Download Gene Section PHLPP1 (PH domain leucine rich repeat protein phosphatase 1)

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Mini Review
PHLPP1 (PH domain leucine-rich repeat protein
phosphatase 1)
Audrey K O'Neill, Alexandra C Newton
(AKO, ACN)
Published in Atlas Database: June 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/PHLPP1ID44544ch18q21.html
DOI: 10.4267/2042/44755
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Protein
Other names: PHLPP; KIAA0606; MGC161555;
PLEKHE1; SCOP
HGNC (Hugo): PHLPP1
Location: 18q21.33
Description
The PHLPP1alpha and PHLPP1beta proteins both
contain a pleckstrin homology (PH) domain, a series of
leucine-rich repeats (LRR), a PP2C phosphatase
domain, and a C-terminal PDZ (post synaptic density
protein [PSD95], Drosophila disc large tumor
suppressor [DlgA], and zonula occludens-1 protein [zo1]) binding motif. In addition, PHLPP1beta has a
putative Ras association (RA) domain near its Nterminus. PHLPP1alpha is composed of 1205 amino
acids and has a molecular weight of approximately 133
kDa, while PHLPP1beta has 1717 amino acids and a
molecular weight of approximately 185 kDa. (The
related isoform PHLPP2 has a domain structure similar
to that of PHLPP1beta).
DNA/RNA
Description
The gene for PHLPP1 is located at 18q21.33. It
encompasses
two
different
splice
variants:
PHLPP1alpha and PHLPP1beta. PHLPP1alpha spans
154 kb and includes 16 exons. The PHLPP1beta gene is
identical to the PHLPP1alpha gene except that it has a
much (~1.5 kb) longer exon 1 and a slightly shorter
exon 2. Including the new exon 1, the PHLPP1beta
gene is 265 kb in length. PHLPP1 is one of two
separate genes in the PHLPP gene family; the second
gene, PHLPP2, is located at 16q22.3.
Expression
PHLPP1 is expressed in most human cancer cell lines
and all mouse tissues examined so far. PHLPP1beta
appears to be more abundant than PHLPP1alpha. Rat
PHLPP1beta (termed SCOP for Suprachiasmatic
nucleus circadian oscillatory protein) is also expressed
in the suprachiasmatic nucleus, where its mRNA
expression oscillates in a circadian fashion.
Transcription
The PHLPP1alpha and PHLPP1beta transcripts are
identical except for exon 1 and the beginning of exon 2.
The PHLPP1alpha transcript is 4617 bp; the
PHLPP1beta transcript is 6155 bp.
Genomic organization of the PHLPP1alpha and PHLPP1beta transcripts. Exons are represented by blue (PHLPP1alpha) or red
(PHLPP1beta) boxes, and position along chromosome 18 is indicated by the scale bar at the top.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(5)
464
PHLPP1 (PH domain leucine-rich repeat protein phosphatase 1)
O'Neill AK, Newton AC
PHLPP1alpha and PHLPP1beta protein structure.
LN229, a glioblastoma cell line, and suppresses its
ability to form tumors in nude mice.
PHLPP1 also regulates the phosphorylation and activity
of ERK; it has been suggested to interact directly with
the nucleotide-free form of K-Ras and thus suppress the
Ras/Raf/MEK/ERK pathway. This pathway is
important for the regulation of learning and memory,
and overexpression of rat PHLPP1beta in the
hippocampus of transgenic mice abolishes memory for
novel objects. In addition, training for hippocampusbased learning prompts calpain protease-mediated
degradation of PHLPP1. Together, these results suggest
that proper regulation of PHLPP1 in certain neurons is
crucial for memory formation.
Localisation
PHLPP1 appears to be localized throughout the cell.
Function
PHLPP1 is a phosphatase that specifically
dephosphorylates the hydrophobic motif (HM) of Akt
and
conventional/novel
PKC
isoforms.
HM
phosphorylation is important for the function of both
kinases. For Akt, phosphorylation at serine 473, the
HM site, allows full activation of the kinase and
subsequent phosphorylation of its downstream
substrates. For PKC, phosphorylation of the HM
(serine 660 in PKCbetaII) increases protein stability;
once the HM is dephosphorylated, two other important
regulatory sites on the kinase (the activation loop and
the turn motif) are rendered more sensitive to
dephosphorylation by other phosphatases. The
dephosphorylated PKC is then shunted to the detergentinsoluble fraction of the cell, where it is degraded.
PHLPP1 therefore functions to decrease the activity of
both Akt and PKC, albeit by different mechanisms.
While PHLPP1 and its family member PHLPP2 have
similar functions, their specificity for Akt isoforms
differs.
PHLPP1
preferentially
binds
and
dephosphorylates Akt2 and Akt3, resulting in
decreased phosphorylation of a set of Akt targets that
includes GSK-3beta, TSC2, and FoxO, as well as and
GSK3a. PHLPP2, on the other hand, binds and
dephosphorylates Akt1 and Akt3, resulting in
downregulation of an overlapping yet distinct set of
downstream targets: GSK-3beta, TSC2, and FoxO, as
well as TSC2 and p27.
Interestingly, PHLPP1's regulation of its protein
substrates appears to be regulated by its protein-protein
interaction domains. PHLPP1 lacking a C-terminal
PDZ ligand is unable to dephosphorylate Akt, whereas
deletion of PHLPP1's PH domain decreases its ability
to dephosphorylate PKC.
Since PHLPP1 downregulates the pro-survival kinase
Akt, it is not surprising that this phosphatase plays roles
in apoptosis and suppression of cellular proliferation.
siRNA-mediated reduction of PHLPP1 causes
increased apoptosis in a number of cell lines, whereas
overexpression of PHLPP1 decreases proliferation in
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(5)
Homology
PHLPP is a highly conserved phosphatase; its earliest
orthologue is the yeast protein CYR1. In addition to a
PP2C phosphatase domain, a leucine-rich repeat, and a
Ras association domain, CYR1 contains an adenylate
cyclase domain near its C terminus. Though
invertebrates have only one PHLPP gene, most
vertebrates have genes for both PHLPP1 and PHLPP2.
Mutations
Somatic
One glioblastoma multiforme sample was found to
have a mutation in the catalytic domain of PHLPP1
(M738T in the PHLPP1a transcript). This tumor sample
presented with mutations in several other known tumor
suppressors, including PTEN and Rb.
Implicated in
Glioblastoma multiforme
Oncogenesis
PHLPP1 overexpression in human LN229 cells limits
their ability to form tumors in a xenograft model.
Various human glioblastoma cell lines respond to
PHLPP1
knockdown
with
increased
Akt
phosphorylation. In addition, mRNA expression of both
PHLPP1 and PHLPP2 are decreased by around 30% in
patient glioblastoma samples (relative to normal brain).
465
PHLPP1 (PH domain leucine-rich repeat protein phosphatase 1)
O'Neill AK, Newton AC
Gao T, Furnari F, Newton AC. PHLPP: a phosphatase that
directly dephosphorylates Akt, promotes apoptosis, and
suppresses tumor growth. Mol Cell. 2005 Apr 1;18(1):13-24
Colorectal cancer
Cytogenetics
18q21.33, the chromosomal locus containing the gene
for PHLPP1 as well as the putative tumor suppressors
BCL2 and Maspin, commonly undergoes loss of
heterozygosity in colon cancers.
Oncogenesis
Overexpression of PHLPP1 or PHLPP2 in the human
colon cancer cell lines HCT-116 and HT29 causes
decreased expression of PKC and decreased
phosphorylation of Akt. Cells overexpressing PHLPP
exhibit decreased proliferation and were less able to
induce tumors in nude mice. Conversely, DLD1 cells,
which express high levels of PHLPP, respond to
PHLPP1 or PHLPP2 knockdown with increased Akt
phosphorylation, PKC stability, and proliferation.
Sun L, Hui AM, Su Q, Vortmeyer A, Kotliarov Y, Pastorino S,
Passaniti A, Menon J, Walling J, Bailey R, Rosenblum M,
Mikkelsen T, Fine HA. Neuronal and glioma-derived stem cell
factor induces angiogenesis within the brain. Cancer Cell. 2006
Apr;9(4):287-300
Brognard J, Sierecki E, Gao T, Newton AC. PHLPP and a
second isoform, PHLPP2, differentially attenuate the amplitude
of Akt signaling by regulating distinct Akt isoforms. Mol Cell.
2007 Mar 23;25(6):917-31
Mendoza MC, Blenis J. PHLPPing it off: phosphatases get in
the Akt. Mol Cell. 2007 Mar 23;25(6):798-800
Shimizu K, Phan T, Mansuy IM, Storm DR. Proteolytic
degradation of SCOP in the hippocampus contributes to
activation of MAP kinase and memory. Cell. 2007 Mar
23;128(6):1219-29
Cancer Genome Atlas Research Network. Comprehensive
genomic characterization defines human glioblastoma genes
and core pathways. Nature. 2008 Oct 23;455(7216):1061-8
Leukemia
Disease
Chronic lymphocytic leukemia, chronic myelogenous
leukemia
Oncogenesis
PHLPP1 mRNA expression is frequently reduced to
undetectable levels in patients with chronic
lymphocytic leukemia (CLL). About 50% of CLL
patients have loss of chromosomal region 13q14, and
about 50% of these show drastically reduced PHLPP1
expression. In chronic myelogenous leukemia (CML),
PHLPP mRNA levels may also be decreased, albeit by
a different mechanism. Bcr-Abl, the fusion protein
responsible for CML, downregulates PHLPP1 and
PHLPP2 mRNA levels; decreasing PHLPP levels
interferes with the efficacy of Bcr-Abl inihibitors,
including Gleevec, in CML cell lines.
Brognard J, Newton AC. PHLiPPing the switch on Akt and
protein kinase C signaling. Trends Endocrinol Metab. 2008
Aug;19(6):223-30
Gao T, Brognard J, Newton AC. The phosphatase PHLPP
controls the cellular levels of protein kinase C. J Biol Chem.
2008 Mar 7;283(10):6300-11
Ouillette P, Erba H, Kujawski L, Kaminski M, Shedden K,
Malek SN. Integrated genomic profiling of chronic lymphocytic
leukemia identifies subtypes of deletion 13q14. Cancer Res.
2008 Feb 15;68(4):1012-21
Hirano I, Nakamura S, Yokota D, Ono T, Shigeno K, Fujisawa
S, Shinjo K, Ohnishi K. Depletion of Pleckstrin homology
domain leucine-rich repeat protein phosphatases 1 and 2 by
Bcr-Abl promotes chronic myelogenous leukemia cell
proliferation through continuous phosphorylation of Akt
isoforms. J Biol Chem. 2009 Aug 14;284(33):22155-65
Liu J, Weiss HL, Rychahou P, Jackson LN, Evers BM, Gao T.
Loss of PHLPP expression in colon cancer: role in proliferation
and tumorigenesis. Oncogene. 2009 Feb 19;28(7):994-1004
References
Shimizu K, Okada M, Takano A, Nagai K. SCOP, a novel gene
product expressed in a circadian manner in rat
suprachiasmatic nucleus. FEBS Lett. 1999 Sep 24;458(3):3639
This article should be referenced as such:
O'Neill AK, Newton AC. PHLPP1 (PH domain leucine-rich
repeat protein phosphatase 1). Atlas Genet Cytogenet Oncol
Haematol. 2010; 14(5):464-466.
Shimizu K, Okada M, Nagai K, Fukada Y. Suprachiasmatic
nucleus circadian oscillatory protein, a novel binding partner of
K-Ras in the membrane rafts, negatively regulates MAPK
pathway. J Biol Chem. 2003 Apr 25;278(17):14920-5
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(5)
466