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PTEN at a glance

Yuji Shi1, Benjamin E. Paluch2,Xinjiang Wang2 and XuejunJiang1,*1Cell Biology Program, Memorial Sloan-KetteringCancer Center, 1275 York Avenue, New York,NY 10065, USA2Department of Pharmacology and Therapeutics,Roswell Park Cancer Institute, Elm and CarltonStreets, Buffalo, NY 14263, USA

*Author for correspondence (jiangx@mskcc.org)

Journal of Cell Science 125, 4687–4692� 2012. Published by The Company of Biologists Ltddoi: 10.1242/jcs.093765

Since its discovery in 1997 (Li and Sun,1997; Li et al., 1997; Steck et al., 1997), the

phosphatidylinositol (3,4,5)-trisphosphate[PtdIns(3,4,5)P3] phosphatase and tensinhomolog (PTEN) has been established as

one of the most frequently mutated tumor

suppressor genes in human cancer. PTEN is

a phosphatase that catalyzes the conversion

of the lipid second messenger PtdIns

(3,4,5)P3 to phosphatidylinositol (4,5)-

bisphosphate [PtdIns(4,5)P2] (Maehama

and Dixon, 1998). As such, PTEN

functions as a main regulator of the

cellular PtdIns(3,4,5)P3 concentration to

antagonize the signaling cascades

downstream of receptor tyrosine kinases

(RTKs) and phosphatidylinositol-3-kinase

(PI3K). Interestingly, PTEN might also

possess protein phosphatase activity, and

several potential protein substrates have

been reported (Gu et al., 1999;

Mahimainathan and Choudhury, 2004;

Raftopoulou et al., 2004; Tamura et al., 1998).

PTEN contains multiple domains,

including an N-terminal phosphatase

domain, a central C2 domain and a C-

terminal tail. The phosphatase and C2

domains form a minimal enzymatic unit that

is sufficient for metabolizing PtdIns(3,4,5)P3.

The C-terminal tail is a long flexible fragment

that is mainly involved in PTEN regulation.

Despite having initially been discovered

as a tumor suppressor, PTEN has attracted

great interest from various research fields

because of its diverse physiological functions.

The functional diversity of PTEN demands a

collection of delicate regulatory mechanisms,

including transcriptional and post-

translational regulation in a tissue- and

context-dependent manner. This Cell

Science at a Glance article summarizes the

diversity of PTEN functions, and the

mechanisms that underlie the regulation of

PTEN expression, its enzymatic activity and

subcellular localization.

(See poster insert)

Cell Science at a Glance 4687

mailto:jiangx@mskcc.org

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PTEN has diverse functions inmammalian cellsPTEN as a tumor suppressor

PTEN mutations occur frequently in avariety of human cancers, including

endometrial carcinoma, glioblastomamultiforme, skin and prostate cancers(Chalhoub and Baker, 2009). They include

a mutational spectrum that is scatteredalong the entire gene and predominantlyrepresent monoallelic mutations. A majorityof PTEN mutations cause truncations of the

protein. In addition to cancer-associatedsomatic mutations, PTEN is often mutatedin tumor-prone germline diseases.

Genetic studies in mice have

unambiguously demonstrated that PTEN isa potent tumor suppressor in almost allorgans. Tissue-specific Pten-knockout

mice develop tumors in numerous organs(Knobbe et al., 2008; Suzuki et al., 2008).Intriguingly, subtle changes in PTEN gene

expression, mRNA regulation and proteinsynthesis are sufficient to have a substantialimpact on tumorigenesis, a phenomenonthat is referred to as quasi-insufficiency

(Carracedo et al., 2011). Furthermore, thenotion of PTEN haploinsufficiency seems toapply to human cancer because monoallelic

mutation of PTEN without loss or mutationof the second allele is prevalent in breastand prostate cancers (Salmena et al., 2008).

PTEN is involved in multiple cellularprocesses

PTEN is involved in regulating manycellular processes. Many of thesefunctions can be attributed to its lipid

phosphatase activity. For example, PTENregulates cell proliferation and apoptosis.These effects are mediated by suppressing

AKT (also known as protein kinase B)activation. Because AKT activation requiresPtdIns(3,4,5)P3, dephosphorylation of this

lipid second messenger by PTEN results ininhibition of AKT and subsequent alterationof the function of AKT substrates, such asforkhead box protein O (FOXO), the E3

ubiquitin ligase MDM2, and BCL2 antagonistof cell death (BAD) (Tamguney and Stokoe,2007). PTEN has a crucial role in regulating

the self-renewal and differentiation of humanembryonic stem cells and hematopoietic stemcells as well as the timing of follicle activation

through the regulation of oocyte growth(Reddy et al., 2008). PTEN also regulatesthe chemotaxis of neutrophils (Heit et al.,

2008), and all these functions require its lipidphosphatase activity.

In addition, PTEN can regulate variouscellular events independently of its lipid

phosphatase activity. For example, it can

inhibit cell cycle progression by modulatingthe activity of the anaphase-promotingcomplex/cyclosome (APC/C) in the

nucleus in a manner that is independent ofPTEN enzymatic activity (Song et al.,2011). Furthermore, it can inhibit cellinvasion and migration, probably by

making use of its protein phosphataseactivity (Tamura et al., 1999). PTEN cancontrol the size of DNA-damaged cells by

regulating the actin-remodeling process(Kim et al., 2011) through a mechanismthat is likely to be independent of its lipid

phosphatase activity. Deficiency of anyof these functions can contribute totumorigenesis.

Transcriptional and post-transcriptional regulation of PTENAs mentioned above, subtle changes in theregulation of gene expression and mRNA

of PTEN have a substantial impact onthe normal physiology of organisms.Therefore, both are delicately regulated

through multiple mechanisms (see Poster).

Transcriptional regulation of PTEN

The PTEN promoter is regulated by many

transcription factors that operate at specifictimes and in different cell types.Transcription factors, such as early

growth response protein (EGR1), tumorprotein 53 (Tp53, also referred to as p53)and peroxisome proliferator-activated

receptor gamma (PPARG) were reportedto positively regulate PTEN expression(Martelli et al., 2011). PTEN transcriptioncan also be repressed, for example, by the

polycomb complex protein BMI1 duringepithelial–mesenchymal transition (EMT)of nasopharyngeal epithelial cells, or

through b-catenin/transcription factor(TCF)-mediated downregulation of EGR1in ovarian cancer cells (Lau et al., 2011;

Song et al., 2009). Intriguingly, in a tissue-specific manner, Notch signaling mightlead to upregulation of PTEN by inhibitingone of the PTEN downregulators, the

recombining binding protein suppressorof hairless (RBPJ, also known as andhereafter referred to as CBF-1) (Chappell

et al., 2005; Whelan et al., 2007) or,conversely, to its downregulation byactivating another PTEN downregulator,

the transcription factor hairy and enhancerof split 1 (HES1) (Palomero et al., 2007).Furthermore, epigenetic silencing by

hyper-methylation of the PTEN promoteroccurs in some breast and colorectalcancers, and in gastric carcinoma.

Post-transcriptional regulation of PTENmRNA

PTEN mRNA has been reported to besusceptible to post-transcriptional regulation

by a variety of microRNAs (miRNAs),including miRNA-21, miRNA-22 andmiRNA-26a (Bar and Dikstein, 2010; Huse

et al., 2009; Meng et al., 2007). ThesemiRNAs can, thus, impact both normalbiological and pathological functions ofPTEN.

Additional complexity results from the

regulation of PTEN expression throughnon-coding RNAs, such as the PTENpseudogene PTENP1 mRNA. PTENP1

genetically resembles PTEN in its proteincoding region. Owing to a mutation in itsinitiator codon PTEN1 mRNA, unlike

PTENP mRNA, cannot be translated intoa protein. The PTENP1 mRNA is generallysubject to same miRNA-mediated

regulation and, thus, can function as‘decoy’ that sequesters miRNA-21.Interestingly, in sporadic colon cancer,PTENP1 undergoes a copy number

loss that is concurrent with PTENdownregulation (Poliseno et al., 2010).Similarly, zinc finger E-box-binding

homeobox 2 (ZEB2), which encodesanother endogenous RNA, has beenreported to serve as an miRNA decoy for

the PTEN mRNA, and loss of ZEB2 mRNAcontributes to melanomagenesis (Karrethet al., 2011). However, it is important tobear in mind that only 25% of cancer

patients portray a correlation between theloss of PTEN protein and its mRNA level(Chen et al., 2011), which emphasizes the

importance of PTEN regulation at the post-transcriptional and post-translational levels.

Post-translational modification ofPTENPTEN is subject to various post-translational modifications that regulateits enzymatic activity, interaction with

other proteins and subcellular localization(see Poster).

Phosphorylation

The first phosphorylation sites mapped onPTEN were a cluster of serine and threonine

residues in its C-terminal tail (Vazquezet al., 2000). Mutation of these residues toalanine leads to elevated membrane affinity,

higher enzymatic activity and more-rapiddegradation of PTEN. When these residuesare phosphorylated, the C-terminal tail can

interact with the N-terminal C2 andphosphatase domains (Odriozola et al.,2007; Rahdar et al., 2009), which suggests

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that phosphorylation of the C-terminal tail

functions as an auto-inhibitory mechanism

that controls both PTEN membrane

recruitment and its lipid phosphatase

activity.

Several kinases have been reported to

phosphorylate PTEN. Casein kinase 2

(CK2) mainly phosphorylates Ser370 and

Ser385 (Torres and Pulido, 2001), whereas

glycogen synthase kinase 3 b (GSK3B)targets Ser362 and Thr366 (Al-Khouri

et al., 2005). In contrast to the function

of C-terminal tail phosphorylation, it

seems that Thr366 phosphorylation can

promote PTEN degradation (Maccario

et al., 2007). Additionally, glioma tumor

suppressor candidate region 2 (GLTSCR2,

also known as PICT-1) has been shown

to interact with PTEN, enhance its

phosphorylation at Ser380 and stabilize

the phosphatase (Okahara et al., 2006; Yim

et al., 2007). Moreover, RhoA-associated

kinase (ROCK) has been shown to

phosphorylate PTEN at Ser229, Thr232,

Thr319 and Thr321, which are all located

in the C2 domain and promote membrane

targeting of PTEN in chemoattractant-

stimulated leukocytes (Li et al., 2005).

Recently, a Src family tyrosine kinase, the

fyn-related kinase (FRK, also known and

hereafter referred to as RAK) has been

reported to interact with PTEN and

phosphorylate it on Tyr336, thereby

protecting PTEN from proteasomal

degradation mediated by neural precursor cell

expressed, developmentally downregulated-4

(NEDD4) (Yim et al., 2009).

Acetylation

Similar to phosphorylation, acetylation can

also regulate PTEN activity. The histone

acetyltransferase K(lysine) acetyltransferase

2B (KAT2B, also known and hereafter

referred to as PCAF) has been reported to

interact with PTEN and promote PTEN

acetylation on Lys125 and Lys128 in

response to growth factor stimulation

(Okumura et al., 2006). As these residues

are within the catalytic pocket, PTEN

acetylation by PCAF negatively regulates

its enzymatic activity. PTEN is also

acetylated on Lys402, which is located

within the C-terminal PDZ-domain-binding

motif Thr-Lys-Val sequence. This,

potentially, affects the interaction between

PTEN and PDZ-domain-containing proteins

(Ikenoue et al., 2008). CREB-binding

protein (CREBBP, also known and

hereafter referred to as CBP) and the sirtuin

SIRT1 have been identified as the main

PTEN acetyltransferase and deacetylase,respectively.

Oxidation

Another mechanism that can potentially

regulate the catalytic activity of PTEN isdirect oxidation by reactive oxygen species(ROS). ROS can oxidize Cys124 in

the active site, thereby forming anintramolecular disulfide bond with Cys71(Lee et al., 2002). Oxidative inactivation ofPTEN has been reported in studies

describing the use of hydrogen peroxideor endogenous ROS production inmacrophages (Kwon et al., 2004; Leslie

et al., 2003). PTEN activity can also beindirectly inhibited by oxidation throughmodulation of PTEN-binding partners.

Oxidation of the antioxidant PARK7 (alsoknown as DJ-1) leads to binding to PTENand the subsequent inhibition of the PTEN

lipid phosphatase activity (Kim et al.,2009).

S-nitrosylation

A few studies have demonstrated theimportance of another redox mechanism,

S-nitrosylation, in the regulation of PTEN.The level of S-nitrosylation on PTENsubstantially increases in the early stages

of Alzheimer disease, and this correlateswith reduced PTEN protein levels andelevated AKT phosphorylation (Kwak

et al., 2010a). Nitric oxide (NO) signalinginduces PTEN S-nitrosylation, therebyinactivating the lipid phosphatase,downregulating its protein level through

NEDD4-mediated degradation and leadingto downstream activation of AKT. Anotherreport has shown that PTEN is selectively

S-nitrosylated on Cys83 by lowconcentrations of NO (Numajiri et al.,2011). Moreover, S-nitrosylated PTEN has

been detected in the core and penumbraregions of ischemic mouse brains. S-nitrosylation and downregulation of PTEN

activity in this region are likely to actas protective mechanisms through AKTactivation.

Ubiquitylation

Using a biochemical purification approach,

NEDD4 was identified as an E3 ligase thatubiquitylates PTEN (Wang et al., 2007).NEDD4 physically interacts with PTEN and

its overexpression leads to both mono- andpolyubiquitylation of PTEN. Interestingly,monoubiquitylation of PTEN appears to be

crucial for its nuclear import (Trotman et al.,2007). Consistent with the function of thePTEN C-terminal tail in regulating its

stability, deletion of this region makes

PTEN a stronger binding partner and

better substrate for NEDD4 (Wang et al.,

2008).

Two other E3 ligases have been reported

to target PTEN, X-linked inhibitor of

apoptosis protein (XIAP) (Van Themsche

et al., 2009) and WWP2, a NEDD4-like

protein family member (Maddika et al.,

2011). Although the physiological

relevance of these E3 ligases with regards

to PTEN function has not yet been defined,

it is possible that PTEN is regulated

by multiple E3 ligases, depending on

the context or special physiological

circumstances.

However, in most experimental systems,

PTEN appears to be a rather stable protein.

Thus, what is the biological relevance

of PTEN regulation through ubiquitin-

mediated proteasomal degradation? It

appears that NEDD4 regulates PTEN in a

context-dependent manner to achieve

specific functions. For example, NEDD4

is required for neuronal axonal branching in

retinal ganglion cells (RGCs) and mainly

functions through downregulating PTEN

(Drinjakovic et al., 2010). Blocking

NEDD4 function severely inhibits terminal

branching in RGCs, whereas PTEN

knockdown rescues the branching

deficiency. Also, NEDD4-mediated PTEN

ubiquitylation is essential in the regulataion

of PI3K-AKT signaling for neuronal

survival in response to Zn2+ (Kwak et al.,

2010b). Furthermore, in cultured neuronal

models, NO signaling not only induces

PTEN S-nitrosylation but also results

in enhanced PTEN protein degradation

through NEDD4-mediated ubiquitylation

(Kwak et al., 2010a).

Interestingly, several cellular proteins

have been reported to modulate the

association between NEDD4 and PTEN,

which might provide mechanistic insights

into the context-dependent regulation

of PTEN by NEDD4. In breast

cancer cells, the tyrosine kinase RAK

positively regulates PTEN stability by

phosphorylating PTEN on Tyr336. This

prevents PTEN from binding to NEDD4

and its subsequent degradation (Yim et al.,

2009). Recently, the PY (Pro-Pro-x-Tyr)-

motif-containing membrane proteins

NEDD4-family-interacting proteins 1 and

2 (NDFIP 1 and 2, respectively), which are

potent activators of NEDD4 family

members, have been shown to promote

NEDD4-mediated ubiquitylation and, thus,

promote degradation and nuclear import of

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PTEN (Howitt et al., 2012; Mund and

Pelham, 2010).

PTEN regulation by its interactingproteinsThe enzymatic activity and the biological

effects of PTEN are often regulated by its

interaction with other proteins. The lipid

phosphatase activity of PTEN can be

stimulated by binding to p85, the regulatory

subunit of PI3K (Chagpar et al., 2010). By

contrast, the binding of shank-interacting

protein-like 1 (SIPL1) or PtdIns(3,4,5)P3–

RAC-exchanger 2 (PREX2) to PTEN inhibits

its lipid phosphatase activity, thereby

promoting signaling through the PI3K

pathway (Fine et al., 2009; He et al., 2010).

Binding of the scaffold protein

b-arrestin to PTEN controls the outputof distinct PTEN signals during cell

proliferation and migration; binding of

b-arrestin to PTEN normally activatesthe lipid phosphatase activity and inhibits

cell proliferation. However, following the

activation of RhoA as a result of wounding,

b-arrestin inhibits the lipid phosphatase-independent anti-migratory function of

PTEN. In addition, the binding of several

proteins to PTEN can regulate its stability

(Lima-Fernandes et al., 2011). These proteins

include membrane-associated guanylate kinase

inverted 3 (MAGI), GLTSCR2, NDFIP1

and RAK, whose binding affects PTEN

phosphorylation status, complex recruitment

or NEDD4-mediated ubiquitylation.

Distinct subpopulations of PTENThe fact that the majority of cellular PTEN is

found in the cytosol raises important

questions, such as how PTEN is able to

execute different cellular functions that often

require its membranous lipid phosphatase

activity. Accumulating evidence has

suggested that a small subpopulation of

cellular PTEN is sufficient for each specific

biological function. A PTEN subpopulation

can be defined by either specific post-

translational modification(s) or its interaction

with a particular associating factor. It

should be emphasized that a functional

subpopulation of PTEN might only

represent a small portion of total cellular

PTEN, thus it might evade evaluation when

employing the approaches that are commonly

used to monitor total cellular PTEN.

Regulation of the membrane-associated

PTEN subpopulation

A subpopulation of PTEN is responsible for

its lipid phosphatase activity at the plasma

membrane. A study describing the use ofsingle-molecule microscopy in living cells

has shown that the interaction of PTEN withthe plasma membrane is a dynamic process(Vazquez et al., 2006). PTEN binds tothe membrane for only a few hundred

milliseconds, and this time period issufficient to hydrolyze PtdIns(3,4,5)P3. Theinteraction of PTEN with the membrane

requires the N-terminal lipid-binding motif.Membrane interaction is negatively regulatedby C-terminal tail phosphorylation, which

appears to constrain PTEN in a closedconformation and to limit its associationwith the membrane. Another study hasdemonstrated that phosphorylation of the C-

terminal tail regulates an intra-molecularinteraction between the phosphatase and C2domains. This determines the percentage of

PTEN that is associated with the membraneas well as the resulting PtdIns(3,4,5)P3levels (Rahdar et al., 2009). Interestingly,

plasma membrane targeting of PTENgreatly enhances PTEN ubiquitylationthrough NEDD4, and both mono- and

polyubiquitylation substantially inhibit PTENphosphatase activity in vitro, even inthe absence of proteasomal degradation(Maccario et al., 2010).

The nuclear PTEN subpopulation

Interestingly, PTEN also localizes into the

nucleus, and loss of PTEN nuclearlocalization has been shown to correlatewith cancer progression in certain tissues

(Song et al., 2008; Trotman et al., 2007).The nuclear subpopulation of PTEN iscontrolled by the dynamic regulation of itsubiquitylation, i.e. through NEDD4-

mediated monoubiquitylation anddeubiquitylation mediated through thenetwork of ubiquitin carboxyl-terminal

hydrolase 7 (USP7, also known asHAUSP) and PML (Song et al., 2008;Trotman et al., 2007).

The nuclear subpopulation of PTENclearly has non-canonical functions(Lindsay et al., 2006). Earlier studieshave shown that PTEN regulates p53

protein stability in both phosphatase-dependent and -independent manners (Liet al., 2006). A recent study has shown that

genotoxic stress enhances the interactionbetween PTEN and the p53 family memberp73 in the nucleus. This facilitates the

binding of p73 to apoptotic promoters andinduces the expression of p53-upregulatedmodulator of apoptosis (PUMA, also

known as BBC3) and the apoptosisregulator BAX (Lehman et al., 2011).Nuclear PTEN has also been suggested to

maintain chromosomal integrity through

the physical interaction with centromere

protein C 1 (CENPC1), which is an

integral part of the kinetochore (Shen

et al., 2007). Whether this function

requires the lipid phosphatase activity of

PTEN is under debate. More recently,

nuclear PTEN has been found to interact

with the anaphase-promoting complex/

cyclosome (APC/C), an E3 ubiquitin

ligase that promotes cell cycle

progression by degrading components of

the cell cycle machinery. Nuclear PTEN

increases APC/C activity by enhancing

the association between APC/C and its

cofactor, CDH1 (also known as FZR1).

This role of nuclear PTEN has been shown

to be important for PTEN-mediated tumor

suppression (Song et al., 2011).

Conclusions and perspectives

The function of PTEN as a tumor suppressor

has been well established over the past

decade. Recent studies have revealed more

unexpected – particularly lipid-phosphatase-

independent – roles of PTEN in both cancer

biology and normal physiology. PTEN

activity is tightly regulated by various

mechanisms on the transcriptional,

translational and post-translational levels.

Accumulating evidence suggests that PTEN

can exert diverse physiological and

pathological functions through its context-

specific regulation. Furthermore, a highly

regulated and dynamic subpopulation of

cellular PTEN might be required

specifically for a given contextual function

of PTEN. In summary, to understand the

molecular basis of contextual regulation

of PTEN is crucial in order to understand

the biological function of PTEN and,

subsequently, to develop appropriate

approaches to therapeutically target PTEN

signaling.

Funding

The work in X.J.’s laboratory that is related to

this article is supported by a Geoffrey Beene

Cancer Research fund, an American Cancer

Society scholar award [grant number RSG-

07-081-01-MGO] and the National Institutes

of Health [grant numbers R01CA113890 and

T32CA009072]. Deposited in PMC for

release after 6 months.

A high-resolution version of the poster is available for

downloading in the online version of this article at

jcs.biologists.org. Individual poster panels are available

as JPEG files at http://jcs.biologists.org/lookup/suppl/

doi:10.1242/jcs.093765/-/DC1.

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