Affiliation of authors: Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, Bethesda, MD. Present addresses: M. Tamura, Second Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Fukuoka, Japan; J. Gu, Division of Protein Chemistry, Institute for Protein Research, Osaka University, Japan.
Correspondence to: Kenneth M. Yamada, M.D., Ph.D., National Institutes of Health, Bldg. 30, Rm. 421, 30 Convent Drive MSC 4370, Bethesda, MD 20892-4370 (e-mail: Kenneth.Yamada{at}nih.gov).
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ABSTRACT |
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INTRODUCTION |
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Although integrins were originally characterized as a family of cell surface receptors that are responsible for anchoring cells to the extracellular matrix, they have also been shown to regulate intracellular signaling processes involved in migration, invasion, proliferation, differentiation, and survival of normal and tumor cells (3,5-9).
This review focuses on roles of the recently discovered tumor suppressor PTEN (also termed "MMAC1" or "TEP1"; see below) in integrin-mediated signaling pathways in terms of the way it relates to the behavior of tumor cells. For this review, studies were identified by searching the English language literature in the MEDLINE® (National Library of Medicine) database.
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THE TUMOR SUPPRESSOR GENE PTEN |
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It is interesting that the amino acid sequence of PTEN indicated that it resembles two different types of proteins. The PTEN gene encodes the catalytic signature motif of protein tyrosine phosphatases and functions as a dual-specificity phosphatase in vitro (19-21), but it can also dephosphorylate the lipid signal transduction molecule PIP3 (phosphatidylinositol 3,4,5-trisphosphate) (22). The N-terminal domain of PTEN also shows extensive homology to the cytoskeletal protein tensin (17-19), which plays a role in maintenance of cellular structure and possibly in signal transduction by binding to actin filaments at focal adhesions and to phosphotyrosine-containing proteins through its actin-binding and Src homology-2 (SH2) domains (23). The PTEN gene is ubiquitously expressed in human tissues (Tamura M: unpublished data), and it is essential for embryonic development in mice (24-27).
The PTEN gene is frequently deleted or mutated not only in human glioblastoma and prostatic cancer but also in a wide range of advanced human malignancies, such as endometrial, breast, lung, kidney, bladder, testis, and head and neck cancers, malignant melanoma, and lymphoma (17,18,28-31). The PTEN gene is also mutated in some human genetic diseases, such as Cowden disease (32) and Bannayan-Zonana syndrome (33). [For a recent review on the genetics of PTEN, see Ali et al. (34).]
In cancers involving PTEN gene somatic alterations, mutation of the PTEN gene is reported to occur generally late in tumor development. For example, the PTEN gene is frequently mutated in high-grade but not in low-grade gliomas or prostate cancers (17,18,29,35-41). A majority (but not all) of these mutations are clustered in the phosphatase homology domain, particularly in the core motif of conserved amino acids. Besides mutation, however, the PTEN gene can also be inactivated in advanced prostate cancer through loss of expression (42). These findings suggest that inactivation of the PTEN gene plays important roles in tumor progression in some important cancers. In fact, recent genetic and biochemical studies have implicated PTEN in the regulation of several different cellular processes: cell growth, apoptosis (i.e., programmed cell death), interactions with the extracellular matrix, and cell migration and invasion. It is logical that a tyrosine phosphatase such as PTEN could be a tumor suppressor because certain phosphatases can act directly to counter the action of tyrosine kinases (43,44).
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INTEGRIN SIGNALING |
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The integrin family is composed of pairs of and ß transmembrane subunits, which
are selected from among at least 16
and eight ß subunits to form more than 20
different
ß heterodimeric receptors on cell surfaces; each subunit contributes to ligand
selectivity of the integrin (3,5-7,46). Integrins can directly activate many
intracellular signaling events after stimulation by extracellular matrix proteins or by antibodies that
bind to specific sites of integrins. Both receptor clustering and ligand occupancy are critical for
the activation of intracellular integrin-mediated responses (47). Activation
of intracellular signals includes tyrosine phosphorylation of focal adhesion kinase (FAK), which
binds to the integrin ß1 cytoplasmic domain and is one of the molecules that
co-clusters with ß1 integrins aggregated by noninhibitory anti-integrin antibodies (45,48,49). Integrins and their cytoplasmic tails are involved in forming
large complexes of signaling molecules that include Src family kinases (50); cytoskeletal proteins, such as
-actinin (51,52), talin (53), paxillin (54), and p130Cas (55-57); and other signal transduction molecules, such as growth factor receptors (58-60), mitogen-activated protein (MAP) kinase (61-63), Ras (64), NF-
B (65),
phosphatidylinositol 3-kinase (PI 3-K) (66), protein kinase C (67,68), insulin receptor substrate-1 (69), caveolin-1 (70), and c-Jun amino-terminal kinase (JNK) (45,71).
Furthermore, integrins can function in additive or cooperative fashion with growth factors such as platelet-derived growth factor (PDGF) (58,72-74). Previous studies (60,68) have also implicated serine/threonine kinases in various integrin functions. These additional kinases may provide further layers of control in integrin signaling. Thus, many of the well-known signaling pathways identified previously for growth factors and cytokines are also activated by integrins, thereby making integrin-mediated signaling complex. In fact, integrins are remarkably multifunctional. Integrin signaling regulates the following: cell adhesion, spreading, migration, and invasion; cytoskeletal organization; gene expression, such as immediate early genes; apoptosis; cell cycle and growth; Ca2+ influx; and H+ exchange (6,7,9,75-81).
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ROLES OF INTEGRINS IN GROWTH AND CANCER |
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It is well known that transformed cells frequently (but not always) express less cell surface
fibronectin than their normal counterparts, with the reduced level of fibronectin contributing to
alterations in adhesiveness, motility, and morphology observed in tumor cells (86-88). Roles for integrins 5ß1 and
vß3 in cancer seem relatively well validated, although studies of integrin expression
in transformed cells [reviewed in (85)] suggest that various
integrin subunits may make either positive or negative contributions to the transformed
phenotype. High levels of expression of the
5ß1 integrin are
negatively associated with transformation and tumor formation (89,90),
whereas increased expression of
vß3 is positively associated
with increased malignancy in melanomas (91,92). Integrins on tumor cells
are thought to play intrinsic roles in the progression of some tumors. Overexpression of
5ß1 integrin in Chinese hamster ovary cells or colon carcinoma cells
results in a loss of tumorigenicity and reduced proliferation (90,93).
Conversely, loss of
5ß1 integrin expression in Chinese hamster
ovary cells leads to enhanced tumorigenicity (89). These findings indicate
that
5ß1 integrin is implicated in the growth regulation of tumor
cells.
Integrin activation of signaling, gene expression, and growth regulation is complex (94-96). Integrin-mediated cell adhesion has been found to regulate several cyclins and cyclin-dependent kinases (CDKs) (97-99). Several reports have raised the possibility that the integrin-signaling protein FAK may regulate cell proliferation. In BALB/c 3T3 and human endothelial cells, inhibition of FAK by either microinjection of an inhibitory C-terminal fragment or anti-FAK monoclonal antibody induces cell cycle arrest (100). A recent study (101) showed that overexpression of FAK accelerates the G1- to S-phase transition, whereas a dominant-negative FAK mutant inhibits cell cycle progression at G1. However, certain integrins are reported to regulate cell proliferation via Shc (Src homology 2-containing protein) (69). Shc is an SH2-phosphotyrosine-binding adapter protein that links tyrosine kinases to Ras signaling by recruiting the Grb2-Sos complex (70).
Many mammalian cell types are dependent on adhesion to the extracellular matrix for their continued survival. A variety of normal cell types undergo apoptosis when they lose attachment to an appropriate extracellular matrix in a process termed "anoikis" (102). In contrast, tumor cells frequently lack this requirement for anchorage, which is termed "anchorage independence of growth" and is associated closely with tumorigenicity. Multiple integrin-dependent pathways are likely to be involved in protection from apoptotic cell death. Adhesion mediated by integrins not linked to Shc results in cell cycle arrest and apoptosis even in the presence of mitogens (103), suggesting that Shc may play an important role in integrin-mediated cell survival. In addition, JNK is also activated early after detachment from matrix and has been suggested to be responsible for inducing apoptosis (71).
Some studies have also pointed to key roles for FAK in this cell survival signal from the extracellular matrix. Levels of FAK expression are often increased in proliferating cells or advanced invasive cancers (104-106). Expression of membrane-anchored FAK, which is constitutively activated in suspended cells, prevents cell detachment-induced apoptosis (anoikis) of MDCK (Madin-Darby canine kidney) cells (71). Conversely, inhibition of FAK by microinjection of either the dominant-negative FAK truncation termed "FRNK" (FAK-related non-kinase) or an anti-FAK antibody causes cell cycle arrest and apoptosis (100,107). FAK seems to be an important mediator of integrin-mediated survival signals upstream of the PI 3-K/Akt pathway. (Akt is also termed "protein kinase B" or "PKB.") Akt is a survival-promoting serine-threonine protein kinase regulated by PIP3 that is implicated in survival signaling in a wide variety of cells, including fibroblastic, epithelial, and neuronal cells (108).
Attachment of cells to the matrix leads to the association of the p85 subunit of PI 3-K with
tyrosine residue 397 in FAK (66) and rapid elevation of the levels of PI
3-K lipid products and Akt activity and protection from apoptosis (109).
PI 3-K is required for integrin-stimulated Akt activation (110).
Furthermore, constitutively active forms of FAK or PI 3-K can protect cells from
suspension-induced apoptosis (102,109). FAK is also reported to
suppress a p53-dependent pathway activated by protein kinase C /
and cytosolic
phospholipase A2, and it inhibits apoptosis under serum-starved conditions (111). These results provide evidence that FAK may be a major mediator of
integrin-dependent cell survival.
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PTEN AND FAK IN INTEGRIN SIGNALING |
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FAK is tyrosine phosphorylated upon integrin activation, and focal adhesion-associated
phosphatases could modulate FAK-associated signaling complexes and FAK functions. A couple
of phosphatases have been suggested as candidates for modulating molecules in integrin
complexes: Protein tyrosine phosphatase and PTP-PEST (a protein tyrosine phosphatase
[PTP] with a carboxy-terminal segment rich in proline, glutamic acid, aspartic acid,
serine, and threonine [PEST] residues) negatively regulate Src and paxillin,
respectively (120,121). Protein tyrosine phosphatase 1B directly binds to
p130Cas and N-cadherin and regulates integrin- and cadherin-mediated adhesion (122-124).
Recently, however, it has been shown that PTEN interacts directly with and dephosphorylates FAK tyrosine phosphate and that it inhibits integrin-mediated cell spreading, migration, invasion, and cytoskeletal organization (125,126). The phosphatase domain of PTEN is essential for all of these functions because protein tyrosine phosphatase-inactive mutants of PTEN have no effect. It has been proposed that FAK plays roles in many biologic functions. Studies have further implicated FAK in integrin-mediated regulation of cell spreading and migration. FAK expression is enhanced in rapidly migrating keratinocytes (127) and in invasive human tumors (104), and migration of endothelial cells is also positively associated with FAK phosphorylation and kinase activity (128). Cells from FAK-deficient mice (129) and cells in which FAK signaling is inhibited by microinjection of FRNK (100) exhibit reduced cell migration, whereas overexpression of FAK increases migration toward fibronectin in Chinese hamster ovary cells (130). Overexpression of FRNK inhibits phosphorylation of endogenous FAK and cell spreading and migration (100,131), which is consistent with the observation that PTEN-induced FAK dephosphorylation leads to suppression of cell spreading and migration (125). FAK/PI 3-K association could activate PI 3-K, which is also implicated in stimulating cell migration in PDGF-induced chemotaxis (132).
The signal transduction protein p130Cas seems to be a major mediator of FAK-promoted cell migration. p130Cas binds directly to FAK and is phosphorylated upon cell adhesion to extracellular matrix proteins in an FAK- and Src-dependent manner (55,57,133,134). The proline-rich region of FAK spanning amino acids 711-717 has been demonstrated to be a binding site for the SH3 domain of p130Cas (135). Formation of the FAK/p130Cas complex leads to coupling to the adapter protein c-CrkII and targets downstream pathways in mediating FAK-promoted cell migration (136,137).
FAK is also implicated in cell invasion. Although FAK expression levels are normal in benign adenomatous tissues, its expression is increased in invasive and metastatic tumors (106). FAK is required for fibronectin-mediated invasion in ovarian cancer cells (138). Hepatocyte growth factor/scatter factor-induced activation of FAK promotes migration and invasion by oral squamous cell carcinoma cells (139). Consistent with the role for FAK/p130Cas in cell migration and invasion, PTEN gene restoration in cells with mutated alleles causes a decrease in p130Cas phosphorylation, accompanied by inhibition of cell migration and invasion; overexpression of either FAK or p130Cas can restore their phosphorylation and rescue cell migration and invasion (126). Thus, the elevated FAK observed in transformed cells may form complexes with p130Cas, leading to invasion events involved in the dissemination of tumors. PTEN gene inactivation in cancers may contribute to this event by loss of inhibition of this FAK/p130Cas pathway regulating migration and invasion. An important area for future research will be to determine the mechanisms by which PTEN gene mutations may contribute to tumor progression. When a tumor loses its PTEN gene, a low-grade tumor is likely to become more malignant, but direct information on causality and mechanisms is still lacking.
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PTEN AND CELL GROWTH |
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PTEN can selectively inhibit both integrin- and growth factor-mediated activation of the ERK type of MAP kinase pathway (143), although PTEN has no effect on basal MAP kinase activities without any stimulation (141). The specific point of MAP kinase inhibition by PTEN seems to be at the level of Shc phosphorylation because Shc phosphorylation and Ras activity are inhibited by expression of PTEN, whereas EGF receptor autophosphorylation is unaffected. Furthermore, PTEN can directly interact with and dephosphorylate Shc tyrosine phosphate (144). PTEN negatively regulates two distinct additive pathways regulating cell motility: One involves Shc, an MAP kinase pathway, and random migration, whereas the other involves FAK, p130Cas, more extensive actin cytoskeletal organization, focal contacts, and directionally persistent cell motility (144). EGF receptor signaling does not appear to require PI 3-K activation (110), making it unlikely that the effects of PTEN on MAP kinase activation by this pathway occurs by effects on phosphoinositides. Activation of MAP kinase has been shown to stimulate cell migration by phosphorylating myosin light chain kinase (145). PTEN inhibition of cell spreading and focal contact formation are partially rescued by coexpression of constitutively activated MEK1 (MAP kinase/ERK kinase 1), suggesting the involvement of the Shc/MAP kinase pathway in PTEN-mediated signaling (143,144). It remains to be clarified whether this MAP kinase pathway is also involved in PTEN regulation of cell growth.
Recently, PIP3, which is produced by PI 3-K and can activate protein kinase B (Akt) (146), has also been identified as a substrate of PTEN besides FAK (22). PTEN directly dephosphorylates the D3 position of PIP3 (22), which appears to be an important mechanism in PTEN suppression of cell growth or apoptosis. The Caenorhabditis elegans PTEN gene homologue DAF-18 also has 3-phosphatase activity toward PIP3 (147), supporting the importance of this substrate. Although overexpression of FAK can antagonize the biologic effects of PTEN on cell migration and invasion, overexpression of FAK rescues only partially the action of PTEN on growth suppression, and p130Cas does not affect growth (126), indicating that the cell growth-suppressive effect of PTEN is not mediated by FAK alone and that downstream effectors other than p130Cas, such as PIP3, play a more critical role in cell growth.
Activation of Akt has been implicated in protection of cells from apoptosis in response to
several signals, including growth factors (108,148), cytokines (149), c-Myc overexpression (150), UV irradiation
(108), CD95/Fas-induced cell death (151), and
matrix detachment (109,152). Activation of Akt leads to phosphorylation
of the Bcl-2 family member Bad, thereby suppressing apoptosis and promoting cell survival (153). In PTEN gene-mutated glioblastoma cells and mouse embryonic
fibroblasts, the activity of Akt is constitutively elevated, although activation of Akt by insulin or
PDGF is unaffected (25,143,154). PTEN expression in PTEN
gene-mutated glioma cells increases sensitivity to cell death in response to several apoptotic
stimuli, including UV irradiation and treatment with tumor necrosis factor- (25).
PTEN has also been implicated in regulating the anoikis apoptotic response to loss of integrin-mediated adhesion by detachment from extracellular matrix. In one study (155), restoration of PTEN to glioma cells increased the rate of apoptosis after detachment by approximately twofold. Another study (156), however, found that PTEN expression in a number of breast carcinoma cell lines induced apoptosis even in the presence of cell attachment. A third study (157) has recently found that glioma cells display a striking restoration of sensitivity to anoikis after PTEN reconstitution. PTEN-dependent cell death can be rescued by coexpression of downstream Akt (156). PTEN also impairs activities of the translation repressor 4E-BP1 and the c-fos gene promoter, which are downstream targets of the PI 3-K/Akt pathway (156,158).
In some cells, PTEN-dependent apoptosis could not be rescued by expression of upstream PI 3-K, consistent with PTEN-negative regulation of the PI 3-kinase/Akt pathway at the level of PIP3 (156). Overexpression of FAK in PTEN gene-transfected glioma cells to levels that restored phosphorylated FAK levels, as well as PI 3-K binding to FAK and PI 3-K enzymatic activity, resulted in only partial restoration of PIP3 levels and only partial rescue from anoikis. The latter studies suggest that PTEN can act at two stepsat an upstream site involving FAK that can regulate PI 3-K activity and directly on PIP3 itself as a substrate. Both steps may contribute to a crucial role for the PTEN gene in anoikis (157). In fact, a defect in the regulation of apoptosis is seen in vivo in lymphoid tissues of PTEN-/- mice in which a decrease in annexin V staining was observed (27).
The effects of PTEN on the cell cycle appear to depend on the experimental system. Experimental PTEN overexpression in the human glioma U87MG cell line, in which the endogenous PTEN gene is mutated, induces G1 arrest only when cells are cultured under serum-restricted (2% serum) culture conditions, and there is no suppression in 10% serum (159). However, other studies (141,160,161) have reported G1 arrest under 10% serum conditions involving Akt, CDK2, and Rb (retinoblastoma) downstream of PTEN in cell cycle control. Other studies reported no differences in cell cycle distribution between PTEN gene knockout and wild-type embryonic stem cells (24) or an accelerated G1/S transition with suppression of p27KIP1 activity (162). These divergent in vitro studies suggest that there are cell type and PTEN dosage-dependent differences in the cell cycle effects of PTEN. Examination of in vivo sites of hyperplasia seen in the prostate of PTEN-/- mice revealed increases in mitotic index and Ki-67 staining (24).
Suppression of growth, invasion, and migration in glioma cells with mutated PTEN alleles by expression of exogenous PTEN requires a functional phosphatase catalytic domain (126,140). Certain missense mutations of PTEN flanking the catalytic domain, such as PTEN-G129E (glycine to glutamic acid at position 129), can specifically ablate the ability of PTEN to recognize phospholipids as a substrate but still retain protein phosphatase activity (154). These mutants demonstrate that the lipid phosphatase activity of PTEN is necessary for cell growth function (154) and cell cycle arrest (159). In contrast, studies of this same G129E mutation found in some tumors (125,126) indicate that protein phosphatase activity (without lipid phosphatase effects) can suppress FAK-mediated cell spreading, migration, invasion, and cytoskeletal formation. Taken together, these findings suggest that these latter cellular functions alone are not sufficient to suppress tumorigenesis (or Cowden disease). They may instead contribute to tumor progression, especially since current data suggest that many somatic mutations in the PTEN gene appear later in tumor development.
A second type of mutation that may be valuable to study suggests that there may be potential function(s) in the C-terminal domain of PTEN: Many nonsense mutations described in human tumors cluster around amino acid 233 of PTEN C-terminus outside the tensin homology and phosphatase domains. These mutations would create a truncated PTEN molecule with intact tensin and phosphatase homology domains. In addition, this residue is located at potential tyrosine phosphate acceptor sites (residues 233-240 and 308-315) (18), suggesting a possible role for C-terminal site(s) in post-translational regulation; functions of this region clearly need further exploration.
On the basis of current knowledge in the field, we propose that PTEN has dual functions as a
tumor suppressor: (a) It helps to regulate apoptosis and growth through its lipid
phosphatase activity, which regulates levels of PIP3, activation of Akt/PKB, and the
processes of apoptosis and anoikis; but (b) it also contributes to the regulation of cell
adhesion, migration, tumor cell invasion, cytoskeletal organization, and MAP kinase activation
through its protein tyrosine phosphatase activity targeting FAK and Shc (Fig. 1). The latter effects may be particularly relevant to later cancer progression,
specifically to steps involved in cancer invasion and metastasis. We also suggest that various types
of cross-talk between components of these pathways may exist; e.g., PTEN dephosphorylation of
FAK appears to enhance its effects on PIP3. In addition, there are likely to be cell type
differences in the roles of the PTEN protein in these different processes.
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Manuscript received February 22, 1999; revised August 30, 1999; accepted September 14, 1999.
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