478 Review TRENDS in Cell Biology
9 September 2003
PTEN: from pathology to biology
Maria Luisa Sulis1,2 and Ramon Parsons1,3
1
Institute for Cancer Genetics, College of Physicians & Surgeons, Columbia University, New York, USA
2
Division of Pediatric Oncology, Childrens Hospital of New York, Herbert Irving Cancer Center, College of Physicians & Surgeons,
Columbia University, New York, USA
3
Departments of Pathology and Medicine, Herbert Irving Cancer Center, College of Physicians & Surgeons, Columbia University,
New York, USA
The PTEN tumour suppressor gene is mutated fre-
quently in many malignancies and its importance in the
development of cancer is probably underestimated. As
the primary phosphatase of phosphatidylinositol
(3,4,5)-trisphosphate, PTEN has a central role in reign-
ing in the phosphoinositide 3-kinase (PI 3-kinase) net-
work to control cellular homeostasis. Cells that lack
PTEN are unable to regulate the PtdIns 3-kinase pro-
gramme, which stimulates a variety of cellular pheno-
types that favour oncogenesis. As well as the well-
known role as tumour suppressor, recent studies show
that PTEN is involved in the regulation of several basic
cellular functions, such as cell migration, cell size, con-
tractility of cardiac myocytes and chemotaxis. Here, we
review the roles of PTEN in normal cellular functions
and disease development.
The discovery of phosphatase and tensin homolog on
chromosome ten (PTEN, also known as MMAC1 and
TEP1) has been like the opening of Pandoras box. It has
provided clues for understanding tumourigenesis as well
as other aspects of biology. In a relatively short time, a
highly complex signalling network has been refined and
the pivotal role of PTEN in regulating many biological
functions has been established.
PTEN is a tumour suppressor gene that is located on
chromosome 10q23. Germline mutations of PTEN cause
four rare autosomal-dominant syndromes that have similar
clinical features: Cowden Syndrome; Lhermitte-Duclos syn-
drome; Bannayan-Zonana syndrome; and Proteus syndrome.
These diseases share the tendency to develop hamartomas
and other benign tumours, and Cowden Syndrome is
associated with the development of malignant tumours [1].
Somatic mutations of PTEN are documented in an increasing
variety of malignant tumours at both advanced and early
stages; these mutations lead to complete inactivation of the
phosphatase activity of PTEN as well as to either total or
partial loss of expression of either mRNA and/or protein [2].
The frequency of PTEN mutation rivals that of p53 [1]. Like
p53, mutation of PTEN is associated with the inactivation of
both alleles. Understanding the reason for the preferential
selection of PTEN mutations in tumours is fundamental to
cancer biology and it is now clear that a major selective
pressure for inactivating PTEN is to stimulate the
phosphatidylinositol 3-kinase (PI 3-kinase) pathway.
Corresponding author: Ramon Parsons (rep15@columbia.edu).
http://ticb.trends.com 0962-8924/$ - see front matter q 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0962-8924(03)00175-2
Vol.13 No.
Because this review is limited in length we recommend
several comprehensive reviews for historical perspective
[1 4]. Moreover, most of the proteins discussed here have
complex regulatory inputs from signalling partners other
than PTEN that is not covered in depth for the sake of
simplicity and brevity. We focus on the most recent
progress in understanding the role of PTEN in oncogenesis
as well as the regulation of normal cellular functions.
PTEN has a tyrosine phosphatase domain with dual-
specificity protein-phosphatase and lipid-phosphatase
activity in vitro [5]. The lipid-phosphatase activity of
PTEN is highly specific. PTEN recognizes the substrate
phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3]
and removes the D3 phosphate from the inositol ring.
Work from many groups has established a strong
foundation for the biological importance of the lipid
phosphatase activity of PTEN and here we focus on
this enzymatic function of PTEN (Fig. 1).
The level of PtdIns(3,4,5)P3 is very low in resting cells
that contain wild type PTEN. Activation of cell-surface
receptors recruits PI 3-kinase to the receptor where it
phosphorylates the PtdIns(4,5)P2 substrate to generate
PtdIns(3,4,5)P3. The half-life of PtdIns(3,4,5)P3 is short
and it is metabolized by PTEN and the D5 phosphatases,
including SHIP1 and SHIP2 [6]. Cells that lack PTEN
have elevated levels of PtdIns(3,4,5)P3, even in the resting
state. PtdIns(3,4,5)P3 is a potent second messenger that
binds proteins that contain pleckstrin-homology (PH)
domains to elicit several cellular behaviours that favour
oncogenesis. Among the most important PH-domain-
containing proteins are the AKT family (AKT1, AKT2
and AKT3) and their regulator phosphoinositide-depen-
dent kinase 1 (PDK1). Loss of PTEN creates a state in
which the PI 3-kinase pathway is constitutively active.
This stimulates cell division, increases cell size and
angiogenesis, and inhibits apoptosis. In addition, cell
migration is often increased but can also be impaired.
PTEN: a small gene family lacking redundancy
The gene that encodes PTEN is expressed in all eukaryotic
cells. The crystal structure of human PTEN shows
adjacent phosphatase and C2-domain lobes [7] that is
predicted to be preserved in all metazoans. PTEN
homologues n Saccharomyces cerevisiae and Schizosac-
charomyces pombe fungi have the phosphatase domain,
but they lack the C2 domain [8] that is crucial for
interaction with the plasma membrane. Although there
 Review TRENDS in Cell Biology
Unstimulated Stimulated
PI3K
PTEN
PIP3
TRENDS in Cell Biology
Fig. 1. Proposed model for phosphoinositide 3-kinase (PI 3-kinase)/PTEN mediated
chemotaxis. In resting cells PTEN is distributed uniformly at the membrane,
whereas PI 3-kinase is in the cytoplasm. Following chemoattractant stimulation
with cAMP, activated PI 3-kinase and its product, phosphatidylinositol (3,4,5)-tri-
sphosphate [PtdIns(3,4,5)P3], localize at the leading edge of the cell, whereas PTEN
localizes at the rear and sides. The gradient in PtdIns(3,4,5)P3 that results allows
pseudopods to form [48 50].
is only one PTEN gene in fungi and lower metazoans
(Caenorhabditis elegans and Drosophila melanogaster),
additional orthologues, including TPTE, PTEN 2 and
TPIP, have evolved in mammals [9 11]. In addition to the
phosphatase and C2 domains these proteins have multiple
transmembrane domains at their amino termini. Like
PTEN, PTEN 2 and TPIP are PtdIns(3,4,5)P3 phospha-
tases in vitro. However, unlike PTEN, which is expressed
ubiquitously, expression of TPTE and PTEN 2 is restricted
to the testis, and TPIP is expressed only in the testis, brain
and stomach. Analysis of the cellular localization of these
transmembrane homologs of PTEN demonstrates that the
proteins are limited to either the Golgi apparatus or
endoplasmic reticulum. Based on their defined tissue-
expression patterns and lack of access to the plasma
membrane, these orthologues are not expected to regulate
PI 3-kinase signalling at the plasma membrane. Overall,
the lack of redundancy of PTEN at the plasma membrane
might explain the high frequency with which PTEN
inactivation is selected during tumour development.
Reduced expression of PTEN in tumours
Genetic alteration of both alleles of PTEN occurs in nearly
all types of human cancers examined, with the highest
frequency of inactivation in glioblastoma and endometrial
cancer [12 15]. The typical mechanism of inactivation is
mutation accompanied by loss of heterozygosity, the gold
standard for gene inactivation. However, in some cases
tumours appear to evolve mechanisms to reduce the
concentration of PTEN without mutation of the gene
[16]. Methylation of the PTEN promoter region, which is
associated with reduced PTEN expression, appears to
occur in some cancers [17]. Loss of one allele of PTEN with
the preservation of the remaining wild-type allele is also
very common. Whether PTEN haploinsufficiency favours
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Vol.13 No.9 September 2003 479
tumour progression in humans is controversial. However,
Pten/2 mice develop colonic adenomas and lymph node
hyperplasia at high frequency because of haploinsuffi-
ciency [18]. In recent work with a mouse SV40 T antigen
prostate-tumour model, PTEN haploinsufficiency stimu-
lates tumour progression [19]. In addition, many tumours
have lowered PTEN expression of poorly defined origin.
Stable loss of PTEN expression for any reason is a
significant factor in the development of a tumour because
it leads to the deregulation of PI 3-kinase signalling.
The PTEN2/2 cellular phenotypes
Initial experiments in mice showed that complete loss of
PTEN is lethal early in development. Heterozygous mice
are viable, however, and adults develop a variety of
tumours [1]. Recently, several groups have analysed the
effects of conditionally mutating both alleles of PTEN by
incorporating lox recombination sites that flank PTEN
exons and using tissue-specific promoters to express Cre
recombinase. Recombination elicited by Cre led to the
mutational inactivation of PTEN. Surprisingly, loss of
PTEN by itself in these mice does not appear to be
sufficient for oncogenesis. Instead, a period of time is
required for a subpopulation of PTEN2/2 cells to trans-
form into malignancies. As of now, PTEN has been
conditionally inactivated in mouse T cells, B cells, cardiac
myocytes, mammary epithelium, primordial germ cells,
neurons and keratinocytes [20 25]. In all cases, the loss of
PTEN did not lead to tumour formation initially. Although
unexpected, these data are not unprecedented and
indicate that other, unknown, genetic alterations that
favour oncogenesis cooperate with PTEN inactivation to
produce malignancy. However, several signalling events
and phenotypes are observed consistently, which indicates
a common PTEN pathway.
Cells that lack PTEN have elevated levels of
PtdIns(3,4,5)P3, phosphorylated AKT and p70 S6 kinase
(S6K) [21,23]. These changes are associated with increased
proliferation and reduced apoptosis in T cells, B cells,
immature neurons, keratinocytes and mammary epi-
thelium [24,26]. Paradoxically however, in primordial
germ cells increased proliferation is associated with
increased apoptosis [25]. Increased cell size is observed
in neurons, cardiac myocytes and T cells. Altered
migration is a characteristic of immature neurons and
reduced contractility occurs in cardiac myocytes. The
plethora of phenotypes that are associated with mutation
of PTEN appear to be caused by accumulation of
PtdIns(3,4,5)P3. For example, in myocytes, a dominant-
negative PI 3-kinase-a reverses the increase in cell size,
whereas deletion of PI 3-kinase-g to restores myocyte
contractility.
The effect of PTEN mutation has also been studied in
several model organisms. As with mice, mutation of PTEN
in Drosophila alters cell size, proliferation, apoptosis and
migration [27 30]. Tissue-specific mutation of PTEN in
mice reveals multiple phenotypes, but inactivation of
PTEN in this context is not sufficient to produce tumours.
These data demonstrate that inactivation of PTEN is
insufficient to cause tumour development but that it
creates an environment that selects for tumour growth.
480 Review TRENDS in Cell Biology
Cellular localization of PTEN
Because PTEN regulates PtdIns(3,4,5)P3 at the plasma
membrane, some portion of PTEN must reside at this
location in the cell. Consistent with this, Das et al. found
that a mutant version of PTEN that contains the
phosphatase and C2 domains fused with green fluorescent
protein (GFP) is expressed at the plasma membrane [31].
Thus, it is surprising that most endogenous PTEN is not
found at the plasma membrane. Immunohistochemical
studies show that the cellular distribution of PTEN varies
between tissues. In most epithelial cells, such as skin,
colon, breast and prostate, the bulk of PTEN is in the
cytoplasm [32,33]. By contrast, in neurons, fibroblasts, and
cells of the adrenal medulla and thyroid most PTEN is in
the nucleus [34 36]. Examination of polarized MDCK
cells indicates that PTEN localizes at cell cell tight
junctions [37]. The basis for the different tissue-localiz-
ation patterns is unknown but it might involve the 50
amino acids at the carboxy-terminal of PTEN. This region
contains multiple phosphorylation sites for casein kinase
II and a PDZ-binding domain that can bind to membrane-
associated guanylate kinase inverted (MAGI) proteins
[31,37]. Recent studies by Ginn-Pease and Eng show that
the concentration of PTEN in the nucleus parallels the
cytoplasmic levels during the cell cycle. The highest
concentration of nuclear as well as cytoplasmic PTEN
are associated with the G0 G1 phase, which indicates a
possible role of nuclear PTEN in the well-known, PTEN-
related G1 arrest [38]. These data are intriguing.
Localization of PTEN in the cytoplasm and nucleus
might function merely to separate it from the plasma
membrane; alternatively, PTEN might participate actively
in cellular processes in the cytoplasm and nucleus.
Changes in the subcellular localization of PTEN have
been reported in several malignancies. PTEN is localized
mostly in nucleus in normal pancreatic islets, but occurs
predominantly in the cytoplasm of 80% of endocrine
pancreatic tumours [39]. Similarly, in thyroid carcinoma
and melanoma the decrease in nuclear staining of PTEN is
more marked than in the cytoplasm, particularly in
undifferentiated and metastatic tumours [36,40]. The
reasons for alterations of PTEN in the nucleus are obscure.
Whether and how a shift in the cellular localization of
PTEN might have a role in the pathogenesis of tumours
remains to be elucidated.
PTEN and cell migration
It has been shown that PTEN might exert effects on the
cytoskeleton and have a role in controlling cell migration.
Introducing PTEN into PTEN2/2 human tumour cells
alters actin fibres and inhibits cell migration [41].
Migration is increased in mouse embryo fibroblasts that
lack PTEN. In these cells, elevated PtdIns(3,4,5)P3 leads to
activation of Rac1 and Cdc42, both of which are small
GTPase mediators of cellular migration [42].
In the past 2 years, several studies in Dictyostelium
discoideum have started to define a sophisticated mechan-
ism by which the concerted, opposing action of PI 3-kinase
and PTEN finely regulate cell motility in response to a
point source of extracellular cAMP. Initial studies showed
that PI 3-kinase localized at the leading edge of the
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Vol.13 No.9 September 2003
membrane has a pivotal role in the chemotactic response of
the cell to a cAMP chemoattractant stimulus by creating a
gradient of PtdIns(3,4,5)P3 that enhances intracellular
signalling and directional movement [43 45]. By contrast,
cells with reduced PI 3-kinase at the membrane move
slowly, lose polarity and formed multiple pseudopodia
[46 48]. Interestingly, Iijima et al. have showed that the
effects of loss of PTEN in D. discoideum are similar to those
in PI 3-kinase-null cells; although PTEN-null cells can
sense chemoattractants, as shown by a change in shape,
they are unable to move toward them and form multiple,
changing pseudopodia [49]. In addition, localization and
translocation of PTEN following a chemoattractant stimu-
lus is reciprocal to PI 3-kinase localization [49,50]. The
above studies delineate a model in which a stimulus causes
PI 3-kinase to localize to the front edge of the membrane,
which leads to PtdIns(3,4,5)P3 accumulation, AKT acti-
vation and the formation of a pseudopod. At the same time,
PTEN dissociates from the front edge of the membrane and
localizes posteriorly, thus creating a steeper gradient of
PtdIns(3,4,5)P3 (Fig. 2).
PTEN and PtdIns(3,4,5)P3 targets
Many proteins that containing PH domains bind to
PtdIns(3,4,5)P3 with high affinity. In PTEN2/2 cells, a
large number of different signalling proteins are brought
to the plasma membrane by elevated PtdIns(3,4,5)P3
levels. Surprisingly, however, the primary phenotypic
output of elevated PtdIns(3,4,5)P3 in metazoans streams
through PDK1 to its substrate AKT. Although much
experimental data substantiates the importance of the
link between PTEN and AKT, perhaps the best evidence is
the ability of a hypomorphic allele of AKT to rescue
PTEN2/2 Drosophila embryos from lethality [51]. Other
model systems also demonstrate the importance of PDK1
and AKT. In C. elegans, PTEN2/2 phenotypes are
ameliorated by double-strand RNA interference of AKT1
and AKT2 [52]. Analysis of PDK1 mutants in Drosophila
demonstrates that PDK1 is essential for PI 3-kinase-
mediated activation of AKT [53]. Similarly, in C. elegans,
PDK1 is necessary and sufficient to transmit signals
from PI 3-kinase to AKT1 and AKT2 [54]. Therefore, the
type I PI 3-kinase PtdIns(3,4,5)P3 PDK1 AKT axis is
the major developmental pathway that involves
PtdIns(3,4,5)P3 and is modulated by PTEN in animals.
AKT substrates
Many AKT substrates are phosphorylated when PTEN is
inactive (Fig. 2) Alterations in the transcription profiles
are caused, at least in part, by changes in activity of
nuclear factor kB, HIF1-a and forkhead transcription
factors [55 57]. Phosphorylation and inhibition of GSK3
(which increases cyclin D and myc levels) [58,59], and
phosphorylation and cytoplasmic sequestration of p27
alters the cell cycle. Apoptosis is inhibited by phosphoryl-
ation of caspase 9 and [60,61]. Recent data indicates that
AKT might inhibit p53-dependent apoptosis: several
groups have shown that AKT interacts and phosphorylates
Mdm2. Phosphorylation induces the nuclear localization of
Mdm2, which results in the subsequent export and
degradation of p53 in the cytoplasm [62,63]. Inhibition of
 Review TRENDS in Cell Biology Vol.13 No.9 September 2003 481

PI3K
PI(4,5)P2 PI(3,4,5)P3
PTEN
PH PH
A P
K D
T K

FKHRLI GSK3
FKHR TSC2-TSC1
p21
p27
Caspase 9 mTOR S6K
Cyclin D myc BAD pMDM2
pNFKB

Cell Cell growth

Cell cycle survival translation
entry

TRENDS in Cell Biology

Fig. 2. Schematic representation of the role of PTEN in the phosphoinositide 3-kinase (PI 3-kinase)/Akt pathway. PTEN dephosphorylates phosphatidylinositol (3,4,5)-tri-
sphosphate [PtdIns(3,4,5)P3], at the D3 position. A lower amount of PtdIns(3,4,5)P3 at the membrane decreases the concentration of phosphorylated (active) Akt, thereby
downregulating downstream effectors. As a result, PTEN regulates cell growth, survival and entry into the cell cycle.

AKT, either by PTEN or by expression of a dominant-
negative form of AKT, sensitizes tumour cells to DNA-
damaging agents, perhaps by restoring p53 activity
[62,64]. The interaction between p53 and PTEN is likely
to be complex and occur at different levels. Stambolic et al.
demonstrated direct binding of p53 to the PTEN promoter
and the levels of PTEN mRNA increase in several cell lines
following induction of p53 [65]. In addition, PTEN is
required for p53-mediated apoptosis in PTEN-null mouse
embryonic fibroblasts. More recently, Freeman et al. [66]
have performed GST-pull down experiments that show
that the C-terminus of p53 binds to the C2 domain of
PTEN. This report also provides evidence that wild-type
PTEN, as well as the catalytically inactive form, stabilize
p53 through an MDM2-independent mechanism. It seems
likely that a connection exists between these two major
tumour suppressors, although the precise mechanisms of
interaction and their functional importance need to be
defined completely. Important clinical implications might
result from subsequent studies.
not the catalytically inactive mutant, inhibited phos-
phorylation of TSC2. AKT-mediated phosphorylation of
TSC2 results in the degradation of the TSC1 TSC2
complex, which regulates mTOR and thereby S6K [68].
Therefore, cells lacking either TSC1 or TSC2 have
elevated S6K activity. Both TSC1 and TSC2 are tumour-
suppressor genes that are mutated in TSC, a syndrome
that is associated with benign hamartomatous tumours
and CNS abnormalities. The ability of AKT to phosphor-
ylate TSC2 is linked directly to its ability to stimulate cell
growth, because phosphorylation-site mutants of TSC2 are
resistant to AKT-mediated growth signals [69]. Given that
PTEN and TSC tumour suppressors regulate S6K, it is
likely to play a role in tumour development. It is also
interesting that, although hamartomas develop because of
germline mutations in PTEN and TSC, PTEN mutation
are a much more potent stimulus for malignant trans-
formation. This might be due to the more upstream
location of PTEN in the signalling pathway and, therefore,
the larger number of targets affected by its mutation.

S6K and tuberous sclerosis (TSC) Concluding remarks

Although the importance of the PDK1 AKT connection is
undisputed, other targets of PDK1 such as S6K might also
contribute to tumour development. S6K is a regulator of
cell size that requires PtdIns(3,4,5)P3, PDK1 and the
mammalian target of rapamycin (mTOR) to be activated
(Fig. 1). Mammalian cells that lack PTEN have elevated
S6K activity [67]. Recently, it has been shown that TSC1
and TSC2 form a complex that inactivates mTOR and so
inhibits the activity of S6K [68]. This finding led to further
investigations on the possible interaction between
TSC1 TSC2 and AKT/PTEN. Experiments in vitro and
in vivo show that coexpression of TSC1 TSC2 with wild-
type AKT, but not a kinase-inactive AKT mutant, results
in phosphorylation of TSC2, but no effect on TSC1 was
noted [68]. As expected, expression of wild-type PTEN, but
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The discovery of PTEN represents a milestone in the
understanding of tumourigenesis and solves many pieces
of a complicated puzzle. But, as always in science,
answering one question opens up new ones. In the past
few years, many downstream targets of PTEN have been
identified and the fundamental role of the PI 3-kinase
PTEN AKT axis has been further elucidated, but there is
still much to be explained. Little is known about the
regulation of PTEN transcription and translation, and the
half-life, cellular localization and enzymatic activity of
PTEN protein. It is likely that mutations in the regulatory
circuitry that lead to altered PTEN function will, in turn,
cause tumour development. The rapid activation and
inactivation kinetics of PtdIns(3,4,5)P3 hints at the
possibility that PTEN has equally rapid regulatory
482 Review TRENDS in Cell Biology
mechanisms. The ability of PTEN to reside in the nucleus
indicates that PTEN might function to regulate a nuclear
PI 3-kinase pathway.
Another fascinating area for study is why PTEN is such
a potent tumour suppressor. In tumour development,
PTEN inactivation does not appear to be equivalent to
AKT activation [70]. This indicates that, as yet unknown,
PI 3-kinase-dependent and independent outputs of PTEN
might influence cancer development. However, many
questions remain, such as what is the exact role of the
protein phosphatase activity of PTEN, and is
PtdIns(3,4,5)P3 the only substrate for the lipid phospha-
tase, how is PTEN inactivated in tumours, why does the
localization of PTEN change in different tissues, and what
cooperating genetic events are favoured in PTEN-deficient
tumours?
The high prevalence of alterations in PTEN in a variety
of human tumours stresses the need for better under-
standing of the normal and pathological regulatory
mechanisms of PTEN. Improved knowledge of PTEN
will lead to a fuller understanding of human oncogenesis.
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