conversely, another study
found that PLC␤2 and -␤3 are critical for T-cell chemotaxis
(72). PLC␤2 ⫺/⫺ mice are also impaired in sweet, amino
acid, and bitter taste reception (1091, 1808).
TAMAS BALLA
association via nonspecific electrostatic interactions and PS
binding (43, 409, 935).
1. PLC␦1
PLC␦1 has been linked to several human diseases. Its levels
were shown to increase and accumulate in neurofibrillary
tangles in the brains of Alzheimer’s patients (1399, 1400).
Reduced PLC␦1 levels due to hypermethylation of its gene
have been reported in esophageal, gastric, and colorectal
cancers (320, 471, 658), and the metastatic potency of
breast cancer cells showed correlation with the expression
levels of PLC␦1 and PLC␦3 (1264).
2. PLC␦3
This isoform showed a few notable differences from its
sister, PLC␦1, in cellular distribution and sensitivity to lipids and detergents and in the importance of its PH domain
1062
3. PLC␦4
This enzyme has several isoforms in the rat, a smaller, 90kDa form that is expressed in various tissues and a larger
93-kDa splice form that is specific to the testis (871). A third
splice variant was also reported as a negative regulator of
PLC activity (1105). There are four alternatively spliced
forms in the mouse showing differential tissue expression
(475). PLC␦4 is located primarily in the nucleus and shows
changes with the cell cycle (925) and was shown to be
increased in fast-growing human hepatoma cells (1338).
The PH domain of PLC␦4 was reported not to bind
Ins(1,4,5)P3 (1105), and it was tested whether it would be a
better PtdIns(4,5)P2 reporter (872). However, this PH domain also has a lower PtdIns(4,5)P2 affinity, and it does not
contribute to the localization of the enzyme that this study
found primarily in the ER (872). Overexpression of the
enzyme upregulates the ErB1/2-Erk signaling pathway and
promotes cell proliferation in breast cancer cells (889).
PLC␦4 ⫺/⫺ mice develop normally, but the males are sterile
due to the inability of their sperm to induce normal acrosome reaction and fertilization (476, 477).
C. PLC␥
PLC␥ exists in two forms: PLC␥1, which is widely expressed, and PLC␥2 that is mostly expressed in hematopoetic cells (645). These enzymes have the most complex
structure among PLCs in that they contain a split PH domain, two SH2 and one SH3 domains sandwiched between
their catalytic X and Y domains (FIGURE 9). These enzymes
are regulated by tyrosine phosphorylation by RTKs that
occurs following interaction of the SH2 domains of the
PLC␥ enzymes with specific tyrosine-phosphorylated motifs of a variety of activated RTKs including receptors for
PDGF, EGF, and FGF (and many others) (749, 994, 1008,
1027, 1077, 1086, 1654). It is particularly important for Tand B-cell activation that PLC␥ associates with large cytoplasmic molecular complexes that are recruited to the PM
and which contain non-receptor tyrosine kinases that activate the enzyme (165, 1101, 1197, 1291, 1374, 1694). In
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In addition to its role in hydrolyzing PtdIns(4,5)P2 at the
PM, PLC␦1 shuttles between the cytosol and the nucleus
(1755). The enzyme accumulates in the nucleus during the
G1/S1 boundary (1448, 1753) following an increase in nuclear PtdIns(4,5)P2 levels (1448), and it also regulates cell
cycle progression (1449). It is not clear how these nuclear
changes contribute to the overall functions of the enzyme.
PLC␦1 ⫺/⫺ mice are viable but lose hair within 10 days of
birth and are susceptible to skin inflammation and also
develop skin tumors (1109). These mice have a defect in
keratinocyte differentiation in hair follicles and show an
increased number and highly proliferative interfollicular
epidermal cells and sebaceous glands. Keratinocytes from
PLC␦1-deficient mice showed an impaired Ca2⫹ signal,
PKC activation, and NFAT transcriptional activity (1109).
PLC␦1 is also a downstream intermediate regulated by the
keratinocyte-specific transcription factor Foxn1, the gene
that is mutated in nude mice (1111). It is interesting to note
that Orai1-deficient mice also develop hair loss and skin
abnormalities and show defective keratinocyte differentiation (543). Orai1 is the channel component of the STIM1regulated Ca2⫹ entry pathway that is activated upon ER
Ca2⫹ depletion (435) and is highly expressed in epidermal
keratinocytes (543). Extracellular Ca2⫹ is important to trigger keratinocyte differentiation, and it increases the expression of PLC␥1 and PLC␦1 (1241). PLC␦1 was also shown
to be regulated by store-operated Ca2⫹ entry (795). Therefore, it is reasonable to assume that PLC␦1 and Orai1mediated Ca2⫹ entry work in synergism to control keratinocyte differentiation. PLC␦1 ⫺/⫺ mice also develop skin
inflammation due to the production of proinflammatory
cytokines by the epidermis (676). Most recent studies reported that PLC␦1 ⫺/⫺ mice are protected from obesity
when put on a high-fat diet apparently due to a higher
metabolic rate and altered adipogenesis (622). The mechanism of how this is achieved is still under investigation.
in regulation (1202, 1203). Recent data indicated that
PLC␦3 downregulates RhoA and promotes neurite outgrowth in primary cortical neurons (823). PLC␦3 was
found to interact with myosin VI (Myo6) and contribute to
inner-ear hair cell stereocilia stabilization and possibly to
microvilli maintenance in the colon epithelium (1328). A
uniquely tight coupling between Ca2⫹ entering via arachidonate-activated ARC channels and PLC␦3-mediated
PtdIns(4,5)P2 hydrolysis was also reported (1553). Knockout studies suggest that PLC␦1 and PLC␦3 have overlapping functions. PLC␦3 ⫺/⫺ mice show no obvious abnormalities, whereas a combined PLC␦1/PLC␦3 ⫺/⫺ knockout
results in midgestational lethality caused primarily by a placental defect (1110).
PHOSPHOINOSITIDES
1. PLC␥1
Homozygous PLC␥1 deletion in mice causes embryonic lethality at day 9 (730), apparently due to a loss of vasculogenesis and erythropoiesis (909). This is consistent with
zebrafish studies that showed impaired vasculogenesis and
ventricular contractility upon loss of PLC␥ function (861,
1301). These phenotypes suggest that the effects of VEGF
on vascular endothelium are mediated mostly by PLC␥mediated pathways (1035, 1301, 1516). Since PLC␥1 activation is a major signaling route initiated by RTKs, it has
been assumed, and in many cases shown, to be critical for
the mitogenic, pro-proliferative effects during stimulation
of these receptors. Indeed, elevated levels of PLC␥1 were
found in aggressive breast cancers (56), and the enzyme was
found critical for the metastatic properties of breast cancer
cells (1329). However, even early studies suggested that
RTKs, such as the FGFR, can induce mitogenesis without
activation of PLC␥ (1212), and this is consistent with the
relatively normal development of mice up to day 8 without
PLC␥1 (730). In Drosphila, PLC␥ defects cause impaired
wing and eye development (984).
2. PLC␥2
An additional and unique regulation of PLC␥2 is via interaction with Rac proteins (1221). Rac interacts with the split
PH domain of PLC␥2 (199, 1663) and regulates the membrane recruitment and activity of the enzyme (413, 1221). It
is assumed that Rac interaction with the split PH domain
relieves an autoinhibition, independently of Tyr phosphorylation (413). PLC␥2 ⫺/⫺ mice are viable but are immunecompromised because of defective B-cell responses to immunoglobulins (1666). In addition to B cells, PLC␥2 deficiency also affects neutrophils (717), platelets (698), and
dendritic cells (300). Recently, activating mutations of
PLC␥2 were found in patients with spontaneous inflammations and autoimmunity (414), and activating deletions in
PLC␥2 were found in families with cold urticaria, immunodeficiency, and autoimmunity (1169).
D. PLC␧
This enzyme was a late-comer as it was discovered as a
novel, Ras-regulated PLC enzyme identified in C. elegans
and named PLC210 (1398). The mammalian homologs
were then cloned independently in three laboratories (773,
938, 1431) and named PLC␧. Two splice variants differing
in their NH2 termini, called PLC␧1a and PLC␧1b, exist, but
no functional difference between them has been reported
(1436). It is generally accepted that the enzyme is widely
expressed, although only at low levels making its detection
difficult (1668). PLC␧ has several regulatory domains in
addition to the classical building blocks, namely, an NH2terminal cysteine-rich region followed by a Ras GEF domain (called here CDC25 GEF), and two Ras-association
(RA) domains at the COOH terminus (FIGURE 9). The Ras
GEF domain can activate Rap1 (736), while the two RA
domains bind H-Ras and Rap1, with the second one (R2)
being more important in this regard (1431). Therefore,
PLC␧ is both an activator and a downstream target of Ras/
Rap1 possibly representing a feed-forward activation loop.
Receptor-induced activation of PLC␧ can be achieved from
RTKs, such as the EGF receptor that requires H-Ras (1431)
and probably involves translocation of the lipase from the
cytosol to the PM (736, 1431). PLC␧ also translocates to
the perinuclear area after Rap1 activation (736). It was
proposed that Ras is responsible for the rapid phase of
PLCe activation, while Rap1 is for a prolonged activation
of the enzyme (1432). In addition, GPCR stimulation with
LPA, or thrombin also activates PLC␧, and this activation
involves the G12/13 family of heterotrimeric G proteins
(549, 774). The G12/13-mediated activation of PLC␧ is not
direct; it goes through the Rho GEF proteins p115RhoGEF
or LARG yielding GTP-bound Rho (549). Interestingly,
while the EGF/Ras-mediated activation requires the
COOH-terminal RA domains, the Rho-mediated activation
does not require this segment but one within the conserved
Y catalytic domain (1378). Rho-mediated activation of
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some cases, PLC␥ uses intermediary adaptor proteins to
associate with the macromolecular complex, such as in T
cells where the LAT (439, 1803) and SLP-76 (1751, 1752)
proteins bring the PLC␥1 enzyme to the activated TCR
complex. Recruitment of the PLC␥ enzymes to the membrane via these protein-protein interactions is essential for
the subsequent tyrosine phosphorylation and activation of
the enzymes (786, 1008, 1139, 1653). Five Tyr residues in
PLC␥1 were reported to be phosphorylated by RTKs:
Tyr472, -771, -775, -783, and -1254 (786, 788, 797, 1383,
1652). Although conflicting reports have been published
about the importance of some of these Tyr phosphorylations (1380, 1383), there is a clear consensus that phosphorylation of Tyr783 and perhaps Tyr775 are critical for
the stimulated activity of PLC␥1 (526, 797, 1380). Phosphorylation of the equivalent residues in PLC␥2 (Tyr753
and Tyr759) are also critical in B-cell activation (797,
1278). How tyrosine phosphorylation affects enzymatic activity is a question that is just beginning to unfold (526). An
intramolecular interaction between the COOH-terminal
SH2 domain and the phosphorylated Tyr783 evokes a conformational change that relieves autoinhibition of the enzyme (526, 658). In addition to Tyr-phosphorylation, PLC␥1
was shown to be directly regulated by PtdIns(3,4,5)P3 either
via interaction with the PH domain (419) or the SH2 domain
(77, 1253). In addition, PtdIns(3,4,5)P3 also regulates PLC␥
activity via activation of Tec-family tyrosine kinases, an effect
that is most pronounced in immune cells and controlled by
SHIP1 (448, 1356, 1357). Recent studies suggest that the
sprouty proteins, negative regulators of RTK signaling (220),
can associate with both PLC␥ isoforms and inhibit their activation by RTKs (19).
TAMAS BALLA
PLC␧ can also be achieved via Gq-coupled receptors, but in
this case it is the p63RhoGEF that mediates Rho activation
(18). The Ras and Rho-mediated activation of PLC␧ via the
two different regions of the protein can work in a synergistic manner (1379). PLC␧ can also be activated via increases
in cAMP levels mediated by the guanine exchange factor
Epac, which acts on Rap2B (412, 1161, 1364).
1064
This is the smallest PLC enzyme that even lacks a PH domain (FIGURE 9). It was first isolated from mouse testis and
is exclusively expressed in the spermatids (1349). PLC activation during the acrosome reaction has been described
earlier (575), and injection of PLC␨ cRNA into mouse eggs
initiates Ca2⫹ oscillations and triggers egg activation, suggesting that it is the “sperm factor” that initiates egg activation upon fertilization (822, 1349). Human sperm devoid
of PLC␨ fails to trigger Ca2⫹ oscillations and egg activation
(1774). The enzyme is localized at the equatorial region of
human sperm (1774) and is found in the pronucleus during
mouse egg activation (1770). PLC␨ is the most Ca2⫹-sensitive PLC already being activated at basal levels (100 nM) of
Ca2⫹ concentrations (822). Regulation of PLC␨ appears to
be different from the other PLCs. First, expression of the
enzyme in CHO cells failed to induce any Ca2⫹ oscillations
in spite of good expression and high level of PLC activity
measured from the cytosol in vitro (1218). Most recent
studies showed that PLC␨ acts on a distinct vesicular pool of
PtdIns(4,5)P2 within the egg cortex as opposed to the PM,
showing clear distinction from PLC␦1 which affected the
PM pool of the same lipid (1784). Also, unlike in other
PLCs in which the linker region between the X-Y domains
contains several acidic residues and exerts autoinhibition
(612), in PLC␨ this region contains a stretch of basic residues that mediate binding to membrane PtdIns(4,5)P2
(1144), and removal of this region inhibits rather than activates the enzyme (1145). A basic stretch found within the
X-domain has also been implicated in nuclear localization
and nucleo-cytoplasmic shuttling of the enzyme during
Ca2⫹ oscillations (834).
F. PLC␩
These enzymes have two isoforms, PLC␩1 and PLC␩2.
They were identified independently in four laboratories in
2005 (673, 1108, 1471, 1820). They show highest expression in the brain and they are structurally related to PLC␦1
(FIGURE 9). In addition to the usual domains present in
PLCs, they have a serine- and proline-rich region and a
PDZ-domain interacting sequence in their COOH termini
(1470). Relatively little is known about the regulation of
these enzymes. PLC␩2 can be activated by G protein ␤␥
subunits shown both in expression studies in COS-7 cells
(1820) and in reconstitution assays (1819). Neither the PH
domain nor the COOH-terminal unique sequence is required for G␤␥ activation of PLC␩2 (1819), but the PH
domain was shown to be needed for membrane localization
(1108). PLC␩2 also shows high Ca2⫹ sensitivity even more
so than PLC␦1 (1108). A PLC␩2 knockout mouse with a
LacZ knockin has revealed high expression of the enzyme in
the habenula and retina and suggested a possible role in
retina development or maturation, but the mice showed no
major abnormalities (753).
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Since a whole set of other PLCs can respond to stimulation
of a variety of cell surface receptors, it is of particular interest
to what extent PLC␧ contributes to the overall PLC activity
during activation of specific receptors. This question was examined after RNAi-mediated knockdown of PLC␧ or probably more reliably in cells derived from PLC␧ ⫺/⫺ mice (1511,
1668). RNAi studies in Rat1 fibroblasts suggested that
PLC␤3 was more important in the rapid phase, while PLC␧
in the prolonged phase of InsP3/DAG formation during endothelin, ET-1 receptor, LPA, or thrombin stimulation
(772). Studies in astrocytes from PLC␧ ⫺/⫺ mice showed
that PLC␧ is a major contributor to InsP3/DAG generation
after LPA, thrombin, and S1P receptor stimulation and that
LPA and S1P uses pertussis toxin-sensitive Gi/o proteins,
while thrombin uses RhoA via G12/13 (264). Two groups
have generated PLC␧-deficient mice, one eliminating the
entire PLC␧ protein (PLC␧ ⫺/⫺; Ref. 1668), the other making a truncated protein that is catalytically inactive missing
the EF-hands and part of the catalytic domain (PLC␧ ⌬x/⌬x;
Ref. 1511). These mice show some differences in their phenotypes (detailed in Ref. 1424), but they both highlighted
critical roles of the enzyme in cardiac development and
functions. PLC␧ ⌬x/⌬x mice have developmental defects in
the aortic and pulmonary semilunal valves with sequential
ventricular dilation and hypertrophy (1511). This pathology is not seen in PLC␧ ⫺/⫺ mice (1668). PLC␧ ⫺/⫺ mice,
on the other hand, are more susceptible to cardiac hypertrophy, possibly because of upregulation of the Gq-mediated PLC pathways, since downregulation of PLC␧ in vitro
in ventricular cardiomyocytes greatly blunts their “hypertrophic” response, which is the opposite of what the knockout mice would predict (1424). PLC␧ ⫺/⫺ mice also have
impaired cardiac contractility that may be related to scaffolding functions with muscle-specific AKAP proteins as
well as the ryanodine receptors (1424, 1799). In addition,
PLC␧ has been linked to inflammation and tumorigenesis in
skin (687) and intestine (900) in mouse models. As for
human diseases, PLC␧ mutations have been found in patients presenting with childhood nephrotic syndrome probably linked to altered podocyte functions (621). Interestingly, no kidney pathology was found in PLC␧ mice, but
PLC␧ deletion in zebrafish causes developmental problems
with the filtration barrier of the fish “kidney” (621). PLC␧
was found significantly downregulated in patients with sporadic colorectal cancers (1675), and the PLCE1 gene was
found as a susceptibility locus for gastric and esophageal
squamous cell carcinoma (3).
E. PLC␨
PHOSPHOINOSITIDES
G. PLC-Related Proteins
VIII. PHOSPHATIDYLINOSITOL TRANSFER
PROTEINS
The first functional studies on a phosphatidylinositol transfer protein (PITP) were described in yeast, when the Sec14p
protein was found to be important for the transport of
secretory proteins from the Golgi (98, 102). Sec14p is a
cytosolic protein that associates with the Golgi and is capable of either PtdIns or PtdCho transfer (98). Rescue studies
have indicated that expression of Sec14 mutants defective in
PtdIns but not PtdCho transfer are able to rescue the secretory defect of Sec14-deleted strains (1217), questioning
whether PtdIns transfer is the primary role of the protein.
Remarkably, genetic interference with PtdCho synthesis
rescues Sec14p secretory defects (272), and Sec14p itself is
an inhibitor of the CDP-Cho pathway (1018, 1414). Dele-
The first mammalian PITP was isolated from bovine brain
as two proteins of ⬃30 kDa size capable of transferring
PtdIns from labeled liver microsomes to PtdCho vesicles
(597) and subsequently cloned from rat (355). PITPs were
also isolated independently by two separate efforts purifying cytosolic factors that were required for G protein-mediated PLC activation (767, 1551) and ATP-dependent
priming of exocytic vesicles (583). The mammalian PITPs
[PITP␣ and its sister, PITP␤ (1527), now called class I
PITPs] show little sequence homology to the yeast Sec14p
protein, yet mammalian PITPs can partially rescue yeast
Sec14 –1ts defects (but not SEC14 deletions) (1413), and
conversely, Sec14p can restore PLC activity in mammalian
cells (309). Curiously, unlike in the case of the yeast Sec14p
(1217), the PtdIns transfer activity of mammalian PITPs
was found to be important for complementation of the
Sec14 defect is yeast (24, 1413). Another group of PITPs
were initially identified in Drosophila, as one of the genes
responsible for light-induced retinal degeneration phenotype, called RdgB (1636). Mammalian homologs of RdgB
(variably named PITPnm or RdgB␣) have been subsequently found (15, 232, 537), and it was recognized that
these larger proteins possess at their NH2 termini a PITPdomain that is highly homologous to the class I mammalian
PITP␣ and PITP␤. The same group of proteins was also
isolated as interactors with the Ca2⫹-regulated tyrosine kinase, PYK2 and called Nir1–3 (891). Nir1, however, lacks
the NH2-terminal PITP domain but shows homology to the
other Nir proteins in the rest of their sequences (891). Finally, a PITP that is most homologous to the PITP domain
of RdgBs but lacks all the other domains of the RdgB homologs was cloned and named RdgB␤ (480). Nir2 and Nir3
are now called class IIA, while RdgB␤ is named class IIB
PITP (1575) (see FIGURE 10). Given the functional similarity between mammalian PITPs and Sec14p, it is noteworthy that both yeast and mammalian cells have Sec14 homologs that are lipid transfer proteins with cargoes other
than PtdIns (1088, 1136). This raises the question of why
the Sec14 scaffold was replaced by that of PITPs in metazoans for PtdIns/PtdCho transfer while still kept for other
lipid transport purposes.
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In 1992 the Hirata laboratory isolated a protein from rat brain
cytosol that showed high-affinity binding to Ins(1,4,5)P3 (756).
This protein, initially named p130, turned out to be identical to a PLC-like protein called PLC-L that was deleted in
the cancer tissue of a patient suffering from small cell lung
carcinoma (755, 811). Another homolog named PLC-L(2)
was also described and showed that these enzymes have
high sequence homology to PLC␦1 but are inactive because
of a mutation of a conserved His within their catalytic domains (755, 1181). These proteins were later named PRIP-1
and -2 (for PLC-related but catalytically inactive protein),
the former being highly expressed in brain, while the latter
showing wider tissue distribution (1007, 1181). PRIP-2 localizes to the ER and perinuclear region (1181). The isolated PH domains of both proteins showed high-affinity
binding to Ins(1,4,5)P3 and PtdIns(4,5)P2 and in the case of
PLC-L(2)/PRIP-2 it also localized to the perinuclear ER
(1181), while in the case of PLC-L/p130/PRIP-1 it was
found cytosolic (1616). Contrary to these findings, the
PH domains of PRIP-1 and -2 both showed PM localization (490). PRIP-1 has a role in GABA receptor function
indirectly by affecting the trafficking and phosphoregulation of GABA receptors (757, 1546). PRIP-1 interacts
with the ␤-subunit of GABAA receptors and the associated protein GABARAP (754), and it augments the transport of ␥2-containing GABAA receptors to the cell surface (1071). PRIP-1 knockout mice show anxiety-related
behavior and reduced benzodiazepine sensitivity (754)
and also exhibit seizurelike EEG activities (1822) indicating dysfunction of the GABAA receptors. PRIP-2
knockout mice develop normally and show no obvious
abnormalities, but their B cells are hyperresponsive and
display increased Ca2⫹ influx and NFAT activity after
receptor crosslinking (1519). This may be related to the
inhibitory effect of PRIP-1 on endogenous PLC activation and quenching some of the Ins(1,4,5)P3 generated
(1524).
tion of Kes1p, one of the oxysterol binding proteins of yeast
also “bypasses” Sec14 defects initially raising the possibility
that Kes1p mediates the PtdCho “toxicity” seen in Sec14deleted strains (424). More recent studies indicate that
Sec14p is essential for the maintenance of a Golgi pool of
DG, which is spared when PtdCho syntheis is limited. Also,
deletion of Kes1p, which can “extract” PtdIns4P and exchanges it for ER-derived sterols, spares the Golgi PtdIns4P
pool (339). Importantly, “Sec14 bypass” conditions require
a functional yeast PLD enzyme, Spo14p, presumably to
supply DG from PtdCho (1748). More on Sec14 and its
possible modes of action can be found in several recent
reviews (100, 103).
TAMAS BALLA
Class I
PITP
PITPα
270 aa
PITP
PITPβsp1
PITPβsp2
270 aa
271 aa
Class IIA
PITP
FFAT
DDHD
LNS2
Nir-2/PITPnm1/RdgBαI
1,244 aa
PITP
FFAT
DDHD
LNS2
Nir-3/PITPnm2/RdgBαII
PI
TP
DDHD
LNS2
974 aa
no
ta
FFAT
Class IIB
PITP
RdgBβsp1
RdgBβsp2
269 aa
332 aa
FIGURE 10. The mammalian phosphatidylinositol transfer proteins. The PITP domain is capable of transferring PtdIns and PtdCho between natural membranes and artificial liposomes and hence are functionally similar
to the yeast Sec14 protein. The class I PITPs are encoded by two genes, PITP␣ and PITP␤, the latter having two
splice forms differing at the very COOH termini. A highly similar PITP domain is found in the NH2 terminus of a
group of larger proteins that were first described in Drosophila as the RdgB proteins. These proteins were later
identified in mammalian cells as membrane-associated PITPs (hence the name PITPnm) or as a family of
proteins that interact with the Ca2⫹-regulated tyrosine kinase Pyk2 and named Nir1–3. In fact, one of these
family members, Nir1/PITPnm3/RdgB␣III, lacks the PITP domain, so it is not a PITP. These proteins (called
class IIA proteins) have an acidic region, initially defined as a Ca2⫹ binding domain but now recognized as a
region containing an FFAT domain that provides ER localization through interaction with the ER resident VAP
proteins. The DDHD domain is similar to a domain found in some PLA1 proteins, whereas the LNS2 domain
is found in lipins that are PtdOH phosphohydrolases. The Pyk2 binding site, which is also located in the COOH
terminus, probably overlaps with the LNS2. A third form of PITPs, called class IIB, is similar to the PITP region
of the class IIA forms but lacks all other domains and has two splice variants differing in their COOH termini.
A. Class I PITPs
PITP␣ and PITP␤ belong to this group, the latter having two
splice variants that differ in their very COOH termini
(277). Several details on the structure and PI-transfer
characteristics of these PITPs have been uncovered, yet
we still do not fully understand what these proteins do
and how they work inside the cells. The structure of
PITP␣ has been solved both with and without a PtdIns
cargo molecule within the binding cavity (1366, 1557),
and the headgroup of the lipid faces the interior of the
cavity. Notably, this is the opposite orientation from
what is found in the structure of the Sac14p protein
(1387). The COOH-terminal last 10 amino acids are important to close onto the bound lipid, and PITP␣ mutants
lacking the 5 or 10 last residues at the COOH terminus
exert dominant negative effects when expressed in cells,
while they still retain PI transfer activity (568). PITP␣ is
mostly cytosolic, but PITP␤ is found Golgi-associated
1066
(1216). Membrane association of PITP␤ depends on specific COOH-terminal sequences unique to the PITP␤
form (1216) but also require two conserved hydrophobic
residues (Trp202, Trp203) found in all PITPs (1557).
Since PITPs can transfer PtdIns (and to a smaller extent
PtdCho) between membranes, it was initially believed
that they transfer the ER-synthesized PtdIns to the PM
(and perhaps to other membranes) for phosphorylation
by PI4Ks and PIP5Ks, and hence supply PLC with its
substrate PtdIns(4,5)P2. However, it appears that the
mode of actions of PITPs is more complex (279, 1136),
and recent models suggest that they can also present PtdIns for enzymes that use it as substrate (PI kinases or
PLC enzymes) (830, 1354). Recent models posit that the
cycling of the lipid through PITPs is an integral part of
the ability of lipid modifying enzymes to act upon PtdIns.
The term nanoreactor has been introduced to emphasize
this catalytic/chaperone rather than transport function
(689, 1136, 1354).
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Nir-1/PITPnm3/RdgBαIII
1,349 aa
PHOSPHOINOSITIDES
domains initially believed to be membrane-spanning segments. The acidic region also includes an FFAT domain
that anchors the protein to the ER via binding of VAP
proteins. The RdgB proteins also contain a DDHD domain with homology to some of the PLA1 enzymes. Another conserved section, called LNS2, is homologous to
that found in lipins, the phosphatidic acid phosphohydrolases. It is located close to the COOH terminus which
also was identified as the site of PYK2 interaction (890)
(FIGURE 10). The founding member of this family, the
RdgB protein of Drosphila, has a uniquely important role
in invertebrate photosignal transdcution. Flies mutated
in this gene develop light-induced retinal degeneration
and show impaired electric response to light evident in
electroretinograms (1636). These defects can be fully
remedied by expression of the full-length RdgB protein or
its isolated PITP domain, but not by rat PITP␣ or a chimeric protein with a rat PITP␣ fused to the rest of Drosophila RdgB (1055). The two mammalian homolgs of
RdgB (called RdgB␣1, Nir2 or PITPnm1 and RdgB␣2,
Nir3 or PITPnm2) are also able to rescue the visual defects of the RdgB fly, although Nir2 works better than
Nir3 (232). The Drosophila protein is localized to submicrovillar cisternae that are special regions of the ER at
the base of the rhabdomeres (1502). It is currently assumed that RdgB is essential for the transfer of PtdIns
from the ER to the PM (rhabdomeres) in the fly retina,
and its defects interrupt the supply of this lipid to the PM
and hence rapidly deplete the PtdIns(4,5)P2 pools that are
important for proper PLC-generated signals during light
exposure (1575).
PITP␤ deletion is incompatible with life resulting in an
early implantation defect in mice (25). The zebrafish homolog PITP␤ is required for proper development of double cone cell outer segments in the retina (688). Knockdown of PITP␤ in HeLa cells causes altered Golgi morphology and distorted nuclei and a retrograde transport
defect between the Golgi and the ER (219). A few studies
suggested that the sp1 splice variant of PITP␤ is capable
of sphingomyelin binding and transport in vitro and inside cells (341, 1605). However, other studies concluded
that this feature of the protein might not be critical for its
cellular functions (219, 1377). Given its essential role in
mammalian organisms, it is generally believed that
PITP␤ delivers PtdIns for PI kinases and hence is necessary to maintain the PtdIns(4,5)P2 pools available for
PLC enzymes (279, 310). However, a direct proof of this
concept is still to be obtained.
Less is known about the mammalian RdgB homologs. In
the mouse, Nir2 is ubiquitously expressed, while Nir3 is
primarily found in the retina and some regions in the
brain (948). Nir3 knockout mice show no obvious phenotype while Nir2 knockout is embryonic lethal (947).
At the cellular level, Nir2 is Golgi localized (16, 921)
where it helps maintain DG levels (919). However, Nir2
also gets associated with lipid droplets after oleic acid
treatment (920), and it changes localization with the cell
cyle, being found in the midbody and the cleavage furrow
in telophase and anaphase, respectively (921). Functionally speaking, Nir2 was shown to regulate protein export
from the ER and contributes to the structural integrity of
the ER (39). The interaction of the Nir2 and Nir3 proteins with the ER is mediated via the acidic FFAT domain
that is responsible for interaction with the ER-resident
VAP-B proteins (39). It is very likely that Nir2 proteins
work at membrane contact zones between the ER and the
Golgi, and the interaction of Nir2 with PI4KA suggests
that it may help deliver PtdIns for this PI 4-kinase to
regulate exit of proteins from the Golgi (16). The small
RdgB␤ protein also having two splice forms is mostly
found in the cytosol (480). Although the function of this
protein is still unknown, it was shown to interact with the
B. Class II PITPs
The RdgB proteins contain several domains other than
the PITP domain: their NH2-terminal PITP domain is
followed by an acidic stretch and several hydrophobic
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The vibrator mouse that shows early-onset action
tremor, progressive spinocerebellar neurodegeneration,
and juvenile death expresses very low level of PITP␣
(557, 1692). PITP␣ deleted mice are born normal, but
develop spinocerebellar degeneration and soon succumb
into hypoglycemia as well as intestinal and hepatic steatosis and die by day 12, apparently due to their inability
to handle the milk fat during suckling (23). Cells obtained from these mice showed no significant change in
phosphoinositide content, or problems with ER to PM secretion, exocytosis, endocytosis, or signaling, and therefore,
the defects seemed to be confined to the defects in neurons, enterocytes, and liver cells, probably all related to
problems with lipid handling (25, 99). The PtdIns binding of PITP␣ is critical for its function, as a PtdIns binding-deficient mutant protein cannot rescue the null phenotype (26). A detailed analysis of the pathology of mice
expressing various levels of PITP␣ suggested that the
lifespans of these animals were proportionally shortened
with decreased level of the protein. These studies also
showed a close relationship between the steatotic defect,
hypoglycemia, and cerebellar inflammation, but the neuronal defects and early lethality still are maintained even
when the lipid defects are corrected in the intestine (26).
At the cellular level, PITP␣ was shown to associate with
the netrin receptor and to play a role in neurite outgrowth (1747). Morpholino-mediated knockdown of
PITP␣ in zebrafish causes early developmental arrest
(688). In Drosophila, mutation of the single class I PITP
Giotto causes defects in male germline cytokenesis (500,
508), with a phenotype, similar to the defect in the PI4KB
homolog fwd (182).
TAMAS BALLA
angiotensin II AT1 receptor interacting protein ATRAP
with its lipid-binding domain, whereas it interacts with
14-3-3 proteins at its COOH terminus, and this latter
interaction affects the rapid degradation of the protein
(278, 495). Most recent studies found that RdgB␤ is
capable of PtdOH binding and hence may function as a
PtdOH transfer protein (494).
IX. PHOSPHOINOSITIDES AT THE
PLASMA MEMBRANE
1068
This topic has been in the frontiers of inositide research for
some time, receiving enormous coverage and could fill a
book easily by itself. This will be summarized only briefly
just for the sake of completeness. Studies unraveling the
connection between receptor-mediated stimulation of “PIturnover” and Ca2⫹ signaling placed phosphoinositides in
the center of attention in the early 1980s and generated
knowledge that has become part of every textbook on cell
physiology. The basic principle of receptor-initiated PLC
activation with generation of Ins(1,4,5)P3 and DAG, two
very different messenger molecules, has been firmly consolidated (130, 135). Yet, the variations of how many different
PLC enzymes can be activated in how many different ways
could not have been foreseen even with the wildest imagination (see sect. VII on PLCs). There are a large number of
molecules regulated by DAG, starting with numerous PKC
isoforms (1270, 1298) and extending beyond them (216,
1306). Similarly, the details of how Ins(1,4,5)P3 releases
Ca2⫹ from the ER via three different types of InsP3 receptors (1050) and the complex regulation of the gating of
these receptor/channels by Ca2⫹ and Ins(1,4,5)P3 (1535)
now represents a whole new research field. The same features of the InsP3 receptors underlie Ca2⫹ waves and oscillations (136). A new chapter in PI signaling from the PM
has begun with the identification of PI 3-kinases. Their close
association with growth factor and oncogenic signaling has
propelled this field and the literature on various isoforms of
PI3Ks, and the variety of their activation mechanisms have
been overwhelming (see sect. VC). This diversity is only
paralleled by the number of effector proteins that bind and
are regulated by the 3-phsophorylated PIs. The list includes
guanine exchange factors and GTPase activating proteins
for a variety of small GTP binding proteins, serine/threonine and soluble tyrosine kinases, and scaffolding proteins
that organize signaling complexes. Through these pathways, inositides play pivotal roles in transmembrane signaling of every cell in an organism. These processes have been
touched upon in the respective sections describing the enzymes and will not be further discussed here. However,
there are several processes regulated by PIs in various membranes that historically are not covered under the canonical
PI signaling umbrella but rather belong to membrane trafficking or to the ion channel fields. These are the areas that
will be reviewed in some detail in the subsequent sections.
B. Ion Channels and Other Transporters
Early observations already hinted that phosphoinositides
can directly influence ion transport pathways. A stimulatory effect of membrane PtdIns(4,5)P2 on PM Ca2⫹ pump
activity was found as early as 1981 (1132), and the sarcoplasmic reticulum Ca2⫹-ATPase was shown to tightly
associate with phosphoinositides (1619). However, the
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It is hard not to notice the hierarchical organization of
phosphoinositide distribution between the various membrane compartments. As one moves outward from the
nucleus toward the PM, the extent of inositol lipid phosphorylation is increased in the membranes: the ER and
nuclear envelope mainly contain PtdIns and the Sac1
phosphatase that localizes to these membranes ensures
that any phosphorylation of PtdIns would be properly
counteracted. The endosomal compartments, including
the Golgi, contain monophosphorylated PtdIns, such as
PtdIns4P or PtdIns3P, and have phosphatase enzymes
that act both on mono- and bis-phosphorylated PtdIns,
such as the MTMs and the 5- or 4-phosphatases. The PM
has the bulk of PtdIns(4,5)P2 and PtdIns(3,4,5)P3 and the
phosphatases that dephosphorylate them. The one exception to this rule is PtdIns(3,5)P2 that is formed at the
multivesicular body, which is an endomembrane compartment. Yet, one can argue that MVB invaginating
membranes [where PtdIns(3,5)P2 function is critical] are
destined to the lysosome, the content of which can be
viewed as “external” to the cell (FIGURE 11). The existence of the same process supporting the externalization
of membranes at the PM (as in the case for virus budding)
lends some support to these views (1016). Based on this
distribution, PtdIns4P, PtdIns(4,5)P2, and PtdIns(3,4,5)P3 are
the major inositol lipids in the PM. PtdIns4P in the PM is
used to be considered only as an intermediate of
PtdIns(4,5)P2 synthesis, but this simplistic view is increasingly challenged by solid data that suggest that
PtdIns4P can support the functions of ion channels (see
Ref. 559 and discussions below) and also contributes to
the anchoring of lipid-modified targeting sequences that
contain polybasic domains (559). We still need to learn
more about PM PtdIns4P, but currently PtdIns(4,5)P2 is
recognized as the most important inositide at the PM
with diverse processes being controlled by changes in its
levels (FIGURE 12). PtdIns(4,5)P2 is the precursor of
Ins(1,4,5)P3 and DAG after PLC activation and hence is
pivotal for early signaling from cell surface receptors.
Second, PtdIns(4,5)P2 is a substrate of class I PI3Ks and
the precursor of PtdIns(3,4,5)P3, the latter being critical
for growth factor signaling, and also for PM polarization
and membrane dynamics. Third, PtdIns(4,5)P2 itself is
probably important for the proper operation of ion channels and transproters and plays roles in exo- and endocytosis. These processes will be briefly discussed below.
A. Canonical PI Signaling Triggered From
Cell Surface Receptors
PHOSPHOINOSITIDES
Plasma membrane
PtdIns(4,5)P2
PtdIns4P
PtdIns(3,4,5)P3
CCV
EE
RE
PtdIns3P
SE
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PtdIns(3,5)P2
MVB
TGN
PtdIns4P
Golgi
Lyso
ER
PtdIns
FIGURE 11. Distribution of phosphoinositides in various membrane compartments in a generic cell. The
majority of PtdIns(4,5)P2 is located in the plasma membrane (PM), and that is where it is converted to
PtdIns(3,4,5)P3. PtdIns4P is also found in the PM, but it is also highly enriched in the Golgi and in some
endosomes that are part of the TGN. PtdIns3P is formed on endosomes such as the early endosmes (EE) and
their precursors and is converted to PtdIns(3,5)P2 at the level of sorting endosomes (SE) at regions that form
the invaginating membranes destined to become luminal in multivesicular bodies (MVB). PtdIns is generated in
ER-derived compartments that can reach every other membrane, but the mechanism of lipid transfer between
these compartments is still unknown. It is important to note that this distribution does not rule out that each
of these lipids can be present in small, undetected amounts in other membrane compartments.
phosphoinositide regulation of ion channels/transporters
has been first clearly postulated in the case of Na⫹/Ca2⫹
exchanger (NCX1) and KATP potassium channels studied
in giant excised patches of the heart (616). In this and
many subsequent studies, the lipid regulation was noted
in excised patch recordings as a “rundown” of the current with time, which then was reversed by the inclusion
of ATP (to resynthesize PPIs) or inositol lipids themselves
to the cytosolic face of the membrane. The explanation
for this phenomenon was that inositol lipids slowly disappear via dephosphorylation in the excised membrane
patches. Most of our knowledge on the direct regulation
of ion channels by inositides has originated from studies
on excised patches taken from Xenopus oocytes expressing the channels in question (1282). Only recently had it
become possible to test the regulation of these channels in
intact cells with the aid of drug-induced inositol lipid
manipulations (1489, 1617). There is ample literature on
the regulation of ion channels and transporters by phosphoinositides (488, 617, 932, 1138, 1285, 1487). Here
we only provide a summary of these studies in TABLE 2,
which might be more useful for a quick overview. Inter-
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TAMAS BALLA
A
PtdIns4P
PtdIns(4,5)P2
PtdIns(3,4,5)P3
Ins(1,4,5)P3
DG
B
Plasma membrane
PLC
PLD
PtdIns(4,5)P2
βarr
AP-2
PtdIns(4,5)P2
FERM
ActBP
PtdIns(4,5)P2
CAPS
SYT1
Dab
Signaling
Endocytosis
Actin cytoskeleton
Exocytosis
Ion channels and
transporters
C
FIGURE 12. The multiple functions of PtdIns(4,5)P2 in the plasma membrane. A: this lipid serves as a
precursor of the second messengers, Ins(1,4,5)P3 and DG upon PLC activation, or of PtdIns(3,4,5)P3 during
PI3K action. It can also be dephosphorylated by 5-phosphatases to PtdIns4P. B: in addition to this “precursor”
role, PtdIns(4,5)P2 can 1) regulate the activity of enzymes such as PLC␦1 or PLD; 2) contribute to the
recruitment of endocytic clathrin adaptors; 3) anchor the actin cytoskeleton to the PM; 4) help dock secretory
vesicles and presynatptic vesicles to the membrane during exocytosis; and 5) maintain or regulate the active
conformation of a variety of ion channels and transporters. C: polarized or localized distribution of
PtdIns(4,5)P2 and PtdIns(3,4,5)P3 play important roles in establishing and/or maintaining polarity, such as in
directional migration, in local events, such as in phagocytosis, or in polarized epithelial cells that form barriers
between their luminal and basolateral sides.
ested readers can turn to more detailed reviews on this
topic.
Calcium signaling has always been very closely linked
to PLC-mediated phosphoinositide breakdown, namely
1070
through InsP3-induced Ca2⫹ release from the ER. The
enormous progress concerning the details of InsP 3 induced Ca2⫹ signals will not be discussed here but have
been the subject of numerous great reviews (129, 1050,
1051, 1534). However, less is known about how phos-
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PtdIns(4,5)P2
PHOSPHOINOSITIDES
phoinositides control Ca2⫹ influx, a topic I will dicuss in
some detail.
1. Store-operated Ca2⫹ entry (SOCE)
2. Voltage-regulated Ca2⫹ entry
The old classification that “excitable” cells contain voltagegated Ca2⫹ channels and “nonexcitable” cells use SOCE
has now become outdated, since most excitable cells do
contain channels formerly thought to operate in nonexcitable cells (e.g., CRAC and Trp channels) and, conversely,
many cells formerly considered nonexcitable do have Ca2⫹
entry channels that are regulated by voltage changes (e.g.,
most endocrine cells). As detailed in the next paragraph, a
3. Phosphoinositides: regulators or permissive
factors for channels?
An important question often debated about inositol lipids
and channel/transporter function is whether the lipids are
permissive for optimal function of the proteins, or indeed
are regulatory within the range of inositol lipid changes that
occur under physiological conditions. One can easily envision that highly acidic inositol lipids in the inner leaflet of
the PM engage positive residues at the cytoplasmic aspect of
the TM helices of channels, thereby serving as structural
reference points keeping the protein in the right conformation. This would ensure that channels are not active during
their transport in the internal membranes and become functionally competent only in the PM. On the other hand, it has
also been shown convincingly that PtdIns(4,5)P2 changes
evoked by agonist stimulation are faithfully followed by
changes in the activity of several potassium channels to the
extent that these channels are used as “PtdIns(4,5)P2 reporters” (422). It is worth pointing out, however, that we
often use very high supraphysiological concentrations of
agonists in our cellular studies and at normal level of receptor occupancy the overall lipid changes in the PM may not
be very significant. Whether a channel responds to small
changes in phosphoinositides also depends on the binding
affinity of the channel to the lipid; in fact, the activity of a
channel with very high affinity to an inositide may depend
on this lipid, yet even large lipid changes will not cause a
change in channel activity.
The molecular mechanisms by which inositol lipids can
control ion channels mostly remain elusive. Almost all ion
channels and transporters contain clusters of basic residues
in their membrane-adjacent regions facing the cytosol or
within their COOH-terminal tails. For example, inositol
lipid regulation was mapped to the TRP domains of the
cytoplasmic tails of TrpM8 channels (1138, 1284). An interesting and common feature of the PtdIns(4,5)P2 regulation of many potassium and TRP channels is that the lipid
alters the interaction of the channels with other specific
regulators such as calmodulin (843), ␤␥-subunits (661), or
ligands such as ATP (113). In addition, indirect regulation
of channels via inositide-binding and channel-interacting
proteins is also possible as suggested for Pirt, a molecule
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It was recognized in the late 1970s and early 1980s that
Ca2⫹ influx increases after stimulation of so-called “Ca2⫹mobilizing receptors,” which led James Putney to postulate
a Ca2⫹ entry pathway that is activated by emptying the ER
Ca2⫹ stores (capacitative Ca2⫹ entry) and thus currently
named store-operated Ca2⫹ entry (SOCE) (1242). The molecular entities that constitute this pathway had been enigmatic for a long period, with the nonspecific cation Trp
(transient receptor potential) channels taking center stage
(1193). The breakthrough in this field came when largescale small interfering RNA (RNAi) studies identified the
STIM1 protein as the ER Ca2⫹ sensor necessary for SOCE
(916, 1296). This was followed within a year by the discovery of the Orai1 protein as the channel component of ICRAC,
the highly Ca2⫹-selective current representing the major
form of SOCE (435, 1635, 1802). A lot of progress has been
made in understanding the mechanism of STIM1-Orai1 activation during ER Ca2⫹-store depletion covered by several
recent reviews (345, 896, 1427). For this summary it is
enough to say that the ER-resident single transmembrane
STIM1 protein has a luminal Ca2⫹-sensing EF hand domain
that triggers the oligomerization of the protein upon Ca2⫹
unbinding. This, in turn, induces a conformational change
in the cytoplasmic aspect of STIM1 allowing it to interact
and activate the Orai1 channels at junctions where the ER
and the PM are in close proximity. The connection of this
form of Ca2⫹ entry to inositol lipids was first noted when
Wm was shown to inhibit the ICRAC channels, and curiously
the inhibition seemed to be related to changes in PtdIns4P
rather than PtdIns(4,5)P2 (184). Since STIM1 has a polybasic tail at its very COOH terminus, it has been suggested
that it interacts with the acidic phospholipids possibly with
PtdIns(4,5)P2 in the PM, a view now generally accepted
(217, 1664). In contrasting findings, PtdIns(4,5)P2 was
found not to play a significant role in STIM1 movements or
activation of Orai1, and instead, PtdIns4P seemed to be
implicated in the regulation of Orai1 itself (820, 1618).
More studies will clarify which, if any, of these inositides
and by what mechanism regulate this important Ca2⫹ entry
pathway.
great number of ion channels and transporters require
phosphoinositides for proper function or are even regulated
by physiological changes in the PM levels of these lipids,
most notably PtdIns(4,5)P2 or PtdIns4P. These can have
direct effects on Ca2⫹ entry when the affected channels
conduct Ca2⫹, but they can also indirectly influence Ca2⫹
influx if they change the membrane potential through modification of potassium channels or chloride channels. Membrane potential changes not only influence the gating of
channels (such as the voltage-gated Ca2⫹ or Na⫹ channels),
they also change the electrical driving force for Ca2⫹ (as in
the case for CRAC channels).
TAMAS BALLA
Table 2. Effects of phosphoinositides on ion channels and transporters
Channel
Ins Lipid Regulator
Voltage-gated Ca2⫹ channels
T-type channels
L-type channels
KATP (Kir6.x)
Two pore
Voltage-gated (Kv1.3)
M-type (KCNQ2,3,5)
BK (Ca2⫹ activated)
Ion exchangers and transporters
Na⫹/Ca2⫹ exchanger
Na⫹/H⫹ exchanger
⫺
Na⫹/HCO3
cotransporter
Epithelial sodium channel (ENaC)
CFTR
Ion pumps
PM Ca2⫹-ATPase
Ligand-gated channels
P2X1
P2X2
P2X2/3
???
PtdIns(4,5)P2 (⫹)
PtdIns(4,5)P2 (⫹)
PtdIns(4,5)P2(⫾)
1038, 1490, 1491, 1815
487, 865
1302, 1735
No reports
PtdIns(4,5)P2(⫺)
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2(⫺)
PtdIns(4,5)P2(⫾)
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2, PtdIns4P (⫾)
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2(⫺)
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2(⫺)
PtdIns(4,5)P2(⫺)
410, but (⫹) 662
1331
883
1180
782, 1573
883, but (⫺) 27, 742
883, but (⫺) 742
1568
1137, 1811
923, 1284
1745
1312, but see 850, 1515
319, 922, 1284
257, 559, 951, 1587
1033
365
869, 1284
1556, 1789
783, but (⫹) 761
961
PtdIns(4,5)P2(⫹)
PtdIns(3,4,5)P3 (⫺)
PtdIns4P ???(⫹)
1220, 1826
177, 181, 1724, 1793
184, 820
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2(⫹)
661, 915
807, 1281, 1283, 1795
PtdIns(4,5)P2, PtdIns(3,4,5)P3, PtdIns(3,4)P2
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2, PtdIns(3,4,5)P3 (⫺)
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2(⫹)
661, 807, 1495
423, 616, 1283
937, but see 245, 911
1012
422, 1488, 1794
1598
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2, PtdIns(3,4,5)P3 (⫹)
PtdIns(4,5)P2(⫹)
58, 588, 616, 1763
12
1734
960, 1229, 1230, 1564, 1787
619
PtdIns(4,5)P2(⫹)
249, 438, 1132, 1192
PtdIns(4,5)P2(⫹)
PtdInsP, PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2, PtdIns(3,4,5)P3 (⫹)
126
474
1074
Continued
1072
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N-type channels
P/Q-type channels
TRP channels
TrpL (Drosophila)*
TrpC1
TrpC3
TrpC4a
TrpC5
TrpC6
TrpC7
TrpM2
TrpM4
TrpM5
TrpM6
TrpM7
TrpM8
TrpV1**
TrpV2
TrpV3
TrpV5
TrpV6
TrpA1
TrpP2
Cyclic nucleotide-gated channels
Hyperpolarization-activated HCN2 channels
Cyclic nucleotide-gated (CNG)
ICRAC/Orai1 channels
Potassium channels
ROMK1 (Kir1.1)
IRKs (Kir2.x)
GIRK (Kir3.x)
Reference Nos.
PHOSPHOINOSITIDES
Table 2.—Continued
Channel
P2X4
P2X5
P2X7
NMDA
NR1/NR2
Ins Lipid Regulator
PtdIns(4,5)P2, PtdIns(3,4,5)P3 (⫹)
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2(⫹)
PtdIns(4,5)P2 (⫹)
PtdIns(4,5)P2 (⫹)
Reference Nos.
126
127
127, 291
977
1037
that interacts with TRPV1 channels and also binds phosphoinositides (780), or AKAP150, an A-kinase anchor protein that associates with TrpV1 (728). Two recent reports
on the structures of two closely related Kir channels bound
to PtdIns(4,5)P2 began to shed light on the structural basis
of lipid regulation of these channels: in the case of the
Kir2.2 K⫹ channel, PtdIns(4,5)P2 binds at an interface between the transmembrane domain (TMD) and the cytoplasmic domain of the channel such that the fatty acid chains
interact with the TMD and the phosphorylated headgroup
with the cytoplasmic domain bringing the latter closer to
the membrane and helping to open the inner gate (566). In
the case of the GIRK2 channel, PtdIns(4,5)P2 occupies a
similar position at the interface between the TMD and the
cytoplasmic domain. However, here the position of the cytoplasmic domain already being closer to the inner membrane interface is not affected dramatically with lipid binding. Instead,
PtdIns(4,5)P2 has a more profound effect on the opening of
the inner gates in a mutant channel that mimics the conformation of the G␤␥-activated state (1715). In other words,
the lipid had an important effect on G protein-induced activation, consistent with previous conclusions based on
functional analysis (661, 1795).
Another form of channel regulation by inositol lipids is the
stimulated insertion of the channel from intracellular inactive compartments to the PM. This process is usually regulated by PtdIns(3,4,5)P3 made by PI 3-kinases, such as reported for L-type Ca2⫹ channels (1633) or for the maintenance of AMPA receptors at the postsynaptic density (54).
Since this form of regulation is essentially a trafficking process, it will not be further discussed here.
C. Exocytosis
The earliest indications that phosphoinositides may be important for membrane fusion came from studies on dense
core vesicle (DCV) exocytosis, where it was recognized that
phosphoinositides were important for priming exocytic vesicles (395, 582, 583). In the process of regulated secretion,
DCVs undergo maturation that increases their competence
to dock and fuse with the PM when a rapid rise in Ca2⫹
concentration triggers the fusion process. Some of the mature granules under the membrane will dock to the PM, but
these predocked vesicles still have to undergo “priming” to
become the “readily releasable pool” that is first fused upon
stimulation (312, 715, 1191). During isolation of cytosolic
factors needed for “priming” of DCVs, the mammalian
PITP and PIP 5-kinase proteins have been identified (582,
583). Moreover, it was shown that PLC-mediated PtdIns(4,5)P2
hydrolysis was necessary for exocytosis to take place (558,
1707, 1708). These observations then led to the notion that
PtdIns(4,5)P2 is an obligatory factor required for generating
competent exocytic vesicles, and increased PtdIns(4,5)P2
turnover promotes Ca2⫹-triggered fusion of vesicles with
the PM (643). However, for a long period, the question of
whether PtdIns(4,5)P2 was necessary for priming at the PM
membrane or at the surface of the exocytic vesicle has not
been clarified. In the last 10 years or so, several proteins
relevant to exocytosis have been found to bind and to be
possibly regulated by PtdIns(4,5)P2 (see TABLE 3). There are
other proteins important for exocytosis that bind phospholipids, such as the DOC2 protein that supports slow asynchronous exocytosis (1762). However, DOC2 binds PtdSer
via its C2 domain but does not bind phosphoinositides.
It is not clear at present how PtdIns(4,5)P2 binding to any of
these proteins regulate the exocytic process. The best studied of these is the Ca2⫹-sensitive phosphoinositide-binding
regulator protein of exocytosis CAPS (46, 1313). This protein acts at a Ca2⫹-dependent prefusion step that is rate
limiting and which requires the ATP-dependent priming of
the DCVs (530) to promote the assembly of SNARE complexes (718, 719). CAPS requires PtdIns(4,5)P2 at the PM
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*The Drosophila TrpL channels are stimulated after PLC activation, but the signal responsible for the stimulation is highly debated. DAG and polyunsaturated fatty acids (PUFA) have been the most accepted stimuli
(573), and in some cases it is speculated that the PtdIns(4,5)P2 decrease and proton accumulation contributes to their activation (662). However, several data indicate that these channels still need PtdIns(4,5)P2 for
optimal activity. **TrpV1 channels also called vanilloid receptors that respond to heat and capsaicin (224) are
strongly sensitized by bradykinin and other PLC activators, and it was suggested that PtdIns(4,5)P2 breakdown
relieves a tonic inhibition of these channels by PtdIns(4,5)P2 (257). However, the lipid regulation of these
channels appears to be more complicated as they need phosphoinositides for their activity, and the effects of
PtdIns(4,5)P2 also depend on the extent of stimulation by capsaicin (951, 1286, 1587) or association with
other proteins (728, 780) and PtdIns4P may also support their activities (559, 951).
TAMAS BALLA
Table 3. PtdIns(4,5)P2-interacting proteins related
to exocytosis
Protein
Synaptotagmin-1
Synaptotagmin VII
Syntaxin-1A
CAPS
MUNC13
VAMP-2
Granuphilin
Rabphillin
Interacting
Domain
C2
PH
C2
Reference Nos.
78, 1052, 1358,
1582, 1602
1177
49, 1099, 1603
530, 718, 946
1403
334, 839
1177
260
1074
The role of PI3Ks in exocytosis and secretion has also been
explored. PI 3-kinase inhibition was found to increase exocytosis in adrenal chromaffin cells (1056, 1701) or insulinsecreting beta cells (411, 1790) apparently due to a transient increase in PtdIns(4,5)P2 level. In contrast, a significant amount of literature documents the need for PI3K in
secretion from immune cells, most notably for histamine
release from mast cells following FcR stimulation (997,
1164, 1207, 1761). However, in this case, PI3K, specifically
the PI3K␦ (30) and PI3K␥ isoforms (157, 847), act as important amplifiers to control PLC␥ activation, and hence,
Ca2⫹ signaling and PtdIns(3,4,5)P3 may not be directly involved in the control of the exocytic machinery (30, 157,
847). Recent studies implicated PI3K-C2␣ in the control of
exocytosis of insulin-containing vesicles in pancreatic
␤-cells (370, 879) and neurosecretory cells (1034, 1700). It
should be remembered that PI 3-kinase inhibitors can also
indirectly affect secretion by altering the various Ca2⫹ influx pathways (see above) or actin dynamics as shown in
pancreatic ␤-cells (282, 1222).
D. Endocytosis
Most cell surface molecules undergo endocytosis and recycling, a process that ensures delivery of nutrients to the cell
interior, and one that controls receptor number at the cell
surface and also serves as a quality control mechanism.
There are a number of forms of endocytosis, such as the
clathrin-mediated and clathrin-independent endocytosis
and endocytosis via caveolae as described in many detailed
reviews (366, 655, 1019). The most studied and hence understood form of endocytosis is mediated by clathrin using
a process that requires the participation of a great number
of proteins that form the clathrin lattice and bring cargo
molecules to this structure (1019, 1243, 1537). Endocytosis
is also regulated by inositol lipids at several biochemical
steps along the formation, maturation, and fission of the
endocytic particle. One of the first indications that inositides have to do with endocytosis was the finding that the
tetrameric clathrin adaptor protein AP-2, a key component
of the clathrin-mediated endocytic machinery, was a “receptor” for InsP6 (1639). Subsequently, it was shown that
the natural binding partner of this protein is PtdIns(4,5)P2
(482, 1288). Studies on synaptic vesicles revealed that the
PtdIns(4,5)P2 5-phosphatase synaptojanin (981, 1022) and
the PtdIns4P 5-kinase PIP5K␥ (352, 1704) are crucial regulators of synaptic vesicle cycling and neurotransmission
(1702). Recent studies using rapid depletion of PM
PtdIns(4,5)P2 in intact cells have unequivocally proven that
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side for its activity (718), and it has a central PH domain
capable of binding PtdIns(4,5)P2 and essential for CAPS’
ability to facilitate exocytosis (529). Although there have
been some ambiguities whether PtdIns(4,5)P2 binding of the
PH domain is central to the function of the CAPS protein
(529), the current view is that PtdIns(4,5)P2 at the PM supports CAPS function via interaction with the CAPS PH
domain (778). Single-cell analysis of exocytic events in bovine chromaffin cells also concluded that PM PtdIns(4,5)P2
was the relevant lipid that determined the size of the readily
releasable pool (1056). With the use of reporters for
PtdIns(4,5)P2, such as PLC␦1PH-GFP or fluorescent neomycin analogs, it was possible to show that there is an
increased concentration of PtdIns(4,5)P2 at the sites of exocytosis (258, 551, 643, 718, 1056). A recent study found
that PtdIns(4,5)P2 binding to synaptotagmin-I increases the
Ca2⫹ binding affinity of the protein 40-fold (1602), providing yet another mechanism to promote the fusion process. It
would be of interest to know which PI and PIP kinase(s)
contribute to the generation of PtdIns(4,5)P2 at the PM
during exocytosis. PIP5K␥ is the enzyme that is important
for synaptic vesicle exocytosis in the brain (1704) and is
also critical in DCV exocytosis in neuroendocrine cells
(520). Less clear is the identity of the PI4K enzyme. Isolated
chromaffin granules were found to contain a PAO-sensitive
PI4K (1716), and PAO-sensitive, type III PI4Ks were found
to be crucial to determine the size of the readily releasable
pool of exocytic vesicles in pancreatic beta cells (1168).
However, the PI4K purified from chromaffin granules
turned out to be the type II␣ PI4K enzyme (108) that is not
particularly PAO sensitive (83). In a number of studies,
secretion was inhibited by Wm or LY294002 at higher concentrations, which would be consistent with inhibition of
type III PI4Ks (492, 1256, 1480, 1682). Several data suggest
that PI4K〉 is important for regulated exocytosis: neuronal
calcium sensor 1 (NCS-1), a homolog of the Drosophila and
yeast frequenin, which interacts with PI4KB (see sect. V),
increases glucose-induced insulin secretion by increasing
the readily releasable vesicular pool in pancreatic beta cells,
an effect that requires PI4KB (531). In another study, re-
ducing the level of PI4KB with RNA interference inhibited
nutrient-induced insulin secretion (1683). Since NCS-1 was
discovered as a protein regulating synaptic development
and plasticity (reviewed in Ref. 615), it is a reasonable assumption that PI4KB also functions in the genesis, transport, and/or exocytosis of synaptic vesicles (1702).
PHOSPHOINOSITIDES
clathrin-mediated endocytosis (CME) of nutrient receptors
and GPCRs require PtdIns(4,5)P2 (2, 1569, 1617, 1831).
Moreover, Arf6-regulated non-clathrin-mediated endocytic
pathways also depend on phosphoinositides, although in
this case the molecular identities of the lipid-dependent
steps are less clear (17, 189, 646).
So how does PtdIns(4,5)P2 regulate endocytosis? Several proteins of the endocytic pathways bind phosphoinositides, primarily PtdIns(4,5)P2 with low affinity (see TABLE 4). Lipid
Table 4. PtdIns(4,5)P2-interacting proteins related
to endocytosis
Protein
Dynamin
AP-2
AP180/CALM
Epsin
Dab2/1
HIP1/HIP1R
ARH
SNX9
Arrestin
Myosin VI
Interacting
Domain
PH
␣ and ␮
ANTH
ENTH
PTB
PTB
PX and BAR
Reference Nos.
4, 1332, 1816
482, 1288
453, 819
711
654, 665, 1062, 1788
711
1063
1764, 1765
483
1439
E. Plasma Membrane Polarization
Most cells in an organism develop a lateral organization of
their PM with significant differences in membrane compositions and functions as they make contacts with other cells
and form tissues and organs. The best examples are epithelial cells that have apical and basolateral membranes or
neurons with axons and dendrites with distinct features.
Even solitary cells of the innate and adaptive immune system show significant polarization as cells chemotax and
phagocytose or communicate with one another. Cell migration and the invasive properties of cancer cells also depend
on cell polarization and make all the difference between
curable and deadly forms or stages of the disease. In all of
these processes phosphoinositides play fundamental roles
in multiple ways. There are three areas that will be discussed in some detail: chemotaxis, phagocytosis, and the
organization of polarized cells as they best show the principles that apply to many other polarization processes.
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It has been shown that endocytic vesicles normally lose
PtdIns(4,5)P2 by 5-dephosphorylation during separation
from the PM, and if they do not, they will be coated with
actin and accumulate and aggregate in the cell interior (e.g.,
Ref. 189). This observation fits with the notion that
PtdIns(4,5)P2 is an identity code for PM. However, as more
and more fine details are emerging on the hierarchy of the
molecular events that control CME, it appears that several
rounds of dephosphorylation and rephosphorylation cycles
of PtdIns(4,5)P2 are necessary to maintain the flow of sequential steps in the initiation, maturation, invagination, and fission of internalizing vesicles (48). Moreover, in these different
steps, distinct PtdIns4P 5-kinases and PtdIns(4,5)P2 5-phosphatases may have specific roles. Overexpression or knockdown of PIP5K␣ or -␤ were shown to alter internalization
of transferrin or EGF receptors (106, 1185). At the same
time, several 5-phosphatases, such as SHIP1 (1115), OCRL
(251, 988), and Sjn1 (1209), were all found to associate
with components of the clathrin-coated pits (CCPs). A detailed TIRF analysis of different steps in CME during manipulation of PM PtdIns(4,5)P2 found no recruitment of PIP
5-kinases to CCP, yet their overexpression increased the
number and size of CCPs (433). In the same study, several
5-phosphatases did show association with CCPs (although
to significantly different extent and not to all CCPs), and the
most important of these, Sjn1 inhibited the initiation and
stabilization of early CCPs, but promoted the maturation of
CCVs at later stages (433).
binding contributes to the recruitment of such proteins to
the PM. Most of these molecules are adaptor proteins that
link cargo to clathrin, but they also include proteins that
contain BAR (Bin-Amphiphysin-Rsv), F-BAR, or I-BAR domains (466, 1520, 1606). The latter three domains consist
of dimers of long helical segments that generate a rigid
banana shape with radiuses that differ between the three
families. They have positive residues on the concave (BAR
and F-BAR) or convex (I-BAR) surface that interact with
acidic phospholipids in curved membranes (1211) and also
have membrane-bending and curvature-generating activities (465). Some BAR domain-containing proteins also possess other phosphoinositide binding modules, such as PX
domains that are found in a group of sortin nexin (SNXBAR) proteins (304). Most of these proteins play important
roles in tubulation and scission at different endomembranes
(see below), but SNX9, in particular, is important during the
formation of endocytic tubes (1437, 1537, 1765) and also
interacts with dynamin 1 and N-WASP, a protein that controls
actin polymerization (1402). Dynamin is the GTPase that is
essential for the scission of the endocytic vesicle, and its
PtdIns(4,5)P2 binding PH domain is critical for its function
(1362). Although the PH domain of dynamin has low affinity to PtdIns(4,5)P2, the assembling dynamin molecules on
the neck of endocytic vesicles form a ring of multiple lipid
binding modules (1475, 1506, 1816). How PtdIns(4,5)P2
affects dynamin is not fully understood, but it can recruit
the molecule to CCPs, and it also increases dynamin’s GTPase
activity (1816). It is clear, however, that dynamin interacts with a host of other proteins in the forming of endocytic vesicles via its other domains, and it controls not
only the last step of CCPs life, i.e., its scission from the
PM, but also regulates early steps during the formation
and maturation of CCPs (see Refs. 432, 1362 for recent
reviews on dynamin).
TAMAS BALLA
1. Chemotaxis
Very similar principles were found to drive the chemotactic
responses of mammalian cells, such as neutrophils and macrophages (1463, 1691). Accumulation of PtdIns(3,4,5)P3 in
the leading edge of differentiated HL60 cells have been
described parallel to the findings in Dictyostelium (1385)
and confirmed in many subsequent studies (430, 1667) including mouse neutrophils (1140). In this case, however,
there are some differences in the players that form the positive and negative feedback loops in building up the
PtdIns(3,4,5)P3 gradient. In mouse neutrophils, it was
shown that SHIP1 rather than PTEN is important to serve
1076
2. Phagocytosis
Phagocytosis is a critically important process for innate immunity and for clearance of cell debris during inflammation
and tissue remodeling (6, 1821). It is one of the most spectacular membrane polarization events that one can observe
under the microscope. Particles or cells to be phagocytosed
initially attach to the cell surface, mostly via Fc␥Rs or CR3
complement receptors (1592). This binding initiates a
whole set of signaling events that induce the raising of the
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A significant portion of our knowledge came from studies
using the model species Dictyostelium discoideum, a unicellular organism that responds with chemotaxis to cAMP
signals originating from neighboring cells (reviewed at great
detail in Refs. 206, 815, 1505, 1691). How cells sense and
respond to a chemotactic gradient are exciting problems
since the concentration difference between the cells leading
and trailing edges is extremely low. This makes a tiny difference in signaling strength when considering the doseresponse relationship of the chemotactic receptors (usually
GPCRs) and their G protein activation. These small differences have to be amplified for the cell to be able to respond
with robust polarization. Accordingly, it has been found
that distribution of GPCRs or their G protein activation do
not show prominent polarization (735, 1744). However, it
was recognized for the first time in Dictyostelium that the
PI3K product PtdIns(3,4,5)P3 localizes prominently to the
leading edge of the cell (373, 666, 1026). Deletion of the three
PI3Ks in Dictyostelium indeed compromises although does
not eliminate the ability of cells to respond to chemotactic
stimuli (1518). Importantly, the PtdIns(3,4,5)P3 phosphatase PTEN was found to localize to the trailing end of the
cell (677), and its deletion increases overall PtdIns(3,4,5)P3
levels and dissipates the PtdIns(3,4,5)P3 gradient interfering
with efficient chemotaxis (677). Since PtdIns(4,5)P2 binding
of PTEN is important for PTEN localization (678), a decreased PtdIns(4,5)P2 level at the leading edge because of
the active PI3Ks favors PTEN accumulation at the trailing
end. PLC activity can also modify the distribution of
PtdIns(4,5)P2 and PTEN, affecting the PtdIns(3,4,5)P3 gradient (771). These observations together led to the suggestion that localized stimulation (by PI3Ks) together with a
global inhibition (by PTEN) form the basis of the amplification of gradient sensing in which the lipid PtdIns(3,4,5)P3
has a central role (815, 1505, 1626). Several other molecules also show polarized distribution in Dictyostelium.
These include activated RasC and RasG; the TorC2 complex; a number of downstream PtdIns(3,4,5)P3 effectors
that contain PH domains, such as Crac, PKBA, and PhdA
(1505); and several recently identified proteins with unknown function (1801). RasG acivates PI3Ks, while RasC is
is linked to TorC2, and it is part of the regulatory loops that
control chemotaxis (205, 1342).
as the negative regulator that keeps overall PtdIns(3,4,5)P3
levels down (1140), and that G ␤␥ (1497) subunits liberated
by the activated chemotactic receptors together with Ras
(1342, 1497) strongly stimulate PI3K␥ at the leading edge
of the cell. It has also been shown that a positive feedback
loop between PtdIns(3,4,5)P3 and the small GTPases, Rho,
Rac and Cdc42 and actin polymerization also contributes
to the sharp polarization (1441, 1667, 1693). An additional
positive feedback is provided by the secondary recruitment
and activation of class IA PI3Ks by PI3K␥-mediated increase
in PtdIns(3,4,5)P3 (285, 1131). Although PTEN may not be
the major phosphatase to influence the PtdIns(3,4,5)P3 gradient, it has been shown that PTEN ⫺/⫺ neutrophils are easily
“distracted” and cannot properly “prioritize” their chemotactic cues (591). The complexity of the various ways
PtdIns(3,4,5)P3 influences chemotaxis, and migration is
demonstrated by the enhanced transendothelial migratory
ability of PTEN (⫺/⫺) neutrophils which is counterintuitive
to the concept of too much PtdIns(3,4,5)P3 causing a problem with directional sensing (904, 1341). This is related to
the fact that PtdIns(3,4,5)P3 not only controls the polarization and amplifies the directional sensing of the cells, but
also affects their adhesion, rolling, and motility, via other
effectors including integrins and the actin cytoskeleton
(1463) (and see below). It is important to note, however,
that PtdIns(3,4,5)P3 is not the molecule that sets up the
direction, as chemotaxis in Dictyostelium cells still occurs
without PI3Ks (45, 628) and neutrophil cells will still migrate toward gradients without PI3K␥ (430, 1140). Nevertheless, PtdIns(3,4,5)P3 is definitely a signal that amplifies
and increases the precision of directional sensing, and engages the mechanisms that move cells along chemotactic
gradients. There have been a number of proteins identified
in neutrophils that are regulated by PtdIns(3,4,5)P3 (827).
These included serine/threonine kinases, such as PDK-1,
mTORC2, and Akt/PKB; the tyrosine kinase Btk; GAP and
GEF proteins for Arf; Cdc42; Rho and Rac; and cytoskeletal proteins such as WAVE2 and ezrin (827, 1463). Moreover, motor proteins, such as myosin X that has three PH
domains (one is a split one), can bind PtdIns(3,4,5)P3 and
be recruited or conformationally regulated by this lipid
species (293, 950, 1228, 1591). All these proteins mediate a different aspect of the migrational response, and it is
very likely that they may have their own dedicated source
of PtdIns(3,4,5)P3 produced at different phases of the cell
movement.
PHOSPHOINOSITIDES
As for PtdIns(4,5)P2, the changes in this lipid correlate very
closely with the formation of actin during the pseudopod
extension and with actin disappearance after particle engulfment (1370). The different type I PIP kinases appear to
have subtle and distinct roles in the process: deletion of
PIPKI␥ from bone marrow-derived macrophages yields defective attachment of IgG-coated particles to the cells (989).
These cells have increased amount of highly polymerized
actin and fail to cluster their Fc␥R upon engagement (989).
They also show enhanced RhoA and reduced Rac1 activation. In contrast, PIPKI␣ deletion inhibits the ingestion process and prevents activation of WASP and actin polymerization without altering attachment (989). The connection
between PtdIns(4,5)P2 and actin dynamics has long been
appreciated not only in phagocytosis but in virtually any
membrane deforming events, including chemotaxis (1505,
1691), endocytosis (1320, 1768, 1800), and exocytosis
(1574, 1681). Several actin capping and severing proteins
were shown to bind PtdIns(4,5)P2, and therefore, the lipid
can affect actin polymerization in a number of ways. It can
dissociate the capping protein gelsolin from the (⫹) end of
actin (720, 721), it can increase actin nucleation by the
Arp2/3 complex via binding to the N-WASP protein (1048,
1287), and it can inhibit the actin-severing activities of cofilin and the actin depolimerizing factor ADF (1162, 1772,
1812). Profilin and ␣-actinin, two additional proteins promoting actin assembly and crosslinking, are also regulated
by PtdIns(4,5)P2 (237, 516, 1412). Moreover, several actin
bindin proteins containing FERM (four-point one-ezrin-radixin-moesin) domains contain PtdIns(4,5)P2 binding modules, and their PM association is determined by lipid binding to these domains (255, 556, 982). Hydrolysis of
PtdIns(4,5)P2 by PLC␥ is necessary for completion of
phagosome formation (172, 1370). This not only allows the
drop in PtdIns(4,5)P2 levels and hence facilitates actin disassembly, but also generates DAG to activate other downstream effectors, such as PKC⑀ (238, 859) and Ras/Rap1
(171).
PI 3-kinase inhibition by Wm or LY294002 inhibits phagocytosis of large (⬎3 ␮m) particles but has a relatively small
effect on the smaller ones (50, 295). Yet, localized prominent PtdIns(3,4,5)P3 increases in the phagocytic cup have
been observed (750, 1000). A recent study found a close
connection between PI3K activation and Cdc42 cycling
during development of the phagosome. Cdc42, which promotes actin polymerization, also activates PI3Ks in the
phagocytic cup; the 3-phosphorylated lipids, in turn, inactivate Cdc42 allowing actin depolimerization and recycling,
which is important for phagosome formation (115). Relatively little is known about which PI3K isoform(s) are responsible for the generation of PtdIns(3,4,5)P3, but the class
IA enzyme, via recruitment through p85 adaptors, is believed to be the most important for this process (750). In
contrast, PI3K␥, which is abundant in phagocytic cells,
plays little if any role in phagocytosis of opsonized particles
(1740). However, the role of the PI3K subclasses can be
more specialized, as recent studies found that phagocytosis
of the parasite Leishmania mexicana is strongly impaired in
PI3K␥-deficient cells or by specific inhibitors of this PI3K
isoform (308). As for PtdIns(3,4,5)P3 effectors, the small
GTP binding proteins of the Rho/Rac family have wellestablished roles in phagocytosis (215, 648) and GEFs for
these proteins, such as VAV or the Ras GEF protein SOS,
are activated by PtdIns(3,4,5)P3 (322, 696, 1588, 1624).
PtdIns(3,4,5)P3 also can recruit protein kinases, such as Akt
and Btk, and while the former is not desirable and hence
being limited by several mechanisms (155), the latter serves
as a positive regulator of PLC␥ activation and helps complete phagosome formation (42, 738).
Recruitment of PI 5-phosphatases that act upon PtdIns(4,5)P2
and PtdIns(3,4,5)P3 is necessary to terminate the processes
described above, and prepare the completely ingested
phagosome to its intracellular jurney and maturation. It is
not clear why phagocytic cells need four different 5-phosphatases [OCRL, INPP5B (155), SHIP (14, 294), and Pharbin (649)], but it is likely that each of these is specialized to
disassamble specific protein-lipid signaling complexes. Ac-
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PM around the object (called pseudopods) until this membrane ring is high enough to close above the particle thereby
engulfing it. The engulfed particle surrounded by a membrane then undergoes maturation upon which various endocytic compartments fuse with the phagosome lowering
its pH, changing its membrane composition, and supplying
degradative enzymes that eventually degrade the particle.
This complex coordinated membrane deformation sequence is associated with characteristic changes in membrane phosphoinositides at the different stages of the
phagocytic process (1766). After the particle is bound to the
PM, increased synthesis of PtdIns(4,5)P2 was found to occur during formation of the phagocytic cup due to the recruitment and activation of PIPKI␣ (172). However,
PtdIns(4,5)P2 suddenly disappears upon sealing of the
phagosome caused partially by its PLC␥-mediated hydrolysis (172), and this latter step is essential for proper particle
ingestion (1370). The PtdIns(4,5)P2 decrease is the result of
several additional processes: a drop in the surface charge of the
formed phagosome releases PIPKI␣ (1767), PtdIns(4,5)P2 is consumed by PI3Ks that form PtdIns(3,4,5)P3 on the bottom of
the phagocytic cup as the pseudopod is raising (295, 1000,
1094), and several phosphatases that act both on PtdIns(4,5)P2,
such as OCRL and INPP5B (155), or on PtdIns(3,4,5)P3,
such as SHIP (14, 294) and Pharbin (649) are recruited to
the phagosome. The sequential recruitment of the multiple
inositol lipid metabolizing enzymes and the resulting localized and temporally organized spectacular changes in the
various PI species during phagocytic membrane remodeling
raises the question of what importance these lipid changes
have and how they participate in the organization of this
process.
TAMAS BALLA
An important trivial question rarely asked is what keeps
these very local lipid gradients from spreading given the
rapid rate of lateral diffusion of PIs within the PM. Such
gradients can be maintained only if the lipid production is
highly concentrated at these sites against a high background
of degradative activity. Alternatively, and probably complementary to the former, the engagement of the lipid by
protein binding partners could shield the lipids from degradation. To answer these questions, one would need to know
the diffusion speed of lipids when they are free and when
proteins are bound to them, or the average time a specific
protein module spends bound to a PI species. A few studies
have addressed these issues using fluorescent tools in living
cells (518, 561, 840). They demonstrated that lipids indeed
diffuse rapidly, so there is a need for localized synthesis/degradation or physical diffusion barriers, to maintain gradients.
Second, protein effectors interact only transiently and can only
act over micrometer distances. Recent studies using similar
techniques found that significant diffusion barriers exist
around the phagocytic cup keeping PtdIns(4,5)P2 in place
(517).
3. Epithelial cell polarity
The classical example of membrane polarization is found in
epithelial cells that form a barrier separating the inner millieu from the external world or line cavities in multicellular
organisms. In the classical case, these cells have apical and
basolateral membranes separated by tight junctions that
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link the cells together and the protein and lipid compositions of the apical and basolateral membranes are significantly different. How cells maintain this polarity has been
the subject of intense research as newly synthesized molecules traffic to their proper destination, and to do so, they
must use molecular codes for apical and basolateral targeting (194, 1030, 1696). Since different membrane compartments within the cells have characteristic PPI compositions,
it is an important question whether the apical and basolateral membranes have unique PPIs associated with them.
Indeed, it has been reported that when MDCK cells from an
epithelial layer around a cyst in a three-dimensional culture,
their apical mambranes are enriched in PtdIns(4,5)P2, while
their basolateral membranes are enriched in PtdIns(3,4,5)P3, and
this lipid is excluded from the apical membrane (499,
1004). These studies also found that this lipid distribution is
important for proper targeting of proteins to the respective
membranes, and this process can be disturbed by exogenous
delivery of the lipids to the “inappropriate” membranes
(499, 1004). In subsequent studies, also using human colon
cancer cells, it was found that the PtdIns(3,4,5)P3 3-phosphatase PTEN localizes to the apical membrane explaining
the lack of PtdIns(3,4,5)P3 in that compartment. Indeed,
PTEN downregulation disrupted intestinal epithelial polarity and increased the invasiveness of human colon cancer
cells (851). A possible link between PtdIns(4,5)P2 and the
apical polarity was established when annexin2, which had
been previously shown to bind PtdIns(4,5)P2 (1268), was
found to be enriched in the apical membranes and also to
recruit Cdc42, a small GTP binding protein. Cdc42, in turn,
is critical in defining the apical membrane as it targets and
enriches the Par6/aPKC polarity complex at the apical
membrane (1004). What is not clear is which PI3Ks maintain the high PtdIns(3,4,5)P3 levels at the basolateral membranes during epithelial morphogenesis, but integrins interacting with matrix components are probably part of the
PI3K activation mechanism.
Another role of PtdIns(4,5)P2 in the formation of adherens
junctions has been recently described. One study showed
increased PtdIns(4,5)P2 production by PIPKI␥ at the adherens junctions, which was required to recruit the Exo70
exocyst subunit to the newly formed E-cadherin junctions
(1749). Another study described that OCRL1 5-phosphatase was part of junctional complexes and was critical for
the maturation of polarized epithelial cells (527). Consistent with the role of PtdIns(4,5)P2 in adherens junctions, an
elegant EM study on PtdIns(4,5)P2 distribution found the
lipid highly enriched in gap junctions, but otherwise
showed an even distribution between the apical and basolateral membranes (1183). PIs certainly play additional
roles in intracellular trafficking decisions, driving the selective delivery of cargoes to the respective PMs, but those
processes belong to the intracellular roles of PIs and will be
touched upon later. The aforementioned studies just began
to explore the PM phosphoinositide subcompartments in
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cordingly, Pharbin (INPP5E) inhibited Fc␥R-mediated, but
not CR3 complement receptor-mediated phagocytosis,
while SHIP1 was found to be more important for CR3mediated phagosome fromation (649). OCRL and INPP5B,
on the other hand, were important at a later stage to limit
Akt activation in the already ingested phagosome (155).
The internalized phagosome is then mostly stripped of
PtdIns(4,5)P2 and PtdIns(3,4,5)P3, and the major inositol
lipid associated with it is PtdIns3P generated by the class III
PI3K and possibly PtdIns4P, the product of PtdIns(4,5)P2
dephosphorylation but also produced by type II PI4ks
(156). In this regard, the limiting membrane of the phagosome is similar to that of other endocytic vesicles. There is,
however, an interesting recent observation that suggests
that even the endocytosed phagocytic vacuole has a small
amount of PtdIns(4,5)P2 and PtdIns(3,4,5)P3 associated
with it, which helps generate actin comets that propel the
vacuoles inside the cells. This study suggested the class III
PI3K via generation of PtdIns3P helped dislodge Inpp5B
from the nascent phagosome and allow class I PI3Ks to
generate PtdIns(3,4,5)P3 (156). The subsequent fate of the
maturing phagosome is a complex process involving a number of Rab proteins and the PI lipids PtdIns3P and
PtdIns(3,5)P2. Although phagosome maturation has its
unique features reviewed recently (446), from a PI lipid
standpoint, it is not too dissimilar to other endocytic processes that will be discussed below.
PHOSPHOINOSITIDES
epithelial cell polarity. Clearly, these lipids must have a role
not only in targeting proteins to the right PM domains, but
also in the regulation of channels and transporters that are
so critical to the barrier and transport functions of epithelial
layers. It is also important to note that the PtdIns(3,4,5)P3/
PtdIns(4,5)P2 distribution described above may not be a
general feature of all epithelial cells and could also change
with the developmental stage (1397). It is expected and
certainly hoped that research in this area will significantly
increase and will be extended to planar cell polarity. This
latter refers to the alignment of a collection of cells within a
cell sheet, another exciting form of polarization that has not
yet set an eye on phosphoinositides.
The key role of the PM pool of PtdIns(4,5)P2 to so many
cellular functions makes it essential for the cells to control
the level of this lipid in the membrane. Since PtdIns(4,5)P2
represents only a small fraction of the total cellular PtdIns,
cells have to replenish this pool especially during prolonged
and robust PLC activation. Early studies have already established that the entire PtdIns(45)P2 pool is turning over
several times during even a 10-min stimulation (e.g., Ref.
299). This happens as the larger PM pool of PtdIns undergoes sequential phosphorylations by PI 4-kinases and type I
PIP 5-kinases (see sects. II and III). It has been observed that
Li⫹ inhibits several inositol phosphate phosphatases and
ultimately the inositol monophosphatase that converts inositol monophosphates to inositol (34). Since recycling of
inositol is essential for the maintenance of the “PI turnover,” Li⫹ ions are able to disrupt the cycle leading to the
accumulation of inositol phosphates and CDP-DG and an
eventual rundown of the PtdIns pools (87, 90, 133, 727)
(see sect. IV and FIGURE 2B). Although it takes a longer
period for the smaller PtdIns(4,5)P2 pools to be depleted in
this manner, it has been proposed that the therapeutic benefits of Li⫹ treatment in manic-depressive disease might be
related to the preferential effects of Li⫹ on neurons that
show the highest activity (134). Since Li⫹ also affects other
enzymes, most prominently GSK-3 that acts on the Wnt
signaling pathway (739), this attractive Li⫹ hypothesis has
never been unequivocally proven or disproven.
Another important and unresolved issue is which PI4Ks are
involved in this process and how PtdIns gets to the PM since
it is synthesized in the ER. It has been shown that inhibition
of type III PI4Ks by higher concentrations of pan-PI3K inhibitors, such as Wm, are able to block PtdIns 4-phosphorylation and PtdIns(4,5)P2 maintenance in highly stimulated
cells (1112). Since type II PI4Ks are insensitive to Wm (386,
1112), and PI4KB-specific inhibitors do not have the same
effects, by way of exclusion it was concluded that PI4KA is
the enzyme responsible for this process (82, 84). This was
corroborated by earlier findings that the yeast homolog of
Another related question is how the PtdIns(4,5)P2 5-phosphatase-PIP5-kinase cycle affects PM PtdIns(4,5)P2 levels.
The rapid turnover of the 5-phosphate in PtdIns(4,5)P2 has
long been described, and it was attributed to “futile cycles”
of dephosphorylation and rephosphorylation believed to
take place in the PM as it happens in erythrocyte membranes (580). However, it must be clear by now that the
multiple 5-phosphatases and 5-kinases that are often part of
the same signaling complex and regulate several steps at the
endocytic cylcle, must be, in big part, responsible for the
high turnover of the 5-phosphate. This means that what
appeared to be “futile cycle” might be the sum of several
processes along the endocytic pathway in which PIP5Ks and
5-phosphatases generate a local turnover feeding specific
signaling steps. This raises the question of whether a pathway exists by which the bulk of uncoated endocytic vesicles
recycle back to the PM before reaching the early endosome/
sorting endosome stage allowing their PtdIns4P content to
be rephosphorylated by PIP5Ks? Another recent puzzling
observation was that PtdIns(4,5)P2 levels can be maintained
at apparently very different and greatly reduced PM
PtdIns4P levels, a finding that is hard to reconcile with the
high turnover rate of the phosphate in the 5-position (559).
We do not have a clear answer to these observations, nor do
we undertsand what happens to the PtdIns4P that is left
behind on the early endocytic compartments, since another
lipid, namely, PtdIns3P, is found to be important for the
formation of early endosomes from the CCVs. Lastly, it is
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F. How Do Cells Maintain Their PM
PtdIns(4,5)P2 Pools?
PI4KA, Stt4p is responsible for PM PtdIns(4,5)P2 maintenance in yeast (63). However, the primarily ER localization
of the mammalian PI4KA enzyme (1107, 1726) and the
modest effects of its cellular knockdown on PtdIns(4,5)P2
maintenance in stimulated cells made these conclusions
somewhat circumstantial (82, 84). A recent study shed new
light on this question: this study found that the EFR3 and
TTC7 proteins are capable of recruiting PI4KA to the PM
and confirmed that this kinase is the primary source of
PtdIns4P in the PM (1114). That still leaves us with the
question of how PtdIns gets to the PM. Although PI transfer
proteins (PITPs) are capable of PtdIns transfer between
membranes (1551) and have been shown to present the lipid
for PI4Ks (1354) and PI3Ks (1189), there are no solid evidence that these proteins are indded mediate PtdIns transfer
from the ER to the PM. In fact, PITPs were mostly implicated in the synthesis of PtdIns4P at the Golgi (1354) and
not at the PM. In a recent study we found that the PI synthase enzyme that was formerly believed to reside in the ER,
can associate with a highly mobile membrane compartment
that originates from but is not identical to the ER intermediate compartment (ERGIC). This mobile platform might
be able to deliver PtdIns to various membranes via transient
contacts (796). However, how lipid transfer takes place
during these membrane contacts, and how the system senses
and adapts to the PtdIns(4,5)P2 needs of the PM still needs
to be clarified.
TAMAS BALLA
completely unknown what mechanism delivers the PtdOH
generated at the PM by the phosphorylation of DG to the
ER-localized CDS enzyme(s) for the recycling of the DG for
PtdIns synthesis (see FIGURE 2B).
X. PHOSPHOINOSITIDES AT INTERNAL
MEMBRANES
1080
As described in earlier sections, PtdIns is produced in the ER
and in a highly mobile organelle that still awaits further
characterization (796). Further phosphorylated PtdIns are
not detectable in the ER, probably due to the high enrichment of the PtdInsP monophosphatase enzyme Sac1 in the
ER. In fact, Sac1 cycles between the ER and the cis-Golgi
compartments (147, 426, 427) and according to recent
studies it can also act in trans on PtdIns4P located in the PM
at ER-PM contact zones (1454). There are, however, PI
kinases found associated with the ER, namely, PI4KA (and
possibly its yeast ortholog, Stt4p), which has been shown to
regulate ER exit sites in mammalian cells (154, 425). In
other studies, PtdIns4P made by the PI4KB (or Pik1p in
yeast) was found necessary for fusion of COPII vesicles with
the early Golgi compartment but not for budding from the
ER (940). The inhibition of HCV repication by PI4KA
knock-down or inhibitors revealed that this enzyme is important for the generation of the membranous webb, the
membrane platform of HCV replication that is likely to be
of ER origin (122, 1267, 1513, 1514, 1577, 1597). Our
knowledge is still very limited on the question of what proteins and by what mechanism respond to PtdIns4P made in
ER membranes or on the surface of vesicles that leave the
ER. PtdIns4P is also targeted by the pathogen Legionella
pneumophila, which uses its SidC (1248) and SidM (188,
1824) proteins, together with Rab1 to form a replicationpermissive vacuole from ER-derived vesicles (1248).
B. Golgi
It has been the identification and cloning of the first yeast
PI4K, Pik1p, that drew attention to the fact that the Golgi is an
important site of PtdIns4P production and actions (444,
555, 1479, 1655). This was soon followed by studies showing the presence of mammalian PI4Ks in the Golgi (1036,
1106, 1107) and the role of Arf1 in their Golgi recruitment
(514). Moreover, several PH domains with PtdIns4P binding were identified in proteins that showed Golgi localization (381, 893– 895, 1783), strongly suggesting that
PtdIns4P is an important regulator of Golgi functions (337).
Functional studies showed that PI4KB (or Pik1p in yeast) is
responsible for post-Golgi trafficking of several protein cargoes (64, 193, 514, 555, 1509, 1655). Since all four mammalian PI4Ks are found in the Golgi/TGN compartment
(81), the question arises as to what extent can PI4Ks be
linked to specific Golgi-related functions and how much
functional overlap and redundancy exist among these enzymes. PI4KA is found in the ER and probably the cis-side
of the Golgi (1107, 1726), PI4KB is localized along the
whole Golgi compartments (337), while PI4K2A and
PI4K2B are found in the trans-side of the Golgi and the
TGN (83, 1680, 1690, 1697). This distribution, however,
probably shows some changes depending on the status of
the cell. More on the regulation of the PI4Ks in the Golgi
can be found in section V.
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The ultimate precursor of all phosphoinositides is PtdIns, a
lipid synthesized in the ER and in an ER-derived subcompartment (796). PtdIns is first phosphorylated to PtdIns3P
and PtdIns4P in endosomes and Golgi, respectively, and
then further to PtdIns(3,5)P2 and PtdIns(4,5)P2 in late endosomes/MVB and the PM. Parallel to these “synthetic”
intermediates exist the “degradative” intermediates that are
derived from the dephosphorylation of PtdIns(4,5)P2 and
PtdIns(3,4,5)P3 producing PtdIns(3,4)P2 and PtdIns4P in
membranes that are moving inside from the PM. As a result,
internal membranes contain a variety of PI lipids, most of
which have been linked to the regulation of specific trafficking pathways. Some authors refer to PI lipids as identity
codes marking specific membrane compartments. While
these lipids, indeed, can be characteristic of specific intracellular membranes, it may be misleading to assign their
functions to those membranes as much as it can be misleading to draw conclusions from the steady-state distribution
of proteins concerning their functions when they cycle between various compartments (e.g., transferrin receptors are
mostly found in ER, yet their function clearly requires visiting the PM). Also, using our imaging and antibody tools,
we make conclusions about the lack of lipids in internal
compartments just as much as we do about their presence.
This can also be misleading. It is quite possible that what we
see is a larger “precursor” pool that is phosphorylated and
dephophorylated with a very short-lived intermediate, and
the invisible, short-lived lipid is in fact the important regulator. Contrast this with the opposite view that the lipid
what we see is the “product” that must be the regulatory
entity. There are probably cases for both, as we can draw
parallels from the PM, where PtdIns(4,5)P2 is a regulatory
lipid, a product of PIP5Ks, but it also is a precursor of
PtdIns(3,4,5)P3 made by the PI3Ks and PtdIns(3,4,5)P3 is
rapidly removed by 3- or 5-phosphatases. Therefore, one
should be careful making strong inferences just from the
localization of inositol lipids or the lack thereof, and also
consider the location of the enzymes both for the production and elimination. Even though it seems counterintuitive
to have both the kinase and the phosphatase enzymes at the
same place apparently working against one another, it
makes perfect sense if one sees this arrangement as a rapid
cycling between active and inactive forms of a regulator (a
lipid, in this case) just as it happens with small GTP binding
proteins with their GEFs and GAPs (see this analogy discussed in Ref. 85) (FIGURE 13).
A. ER
PHOSPHOINOSITIDES
GEF
GAP
PI ptase
O
O
O
O
PI kinase
O
O
HO P
O
O
GTP
HO P
OH
OH
HO
P
GDP
OH
HO
P
P
FIGURE 13. The general principle of signaling by phosphoinositides. There are a large number of molecules that
possess domains capable of recognizing phosphoinositides (effectors). These domains usually also detect the
GTP-bound form of small GTP-binding proteins. The coincidental detection of the G protein and the inositol lipid either
recruits the effector to the membrane or induces a conformational change in the molecule. The effector is usually
found in a macromolecular complex that also contains the lipid kinase (and probably the phosphatase) as well as the
GEF and GAP proteins of the small GTP binding protein. The “regulation” of the effector then depends on the speed
of the respective activation-inactivation cycles on phosphoinositides and G proteins. In this model, the strict
lipid-specificity of the effector is less important than the identity of the enzymes that are part of the protein
signaling complex. This model also explains why enzymes producing or eliminating the same lipid cannot
substitute for one another’s functions. Note that there is no need to substantially increase the level of the lipids
in the membrane where these processes take place. This model assumes some sort of “channeling” lipids to
the effectors. It is important to note, however, that this may not be the sole mode of regulation by inositol lipids,
and there are other situations where the overall lipid levels show larger changes, and the “free lipid” produced
is available for multiple inositol lipid interacting proteins. These latter ones might be more easily detectable with
our current molecular tools. The question of how to limit the diffusion of lipids is a critical one to maintain
specificity and local control in either case.
The known effectors regulated by PtdIns4P at the Golgi can
be grouped into three categories: the first includes clathrin
adaptors, both the tetrameric forms, such as AP-1 and AP-3
(1330, 1680) and the monomeric GGA proteins (344,
1671). These proteins can bind PtdIns4P, and in mammalian cells their Golgi/TGN recruitment is closely associated
with the functions of the type II PI4Ks (344, 1671). However, in yeast, the Golgi binding of the AP-1 and Gga2p
proteins is functionally linked to Pik1p (316, 344). A significant complexity is layered on this process by the fact that
the Golgi recruitment of either the clathrin adaptors or the
Pik1p/PI4KB enzymes depends on the activation of Arf1
proteins (512, 514). This is clearly illustrated in a recent
study showing in yeast that AP-1 and Gga2p are sequentially recruited to the TGN membrane and that PdIns4P
made by Pik1p determines how tightly these two events are
coupled. Moreover, Pik1p itself is helped in its recruitment
by direct bidning to Gga2p (316) and also to the Arf1 GEF
protein, Sec7p (512). It is clear from these yeast studies that
Arf1- and PtdIns4P cycling is tightly coordinated at the level
of both the regulators (Arf1 GEFs and PI4Ks) and the effectors (in this case the clathrin adaptors) at the Golgi/TGN
compartment. The mutual reliance on a physical association between PI4K2A with AP-3 in the localization and
functions of these two proteins has also been shown in
mammalian cells. Here, PI4K2A is both a regulator of AP-3
and a “cargo” via its dileucine-based sorting motif, and
these two proteins are mutually required for correct localization and for proper sorting of cargos to the lysosome
(298). More details on the dual requirement for Arf1 and
PtdIns4P of clathrin-dependent sorting out of the Golgi can
be found in several recent reviews (314, 315, 523).
The second group of effectors is comprised of lipid binding
proteins. Notably, most PH domains that recognize
PtdIns4P are found in proteins that transfer lipids between
membranes (381, 894, 1783). These include the mammalian oxysterol binding protein (OSBP) (894), some of its
mammalian homolog ORPs (1167), and the yeast homolog
OSH proteins (893, 1304, 1783). Further members of this
group are the ceramide transfer protein CERT (564, 895)
and the glycosyl-ceramide transfer protein FAPP2 (381,
513) and its truncated sister protein, FAPP2 (381). All of
these proteins contain PtdIns4P binding PH domains that
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Effector
TAMAS BALLA
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important for lipid transport and maintenance of lipid homeostasis, it is expected that the lipid composition of membranes have an impact on PtdIns4P levels. Indeed, spingolipids were found to be important for the PM association of
the yeast PIP 5-kinase Mss4p (806). Similarly, an association was found between the Sac1 PtdIns4P phosphatase and
the Orm proteins that control the rate-limiting step in sphingolipid syntheis in yeast. This also suggests a link between
sphingolipid status and PtdIns4P regulation (178). Although much less is known about lipid regulation of PI
synthesis in mammalian cells, it is notable that the distribution, palmitoylation, and activity of PI4K2A is regulated by
the cholesterol content of internal membranes (949, 1686).
A third and different kind of PtdIns4P effector was discovered by a study that identified novel PtdIns4P-binding domains (357). This study found that the mammalian Golgi
protein GOLPH3 binds specifically to PtdIns4P and controls Golgi morphology by forming a bridge between the
Golgi membranes and the actin cytoskeleton through its
binding to unconventional myosin, MYO18A (357). This
finding that linked Golgi morphology to the actin cytoskeleton was somewhat surprising in light of the well-documented importance of the microtubular rather than the actin network in the maintenance of Golgi structure. The
yeast homolog of GOLPH3, Vps74p, also binds PtdIns4P,
and its steady-state Golgi localization requires Pik1p (357,
1731). The Vps74p protein was found necessary to retain
several gycosyl-transferases in the Golgi (1365) and was
identified as an essential component of the retrograde trafficking of these enzymes (1731). These studies also suggested that in addition to regulating anterograde trafficking, Pik1p was also important for the retrieval of specific
cargoes, namely, Golgi glucosyltransferases. Curiously, the
GOLPH3 locus is amplified in a number of human cancers
and was linked to oncogenesis through enhanced mTOR1
signaling (1371). How these three aspects of GOLPH3/
Vps74 biology are linked together is an exciting question
that is surely being studied in several laboratories.
C. Endosomes and Lysosomes
Endosomal function is a term that covers a lot of processes.
Newly synthesized molecules leaving either the ER or the
Golgi (where PtdIns4P is the critical regulatory PI lipid)
have to be sorted either toward the PM or the lysosome. At
the same time, the PM undergoes constant internalization [a
process where PtdIns(4,5)P2 is a major controlling PI lipid]
and the internalized membranes and luminal contents have
to be sorted either to the lysosome for degradation or back
to the PM (FIGURE 11). During these processes membrane
vesicles fuse, their membranes and luminal contents can
mix, and then the membranes get separated segregating
both luminal and membrane components to form new vesicular entities. At all of these steps, PI lipids, namely,
PtdIns3P, PtdIns(3,5)P2, and PtdIns4P have fundamental
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require both Arf1-GTP and PtdIns4P for Golgi association
(895). The recently solved structure of the FAPP1 PH domain identified separate binding sites for binding of these
two regulatory components (587, 885). An important common feature of all of these lipid-transfer proteins is the
presence of a FFAT [two phenylalanines (FF) in an acidic
tract] motif that provides an ER-association signal via interaction with ER-localized VAP (VAMP-associated) proteins (747, 931, 1049). Both the FFAT domain and the PH
domain is essential for the lipid transfer (but not lipid cargo
binding) functions of the proteins (564, 769, 1210), although the exact mechanism of how PtdIns4P regulates this
process remains obscure (1262). The obvious question regarding the physiology of these proteins is which PI4K(s)
are associated with their functions. Based on studies using
the isolated PH domains of these proteins, their Golgi localization is supported by both PI4KB and PI4K2A (84), but
the OSBP and FAPP1 PH domains show slightly different
localization, and more importantly, their overexpression
distorts Golgi structure differently (94). This probably reflects their PtdIns4P-dependent binding to additional and
different proteins. When studying the lipid transfer functions of these proteins, it was found that ceramide transfer
by CERT (that is needed for SM synthesis) relies on PI4KB
more than PI4K2A (313, 1567), whereas FAPP2-mediated
GlcCer transfer (required for synthesis of complex glycosphingolipids) is linked to PI4K2A more than to PI4KB
(313). However, this kinase preference may not be absolute
as the upregulation of SM synthesis by oxysterols was
shown to depend on PI4K2A (97). In yeast, where the type
II PI4K homolog Lsb6p is not a major Golgi regulator, the
Golgi recruitment of all of the OSH proteins studied were
dependent on Pik1p (1783). Moreover, the unique OSBP
homolog Kes1p, the deletion of which alleviates the need
for the PI transfer protein Sec14p (902), has a complex
sterol-regulated antagonistic relationship with TGN/endosomal PtdIns4P signaling (1089). Recent studies have
shown that Kes1p (also called Osh4p) exchanges sterols
picked up from the ER for PtdIns4P at the Golgi membrane
and, hence, the Golgi PtdIns4P made by Pik1p drives
Kes1p-mediated sterol transport between the ER and Golgi
membranes (339). This suggests a reciprocal relationship
between PtdIns4P controlling lipid transfer and lipid transfer proteins regulating PtdIns4P-mediated signaling. The
existence of additional links between PI4Ks and lipid metabolism is revealed by yeast studies finding genetic interactions between Stt4p and sphingolipid synthesis (1510). Although this connection is more closely related to the role of
Stt4p in producing PtdIns(4,5)P2 at the PM (415), an ERcomponent is indicated by the synthetic lethality (1510) and
physical association of Stt4p (502) with the ER-localized
Scs2p protein, the yeast homolog of the mammalian VAP
proteins. Moreover, Scs2p was shown to bind phosphoinositides, and this binding was found important for Scs2p
function (745). There have been no similar studies described for PI4KA in mammalian cells. Finally, if PI4Ks are
PHOSPHOINOSITIDES
roles. This is a huge research area that will be summarized
here only with broad brush strokes.
1. PtdIns3P and PtdIns(3,5)P2
in endomembranes
For example, soluble proteases have to reach their destination, the lysosomes. For these proteins, special receptors
exist such as the yeast Vps10p and the mammalian mannose-6-phosphate receptor (M6PR). These transmembrane
proteins cycle between the Golgi and prevacuolar compartments, with each round delivering a batch of enzymes for
Another role of PtdIns3P is to promote homotypic fusion of
endocytosed uncoated vesicles. For this, tethering by the
EEA1 proteins and Rab5 are both essential (1409). However, not all endocytic vesicles are equal, and different cell
surface receptors are already routed to different destinations even at the early steps of the endocytic process. FYVE
domain containing proteins other than EEA1, such as
WDFY2 (585), can define special endocytic compartments
with unique signaling properties (1665). The recycling of
several receptors back to the cell surface requires PI3Ks (2,
670, 886, 1601). In this process, proteins are retrieved at
different stages of vesicle maturation as they progress from
early endosomes to late endosomes. A whole set of PtdIns3P
binding proteins participate in this process that seems to be
different for specific groups of molecules. Various PX domain-containing SNX proteins were identified as uniquely
important for these processes (305, 307). For example,
SNX4 controls trafficking of TfRs between the early and
recycling endosomes (1571), and SNX3 is central to a newly
recognized unique retromer pathway by which the Wnt
sorting receptor Wntless is retrieved from the endosomes to
the TGN (307, 576). Yet another SNX, SNX17, which has
a FERM domain that recognizes NPxY sequences on transmemembrane proteins, is important for LDL-like receptor
cycling (372, 1472) as well as the maintenance of integrins
in the PM (1456).
Molecules that are not recycled back to the PM are taking a
route toward degradation. This process uses another form
of cargo selection that is based on poly-ubiquitylation,
which can also serve as part of ER quality control of misfolded proteins. Many PM proteins such as RTKs that undergo endocytosis and are destined for degradation become
multi- or polyubiquitylated and recognized by proteins that
possess Ubi-binding domains. Here the Vps27 protein and
its mammalian homolog Hrs are master regulators, both
having a FYVE domain and being regulated by PtdIns3P
(73, 146, 766, 1250, 1447). The central compartment
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Identification of the yeast Vps34p protein as a PI 3-kinase
was a major milestone in highlighting the importance of
PtdIns3P in intracellular trafficking (1367). It was soon followed by the recognition that a unique cysteine-finger protein module present in several proteins, namely, the yeast
Fab1, the C. elegans YOTB/ZK632, the yeast Vac1, and the
mammalian EEA1 (hence comes the name FYVE domain)
(1090), is necessary to target the EEA1 protein to endocytic
membranes (1458), and it is a PtdIns3P recognition module
(200, 501, 836, 1064). FYVE domains have since been
found in a great number of proteins (1457), and it has been
firmly established that PtdIns3P, together with Rab5 proteins controls endocytic vesicle fusion (1100, 1409). The
yeast PI3K Vps34p is essential for sorting proteins to the
yeast vacuole (605, 1367), and among the FYVE domain
containing proteins, the yeast Fab1p turned out to be a
PtdIns3P 5-kinase that was necessary for maintaining vacuolar morphology and function (498, 1757). These studies
have established PtdIns3P and PtdIns(3,5)P2 as key lipid
regulators of endocytic trafficking. Another PtdIns3P binding module called phox-homology (PX) domain was later
found in several proteins such as the sorting nexins (SNX)
(304, 1540). Although the first PX domains were found to
bind PtdIns3P (752, 1750), and all yeast PX domains bind
this lipid (1782), some metazoan PX domains bind
PtdIns(4,5)P2 (327, 810), and the lipid-binding specificity of
many mammalian PX domains remains unknown. It is also
important to note that PX domains also bind proteins
(1540, 1643). Recent studies also suggest that class II PI3Ks
produce some of the PtdIns3P in higher eukaryotes (370,
970, 1700), and the molecular cloning of the type II PI4Ks
(108, 1058) revealing their presence in endosomes (83,
1060) also suggested the involvement of these latter enzymes in endocytic trafficking in mammalian cells (83,
1060). PtdIns3P controls several aspects of the biology of
endosomes. It has a role in targeting newly synthesized lysosomal proteins to the lysosomes (vacuole in yeast), and it
also controls retrieval of proteins from the lysosome to
endosomes. It regulates the sorting of endocytosed cargoes
for recycling or degradation and also plays a critical role in
autophagy, a process by which starving cells degrade their
own cytoplasm and organelles (1631). For all these different processes, a whole set of regulatory proteins are recruited to the endocytic membrane in specific sequences.
further sorting to the lysosomes. As pointed out in earlier
sections, PtdIns4P is important for the exit of these transport carriers from the Golgi using clathrin-coated vesicles.
However, retrieval of Vps10 from the endosomes relies on
other inositol lipids and proteins that form a complex called
the “retromer” (1373). In yeast, Vps29, Vps30, and Vps35
are important components of the retromer (1373), and one
of these, Vps30, as well as another protein, Vps38, are both
accessory proteins to the PI 3-kinase Vps34 (201). Moreover, two proteins, important for vesicle budding, Vps5 and
Vps17 that are also part of the retromer (1372) possess PX
domains that bind PtdIns3P (201). The mammalian Vps5
homologs SNX1 and SNX2 play similar roles in mammalian cells as part of the mammalian retromer complex.
SNX1 shows PtdIns3P and PtdIns(3,5)P2 binding via its PX
domains (297) and was found responsible for retrograde
trafficking of the M6PR (213, 307).
TAMAS BALLA
Another important endomembrane process that requires
PtdIns3P is autophagy (more precisely, macroautophagy)
(281, 1073). Starving cells use this process to degrade a
fraction of their cytoplasmic proteins and organelles, such
as mitochondria. The hallmark of this process is the formation of a double membrane from internal membranes (also
called phagophore), the origin of which is somewhat debated but likely being the ER with mitochondrial and possibly other membrane participation (548, 1565). This membrane gradually engulfs a piece of the cytosol and organelles
to be degraded and eventually fuses with the lysosome. The
phagophore can be recognized because of its high enrichment of the protein LC3 (microtubule-associated protein
light chain 3, Atg8p in yeast) that gets phosphatidylethanolaminated, a unique lipid modification characteristic of this
process (675). The initiation of the phagophore requires the
class III PI3K, Vps34, its regulator, Vps15, and Atg6/Beclin1 forming a core complex. There are several additional
proteins associated with this complex that play a role in the
maturation and subsequenct fusion of the autophagosome
with the lysosome, and some are shared with the vacuolar
sorting pathway. For example, the Vps34/Vps15/Atg6
complex related to autophagy (also called complex I) contains Atg14 (Barkor/Atg14L in mammalian cells), whereas
complex II that functions in vacuolar sorting contains
Vps38 (UVRAG in mammals) instead of Vps14/Barkor
(234, 1157). It is not surprising that some of the steps in
phagophore maturation and lysosomal fusion show the
same PI3K involvement as the vacuolar sorting pathway.
What was surprising, though, was the finding that autophagosome formation also requires PtdIns 3-phosphatases,
1084
such as Jumpy (MTMR14) (1631, 1632), which suggests
that the turnover of PtdIns3P must be more important than
the actual levels during this process. Although the literature
of autophagy is increasing every day with intimidating complexity (281, 1073), the exact role(s) of PtdIns3P in this
process remains to be understood.
An important point to be emphasized is the close connection between autophagy and nutrient sensing, both of
which have 3-phosphorylated inositide regulatory components (FIGURE 14). All metabolic processes in the cell have
to be harmonized with the supply of nutrients, and the
central hubs for this information network are the TOR
proteins identified in 1991 as the yeast targets of the drug
rapamycin (592). The TOR protein (TOR1 and TOR2 in
yeast, and mTOR in mammalian cells) is a Ser/Thr kinase
that belongs to the PI kinase-related kinase family and is
evolutionary highly conserved. The mTOR catalytic subunit exists in two functionally distinct protein complexes,
mTORC1 and mTORC2 (454). Each of these complexes
contains several proteins, some of which are shared, but
mTORC1 contains Raptor, while mTORC2 contains Rictor as unique scaffolding protein components. Rapamycin
binding to FKBP12 induces a complex formation with
mTORC1 (but not mTORC2), which, in turn, allosterically
inhibits mTORC1 activity, explaining why acute rapamycin treatment only inhibits mTORC1. mTORC1 collects
information through various pathways on cellular stress,
energy levels, amino acids, and growth factors and controls
cell growth, metabolism, cell cycle progression, and macroautophagy (854). In contrast, mTORC2 is regulated by
growth factors and acts on several downstream AGC protein kinases to control actin cytoskeleton, apoptosis, and
cell proliferation (454). It is beyond the scope of this review
to get a detailed summary of the mTOR literature (for reviews, see Refs. 454, 854, 1830), but there are important
connections between mTOR and PI3Ks that are worth mentioning. Most, if not all, growth factors activate the PI 3-kinase signaling cascade at the cell surface, primarily the class I
p85/p110␣ complex. The resulting PtdIns(3,4,5)P3 engages a
range of proteins that signal to mTORs. PtdIns(3,4,5)P3 recruits to the membrane both the PDK1 protein kinase and
its downstream target, the Akt/PKB kinase, via their PH
domains that bind PtdIns(3,4,5)P3 [and PtdIns(3,4)P2].
PDK1 phosphorylates Akt/PKB at position Thr308, and
another phosphorylation at Ser473 within the hydrophobic
motif, carried out by mTORC2, is needed for full activation. PtdIns(3,4,5)P3 also activates mTORC2 kinase activity by a poorly understood mechanism (489, 1430). Akt/
PKB have several downstream targets that are part of the
cell survival pathway (860, 1620, 1806). Akt/PKB inactivates the TSC1-TSC2 (hamartin-tuberin) complex, which is
a critical inhibitory regulator of mTORC1 (491, 697,
1541). The TSC1/2 complex is a GTPase activating protein
for the Rheb (Ras homologue enriched in brain) GTP binding protein that integrates signals from energy levels, O2
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where proteins are sorted for degradation is the MVB where
the sequential assembly of a protein complex called the
ESCRT machinery (ESCRT-0, -I, -II, and -III complexes) is
essential for segregation of the ubiquitylated proteins into
inwardly invaginating membranes (70, 71, 671, 765).
PtdIns3P and Vps27/Hrs are necessary for the recruitment
of the ESCRT-0 and hence the subsequent members of the
complex to the MVB (73, 766, 1251, 1542). ESCRT-I does
not show PtdIns3P binding on its own (821), but ESCRT-II
does via the PH domain-like GLUE domain of Eap45 (the
mammalian Vps36) (1416). ESCRT-III complexes are the
ones that deform membranes of the MVB and generate the
inwardly budding vesicles (567, 1327), and several proteins of
this complex, such as CHMP3 (and its yeast homolog Vps24p)
(1710) and CHMP2a and CHMP4b (225) can bind PtdIns3P,
PtdIns(3,5)P2, or both. Recent studies reconstituted the assembly and lipid deforming effects of the ESCRT machinery
in giant unilammellar vesicles in vitro and only found a
moderate enhancement of intraluminal vesicle release by
PtdIns3P or PtdIns(3,5)P2 (1723). Although this finding
suggests that these lipids promote but are not essential for
this reaction, they probably play a significantly more important facilitating role within the cell where these proteins
are not supplied in such abundance.
PHOSPHOINOSITIDES
Growth factors
PtdIns(4,5)P2
PtdIns(3,4,5)P3
PI3KCI
PtdIns(3,4)P2
SHIP
Plasma membrane
PDK1
mTORC2
Akt
Energy status
(AMP )
PI3KC2
PtdIns3P
PIKfyve
Tsc1/Tsc2
REDD1/2
Stress
Hypoxia
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PtdIns
AMPK
Rheb
PtdIns(3,5)P2
Endosomes-lysosomes
Autophagy
mTORC1
RagA-D
PLD1
PtdIns
hVps34/hVps15
p70S6K
PtdIns3P
Endosomes-lysosomes
PtdIns
hVps34/hVps15
Amino
acids
??
PtdIns3P
Endosomes-lysosomes
Proliferation
FIGURE 14. Integration of metabolic control, cell growth and proliferation, and their regulation by phosphoinositides. One of the main effectors of PI3K activation is the Akt/PKB protein kinase that is activated by translocation to
the membrane by binding via its PH domain to PtdIns(3,4,5)P3 [and PtdIns(3,4)P2]. This recruitment is important
for phosphorylation of Akt/PKB by two protein kinases, PDK1 (on Thr308) and the mTORC2 complex (on Ser473).
These two kinases are also activated by PtdIns(3,4,5)P3. Although Akt signals in a number of other directions (not
shown here for simplicity), one of its major functions is to control the activity of the mTORC1 complex. Active Akt
stimulates mTORC1 by inhibiting the GAP activity of the TSC1/2 complex, the latter limiting the activity of the Rheb
GTP binding proteins that are upstream activators of the mTORC1 complex. Active mTORC1 is a signal for cell
growth and proliferation and inhibits apoptosis and autophagy. In case of starvation, energy depletion, stress, or
hypoxia, mTORC1 is inhibited, and these signals activate the TSC1/2 complex. Under these conditions autophagy
is stimulated. A different pathway is used during amino acid sensing. Amino acids activate the Rag GTPases and
induce translocation of the mTORC1 complex to the surface of the lysosomes. The classIII PI3K hVPS34 is also
important for the amino acid sensing pathway for mTORC1 activation using a pathway that works parallel to the Rag
GTPases and which requires PLD1, and PtdIns3P binding to the PX domain of PLD. Recently, the class II PI3Ks and
PtdIns(3,5)P2 production was also shown to stimulate mTORC1. Paradoxically, autophagy also requires PtdIns3P
and VPS34, and it is most likely that the VPS34 that serves as a mediator of mTORC1 activation by amino acids
works in a different complex and location than the one that promotes autophagy.
supply, and growth factors (985). The amino acid sensing,
however, is mediated by a different pathway that involves
the Rag GTPases (785, 1336) and one that requires translocation of the mTORC1 complex to the surface of the
lysosomes (1335, 1829). Curiously, the Class III PI3K
hVPS34 was found to be important for the amino acid
sensing pathway for mTORC1 activation (536, 1143). It
has also been shown that this pathway works parallel to the
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TAMAS BALLA
Rag GTPases and requires PLD1 and binding of PtdIns3P
made by hVPS34 to the PX domain of PLD1 (1773). Since
mTORC1 inhibits autophagy, and autophagy also needs
VPS34, it is most likely that the VPS34 that serves as a
mediator of mTORC1 activation by amino acids is found in
a different complex and location than the one that promotes autophagy. Another study found that inositol
phosphate multikinase (IPMK) also has a noncatalytic
role keeping the mTORC1 complex together during its
translocation to the lysosomal surface (791). More studies are needed to explore the complex PPI regulation of
the mTOR-metabolic network with special emphasis on
the compartmental organization and membrane association of these complexes.
1086
Although PtdIns4P has been primarily linked with Golgi
and PM functions, the endosomal localization of type II
PI4Ks suggests that this lipid may also be important for
certain trafficking steps in endosomes. Knock-down of
PI4KII␣ abolished the Golgi recruitment of the heterotetrameric adaptor AP-1 (1680), and also impaired the recruitment of AP-3 in endosomes (1330). PI4KII␣ was also
shown to regulate the late-Golgi transport of VSV-G and
influenza hemagglutinin (1680). The type II PI4Ks were
implicated in transferrin receptor endocytosis and recycling
(83), and PI4KII␣ has a major role in EGF receptor degradation in the late endosomal pathway (1060). Recent studies showed that knock-down of type II PI4K␣ causes enlargement of prelysosomal/lysosomal compartments (298,
741, 1128), and PI4K␣ is required for lysosomal delivery of
the Gaucher disease enzyme ␤-glucocerebrosidase and its
receptor, LIMP-2 (741). It will be important to understand
where and how the PtdIns4P to PtdIns3P switch happens in
the various endocytic compartments. Transport vesicles
coming from the ER and the Golgi contain PtdIns4P. Moreover, the endocytosed vesicles also should have PtdIns4P as
a result of the action of numerous 5-phosphatases. All of
these internal vesicular intermediates will have to lose their
PtdIns4P and acquire PtdIns3P. How this process is regulated enzymatically and why this switching is important are
questions still to be investigated.
D. Nucleus
The presence of several enzymatic activities related to the
“PI cycle,” such as PLC, DG kinase, and PI kinase in nuclear
matrix, raised the possibility that a separate nuclear phosphoinositide system exists (275, 1205). Since PPIs are presumed to be membrane associated, the presence of the lipid
as well as the enzymes in the nucleus initially raised suspicions that contamination with nuclear membranes might be
responsible for these activities. However, phosphoinositide
changes in the nuclei of Swiss 3T3 cells stimulated with
IGF-I were found significantly different from those elicited
at the PM, and the nuclear lipids were identified in the
nuclear lamina rather than in the membranes (360, 1001).
With the cloning of the various PI lipid metabolizing enzymes and the availability of antibodies for immunofluorescence, it has become clear that many enzymes of the PI cycle
do localize to the nucleus. These include several isoforms of
PLC enzymes [␤1 (451, 952, 987), ␦1 (302, 1448), and ␦4
(925)], both forms of the type III PI4Ks [PI4KA (748) and
PI4KB/Pik1 (332, 343, 1478)], the yeast PIP 5-kinase Mss4
(62) and the mammalian PIP 5-kinase I␣ (168, 1029), and
the type II PIPK␤ (263). In addition to the kinases, inositide
phosphatases were also shown to move in and out of the
nucleus. An increased nuclear retention of PTEN was
shown after oxidative stress (229), and the Ser132-phosphorylated SHIP2 was found localized to the nucleus and
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Significantly less clear are the mechanistic details of how the
PtdIns3P to PtdIns(3,5)P2 conversion controls the lysosomal sorting process and the relevant downstream targets
of the lipid PtdIns(3,5)P2 (377). It is well established that
Fab1p deleted yeast strains have huge vacuoles and impaired transport of CPY to the vacuole (498). These defects
are also associated with weakened vacuole acidification
(1159) and chromosomal segregation defects, the latter
probably secondary to the enlarged vacuoles (1757). However, autophagy in yeast does not require PtdIns(3,5)P2
(379). The limited known PtdIns(3,5)P2 targets include the
PROPPINs that are seven ␤-propeller containing proteins,
such as the yeast Atg18p (also known as Svp1p) (379) or its
mammalian homolog WIPI1(725). Atg18p and WIPI1 and
the other PROPPINs (Atg21p and WIPI1– 4) are important
in autophagy (397, 533, 825, 1238). Atg18p depletion
leads to PtdIns(3,5)P2 accumulation and to enlarged vacuoles, a phenotype similar to that of Fab1p deletion, indicating a role in determining vacuolar size (397). However, as
pointed out above, the sorting of hydrolyses and initiation
of autophagy are two separable functions of Vps34p linked
to complex II and complex I, respectively (779, 825). Since
autophagy in yeast does not require PtdIns(3,5)P2 (379),
Atg18p may have a dual role: it could be important for
autophagy as a PtdIns3P effector and for vacuolar morphology as a PtdIns(3,5)P2-regulated protein. A recent study
also found that PtdIns(3,5)P2 regulates the activation and
localization of mTORC1 in mammalian cells and that the
lipid interacts with the mTORC1 component raptor (180).
Another group of effectors of PtdIns(3,5)P2 was recently
identified as the mammalian TRPML proteins or mucolipins and their yeast homolog, Yvc1/TRPY1 (371). These are
endolysosomal cation channels that are mutated in various
forms of mucolipidosis (233, 246). In yeast they are regulated by cytoplasmic Ca2⫹ and activated by hyperosmotic
shock (233), the latter also being a strong inducer of
PtdIns(3,5)P2 (376). This is a new area of research that will
rapidly expand and help us understand the conrtrol of lysosomal ion composition and function and the role of
PtdIns(3,5)P2 in the process.
2. The role of PtdIns4P in endomembranes
PHOSPHOINOSITIDES
also becoming active against PtdIns(4,5)P2 (400). Moreover, the lipid PtdIns(4,5)P2 itself could be localized by
antibodies or by PtdIns(4,5)P2 recognizing PH domains in
the nuclear matrix, especially enriched in nuclear speckles
(1087, 1176, 1684), the dynamic organelles that have high
pre-mRNA splicing activity (849).
Although PtdIns(4,5)P2 appears to be the most abundant
and recognized nuclear phosphoinositide, studies on type II
PIPKs that phosphorylate PtdIns5P to PtdIns(4,5)P2 revealed an unexpected twist in their nuclear functions. The
nucleus-localized PIPKII␤ (263), most likely in the form of
a heterodimer with the catalytically more active PIPKII␣
(1672), has an equally, if not more, important role in regulating PtdIns5P levels than controlling nuclear PtdIns(4,5)P2
(522). PtdIns5P has been linked to stress-induced nuclear
signaling and apoptosis (737, 1833). The protein that responds to nuclear PtdIns5P is ING2, which specifically
binds this lipid with its PHD domain. The ING2 protein
associates with histone deacetylases and the chromatin
(522, 837) and, hence, regulates histone acetylation. ING2
induces apoptosis via increased p53 acetylation both of
which requires PtdIns5P (522). PtdIns5P levels are then regulated either by inhibition of PIPKII␤ (such as in stress
responses where p38 MAPK phosphorylates PIPKII␤) (522)
or by stimulation of the type I PtdIsn(4,5)P2 4-phosphatase
(1833). Another mechanism by which PIPKII␤ and PtdIns5P
regulates nuclear functions is the association of the kinase with
a nuclear ubiquitin ligase, Cul3-SPOP and stimulation of its
activity (198).
The presence of PLC and DG kinase enzymes in the nucleus
also suggest that Ins(1,4,5)P3 and DG formation both can
initiate further nuclear signaling events. Nuclear Ca2⫹ signaling initiated from the nuclear membrane-derived intranuclear canaliculi has been demonstrated (396). However, this is not the only way Ins(1,4,5)P3 can be utilized.
Ins(1,4,5)P3 can be phosphorylated to higher inositol phosphates, and these soluble, highly charged molecules have
been found to be critical for mRNA export (1777). The
enzymatic pathways of InsP6 formation and their importance have been first described and delineated in yeast studies (1158, 1455), but these metabolites had already been
described earlier in mammalian cells (86, 610, 1466, 1776).
By now all the enzymes producing them have been identified
and cloned (1629, 1719). These pathways are essential in
development of higher organisms (463, 1628). The higher
inositol phosphates have multiple regulatory functions in
the nucleus that have been recently reviewed and will not be
further detailed here (28, 1324, 1375, 1390, 1455).
XI. PHOSPHOINOSITIDES IN DISEASE
A. Somatic Diseases
It may be an exaggeration, but with some efforts every
human disease can be linked to altered inositol lipid metabolism. Although phosphoinositides are likely to be important in multifactorial diseases, it is easier to define the role of
these lipids in disorders caused by a clearly identifiable single defect in inositol lipid metabolizing enzymes or effector
proteins. Some of these are profoundly apparent, such as
the combined immunodeficiency seen in Bruton’s tyrosine
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There are two major questions raised by these findings; one
is related to the physical state of the lipids and another to
the nuclear proteins that are regulatd by the nuclear lipids.
Although we have yet to find answers to the first question,
our mind has to be open to the possibility that nuclear lipids
may exist in association with proteins, or forming a unique
lipid phase like a micelle or liposome. For example, phospholipids, including phosphoinositides, have been found
tightly bound to nuclear receptors (151, 828, 903). This
does not rule out that phosphoinositides are functionally
important in the inner nuclear membrane, where several
studies showed their presence (204, 496, 1421). This latter
might be significant in light of the nuclear Ins(1,4,5)P3 (519)
and Ca2⫹ signals (396) and the high transcriptional activity
located in juxtamembrane regions of the nucleus (20,
1512). There have been more advances in the identification
of nuclear proteins that respond to lipid changes. A noncanonical poly(A) polymerase, named Star-PAP, has been
identified as a protein that interacts with PIPKI␣ in nuclear
speckles (1029). This protein adds poly(A) tails to a selected
group of mRNAs, and its activity is highly stimulated by
PtdIns(4,5)P2 (1028, 1029). Curiously, a low activity form
of a DNA polymerase was also shown to be activated by
PtdIns4P or its hydrolytic product, Ins(1,4)P2 (1507, 1508).
In addition to these mechanisms, PtdIns(4,5)P2 may have an
indirect role as a precursor of other regulators. The
PtdIns(3,4,5)P3-Akt pathway was shown to regulate
mRNA splicing, although it is not clear at what location
Akt needs to be activated (148, 1709). It is generally believed that the classical PI3Ks are not associated with the
nucleus (but see Refs. 831, 998), even though ample evidence suggests that PI3Ks control nuclear signaling (e.g.,
Ref. 781, 1809). However, the nucleus-localized inositol
polyphosphate multikinase (IPMK) was shown to function
as a PtdIns(4,5)P2 3-kinase (1269) capable of activating Akt
(962). Still, in a somewhat convoluted manner, the nuclear
IPMK lipid kinase activity requires the formation of
PtdIns(3,4,5)P3 in the PM by the class I PI3Ks, presumably
controlling the phosphorylation state of IPMK (962). Recent studies showed that IPMK-phosphorylated PtdIns(4,5)P2
was bound to the nuclear receptor steroidogenic factor 1
(SF-1) and PTEN was able to reverse this reaction (151). In
the same study, IPMK was unable to phosphorylate free
PtdIns(4,5)P2 and, conversely, class I PI3K could not phosphorylate PtdIns(4,5)P2 bound to SF-1. These results also
speak to the question of the physical form(s) the lipids may
take up in the nucleus.
TAMAS BALLA
kinase patients, due to a single mutation within the PH
domain of the Btk tyrosine kinase that prevents its interaction with PtdIns(3,4,5)P3 (1260). Others cause more subtle
aberrations such as the activating mutations of PLC␥2 in
patients with spontaneous inflammations, cold urticaria,
and autoimmunity (414, 1169).
Apart from the class IA PI3Ks, human diseases are rarely
caused by activating mutations of inositide lipid kinases. In
contrast, an increasing number of rare human diseases are
linked to phosphoinositide phosphatase defects. These have
been discussed in the respective individual sections but will
be listed here in TABLE 5.
The general lesson learned from these studies is that these
phosphatase defects cause very specific phenotypes because
the affected enzymes control a very specific pool of the
inositol lipid, and for these narrowly defined biochemical
events, the other enzymes do not provide alternative coverage in spite of their identical enzymatic activities. These
Table 5. Human diseases caused by defective inositol lipid phosphatases
Disease
Enzyme Defect
OCRL
OCRL 5-phosphatase
Dent disease
ALS, PLS (small %)
Charcot-Marie-Tooth type CMT4J
Downs syndrome??
Joubert syndrome
OCRL 5-phosphatase
Sac3/Fig4
Sac3/Fig4
Synaptojanin 1 trisomy?
INPP5E/Pharbin
X-linked myotubular myopathy
MTM1
Charcot-Marie-Tooth disease type CMT4B1
Charcot-Marie-Tooth disease type CMT4B1
Autosomal recessive centronuclear myopathy
MTMR2
MTMR13
MTMR14/hJUMPY
1088
Main Symptoms and Pathology
Early cataract, mental retardation, renal
tubular acidosis, aminoaciduria
Variable, milder forms of Lowe’s syndrome
Progressive degeneration of motor neurons
Peripheral sensorimotor neuropathy
Multiple neurological symptoms in CNS
Midbrain-hindbrain malformation,
retinodystrophy, nephronophthisis, liver
cirrhosis, polydactyly
Skeletal muscle weakness, centronuclear
myopathy
Peripheral neuropathy with demyelinization
Peripheral neuropathy with demyelinization
Centronuclear myopathy
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Reference
Nos.
61, 1483
647
252
253
1647
145
858
159, 653
69
1566
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A lot more human diseases are caused by excess phosphoinositides than the lack of them as exemplified by the cancer-causing elevations of PtdIns(3,4,5)P3. As detailed in section V, class I PI3K␣ mutations are found in a large percentage of human cancers (1190, 1333), and the same is true for
the loss of PTEN (210, 898), the phosphatase that converts
PtdIns(3,4,5)P3 back to PtdIns(4,5)P2 (968). There is general
agreement that PtdIns(3,4,5)P3 is an oncogenic lipid, and enormous information is available on how PtdIns(3,4,5)P3 can help
tumor cells to survive and metastasize. First and most importantly, PtdIns(3,4,5)P3 promotes both proliferation and
protects cells from apoptosis, two processes that are hallmarks of tumor cells. PtdIns(3,4,5)P3 activates numerous
GEF proteins that act on small GTP binding proteins such
as Ras, Rac, Rho, and Cdc42 and, therefore, can activate all
of the processes that are used for invasion and metastasis,
such as cell migration and attachment. The effects of
PtdIns(3,4,5)P3 can be cell autonomous, but they can also
affect the interaction of the cells with their tissue environment, something we still have to learn more about. This
may explain why certain cancers have preferential sites of
metastasis and avoid other organs. A fundamental question, however, that we still do not fully understand is
whether PI3K activation per se is sufficient to transform
cells. Several studies have shown that activating class I PI3K
mutations are sufficient to transform cells or generate tumors in mouse models (541, 758, 873). However, often in
these cancers other mutations show up that drive tumorigeneseis. It appears that cells need a driver for the transformation process, which will then be greatly aided by elevated
PI3K activation. Therefore, activating PI3K mutations may
just represent a sensitized state upon which any other oncogenic event can easily initiate the transformation process
(1785). Especially important is the connection between KRas mutations and PI3Ks in cancer cell growth. K-Ras can
activate all forms of class I PI3Ks, and hence is always
associated with increased PI3K activity. However, PI3K inhibition alone is not very effective in K-Ras mutant-driven
cancer cell lines (539), although it has been shown that
K-Ras-p110␣ interaction (539) or the presence of p85 subunits is important for K-Ras-induced carcinogenesis (404).
These data suggest that there could be a difference in PI3K
participation at the onset of cell transformation and during
the later phase of cancer expansion and maintenance (404).
Nonetheless, ample evidence suggests that PI3K inhibition
is a promising way of complementing cancer therapy. The
close connection between PI3K activation and mTORC1
(and -2) (1830) and the characteristic metabolic realignment of cancer cells (930, 1608, 1769) explain why PI3K
inhibitors and mTOR inhibitors are both in the frontiers as
potential cancer therapies and that combined PI3K/mTOR
inhibitors are also gaining significant momentum (600,
926, 1727).
PHOSPHOINOSITIDES
susceptibilities may depend on species and probably even
on other genetic modifiers as perfectly exemplified by the
OCRL disease that is not easily reproducible in mice (173)
and in which the apparently same enzyme defect can produce a range of symptoms with different severities (647).
B. Infectious Diseases
It has been increasingly recognized that various intracellular parasites utilize the host’s intrinsic cellular machinery to
enter the cells, move around, and evade the natural protective mechanisms (1204, 1225). In addition, many organisms, especially viruses, generate a platform for the reproduction of the organism and then get released from the cell
interior (38). Identification of host proteins that these
pathogens require at any point of their life cycle is an important goal that may uncover new therapeutic opportunities (777, 1239). Phosphoinositides, again, are important
regulators of many of these processes. For example, the
endocytosis of several pathogens uses the same routes by
which cell surface proteins enter the endocytic pathways
and hence rely upon PtdIns(4,5)P2 as detailed in section
IXD. Examples include the entry of bacteria such as Listeria
(1226, 1548), Yersinia (1340), enterohepatic E. coli (1348),
Salmonella (1544), or viruses such as hepatitis C (1577),
HIV (1069), or influenza (472), just to name a few from an
ever-increasing list. Another role of PtdIns(4,5)P2 and
PtdIns(3,4,5)P3 has been reported in filopod formation, actin polymerization, and movement of Listeria within the
infected cells (1405). PtdIns4P is also utilized by several
pathogens to shape their intracellular milieu. Legionella
pneumophila uses several of its virulence proteins, such as
SidC and SidM that bind PtdIns4P, to form its replicative
vacuole within the cell (188, 613, 1248, 1492, 1824). Another intracellular bacteria Clamydia uses both type II
PI4Ks and the OCRL 5-phosphatase to modify its vacuole
for production of infectious progeny (1080). Most recently
it was discovered that hepatitis C virus requires PtdIns4P,
specifically made by PI4KA for replication (122, 1513,
1577, 1597). It is not clear for what purpose PI4KA is
needed, but most likely generation of the “membranous
webb,” which serves as the replication platform of the virus
(1082), requires the PI4KA enzyme whose activity is stimulated by one of the viral proteins, NS5A (38, 910, 1267,
1514). Some enteroviruses, such as Polio or Coxsackie,
need PtdIns4P made by PI4KB to generate their replication
organelle (656). Development of specific PI4K inhibitors
now attracts a lot more interest than it did a few years ago.
Another process where phosphoinositides can be important
is the budding of viruses when they leave the cell. This
process uses several of the same lipid and protein regulators
that are required for the biogenesis of the MVB during the
formation of inwardly budding vesicles (1016), and inhibition
of PIKfyve-catalyzed formation of PtdIns(3,5)P2 was found to
inhibit retroviral budding (686).
Other pathogens do not rely upon the host cell’s phosphoinositide metabolizing enzymes to create the lipid environ-
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It is notable that loss of function of inositol lipid kinases is
rarely seen (or have not been yet recognized) in human
diseases. This either means that such mutations are incompatible with normal development [see the only report on an
inactivating mutation within the PIP 5-kinase I␥ gene that
causes severe developmental abnormalities with perinatal
lethality (1119)], or there is enough redundancy in the system to overcome such defects. However, it is quite likely
that more subtle functional defects, either structural or regulatory, contribute to the development of human diseases.
Given the role of the PI4Ks and classs III PI3K in ER-Golgi
and endosomal functions, respectively, it would be almost
surprising if they did not have a role in diseases where
protein misfolding and quality control problems are part of
the etiology such as in neurodegenerative diseases. A few
examples have started to appear in the literature: for example, mutations in one allele of the Sac3/Fig4 phosphatase
have been detected in 2% of ALS (amyotrophic lateral sclerosis or Lou Gehrig’s disease) and PLS (primary lateral sclerosis) patients (252). As discussed in section VI, this phosphatase also impacts the function of the type III PIP kinase
PIKfyve. PI4K2A gene-trapped mice develop late-onset
spinocerebellar degeneration (1408). Notably, though, no
mutations in the human PI4K2A gene were found in patients suffering from a similar condition (270). Given the
slow onset of many of these diseases (like Alzheimer’s or
Parkinson’s disease) and their multifactorial backround,
one would not expect to see a very drastic change attributed
to a phosphoinositide signaling defect but rather a subtle
one that will have a gradual and compounding effect on
protein trafficking and folding. Other subtle differences
could cause developmental alterations in the brain that do
not manifest in any recognizable anatomical abnormality,
but manifests in diseases such as schizophrenia, depression,
or autism. For example, the PI4KA gene is located in chromosome 22 in the q11.2 region that is often deleted in
“22q11.2 deletion syndromes” such as in DeGeorge syndrome or Velocardiofacial syndrome (808). A strong association has been observed between 22q11.2 deletion syndromes and schizophrenia (55, 111). Several obvious
schizophrenia susceptibility genes can be found in this chromosomal region, such as the catecholamine metabolizing
COMT, the DeGeorge critical region gene (DGCR6) and
the proline dehydrogenase gene (PRODH2) (227, 1730) or
SNAP29 whose promoter region also showed association
with schizophrenia (1729). However, some studies also
found association with an SNP in the PI4KA promoter region with the schizophrenia phenotype (1326, 1648) and
suggested that the PI4KA gene could be a modifier in cases
of schizophrenia associated with 22q11.2 deletion syn-
dromes (1648). It is almost certain that an increasing number of neurological and psyhiatric diseases will be linked to
altered phosphoinositide metabolism (269).
TAMAS BALLA
A lot more details about these processes can be found in
several recent reviews (290, 613, 1204). Nevertheless,
even this short summary makes it clear that pharmacological targeting of phosphoinositide metabolizing enzymes could be beneficial in fighting a variety of infectious agents and, indeed, has already attracted significant
attention (38, 144, 243).
XII. CONCLUDING REMARKS
Even a lengthy review like this is unable to cover all of what
has been learned about phosphoinositides over the last 50
1090
years. It is clear that these lipids are fundamental in the
regulation of all aspects of membrane dynamics in eukaryotic cells. However, it is also clear that we do not have a
clear understanding of the overall underlying principles of
how these lipids work and why we run into them wherever
we look in biological research and medicine. The arrival of
such a fundamental understanding will be marked when a
single short paper can summarize much of what is covered
here in hundreds of pages. From an evolutionary and teleological standpoint, phosphorylation of lipids (as well as
proteins) is a way for simple organisms to store phosphate,
a uniquely important commodity, whether a component of
DNA or of the energy currency ATP. The inositol ring is a
very useful structure for this purpose as it can take several
phosphate molecules, especially in its soluble form, and
indeed, it has been recognized as a phosphate storage molecule in seeds (1246). Phosphorylated inositides, therefore,
must have served as signals to indicate the phosphate status
of simple organisms and molecules capable of recognizing
the phosphorylated headgroups must have developed to
communicate this information to the processes that responded to the availability of phosphate from external
sources. These primitive information circuits have evolved
and been utilized in a number of new ways creating the
seven inositol lipid isomers, produced by the multiple kinases and phosphatases and talking to the myriad of effector molecules. The permutation of these elements provides
ample variations to serve the signaling needs of a variety of
cellular processes discussed in this review.
As in any other scientific discipline, the progress in inositide
research has been tightly linked with methodological advances. Much of what was learned from the metabolic studies using radioactive tracers and bulk lipid separation techniques paved the road for subsequent work on isolation and
cloning of the enzymes. Progress in molecular biology techniques and the sequencing of the various genomes gave an
enormous boost to these efforts and helped identify many of
the inositide converting enzymes known today. Advances in
genetics and positional cloning identified enzyme defects in
inositide metabolism in several human diseases, and gene
knockout and transgenic technologies allowed the creation
of animal models for better understanding the physiological
and pathological roles of these lipids and their selected metabolic enzymes. As we understand more and more about the
importance of spatial and temporal organization of inositol
lipid signals, it has become clear that we needed to follow
lipid changes in live cells with subcellular resolution (94).
Moreover, now we want to artificially induce inositol lipid
changes in localized compartments to see the consequences
for specific cellular processes (437, 1489, 1586, 1617).
These techniques are now being extended to achieve superresolution level imaging (141, 917). These advances will
surely help us better understand the biology of phosphoinositides.
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ment that is required for infection or survival. For example,
Listeria produces a PLC enzyme as an important virulence
factor that helps the bacterium escape from the vacuole of
infected cells (1235). Salmonella enterica and Shigella flexneri inject an enzyme, called SigD/SopB and IpgD in the two
strains, respectively, into the prospective host cells that induce active membrane remodeling to help the bacterial invasion at the entry process and, in the case of Shigella, its
intracellular release from the endocytic compartment. Both
of these enzymes show homology to mammalian inositol
lipid phosphatases with a relatively broad in vitro specificity
(993, 1151). However, inside the cells, these enzymes appear to hydrolyze primarily PtdIns(4,5)P2 with production
of the rare and enigmatic PtdIns5P (607, 1130, 1544).
These enzymes also lead to the production of 3-phosphorylated lipids (1130, 1206) by mechanisms that are not all
that clear and, curiously, are not inhibited by classical PI3K
inhibitors in the case of Salmonella SigD/SopB (975, 993).
A similar phosphatase acting upon PtdIns(4,5)P2, called
VPA0450, was identified in Vibrio parahaemolyticus (185),
and a previously described acid phosphatase of Legionella
that inhibits superoxide production of neutrophil cells is
also capable of PtdIns(4,5)P2 hydrolysis (1323). The intracellular parasite, Plasmodium falciparum that causes malaria also produces its own inositol lipid kinases, a class III
PI3K ortholog PfPI3K (1533, 1596), a PI4K ortholog
PFE0485w (826), and a PIP 5-kinase (864) and also increases the levels of several inositol lipid isomers in the
infected red blood cells (399, 1533). A plasmodium PLC
enzyme has also been described (1245), and activation of Ca2⫹
signaling within the parasite has also been observed (37). Mycobacterium tuberculosis uses its own tricks to stay dormant
in macrophages and evade the lysosome. It uses its own PtdInsmannoside to inhibit PtdIns3P production (256) but also secretes a phosphatase, called SapM capable of dephosphorylating PtdIns3P (1630). Another phosphatase, MptpB, which is
an important virulence factor of Mycobacterium tuberculosis
(1411), is a trifunctional enzyme that hydrolyzes phosphoserine/threonines, phosphotyrosines, and phosphoinositides
(120, 121). While inhibiting PtdIns3P production of the host,
Mycobacteria also synthesize PtdIns3P (1085), apparently as
an intermediate of PtdIns synthesis and not as a result of PtdIns
phosphorylation (1084).
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ACKNOWLEDGMENTS
I thank Dr. Robert Michell for his kind reading and suggestions on the historical overview and Drs. Tibor Rohacs and
Gerald Hammond for their valuable comments. I am grateful to Anna Mezey-Brownstein for proofreading the article.
Address for reprint requests and other correspondence: T.
Balla, National Institutes of Health, Bldg. 49, Rm. 5A22, 49
Convent Dr., Bethesda, MD 20892 (e-mail: ballat@mail.
nih.gov).
GRANTS
The author’s research is supported by the Intramural Research Program of the Eunice Kennedy Shriver National
Institute of Child Health and Human Development of the
National Institutes of Health.
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DISCLOSURES
No conflicts of interest, financial or otherwise, are declared
by the author.
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Lastly, a word about how public health has benefitted from
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