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Transcript
Physiol Rev
84: 411– 430, 2004; 10.1152/physrev.00027.2003.
Apoptosis and Dependence Receptors:
A Molecular Basis for Cellular Addiction
DALE E. BREDESEN, PATRICK MEHLEN, AND SHAHROOZ RABIZADEH
The Buck Institute for Age Research, Novato, and University of California, San Francisco, San Francisco,
California; and Centre Genetique Moleculaire et Cellulaire, Equipe Labellisée “La Ligue,” Centre
National de la Recherche Scientifique UMR5534, University of Lyon, and the International
Agency For Research in Cancer, Lyon, France
VIII.
IX.
X.
XI.
XII.
XIII.
Introduction
Apoptosis and Programmed Cell Death
Nomenclature
The Common Neurotrophin Receptor p75NTR as a Dependence Receptor
DCC (Deleted in Colorectal Cancer, a Netrin-1 Receptor) as a Dependence Receptor
Unc5H1–3 (Uncoordinated Gene-5 Homologs 1–3) as Dependence Receptors
RET (Rearranged During Transfection, a Glial-Derived Neurotrophic Factor Receptor) as a
Dependence Receptor
The Androgen Receptor as a Dependence Receptor
Other Dependence Receptors
A Model for Apoptosis Induction by Dependence Receptors
A Potential Role for Dependence Receptors in Tumor Invasion and Metastasis
A Potential Role for Dependence Receptors During Nervous System Development
A Potential Role for Dependence Receptors in Neurodegeneration: Neurodegenerative Diseases
as States of Altered Dependence
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I.
II.
III.
IV.
V.
VI.
VII.
411
412
415
416
418
419
421
422
422
423
424
425
426
Bredesen, Dale E., Patrick Mehlen, and Shahrooz Rabizadeh. Apoptosis and Dependence Receptors: A
Molecular Basis for Cellular Addiction. Physiol Rev 84: 411– 430, 2004; 10.1152/physrev.00027.2003.—Classical signal
transduction is initiated by ligand-receptor interactions. We have described an alternative form of signal transduction that
is initiated by the withdrawal of ligands from specific receptors referred to as dependence receptors. This process is
widespread, featuring in developmental cell death, carcinogenesis (especially metastasis), neurodegeneration, and
possibly subapoptotic events such as neurite retraction and somal atrophy. Initial mechanistic studies of dependence
receptors suggest that these receptors form complexes that include specific caspases. Complex formation appears to be
a function of ligand-receptor interaction, and dependence receptors appear to exist in at least two conformational states.
Complex formation in the absence of ligand leads to caspase activation by a mechanism that in at least some cases is
dependent on caspase cleavage of the receptor itself, releasing proapoptotic peptides. Thus these receptors may serve in
caspase amplification, and in so doing create cellular states of dependence on their respective ligands.
I. INTRODUCTION
Cells depend for their survival on stimulation that is
mediated by various receptors and sensors. For example,
some cells respond to the loss of extracellular matrix adhesion by undergoing anoikis (“homelessness”) (45), i.e., programmed cell death induced by loss of adhesion. Other cells
may undergo programmed cell death [a term often used
interchangeably with apoptosis (from the Greek apo ⫽ away
from and ptosis ⫽ falling)] following the withdrawal of
trophic factors (e.g., the neurotrophins), cytokines, hormonal support, electrical activity, or other stimuli (15).
www.prv.org
Depending on cell type and state of differentiation,
cells require different stimuli for survival. For example,
prostate epithelial cells require testosterone for survival,
and the withdrawal of testosterone leads to apoptosis in
these cells. Similarly, neoplastic prostate epithelial cells
are often treated by testosterone withdrawal because it
leads to apoptosis, and therefore tumor shrinkage; unfortunately, the few remaining cells that are not androgen
dependent usually repopulate the tumors, and therefore
alternative therapy is required.
For any given required stimulus, withdrawal leads to
a form of cellular suicide; that is, the cell plays an active
0031-9333/04 $15.00 Copyright © 2004 the American Physiological Society
411
412
BREDESEN, MEHLEN, AND RABIZADEH
Physiol Rev • VOL
lowing binding to their respective ligands (15, 100, 102).
Expression of these dependence receptors creates cellular states of dependence on the associated ligands. These
states of dependence are not absolute, since they can be
blocked downstream in some cases by the expression of
antiapoptotic genes such as bcl-2 or p35 (15, 42, 81);
however, they result in a shift of the apostat (13, 110), the
probability of a given cell’s undergoing apoptosis, toward
an increased likelihood of undergoing apoptosis.
The terms dependence receptor and addiction receptor are used interchangeably here, since it is not yet clear
whether these receptors serve both functions, or whether
specific ones mediate cellular dependent states and others mediate cellular addictive states. By definition, addiction requires previous exposure, whereas dependence
does not. In vivo, it is likely that at least some of these
receptors are expressed following initial cellular exposure to their associated ligands, which would label them
as addiction receptors; however, cell culture experiments
have shown that the expression of these receptors in cells
not previously exposed to the ligands in question may
nevertheless lead to apoptosis induction, and therefore
create cellular states of dependence (15, 37, 84, 102).
Functionally, therefore, these receptors may be dependence receptors, but physiologically they may be either
addiction receptors or dependence receptors or both;
hence, in this review, the terms are used interchangeably.
It should be added that the biochemical mechanisms underlying addiction may well turn out to be separable from,
and complementary to, those mediating dependence.
II. APOPTOSIS AND PROGRAMMED
CELL DEATH
In 1964, Lockshin and Williams (76) introduced the
term programmed cell death to describe the apparently
predetermined reproducibility with which specific cells
die during insect development. In 1966, it was shown that
this process requires protein synthesis, at least in some
cases (127), arguing that it is the result of a cellular
suicide process. Then in 1972, John Kerr et al. (59) coined
the term apoptosis to describe a morphologically relatively uniform set of cell deaths that occurs in many
different situations, from development to insult response
to cell turnover (Table 2).
Although programmed cell death and apoptosis were
described in somewhat different physiological situations,
and for different phyla, studies of the gene products that
control these two forms of cell suicide suggest that they
are very similar and it may turn out that apoptosis represents a subset of all programmed cell deaths (see below).
Genetic dissection of this process in the nematode worm,
Caenorhabditis elegans, carried out largely in the laboratory of H. Robert Horvitz, identified a set of genes re-
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role in its own demise. The term programmed cell death
was first suggested by Richard Lockshin in 1964 (76)
based on the regularity with which specific insect cells die
during development. Apoptosis, a form of programmed
cell death defined morphologically, was first described by
Kerr et al. in 1972 (59), although the earliest references to
the morphological appearance of such cells may date
back to the late 19th century (77).
Cells undergoing apoptosis are characterized by
chromatin condensation, nuclear fragmentation, internucleosomal DNA fragmentation, plasma membrane bleb
formation, zeiosis (a boiling appearance of the plasma
membrane, typically occurring over minutes), budding of
cell fragments (apoptotic bodies), retention of organellar
integrity, and ultimately, phagocytosis (60). Execution of
the program is dependent on the activation of a family of
cysteine proteases called caspases (cysteine aspartyl-specific proteases; see below).
How do cells “recognize” a lack of stimulus? It has
generally been assumed that cells dying as a result of the
withdrawal of required stimuli do so because of the loss
of a positive survival signal. For example, nerve growth
factor (NGF) provides a survival signal to certain sympathetic neurons and sensory neurons (as well as some
other populations of neurons), which is mediated by
dimerization of the receptor tyrosine kinase TrkA, followed by autophosphorylation and downstream signaling
featuring phosphatidylinositol (PI) 3-kinase and Akt phosphorylation (147). While such positive survival signals are
clearly extremely important, data obtained over the past
few years argue for a complementary and novel form of
signal transduction that is proapoptotic and is activated
or propagated by stimulus withdrawal (7, 8, 10, 14, 15, 37,
42, 75, 84, 100, 102, 122). Furthermore, whereas positive
survival signals, such as those mediated by TrkA, involve
classical signal transduction—i.e., ligand-receptor interaction initiates the signal-negative survival signals, such
as those mediated by the netrin-1 receptors, DCC and
Unc5H1–3 (see below for a more detailed description),
involve nonclassical signal transduction, in which typically the unbound, monomeric receptor is activated to
induce cell death by proteolytic processing, generating
proapoptotic fragments (Figs. 1 and 2 and Table 1), and
ligand binding blocks the proteolytic processing and/or
the proapoptotic effect of the fragments (15, 37). This
form of signal transduction has been referred to as negative signal transduction (15), and its key features are
compared with those of classical signal transduction in
Table 1.
Thus cellular dependence on specific signals for survival is mediated, at least in part, by specific “dependence
receptors” or “addiction receptors,” which induce apoptosis in the absence of the required stimulus (when unoccupied by a trophic ligand, or possibly when bound by a
competing, nontrophic ligand), but block apoptosis fol-
DEPENDENCE RECEPTORS
413
quired for programmed cell death (49, 52, 95, 151). Central
to the process are three genes, ced-3, ced-4, and ced-9.
The ced-3 and ced-4 gene products are required for programmed cell death to occur, whereas the ced-9 gene
product inhibits programmed cell death.
Probable mammalian orthologs for all of these have
been discovered. Ced-3 has been shown to be a member
of a growing family of cysteine proteases dubbed
caspases (Table 3). These are intracellular proteases that
are synthesized as zymogens, then activated by proteolytic cleavage. The active enzymes probably consist of
tetramers composed of two identical heterodimers, each
containing a p10 –12 and a p17–20. Interestingly, the
caspase zymogens appear to possess some activity, although less than that of the activated forms (88, 91, 144,
146), and it is likely that simply increasing the local concentration of a caspase zymogen may, at least in some
cases, be sufficient to induce autocatalytic processing (88,
Physiol Rev • VOL
146). This has led to the concept of “induced proximity”
for the activation of some caspases (88, 146).
The selectivity of the caspases is remarkable in that
cleavage is virtually completely confined to aspartate residues in the P1 position (132), although anecdotally cleavage with a glutamate residue in the P1 position has been
reported (38, 73). Lesser degrees of specificity occur for
the P2, P3, and P4 positions (91), and probably for the P1⬘
position, such that the caspases can be grouped into three
subfamilies based on these preferences (91). The
caspases can also be divided by function, into those acting as effectors in the cell death process (e.g., caspase-3
and caspase-7), those initiating cleavage of the effectors
(e.g., caspases-8, -9, and -10), and those involved in inflammatory responses (e.g., caspases-1, -4, and -5).
The specificity of the caspases leads to a highly selective group of substrates, many of which appear to play
important roles in the apoptotic process (37, 72, 88).
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FIG. 1. Schematic representation of dependence receptors. Included are caspase cleavage
sites (e.g., D412 for Unc5h2) at which proteolysis generates proapoptotic fragments. EC, extracellular; IC, intracellular; TM, transmembrane domain.
414
BREDESEN, MEHLEN, AND RABIZADEH
Although only a few dozen such substrates have been
identified (110), in vitro studies suggest that the number
of cellular caspase substrates may ultimately prove to be
much larger, perhaps several hundred to one thousand (Z.
Li, L. Zhong, and D. Bredesen, unpublished results). In any
case, however, the majority of cellular proteins do not
appear to be caspase substrates.
The mammalian homolog (or at least one homolog)
of ced-4 appears to be Apaf-1 (152). This protein, along
with ATP, caspase-9 zymogen, and cytochrome c (which
is released from the intermembrane space of mitochondria during apoptosis), forms an “apoptosome” that
cleaves and activates procaspase-3 (153). The activation
of caspase-9 via the apoptosome represents one of two
major pathways for caspase activation and resultant apoptosis and has been referred to as the intrinsic pathway
for apoptosis. A second general pathway, referred to as
Physiol Rev • VOL
the extrinsic pathway, is triggered by death receptor activation (e.g., Fas), with subsequent formation of a deathinducing signaling complex (DISC, Ref. 110), recruitment
of caspase-8 or in some cases caspase-10, and activation.
Both pathways share the downstream activation of effector caspases such as caspase-3 and caspase-7. Furthermore, cross-talk between the intrinsic and extrinsic pathway is provided by the cleavage of Bid, carried out by
caspase-8; this cleavage produces tBid (truncated Bid),
which inserts into the mitochondria and leads to cytochrome c release, activating the intrinsic pathway. Thus
the activation of caspase-8 via the extrinsic pathway results in both the direct activation of effector caspases and
a secondary activation via the intrinsic pathway (72).
In addition to the intrinsic and extrinsic pathways of
apoptosis, recent studies have suggested additional pathways to caspase activation. Misfolded proteins and other
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FIG. 2. Proposed mechanism for dependence
receptor function. When bound by the appropriate
ligand, antiapoptotic signaling is mediated by dependence receptors through classical signal transduction; however, when unbound (or bound by a
nontrophic ligand), a proapoptotic signal occurs via
negative signal transduction. In at least some cases,
this is mediated by conformational change in the
receptor, proteolytic cleavage, and resulting proapoptotic dependence peptides. Such cytotoxic
peptides may potentially act through mitochondria
or other as yet undescribed intermediates to induce
cell death. ADD, addiction dependence domain;
AR, androgen receptor; CP1, contingency peptide 1;
CP2, contingency peptide 2.
415
DEPENDENCE RECEPTORS
TABLE
1. Comparison of classical signal transduction and negative signal transduction
Classical
Negative
Ligand-receptor binding
Receptor multimerization
Signal initiation
Initiates the signal
Often activates
Ligand binding
Unbound receptor*
Usually inactive relative to bound receptor
Kinetics
Rapid (Fas-induced apoptosis, ⬃1–4 h)
Examples of receptors
Receptor tyrosine kinases, G protein-coupled receptors, etc.
Inhibits one signal and activates a second
Usually blocks proapoptotic signal
Usually receptor-protease complex
formation and proteolytic processing
Active (may require conformational
change and/or processing)
Slower (NGF withdrawal-induced
apoptosis, ⬃20 h)
Dependence receptors [e.g., Unc5H1–3,
p75NTR, the androgen receptor, and
DCC (deleted in colorectal cancer)]
activators of endoplasmic reticulum stress trigger an alternative pathway that leads to caspase-9 activation, apparently via caspase-12, but does not require cytochrome
c or Apaf-1 (89, 106, 107). Another Apaf-1 and cytochrome
c-independent pathway leading to the activation of
caspase-9 is activated by DCC (see below).
The mammalian homologs of ced-9 are represented
by the Bcl-2/BH3-containing family of apoptosis-modulating genes (108). These include both apoptosis inhibitors,
such as Bcl-2 and Bcl-xL, and apoptosis inducers, such as
Bax, Bad, Bak, and Bcl-xS. The structure of Bcl-xL demonstrates similarity to pore-forming proteins such as colicin E1 and the diphtheria toxin B-chain (85). Bcl-2 is
targeted to the mitochondrial outer membrane and blocks
the release of cytochrome c following insults (64, 145),
thus blocking the assembly of the apoptosome. It is also
possible that Bcl-2 has additional antiapoptotic mechanisms. In contrast, the proapoptotic family members fall
into two groups, one of which may mediate pore formation directly (e.g., Bax) and the other of which (e.g.,
Bcl-xS) apparently exerts its proapoptotic effect by binding to the antiapoptotic family members and antagonizing
their antiapoptotic effects.
In addition to the homologs of ced-3, ced-4, and
ced-9, additional modulators of apoptosis have been discovered. For example, iap (inhibitor of apoptosis) family
members such as xiap, ciap-1, and ciap-2, inhibit apopto-
TABLE
sis at least in part through a direct inhibition of specific
caspases (31). SMAC/Diablo, on the other hand, participates in apoptosis induction by displacing the iap-mediated block of caspases (32, 136).
III. NOMENCLATURE
To make this review more readable, the terms used
will be defined in this section. We define a dependence
receptor as any receptor that creates a state of cellular
dependence on its cognate ligand, i.e., in the absence of
the ligand, expression of the receptor shifts the cellular
apostat toward a greater likelihood that the cell will undergo apoptosis. Some examples of dependence receptors are listed in Table 1 and Figures 1 and 2.
The apostat (12, 110) is a hypothetical entity that
refers to the set point of the cell with respect to apoptosis.
Some cells undergo apoptosis readily in response to an
insult, whereas others are resistant. This set point is
controlled by modulators such as Bcl-2 (an anti-apoptotic
protein, Ref. 53), Bax (a pro-apoptotic protein, Ref. 92),
the cellular iap (inhibitor of apoptosis) proteins (which
inhibit specific caspases, Ref. 31), and dependence receptors, among other modulators.
Dependence receptors include domains required for
the proapoptotic effect that occurs in the absence of
2. Some examples of apoptosis
Many developmental cell deaths
Cell turnover
Virus-induced cell death
Chemotherapy response in tumors
Immune-mediated cell death
Response to intracellular alterations (e.g., low intracellular
calcium in developing neurons)
Physiol Rev • VOL
Cell death in response to trophic factor withdrawal
Response to injury (e.g., radiation)
Response to many toxins
Some cell deaths in degenerative diseases (e.g., Alzheimer’s disease)
Some ischemic cell deaths
Some cell deaths induced by reactive oxygen or nitrogen species
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* It is important to point out that dependence receptors may potentially be activated to induce programmed cell death following ligand
withdrawal either by intracytoplasmic complex formation involving an unbound receptor or by binding an alternative (as yet unidentified),
nontrophic ligand (15). In the latter case, the alternative, nontrophic ligand would be predicted to have a lower affinity than the trophic ligand.
Studies of the common neurotrophin receptor p75NTR have suggested that whereas mature nerve growth factor (NGF) inhibits cell death induction,
pro-NGF induces cell death (69).
416
BREDESEN, MEHLEN, AND RABIZADEH
TABLE 3. Similarities and differences between caspase
family members
Substrate Preference
(P4-P1)*
Caspase-1
CARD
(W/Y/F)EHD
Caspase-2
CARD
DXXD
Caspase-3
Caspase-4
Caspase-5
Caspase-6
Short
CARD
Long
Short
DEXD
(W/L/F)EHD
(W/L/F)EHD
(V/T/I)EHD
Caspase-7
Caspase-8
Caspase-9
Caspase-10
Caspase-11
Caspase-12
Short
DED
CARD
DED
Long
Long
DEXD
(L/V/D)EXD
(I/V/L)EHD
Unknown
Unknown
Unknown
Caspase-14
CED-3
Short
CARD
Unknown
DEXD
* From Thornberry et al. (134).
Comments
Interleukin-1␤ converting
enzyme (inflammatory
group)
Prodomain resembles
initiators; preference
resembles effectors
Effector
Inflammatory
Inflammatory
Prodomain resembles
effectors; preference
resembles initiators
Effector
Initiator
Initiator
Initiator
Inflammatory (murine)
Role in ER stress†
(murine)
Murine
Caenorhabditis elegans
† See Nakagawa et al. (90).
ligand. These domains are referred to as dependence
domains or addiction/dependence domains (ADDs). In at
least some cases, such as those of p75NTR and the androgen receptor, these domains can simply be synthesized as
peptides and shown to be proapoptotic when coupled to
a cellular entry peptide (which facilitates entry into cells,
Refs. 61, 99, 103). Such proapoptotic peptides are referred
to as dependence peptides. Dependence domains display
as a constant feature an inductive effect on programmed
cell death (typically apoptotic) but do not display structural uniformity, i.e., their proapoptotic effects are
achieved with a variety of structures (see below).
In some cases, such as the androgen receptor, DCC
(deleted in colorectal cancer) and Unc5H2 [the human
homolog of the C. elegans uncoordinated-5 (unc-5) protein], cleavage of the full-length protein is a critical event
in apoptosis induction, and blocking the cleavage (e.g., by
mutating the cleavage site) inhibits the apoptosis induction. Typically, cleavage occurs in the absence of ligand,
but in at least some cases may be prevented by the
binding of ligand (e.g., testosterone) to the dependence
receptor. The peptides generated by the cleavage of dependence receptors in their unliganded state are referred
to as contingency peptides (Fig. 1), since they are generated under one set of conditions but not another [usually
these peptides are generated when ligand is withdrawn,
whereas no cleavage (or alternative cleavage) occurs
when ligand is present]. The distinction between contingency peptides and dependence peptides is that the
former are generated in vivo and may or may not induce
apoptosis (depending on whether a given contingency
Physiol Rev • VOL
IV. THE COMMON NEUROTROPHIN RECEPTOR
p75NTR AS A DEPENDENCE RECEPTOR
Classic experiments by Levi-Montalcini and Hamburger (71) demonstrated that developing neurons pass
through a critical phase, during which typically approximately one-half of the neurons from various subsets die.
Death of developing neurons may occur in three different
morphological patterns: the majority die with a morphology consistent with apoptosis (this pattern has also been
referred to as type I or nuclear pcd). However, others die
by one of two alternative morphological patterns: type II,
also referred to as autophagic, cell death or type III, also
referred to as cytoplasmic (type III is also morphologically indistinguishable from a recently described receptor-induced form of programmed cell death dubbed
paraptosis, Ref. 119). The location and fraction of developing neurons that die by type I, II, or III pcd are relatively
constant; for example, type III pcd is typically seen in the
trochlear nucleus and in some developing motor neurons,
among other locations (27). However, as noted above,
most developmental neuronal cell death is apoptotic (82)
and is critically dependent on the availability of neurotrophic factors: supraphysiological concentrations of neurotrophic factors can block developmental neuronal apoptosis, whereas neurotrophin withdrawal results in enhanced apoptosis.
Searches for a receptor for nerve growth factor, the
first trophic factor identified, led to the discovery of two
distinct receptors, p75NTR (20, 105) and TrkA (2, 33, 51,
135). TrkA was shown to be capable of mediating the
known responses to NGF, such as neurite outgrowth and
neuronal survival (135). These studies initially left the role
of p75 unexplained. Subsequent studies demonstrated
that p75NTR and TrkA collaborate to produce high-affinity
sites for NGF binding and that p75NTR expression may
enhance the selectivity of neurotrophin binding for specific Trks (TrkA, -B, and -C; Ref. 133).
However, p75NTR was also shown to have Trk-independent effects. p75NTR is a member of a superfamily of
receptors that includes the tumor necrosis factor receptors and Fas, among others (139). The relationship be-
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Prodomain
Caspase
peptide includes the dependence domain), whereas the
latter are pro-apoptotic peptides, but may or may not be
generated physiologically (e.g., they may be part of a
larger contingency peptide, or may conceivably function
with the full-length protein).
Negative signal transduction is a hypothetical form of
signal transduction initiated or propagated by the withdrawal of a trophic factor or other stimulus; this form of
signal transduction has been proposed based on the results obtained in studies of dependence receptors (15,
100, 102).
DEPENDENCE RECEPTORS
Physiol Rev • VOL
ment those of Longo et al. (78), in which cyclic dimeric
peptides binding to p75NTR were shown to inhibit apoptosis, whereas monomers were completely ineffective.
While these studies demonstrate that p75NTR homomultimerization does not induce apoptosis (at least under the
conditions of the reported studies), however, neither of
these studies excludes the possibility that monomeric
p75NTR leads to apoptosis by a mechanism requiring heteromultimerization with another receptor, or alternatively, that monomeric p75NTR may undergo an activating
modification (e.g., cleavage, phosphorylation, etc.) that
may lead to multimerization and cell death induction.
Site-directed mutagenesis studies of the proapoptotic
effects of p75NTR have disclosed two regions crucial for
this effect: the juxtamembrane intracytoplasmic region,
dubbed chopper (30), and a region that lies in the fourth
and fifth helices of the six-helical death domain (so-called
because of its similarity to the death domains of Fas and
TNFR I, not because of functional analysis). This latter
30-amino acid region was dubbed a dependence domain
because of its requirement for apoptosis induction by the
dependence receptor p75NTR (103). On the other hand,
reversal of the death-inducing effect of p75NTR by ligand
binding was shown to require a region at the carboxy
terminus, dubbed the neurotrophin response domain
(104, 137).
One of the ramifications of the identification of dependence domains is their use in homing proapoptotic
peptides (35), also referred to as hunter-killer peptides.
These tripartite peptides couple a targeting peptide, a
bridging peptide, and a proapoptotic peptide, the latter of
which was initially based on dependence peptide sequences. These peptides may be targeted to angiogenic
vasculature to treat malignant tumors or may be targeted
to other structures such as the prostate, resulting in
“chemical prostatectomy” (3). Exploration into potential
additional applications is ongoing.
It is important to point out that, following the initial
report of apoptosis induction by p75NTR, p75NTR was also
shown to mediate apoptosis in response to ligand binding
rather than ligand withdrawal (2, 18, 43). Interestingly,
despite this apparent functional similarity to Fas and
TNFR I, and the similarities in structure of these three
proteins, Fas-p75NTR chimeras consisting of the extracellular domain of Fas and the intracellular domain of
p75NTR failed to induce apoptosis (65). Thus the induction
of apoptosis following NGF binding to p75NTR is somehow
different than the induction of apoptosis following the
binding of death factors to Fas and TNFR I. This may be
a Trk-dependent phenomenon, since to date it has been
described almost exclusively in systems in which mismatched Trk members were expressed (e.g., Trk B was
expressed and NGF addition was shown to lead to apoptosis) (14, 15). Alternatively, the decision between ligand-induced apoptosis and ligand-inhibited apoptosis
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tween these “death factor” (proapoptotic factor) receptors and p75NTR, which had been shown to bind a trophic
factor (which has antiapoptotic effects rather than proapoptotic effects), was unclear until 1993, when reports
began to appear implicating p75NTR in neural cell death (7,
18, 43, 100, 102, 150). Consistent with the notion that
p75NTR binds a trophic factor rather than a death factor,
the initial reports suggested a novel phenomenon: that the
expression of p75NTR induced apoptosis when p75NTR was
unoccupied by NGF, whereas binding of NGF blocked
apoptosis (7, 100, 102). This is the reverse of the effect of
binding of Fas ligand to the Fas receptor (56).
The finding that p75NTR expression induces apoptosis
in the absence of ligand, but inhibits apoptosis following
ligand binding, suggested that p75NTR expression creates
a state of cellular dependence on NGF [or other neurotrophins that serve as p75NTR ligands, such as brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3),
and neurotrophin-4/5 (NT-4/5)]. Follow-up studies provided further evidence for this notion; for example, p75deficient mice were shown to have an increased number
of cholinergic neurons in the medial septal and diagonal
band regions and hyperinnervation in some areas of the
hippocampus (90, 150). Furthermore, Sauer et al. (113)
crossed NGF hemizygous mice, which display reductions
in cholinergic cell number and size within the medial
septal region, with p75NTR null mice. This restored cell
number and size to supranormal (and indistinguishable
from the p75-deficient controls). They concluded that, in
the presence of a reduced concentration of NGF, p75NTR
mediates a reduction in cholinergic neuronal number and
size.
The effect of p75NTR on cellular neurotrophin dependence may underlie aspects of both neural and extraneural cellular behavior; for example, prostate epithelial cells
express p75NTR, which may tie them to a source of neurotrophin (11), supplied by the stromal cells. Pflug et al.
(96) found a progressive decrease in p75NTR expression
associated with the development of prostate neoplasia,
with cell lines from metastatic prostate carcinomas failing
to express p75NTR. The reexpression of p75NTR in PC3
prostate carcinoma cells restores a state of neurotrophin
dependence, resulting in apoptosis if NGF is not supplied
(103). Thus p75NTR may play a role in both neural and
extraneural cellular paradigms that share the common
thread of neurotrophin dependence.
One of the predictions of the initial reports of unoccupied p75-induced apoptosis is that, unlike Fas, which
requires multimerization for apoptosis induction, p75NTR
should exert its proapoptotic effects as a monomer. Studies using FK binding protein chimeras (as developed by
Spencer et al., Ref. 118) have indeed shown that the
proapoptotic effect of p75NTR requires the monomer, with
dimerization and higher order multimerization completely
suppressing this effect (103, 137). These studies comple-
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V. DCC (DELETED IN COLORECTAL CANCER,
A NETRIN-1 RECEPTOR) AS A
DEPENDENCE RECEPTOR
Vogelstein and colleagues (41) have shown that the
development of colonic carcinoma from normal colonic
epithelium is associated with the mutation of a specific
set of genes. Allelic deletions (loss of heterozygosity,
LOH) on chromosome 18q in more than 70% of primary
colorectal tumors led to a search for a tumor suppressor
gene at that locus, which resulted in the cloning of a
putative cell-surface receptor, DCC (deleted in colorectal
cancer) (41). DCC expression has been shown to be absent or markedly reduced in ⬎50% of colorectal tumors.
Furthermore, the loss of DCC expression is not restricted
to colon carcinoma but has been observed in other tumor
types, including carcinoma of the stomach, pancreas,
esophagus, prostate, bladder, and breast, as well as in
male germ cell tumors, neuroblastomas, gliomas, and
some leukemias (25, 40). It is important to point out,
however, that support for DCC as a tumor suppressor
gene has not been uniform. Although in vitro studies have
supported DCC’s potential role as a tumor suppressor
gene (57, 62, 63, 125, 134), other data have raised questions about the legitimacy of DCC as a tumor suppressor
gene: the rarity of point mutations identified in DCC coding sequences (83), the lack of a tumor predisposition
phenotype in mice heterozygous for DCC-inactivating mutations (39), and the presence of other known and candidate tumor suppressor genes (129) on chromosome 18q.
Reconciliation of this combination of supportive and
countersupportive data may ultimately indicate that DCC
is an atypical tumor suppressor or that it is not a tumor
suppressor.
DCC encodes a type I transmembrane protein of
1,447 amino acids, with a relative molecular mass of ⬃200
kDa. DCC displays homology in its extracellular domain
with cell adhesion molecules (25), suggesting that it may
play a role in cell-cell or cell-matrix interactions (50).
However, DCC-mediated cell aggregation has not been
clearly established (26).
In addition to its putative role as a tumor suppressor,
DCC has been shown to play a role in neural development. During neural development, migrating axons and
cells receive guidance cues that derive from several
sources, such as members of the netrin, semaphorin,
ephrin, and slit protein families (28, 128). Tessier-Lavigne
and collaborators (58, 115, 121) have shown that DCC
may function as a component of a receptor complex that
mediates the effects of the axonal chemoattractant netrin-1. The role of DCC in mediating growth cone extension has been supported by the analysis of DCC-null
(“knock-out”) mice, the latter of which display abnormal
brain development (39).
The relationship between the putative role of DCC as
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mediated by p75NTR may depend on downstream mediators: for example, the interaction of p75NTR with NADE
has been shown to induce apoptosis following ligand
binding (86); conversely, TRAF2 has been shown to interact preferentially with monomeric p75NTR and to be capable of inducing apoptosis in the absence of NGF (148).
Other potential death-mediating p75NTR interactors include NRAGE (109) and NRIF (19). In addition, another
proapoptotic transmembrane protein has recently been
identified that has a death domain very similar to that of
p75NTR, and this protein interacts with p75NTR (44). The
protein, dubbed PLAIDD (p75NTR-like apoptosis-inducing
death domain protein), displays a type II death domain
(which is structurally slightly different from the type I
death domains displayed by death receptors such as Fas
and TNFR I) that is closely related to the type II death
domain of p75NTR, with 42% identity (44). Thus p75NTR
may function as both dependence receptor and death
receptor, depending on associated Trk expression, ligand
presentation, expression of p75NTR-interacting molecules,
patent downstream signaling pathways, and probably additional factors. One potential implication of this dual role
in cell death is that p75NTR may mediate the cellular
response to neurotrophin withdrawal through its function
as a dependence receptor, whereas it may mediate the
cellular response to a mismatched neurotrophin (e.g.,
exposure of a neuron expressing TrkB and p75NTR to
NGF, which binds TrkA and p75NTR) via an alternative
mechanism, through its function as a death receptor (15).
The observations that p75NTR may mediate pcd both
in response to ligand withdrawal and in response to ligand
binding has suggested a model in which p75NTR serves a
“quality control” function: it mediates apoptosis when
cells experience the loss of trophic support, the inappropriate trophic support (here, mismatched for the expressed Trk), unprocessed trophic factor (here, proNGF), or the binding of neurotrophin to an inappropriately immature cell (101). This “quality control”
hypothesis extends beyond cell death mediation, since, as
noted above, p75NTR also mediates neurotrophin binding
specificity by reducing the promiscuity of neurotrophinTrk interactions.
Finally, p75NTR also appears to mediate subapoptotic
events such as neurite retraction and somal atrophy (11,
150). Recently, p75NTR has been shown to be the transducing receptor for Nogo, which binds to a glycosylphosphatidylinositol (GPI)-anchored receptor (138). In this
case, p75NTR may be a mediator of neurite retraction.
Although the effect of neurotrophin binding to p75 on
Nogo signal transduction is not yet clear, the involvement
of p75 in neurite retraction suggests the possibility that at
least part of the neurotrophic effect on process outgrowth
occurs via a block of Nogo-mediated neurite retraction.
DEPENDENCE RECEPTORS
Physiol Rev • VOL
caspase-activating complex, although the precise mechanism involved, and the identification of the molecular
components of the complex, will require further analysis.
The search for DCC-interacting proteins also disclosed an interaction between DCC and a DCC-interacting
protein dubbed DIP13␣ (74). DIP13␣ was implicated in
DCC-induced apoptosis based on the following findings:
1) DIP13␣ interacted with the dependence domain of
DCC, 2) DCC-DIP13␣ coexpression enhanced apoptosis
induction over that observed with DCC alone, 3) the
region of DIP13␣ required for interaction with DCC was
also required for the proapoptotic effect, and 4) small
interfering RNA (siRNA) directed against DIP13␣ inhibited DCC-induced apoptosis (74). The mechanism by
which DIP13␣ mediates the DCC-induced proapoptotic
effect is unknown.
DCC has also been shown to cooperate with a coreceptor, the A2b purinoceptor, the latter of which is a G
protein-coupled receptor (10). This interaction has been
shown to be involved in netrin-1-mediated neurite outgrowth and cAMP increases (29, 117). DCC has also been
shown to interact with other guidance-related receptors
such as Unc5H (see below) (54) and Robo (121), but
whether these interactions mediate or modulate any of
the proapoptotic effect of DCC is not yet known.
In summary, data accumulated thus far suggest that
DCC functions as a dependence receptor, with effects on
both neoplasia and neural development. With respect to
neural development, DCC may mediate apoptosis in the
absence of netrin-1, whereas binding of netrin-1 supports
survival and neurite outgrowth. These results suggest that
netrin-1 not only mediates chemoattractive and chemorepulsive axonal effects, but also functions as a survival
factor during the process of neuronal guidance. In keeping with this notion, it was observed that olivary neurons
that express DCC and normally migrate through a netrin1-dependent mechanism undergo apoptosis in the netrin-1
knock-out mice at the period of time when migration is
typically initiated (75). Similarly, developing commissural
neurons require netrin-1 for their survival in ex vivo experiments (42).
With respect to neoplasia, DCC may function as a
“metastasis suppressor” by inducing apoptosis when ligand is limited by metastasis or growth beyond local
ligand availability. However, in vivo experiments on animal models are required to validate this hypothesis.
VI. Unc5H1–3 (UNCOORDINATED
GENE-5 HOMOLOGS 1–3) AS
DEPENDENCE RECEPTORS
In addition to DCC, netrin-1 also binds another family
of receptors, the Unc5 family. Unc5 family members in-
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a tumor suppressor and the ability of DCC to bind netrin-1
and mediate axon guidance was initially unclear. This
dual role in neural development and neoplasia is reminiscent of similar characteristics of p75NTR and has turned
out to be a common feature of dependence receptors (see
below). Indeed, DCC was shown to act as a dependence
receptor: its expression was shown to induce apoptosis in
the absence of its ligand netrin-1 (24, 42, 74, 84, 116, 134),
but to manifest an antiapoptotic effect when bound by
netrin-1 (74, 84). Mutational analysis identified an intracytoplasmic region of DCC required for apoptosis induction (residues 1243–1264). Expression of this dependence
domain was sufficient for apoptosis induction. It is noteworthy that the dependence domain of DCC displays no
similarity to the dependence domain of p75NTR at the level
of primary structure or at the level of predicted secondary
structure.
During studies of the proapoptotic effect of DCC, it
was noted that DCC is a caspase substrate, with cleavage occurring primarily at Asp-1290, just distal to the
dependence domain (84). Point mutation of this
caspase site, Asp-1290, to Asn or Glu, preventing
caspase cleavage, completely suppressed the proapoptotic effect of DCC, and in fact led to a modestly
antiapoptotic effect (42, 84).
Functionally, therefore, DCC serves as a caspase amplifier in the absence of ligand, via exposure of a proapoptotic domain lying in the amino-terminal region of the
intracellular domain, proximal to the cleavage site. As
noted above, DCC was found to induce apoptosis by a
mechanism that did not require Apaf-1 or cytochrome c,
and therefore did not represent the previously described
intrinsic pathway, and yet also did not proceed via the
previously described extrinsic pathway (for example,
caspase-9 was required rather than caspase-8 or -10).
These results argue that DCC induces apoptosis via a
novel pathway (42).
Further mechanistic studies of DCC-induced apoptosis disclosed interactions with caspase-3 and
caspase-9, as well as DIP13␣ (DCC-interacting protein
13␣) (74). Interestingly, the caspase interactions suggested a conformational dependence: whereas
caspase-9 interacts with DCC (or a DCC-containing
complex) in the absence of ligand, it fails to interact in
the presence of ligand, and also fails to interact when
DCC is mutated at Asp-1290. Conversely, caspase-3
interacts with DCC in the presence of ligand and retains
interaction with the Asp-12903 Asn mutant, but fails to
interact in the absence of ligand (42). These results
suggest that DCC exists in at least two conformations,
depending on the presence or absence of ligand binding. The interaction of DCC with both caspase-3 and
caspase-9 recalls the apoptosome complex that catalyzes caspase-3 activation (152). Interestingly, an in
vitro study supported the view that DCC also initiates a
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BREDESEN, MEHLEN, AND RABIZADEH
Physiol Rev • VOL
domain, with the NRAGE protein and mediates apoptosis
via NRAGE (140). Interestingly, this induction of cell
death via NRAGE recalls what was observed for p75NTR
(109).
The observation that both DCC and the three Unc5H
receptors induce apoptosis in the absence of netrin-1
further supports the view of netrin-1 as a survival factor
during development of the nervous system. Interestingly,
because both netrin-1 and Unc5H are also expressed in
the adult, it was hypothesized that, like DCC, Unc5H1–3
may also play roles as tumor suppressors that would
induce apoptosis when netrin-1 concentration is reduced,
either by metastasis or growth beyond local ligand availability. Along this line, it was observed, just as for DCC,
that the expression of the human Unc5H (Unc5A, -B, and
-C) is downregulated in multiple neoplasms, including
colorectal tumors and those of the breast, ovary, uterus,
stomach, lung, and kidney. In colorectal tumors, this
downregulation is associated with LOH occurring within
Unc5H genes but may also be partially related to epigenetic processes such as methylation (131). This loss or
reduction of expression of Unc5H may be a crucial mechanism for tumorigenicity since the expression of Unc5H1,
-2, or -3 inhibits tumor cell anchorage-independent growth
and invasion in vitro. Moreover, these hallmarks of malignant transformation can be restored by netrin-1 addition or by apoptosis inhibition, providing further support
for the notion that Unc5H1–3 may function as dependence
receptors (131).
An exciting recent development has been reported
by Tanikawa et al. (126), who showed that Unc5B, the
human Unc5H2 ortholog, is a direct transcriptional target of the tumor suppressor gene p53. Surprisingly,
netrin-1 was shown to be sufficient to block p53-induced apoptosis, and inhibition of Unc5B blocked p53induced apoptosis. It was thus proposed that Unc5B
expression is required for induction of apoptosis by p53
(126). The “ménage à trois” between p53, Unc5B, and
netrin-1 would then suggest that the output signal of
p53 activity (i.e., cell death induction or cell cycle
inhibition) may depend on Unc5B expression at the
plasma membrane and on the netrin-1 concentration in
the cell environment. Thus p53 expression may create a
state of cellular dependence on netrin-1 (and, by extrapolation, perhaps on other trophic factors or supportive stimuli), such that expressing cells would be
forced into a choice: trophic support would spare the
cells pcd, but a lack of trophic support, which may be
tolerated in cells with minimal or no dependence receptor (here, Unc5B, but potentially also other such
receptors) expression, would prove lethal following
p53-induced upregulation of dependence receptors
such as Unc5B.
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clude the C. elegans Unc5 and four mammalian orthologs,
Unc5H1, -2, -3, and -4 (also named Unc5 A, B, C and D in
humans). Based on genetic screens it was observed that
Unc6, the worm ortholog for netrin-1, was linked to both
Unc-40, the ortholog of DCC, and to Unc5. It was therefore proposed that the mammalian Unc5H1–3 may function as netrin-1 receptors (1, 70). While DCC/Unc-40 is
proposed to mediate the chemoattractive effect of netrin-1, it is thought that Unc5H/Unc5 is related more to the
chemorepulsive effect of netrin-1. In mammals, it has
been proposed that netrin-1-mediated axon attraction occurs in axons expressing only DCC, whereas axon repulsion occurs when both DCC and Unc5H are expressed,
with the pair cooperating by interacting in their intracellular domains (54). However, this view does not explain
the various settings in which netrin-1 attracts axons that
do not express DCC or attracts neurons that express DCC
and Unc5H. Interestingly, the observation of the role of
Unc5H in axon repulsion was studied in an in vitro system
in which Unc5H was truncated 100 amino acid residues
from the carboxy terminus (54). This may have related to
the fact that expressing a full-length form of Unc5H induces apoptosis in settings in which netrin-1 is not
present.
Indeed, the Unc5H proteins Unc5H1, Unc5H2, and
Unc5H3 have also been shown to function as dependence receptors (75). Just as for DCC, these proteins
display a caspase cleavage site in their intracellular
domains, and mutation of this site prevents apoptosis
induction. Furthermore, just as for DCC, the netrin-1
null mice display a marked increase in developmental
neural apoptosis in the cells expressing Unc5H (75).
Unlike DCC, however, Unc5H proteins display a classical death domain in the 100 carboxy-terminal amino
acid residues. This death domain is somewhat similar
to the p75NTR death domain, and although not clearly
classified as type I or type II currently, it is more similar
to the type II death domain of p75NTR than to the type
I death domains of Fas and TNFR I (75). This death
domain is required for apoptosis induction, i.e., it functions as a dependence domain, and this effect requires
membrane targeting. The requirement for caspase
cleavage for activation of this dependence domain suggests the possibility that there is a conformational
change following cleavage, which then results in activation of the dependence domain to induce apoptosis.
Another feature of Unc5H proteins that is distinct from
DCC is that, whereas the Unc5H proteins display a
classical caspase cleavage sequence, DXXD, DCC displays an unusual caspase cleavage site, LSVD (with R in
the P1⬘ position, which is also atypical).
It is interesting to note also that the different Unc5H
receptors Unc5H1, -H2, and -H3 may mediate cell death
through different (and multiple) mechanisms: Unc5H1,
but not Unc5H2 or UncH3, interacts, through its ZU5
421
DEPENDENCE RECEPTORS
VII. RET (REARRANGED DURING
TRANSFECTION, A GLIAL-DERIVED
NEUROTROPHIC FACTOR RECEPTOR) AS
A DEPENDENCE RECEPTOR
FIG. 3. Schematic representation of cellular dependent states created by wild-type and mutant dependence
receptors. In the normal state (associated with wild-type
dependence receptors), cell death is induced in the absence of trophic ligand but is suppressed by ligand binding. Tumor-associated mutants (e.g., of RET) render cells
insensitive to the lack of ligand availability, i.e., the mutant
receptor is “stuck” in the “off” position with respect to cell
death induction. Receptor mutants associated with developmental cell loss (e.g., Hirschsprung’s disease associated
with RET mutants) feature mutant receptors “stuck” in the
“on” position with respect to cell death induction. Receptor mutants associated with neurodegeneration (in this
case, polyglutamine-expanded androgen receptor mutants
associated with Kennedy’s disease) feature an increase in
overall proapoptotic effect but retain some ligand responsiveness. ⫺L, in the absence of (trophic) ligand; ⫹L, in the
presence of trophic ligand.
Physiol Rev • VOL
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The RET (rearranged during transfection) protooncogene is a receptor tyrosine kinase (RTK). As for other
RTKs, it is a type I transmembrane protein that displays
an extracellular ligand-binding domain, a transmembrane
domain, and an intracytoplasmic tyrosine kinase domain
(123). In addition, RET displays a cadherin-like domain
extracellularly, suggesting the possibility that it may function in cell-cell interaction (124).
Reminiscent of other dependence receptors, RET has
been shown to play a role in both neural development and
neoplasia. RET forms part of the receptor complex for
glial-derived neurotrophic factor (GDNF) and its related
trophic factors neurturin, artemin, and persephin (67).
These four trophic factors are related to the transforming
growth factor-␤ (TGF-␤) family. The receptor complex
includes RET and a GPI-anchored protein that is required
for RET dimerization, the latter of which may be GFR␣-1,
-2, -3, or -4 (5). RET and GFR␣-1 mediate a GDNF signal
that plays a role in the development of the enteric nervous
system and the kidney; thus null mutations in either
GDNF, RET, or GFR␣-1 display a similar phenotype (17,
111, 114).
Ligand binding to the RET complex leads to RET
autophosphorylation followed by interaction with effectors that include phospholipase C␥, Shc, Enigma, Grb2,
Grb7/Grb10, Src kinase, and Ras-GAP (4, 79, 112). As for
other RTKs, downstream RET signaling depends on the
molecular complexes assembled with the various adaptor
proteins involved (93).
Mutations in the RET protooncogene have been associated with both neoplasia and neural development:
regarding the former, multiple endocrine neoplasia type 2
(MEN-2) occurs in association with specific RET mutations (87), and regarding the latter, Hirschsprung syndrome occurs in association with other RET mutations
(34). MEN-2 is a neoplastic syndrome that includes the
development of tumors associated with endocrine organs:
tumors of the parathyroid, adrenal gland (pheochromocytoma), and thyroid (medullary carcinoma). Hirschsprung
syndrome is a relatively common (1 in 5,000 live births)
genetic defect in which neural crest-derived parasympathetic neurons of the hindgut are congenitally absent,
leading to a loss of peristalsis and resultant intestinal
dilation.
The profile observed for RET, i.e., its association with
both neural development and neoplasia, led Bordeaux et
al. (10) to evaluate the possibility that RET may function
as a dependence receptor. They reported that the expression of RET in the absence of GDNF induced apoptosis,
whereas GDNF blocked this effect. Furthermore, RET
was found to be a caspase substrate, with cleavage occurring at residues 707 and 1017. Cleavage at both of
these sites was found to be required for apoptosis induction by RET, and the dependence domain was found to lie
between these two sites. This domain did not, however,
display similarity to the dependence domains of p75NTR,
DCC, or Unc5H proteins.
Of perhaps greatest interest was the finding that the
RET mutants displayed two clearly distinct profiles: those
associated with neoplasia demonstrated constitutive kinase activity, such that the antiapoptotic effect was evident both in the presence and absence of ligand. In contrast, those associated with Hirschsprung syndrome demonstrated constitutive proapoptotic activity, again
irrespective of ligand (10). Thus both the proliferative and
the aplastic syndromes appear to result from mutations
that result in a loss of ligand response to the receptor
signaling (Fig. 3): the ligand-dependent on-off apoptosis
“switch” of this dependence receptor is “stuck” in the “on”
422
BREDESEN, MEHLEN, AND RABIZADEH
position for the Hirschsprung-associated mutants, and in
the “off” position for the MEN-2-associated mutants.
These findings suggest that the phenotypes observed in
cell culture may predict those in vivo by indicating what
apoptosis-related effects the receptors will have on their
expressing cells, and what modifying effects (if any) the
ligands will exert. They further suggest that Hirschsprung
syndrome may result, at least in part, from apoptosis
induction during development, resulting in the observed
lack of ganglionic neurons in the hindgut.
The androgen receptor is a nuclear/cytosolic steroid
receptor that includes an amino-terminal region polyglutamine stretch, a DNA-binding domain, and a carboxyterminal region ligand-binding domain. Binding of androgens such as testosterone by the androgen receptor leads
to nuclear translocation and transcriptional activity. Gene
regulation by the androgen receptor affects widespread
processes such as male gonadal development, prostate
cellular survival, motor neuron survival, and muscular
development, among many others.
As for RET, mutations in the androgen receptor are
associated both with neoplasia and neural cell loss. However, in contrast to the RET-associated developmental
lack (or early loss) of neurons in Hirschsprung syndrome,
some androgen receptor mutations are associated with a
neurodegenerative syndrome. In other words, the neurons apparently develop normally, then degenerate, typically during adult life. This syndrome, Kennedy’s disease,
also referred to as spinobulbar muscular atrophy (SBMA),
is associated with the degeneration of motor neurons in
the brain stem and spinal cord, resulting in weakness and
muscular atrophy. The associated mutations, rather than
resulting in point mutants of the androgen receptor, are
polyglutamine expansion mutations similar to those associated with Huntington’s disease, dentatorubropallidoluysian atrophy (DRPLA), and several spinocerebellar degenerations. Disease-associated polyglutamine tracts are typically longer than 30 glutamines, whereas those with
fewer than 30 glutamines in the polyglutamine tract of the
androgen receptor do not develop Kennedy’s disease.
Ellerby et al. (37) showed that the androgen receptor
displays a profile similar to that of other dependence
receptors: expression of the androgen receptor induces
apoptosis in the absence of ligand, whereas the addition
of ligand inhibits the receptor-induced cell death. The
androgen receptor is also a caspase substrate, with a
cleavage site at Asp-146, and, as for other dependence
receptors, mutation of this site results in a marked reduction in the proapoptotic effect of the receptor.
Site-directed mutagenesis of the androgen receptor
Physiol Rev • VOL
IX. OTHER DEPENDENCE RECEPTORS
Similar results to those reported for the receptors
listed above have been obtained with other receptors
such as the ␣v␤3-integrin and the interferon-␥ receptor
(122). Stupack et al. (122) found that the expression of
unligated integrins, or the ␤-subunit cytoplasmic domain,
or the membrane proximal sequence KLLITIHDRKEF, led
to apoptosis induction. Such induction resulted from the
recruitment of a proapoptotic complex that included
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VIII. THE ANDROGEN RECEPTOR AS A
DEPENDENCE RECEPTOR
revealed that the dependence domain of the androgen
receptor spans the polyglutamine region (37). Transfection studies demonstrated that an expanded polyglutamine domain is associated with an increase in cell
death, whereas a polyglutamine-deleted androgen receptor is associated with a decrease in cell death, compared
with the wild-type androgen receptor. It is noteworthy,
however, that deletion of the polyglutamine tract did not
completely suppress the proapoptotic activity of the androgen receptor, arguing that the proapoptotic dependence domain extends beyond the polyglutamine tract.
These findings suggest that the length of the polyglutamine tract in the androgen receptor correlates with its
proapoptotic effect, with short polyglutamine tracts having a lesser proapoptotic effect than the wild-type androgen receptor. This may turn out to have important clinical
implications: over the past few years, epidemiological
studies have shown that men with short polyglutamine
stretches (less than or equal to 15 glutamines) in their
androgen receptors have a statistically significantly
higher likelihood of developing prostate cancer, especially metastatic prostatic cancer (48, 120). Although
clearly not by an identical mechanism, this association of
neoplasia with a reduction in the proapoptotic effect of a
dependence receptor is reminiscent of the situation noted
above for RET.
In contrast, as noted above, an increase in the polyglutamine stretch is associated with the neurodegeneration of Kennedy’s disease. Again, somewhat reminiscent
of RET, a neoplastic syndrome is associated with a decrease in dependence, and a syndrome of neuronal loss is
associated with an increase in dependence. One distinction may or may not turn out to be revealing: whereas
Hirschsprung’s syndrome is associated with a developmental neuronal loss, Kennedy’s disease is associated
with postdevelopmental neurodegeneration; similarly,
there is a distinction in the effects of the mutations on the
dependence receptor effects. Specifically, Hirschsprungassociated mutants fail to respond to ligand inhibition but
have a proapoptotic effect similar to that of the wild type;
in contrast, Kennedy’s associated mutants do respond to
ligand inhibition but clearly demonstrate an increased
overall proapoptotic effect (37).
DEPENDENCE RECEPTORS
X. A MODEL FOR APOPTOSIS INDUCTION
BY DEPENDENCE RECEPTORS
Similarities between the effects of p75NTR, the androgen receptor, DCC, RET, Unc5H2, the interleukin-3 receptor, the ␣v␤3-integrin and Ptc suggest the model presented
in Figure 2. Analysis of the other dependence receptors
recognized to date has not yet proceeded far enough to
determine whether they will follow the pattern described
in Figure 2, but none of the data gathered to date exclude
this possibility.
The crux of the model proposed is that (at least) two
distinct pathways exist for these receptors: a classical
signal transduction pathway that leads to signals that
include an antiapoptotic response, and a nonclassical
signal transduction pathway that results in a proapoptotic
signal. In the absence of ligand, at least some dependence
receptors (e.g., the androgen receptor, DCC, RET, Ptc,
and Unc5H) undergo proteolytic processing, generating
stable contingency peptides (37, 84). This processing is
blocked when the receptors are ligand bound.
For DCC, cleavage is carried out by caspase-3 (or
possibly a related caspase member) at Asp-1290. This
cleavage is critical to the proapoptotic effect of DCC,
since mutation of Asp-1290 to Asn, which blocks caspase
cleavage, completely suppresses apoptosis induction (84).
Similarly, the androgen receptor is cleaved by
caspase-3, or a related subfamily caspase member, at
Asp-146 and at a second site in the carboxy-terminal
region of the protein. Mutation of Asp-146 to Asn supPhysiol Rev • VOL
presses apoptosis induction by the androgen receptor by
⬃60 – 80% (37).
Whether or not proteolytic cleavage of p75NTR plays
a role in apoptosis induction is not yet clear: p75NTR is
indeed processed proteolytically by an unknown (probably endosomal/lysosomal) protease (154) and can be
cleaved in vitro by caspases (S. Rabizadeh, X. Ye, and D.
Bredesen, unpublished data); however, it is currently unclear whether cleavage is required for the proapoptotic
effect of p75NTR.
In the model proposed, the presence or absence of
ligand determines the signal transduction pathway that
will be utilized, and feedback loops create two stable
states, full apoptosis induction or complete suppression,
rather than supporting intermediate states.
In the absence of ligand, it is proposed that caspase
cleavage leads to the production of contingency peptides,
at least one of which includes a dependence domain (Fig.
2). It is possible that the cleavage event may also lead to
a change in secondary structure that allows presentation
of the dependence domain (42).
The proapoptotic peptides that are produced then, by
definition of their proapoptotic activity, lead directly or
indirectly to the processing of caspase zymogens to active
caspases. Our preliminary results, utilizing a cell-free system of neuronal apoptosis (36), suggest that at least in
some cases, the effect is indirect, since the dependence
peptides have not shown direct caspase activation. However, there may be additional mechanisms involved: both
caspase zymogens and active caspases may interact specifically with dependence receptors (42, 84, 122), and it is
conceivable that this interaction may lead to caspase
processing and activation. As previously described, in the
case of DCC, caspase-3 and caspase-9 were found to
interact with the intracellular domain of DCC. Similarly,
caspase-8 was found to interact with ␤-integrin. However,
in vitro the presence of DCC, caspase-9, and caspase-3
was not sufficient to induce caspase activation unless a
cell lysate was added. This would suggest that intermediates
are probably necessary to allow caspase activation (42).
By serving as caspase substrates and generating peptides that induce caspase zymogen activation, these receptors appear to act as functional caspase amplifiers.
Cotransfection of expression constructs for caspase zymogens with constructs for dependence receptors supports this possibility, since caspase activation is markedly
enhanced in the presence of the receptor (S. Rabizadeh
and D. Bredesen, unpublished data).
However, this proposed mechanism raises a question
concerning initiation: if caspase activation requires apoptosis, yet apoptosis induced by dependence receptors
requires caspase cleavage, then how is the process initiated? How can a receptor that requires caspase cleavage
to produce a proapoptotic moiety participate in apoptosis
induction, rather than simply serving a passive and late
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caspase-8. These results were reminiscent of earlier results from Giancotti and Ruoslahti (47a), in which the
overexpression of the ␣5␤1-integrin led to reduced tumor
growth in vitro and in vivo.
More recently, Thibert et al. (130) proposed that the
receptor for sonic hedgehog (SHH), Patched (Ptc), is also
a dependence receptor. Indeed, the observation made by
LeDouarin and colleagues (21, 22) that the experimental
withdrawal of the classic morphogen SHH in chick embryos (effected by partial destruction of the notochord)
leads to massive cell death of the neuroepithelial cells in
the developing neural tube suggested that SHH is indeed
a survival factor. Thibert et al. (130) then demonstrated
that, both in vitro and in ovo, expression of the 12-transmembrane receptor Ptc in settings of SHH absence leads
to apoptosis induction. Moreover, as for DCC, RET,
UNC5H, and the androgen receptor, Ptc appears to be
cleaved at a caspase site, in this case, Asp-1392, and, just
as for these other dependence receptors, such cleavage is
required for cell death induction. In the case of Ptc,
however, there is no clear evidence yet of the nature of
the ADD, which appears to lie proximal to the caspase
cleavage site (130).
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BREDESEN, MEHLEN, AND RABIZADEH
XI. A POTENTIAL ROLE FOR DEPENDENCE
RECEPTORS IN TUMOR INVASION
AND METASTASIS
Because the expression of proapoptotic receptors
creates a state of cellular dependence on their respective
ligands, we proposed previously (11, 84) that such receptors tie cells to specific contexts in which the dependent
ligands are available. This might conceivably represent a
strategy used by the organism to prevent tumor growth
beyond specific ligand fields, and thus block metastasis
(Fig. 4). Indeed, a number of observations support this
notion.
For example, mapping of the dependence domain of
the androgen receptor indicates that it includes the poly-
glutamine tract that lies near the amino terminal of the
androgen receptor (37). Longer stretches of glutamines
led to a greater proapoptotic effect, and shorter stretches
were less effective at apoptosis induction; however, in all
cases, testosterone binding inhibited the proapoptotic effect. Deletion of the polyglutamine region destroyed
most, but not all, of the proapoptotic effect. These findings suggest that the degree of dependence is a function
of the polyglutamine length.
The length of this polyglutamine tract varies from
individual to individual. As noted above, individuals with
abnormally long polyglutamine tracts in the androgen
receptor (typically, ⬎30 glutamines) develop Kennedy’s
syndrome (68), in which degeneration of motor neurons
occurs. Conversely, individuals with short androgen receptor polyglutamine tracts (ⱕ16 glutamines) are at increased risk for the development of metastatic prostate
cancer (48, 120).
Similarly, p75NTR is expressed by normal prostate
epithelial cells, with the ligand source being the prostate
stromal cells. Pflug et al. (96) demonstrated a progressive
decline in p75NTR expression accompanying prostate neoplasms, from benign prostatic hypertrophy to carcinoma
in situ, with cell lines derived from metastatic prostatic
carcinomas failing to express p75NTR. We found that the
return of p75NTR expression to PC3 prostate carcinoma
cells returns apoptosis induction in the absence of NGF
(103).
A third example is provided by DCC, the loss of
expression of which is associated with invasive and metastatic colorectal carcinomas (41, 83). Ectopic expression
of DCC in a tumorigenic keratinocyte cell line lacking
endogenous DCC expression was shown to suppress tumorigenic growth of the cells in nude mice (63). Interestingly, in this study, it was observed that tumorigenic
reversion was associated with loss of DCC expression and
FIG. 4. Potential role of dependence receptors in
tumor suppression, tumor formation, and metastasis. In
normal tissue (at left), ligand is supplied to expressed
dependence receptors by local sources (such as stromal
cells in the prostate). However, migration away from
locally supplied ligand leads to apoptosis induced by
unbound dependence receptor. Loss of expression of
dependence receptor may allow metastasis due to the
loss of requirement for ligand support. Finally, hypertrophic support is associated with an inhibition of apoptosis
but may activate an alternative cell death program, paraptosis (119).
Physiol Rev • VOL
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role in the process? One possibility is that the process
may be initiated by a noncaspase protease, then propagated via caspase cleavage. Another possibility, which is
not mutually exclusive, relates to the recent finding that
caspase zymogens display some protease activity (110,
146). Additionally, work by Deveraux et al. (31) has
shown that cells express endogenous inhibitors of active
caspases. Taken together, these studies argue for the
importance of cellular control of caspase activation/inhibition and suggest, therefore, that caspase amplification
may indeed be an important cellular apoptosis control.
Thus it is possible that the cellular apostat is modulated by endogenous caspase inhibitors such as xiap, and
by endogenous amplifiers such as the dependence receptors, as well as other parameters. Amplification by dependence receptors would then be blocked by ligand binding
(Fig. 2). Ligand binding would not only block the critical
receptor cleavage, but would also initiate, via classical
signal transduction, signals blocking caspase zymogen
cleavage (Fig. 2).
DEPENDENCE RECEPTORS
the level of olivary neuron precursors that are known to
express DCC and Unc5H. These data support the view
that netrin-1 acts as a survival factor as well as a guidance
factor. As would be predicted from the dependence receptor profiles described above, the DCC knock-out mutant mice display a much less pronounced increase of
olivary neuronal cell death (E. Bloch-Gallego, personal
communication), supporting the view that the olivary neuronal death is the result of not only a loss of the positive
signaling of the pair DCC/netrin-1, but also of apoptosis
triggering by unbound DCC. Hence, the presence of netrin-1 along the pathway of migration may be important
not only to attract or repel axons or neurons but may be
key to support survival of these neurons as well. Beyond
neuronal survival, netrin-1 availability may also contribute to physiological cell turnover, since in the intestine it
is expressed in the crypts but not at the tips of the villi,
where cells turn over following migration from the crypts
(Fig. 5) (131).
Similarly, RET is expressed in the migratory neural
crest cells that colonize the enteric nervous system, and
RET plays a critical role in this migration, since the loss of
function of RET or its ligand GDNF by gene inactivation
in mice led to aganglionosis (6). However, a similar pathological state in humans, dubbed Hirschsprung disease, is
not due simply to the loss of a trophic function mediated
by RET, since some RET mutations associated with
Hirschsprung disease do not interfere with trophic function, at least with the trophic function mediated by ty-
XII. A POTENTIAL ROLE FOR DEPENDENCE
RECEPTORS DURING NERVOUS
SYSTEM DEVELOPMENT
As noted above, the dependence receptors DCC and
Unc5H were described as netrin-1 receptors, and as such,
are involved in axon outgrowth and turning. The knockout mutant mice for netrin-1 and DCC also confirmed the
role of the pair DCC/netrin-1 in the development of numerous commissural projections (39, 115). It is, however,
interesting to note that both DCC and Unc5H receptors
have been shown to induce apoptosis in the absence of
netrin-1, hence suggesting that netrin-1 may be considered not only as a chemotropic molecule that guides
axons or neurons but also as a survival factor that may
determine neuron/axon fate during migratory pathfinding.
Along this line, it has been observed that pontine cells and
olivary neurons in the netrin-1 knock-out mutant mice
were not simply incorrectly targeted, but were actually
absent (9, 149), probably because they had undergone
premature developmental neuronal death (75). Indeed,
Llambi et al. (75) demonstrated an increased cell death at
Physiol Rev • VOL
FIG. 5. Physiological cell turnover mediated by dependence receptors. In the example shown (131), cells at the base of the villus express
netrin-1 receptors but survive in the presence of netrin-1. However, as
these cells migrate up the villus, they are exposed to decreasing concentrations of netrin-1, resulting ultimately in apoptosis at the villus tip.
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loss or rearrangement of the transfected DCC expression
vector (63). Several more recent studies also indicate that
restoration of DCC expression can suppress tumorigenic
growth properties in vitro or in nude mice (57, 134),
supporting a role for DCC in tumor suppression. It is
important to note, however, that, contrary to earlier
thought, DCC may not be the only gene responsible for
colorectal cancer development associated with the loss of
homozygosity at chromosome 18q (39). As noted above,
DCC expression in the absence of ligand leads to apoptosis, whereas in the presence of ligand, apoptosis is inhibited. Therefore, one of the roles of DCC may be to induce
apoptosis in colorectal cancer cells that grow outside the
ligand field (84). This hypothesis is supported by the
recent observation that the Unc5H family of netrin-1 dependence receptors may also show similar features to
those of DCC: loss of Unc5H expression in cancer, LOH in
Unc5H genes, and suppression of the hallmarks of cell
transformation following reexpression of Unc5H in a
colorectal cancer cell line (131).
These results support, but do not prove, the notion
that dependence receptors may play a role in metastasis
suppression. Additional in vivo experiments, such as gene
therapeutic return of expression of specific receptors,
would provide further support for such a role. It should be
added that the modulation of the apoptotic propensity by
dependence receptors does not necessarily limit their
contribution to neoplasia to metastasis suppression; it is
certainly possible that at least some dependence receptors will prove to play a role in early neoplastic transformation.
425
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BREDESEN, MEHLEN, AND RABIZADEH
Physiol Rev • VOL
larly, integrins and their ligands (e.g., laminin) are likely
to be involved in axonal guidance (55, 98). However, the
proapoptotic role of the ␤-integrin in the absence of ligand has not been explored during neuronal migration or
axonal guidance.
XIII. A POTENTIAL ROLE FOR DEPENDENCE
RECEPTORS IN NEURODEGENERATION:
NEURODEGENERATIVE DISEASES AS
STATES OF ALTERED DEPENDENCE
As noted above, Kennedy’s syndrome, also referred
to as SBMA, is associated with expansions of the polyglutamine tract in the androgen receptor. Furthermore, apoptosis induction by the androgen receptor can be inhibited either by testosterone or by mutations of the
caspase-3 cleavage site at Asp-146 (37). Additionally, for
huntingtin, another polyglutamine protein (the expansion
of which is associated with Huntington’s disease, a neurodegenerative disease that affects the caudate nucleus
and, to a lesser extent, other regions of the brain such as
the neocortex), expression of the caspase-generated fragment is much more proapoptotic than expression of the
full-length protein.
These findings, taken together, suggest similarities
between the proposed dependence receptor mechanism
(Fig. 2) and the pathogenesis of polyglutamine expansionassociated neurodegeneration. This raises the more general question of whether neurodegeneration-associated
gene products are overrepresented among the set of
caspase substrates. Our recent studies suggest that they
are; whereas a small minority of cellular proteins whose
cDNAs were cloned at random from a brain cDNA library
were cleaved by caspase-3, six of seven polyglutamine
expansion proteins associated with neurodegeneration
were cleaved: androgen receptor, huntingtin, atrophin-1,
ataxin-2, ataxin-3, ataxin-6, and ataxin-7 (Z. Li, L. Zhong, and
D. Bredesen, unpublished data; Ref. 37). In addition, other
neurodegeneration-associated proteins such as the ␤-amyloid precursor protein (APP), presenilin-1, and presenilin-2,
have also been shown to be cleaved by caspases (47, 80).
Cleavage of APP at its caspase cleavage site, Asp-664,
results in the generation of a 31-residue carboxy-terminal
fragment, APP-C31 (47, 80). It has been suggested that
cleavage at this site enhances the production of the Alzheimer’s-associated ␤-amyloid peptide (47); however, this
finding has been refuted in other studies (66). A second
effect of cleavage at Asp-664 is the generation of APP-C31,
which is a cytotoxic peptide (80). Similar cleavage events,
resulting in similar cytotoxic peptides, may also occur in
the APP-related proteins APLP1 and APLP2 (APP-related
protein 1 and APP-related protein 2) (46). It is not yet
clear whether these cleavage events are modulated by
ligand interactions with APP, in part because it is not
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rosine kinase-related signaling (94). Therefore, it has been
hypothesized that Hirschsprung disease is not due simply
to an aberrant or reduced migration of neural crest cells,
but also to their death (10). Along this line, as noted
above, Bordeaux et al. (10) observed that five Hirschsprung-associated mutations convert RET’s cell deathinducing profile from that of a typical dependence receptor to that of a constitutive proapoptotic molecule, i.e.,
cell death is induced irrespective of ligand (here, GDNF)
presence (10). This finding suggests that adequate neural
crest cell migration is dictated by both positive signaling
that is mediated by the binding of RET ligands to RET and
by an inhibition of negative signaling, here cell death
induction by RET, that regulates cell migration outside
the region of adequate ligand availability.
The most recently described dependence receptor
Ptc and its ligand SHH have been shown to be crucial for
determining cell fate during development, and in particular during early development of the neural tube (97). It is
believed that a ventrodorsal gradient of SHH is produced
by the floor plate and the notochord, allowing cell fate
determination/differentiation of the ventral neurons of
the neural tube. LeDouarin and colleagues (21, 22) have
demonstrated that SHH determines the fate of these cells
not only with respect to their differentiation, but also with
respect to their survival, since the withdrawal of SHH
leads to massive cell death in the neural tube. Thibert et
al. (130) using a mutant of Ptc that blocks endogenous
Ptc-induced cell death then demonstrated that blocking
Ptc-induced cell death during chick neural development is
sufficient to block the cell loss occurring in a neural tube
from which SHH has been withdrawn. Moreover, the introduction of this mutant not only blocks cell death but
actually leads to the development of a neural tube-like
structure despite the lack of SHH. Even though a more
careful study is needed to see the differentiation profile of
the neuroepithelial cells in this rescued neural tube, this
initial result argues for a role of cell death not simply as
a consequence of aberrant or inadequate differentiation,
but as an active process that shapes the neural tube. It
also supports the role of the dependence receptor Ptc in
regulating cell fate during neural tube development. Interestingly, a recent study by Tessier-Lavigne and colleagues
(23) has proposed that SHH is also a guidance cue for
commissural neurons via its receptor Ptc, a finding that is
reminiscent of the dual properties of DCC, UNC5H, and
RET.
Interestingly, other dependence receptors appear to
be closely related to neuronal migration or axonal guidance. Indeed, p75NTR was recently shown to be a coreceptor for Nogo (along with the Nogo receptor), and as
such p75NTR appears to be involved in the retraction of
axons (138, 141). However, whether the proapoptotic activity of p75NTR is modulated by Nogo (or the previously
described Nogo receptor) remains to be explored. Simi-
DEPENDENCE RECEPTORS
Address for reprint requests and other correspondence:
D. E. Bredesen, The Buck Institute for Age Research, 8001
Redwood Blvd., Novato, CA 94945 (E-mail: [email protected]
buckinstitute.org).
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