© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 21, 1820-1828,
November 3, 1999
© 1999 Oxford University Press
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REVIEW |
PTEN Gene and Integrin Signaling in Cancer
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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 Top Abstract IntroductionThe Tumor Suppressor Gene...Integrin SignalingRoles of Integrins in...PTEN and FAK in...PTEN and Cell GrowthReferences |
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Integrins are major adhesion- and signaling-receptor proteins that mediate cell migration and invasion. They also trigger a variety of signal transduction pathways and regulate cytoskeletal organization, specific gene expression, growth control, and apoptosis (programmed cell death). Consequently, integrins are thought to play important roles in embryonic development and in the biology of cancers. The functions of integrins can be negatively regulated by the recently discovered tumor suppressor PTEN, a protein with homology to protein tyrosine phosphatases and tensin. The PTEN gene is mutated in a wide range of human cancers. PTEN inhibits cell migration and invasion by directly dephosphorylating two key tyrosine-phosphorylated proteins, thereby antagonizing interactions of integrins with the extracellular matrix and integrin-triggered signaling pathways. Other studies demonstrate important roles for PTEN in dephosphorylating a key signal transduction lipid. In the absence of PTEN, this lipid signal transduction pathway can protect tumor cells from apoptosis. Thus, PTEN appears to be a unique tumor suppressor—with both lipid phosphatase and protein tyrosine phosphatase activities—that negatively regulates cell interactions with the extracellular matrix and that maintains cell sensitivity to apoptosis, e.g., after loss of cell contact with the extracellular matrix. The complex signal transduction pathways regulated by PTEN are described in this review. PTEN and the signaling pathways it regulates may provide novel targets for potential therapy.
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INTRODUCTION |
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TopAbstractIntroductionThe Tumor Suppressor Gene...Integrin SignalingRoles of Integrins in...PTEN and FAK in...PTEN and Cell GrowthReferences |
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Oncogenes and tumor suppressors are believed to represent key steps in regulatory pathways controlled by soluble growth factors (1). Activation of oncogenes or inactivation of tumor suppressors can lead to irreversible activation of growth regulatory pathways and uncontrolled growth. However, it is also crucial for cancer cells to acquire the ability to escape normal tissue architecture, to invade, and to metastasize. Growth of cancer cells is generally independent not only of serum or growth factors but also of adhesion to the extracellular matrix, which normally regulates cell movement, growth, and tissue remodeling (2-5). It is well established that survival of many cell types requires integrin-mediated adhesion to extracellular matrix proteins, and loss of this requirement is a hallmark of neoplastic cells.
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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TopAbstractIntroductionThe Tumor Suppressor Gene...Integrin SignalingRoles of Integrins in...PTEN and FAK in...PTEN and Cell GrowthReferences |
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A number of genetic alterations are involved in the oncogenesis of cancers, including inactivation of the tumor suppressor genes p53, p16, and retinoblastoma (Rb), amplification of the gene encoding epidermal growth factor (EGF) receptor, and other molecular alterations (10-12). One alteration that occurs at high frequency in a variety of human tumors is loss of heterozygosity at chromosome 10q23. This change occurs in the vast majority (>70%) of glioblastomas and in more than 60% of advanced prostate cancers (13-16). Independent research teams identified a novel tumor suppressor gene from this region called PTEN (phosphatase and tensin homologue deleted on chromosome 10) (17) or MMAC1 (mutated in multiple advanced cancers 1) (18). This gene was also described as TEP1 (transforming growth factor [TGF]-ß-regulated and epithelial cell-enriched phosphatase) because its expression was rapidly repressed by TGF-ß (19).
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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TopAbstractIntroductionThe Tumor Suppressor Gene...Integrin SignalingRoles of Integrins in...PTEN and FAK in...PTEN and Cell GrowthReferences |
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Integrin-mediated adhesion to the extracellular matrix plays important roles in regulating cell survival, proliferation, and motility. It was interesting to determine whether PTEN had effects on integrin signaling because of PTEN's sequence similarity to the cytoskeletal protein tensin (17,18), which is intimately involved in integrin-signaling complexes (45). During the past few years, it has become clear that integrins are involved not only in cell adhesion but also in signal transduction in both normal and tumor cells.
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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TopAbstractIntroductionThe Tumor Suppressor Gene...Integrin SignalingRoles of Integrins in...PTEN and FAK in...PTEN and Cell GrowthReferences |
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The characteristics of malignant cells include uncontrolled cell growth and invasive and metastatic behavior (82,83). There are also frequently major differences in cytoskeletal organization between normal and malignant cells. These differences clearly contribute to the motile, invasive, and metastatic phenotype of malignant cells. A critical aspect of invasive and metastatic behavior involves adhesive interactions of tumor cells with other cells or extracellular matrix through the integrin family of cell surface receptors (3-5,78,79,81,84,85). Integrin-mediated signaling and integrin modulation of mitogenic signals probably play an important role in tumor growth and behavior.
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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TopAbstractIntroductionThe Tumor Suppressor Gene...Integrin SignalingRoles of Integrins in...PTEN and FAK in...PTEN and Cell GrowthReferences |
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A large variety of intracellular regulatory enzyme pathways can control the formation of focal adhesions and actin cytoskeleton organization. Integrin clustering under restrictive conditions induces co-localization of FAK and tensin without other cytoskeletal or signaling proteins (47), suggesting that FAK might play a central role in the signal transduction pathway triggered by integrins. FAK co-localizes with integrins at focal adhesions, and its protein kinase activity is enhanced by cell binding to extracellular matrix proteins (48). Peptides derived from the juxtamembrane region of the ß integrin cytoplasmic domain can bind to the N-terminal domain of FAK in vitro (112). FAK may also interact with integrins through interactions with proteins, such as paxillin and talin, that involve the focal adhesion targeting region in the FAK C-terminal domain, which might contribute to cytoskeletal formation and signal transduction by recruiting cytoskeletal and signaling molecules (6). FAK contains a central kinase domain flanked by large N- and C-terminal domains that contain regions of sequence similarity surrounding phosphorylation sites and proline-rich regions that are binding sites for SH3-domain-containing proteins, such as p130Cas. There are at least six sites of in vivo tyrosine phosphorylation. Integrin-dependent oligomerization of FAK enhances transphosphorylation at tyrosine 397, and this autophosphorylation in turn recruits Src-family protein kinases, resulting in the phosphorylation of other tyrosine residues in FAK including tyrosine 576 and 577 in the FAK activation loop, thereby promoting full catalytic activation (113-116). Tyrosine 397 is also a binding site for the SH2 domains of the regulatory subunit (p85) of PI 3-K, and FAK association with PI 3-K triggers activation of PI 3-K and its signaling pathways (66,117). Tyrosine 925 can also be a binding site for Grb2 (62). Grb2 recruitment to FAK of the Sos guanosine diphosphate/guanosine triphosphate exchange factor for Ras is a direct link to the activation of the extracellular signal-regulated kinase (ERK)/MAP kinase pathway. Besides Grb2, FAK phosphorylation of paxillin and p130Cas could also lead to activation of the MAP kinase pathway through adapter proteins, such as Crk and Nck (57,118). However, FAK may not be the only signaling protein involved in integrin-mediated MAP kinase activation (70,103,118,119). Lin et al. (119) have reported that integrin-mediated activation of MAP kinase can be independent of FAK in fibroblasts. Furthermore, caveolin-1 was recently shown to link certain integrin
subunits to Shc through the tyrosine kinase Fyn, which
leads to Ras/ERK pathway activation (70).
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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TopAbstractIntroductionThe Tumor Suppressor Gene...Integrin SignalingRoles of Integrins in...PTEN and FAK in...PTEN and Cell GrowthReferences |
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PTEN expression in PTEN gene-mutated glioma cells suppresses cell growth (140) and induces apoptosis (25). PTEN inhibits tumorigenicity in glioma cells missing the PTEN gene and in embryonic stem cells (24,141). PTEN gene null (-/-) mouse embryos exhibit extensive proliferation but undergo early embryonic lethality (24,25,27). The role for the PTEN gene in embryonic development is still uncertain (142); Di Cristofano et al. (24) reported that the PTEN gene is required for the differentiation of endoderm, mesoderm, and ectoderm, whereas Suzuki et al. (26) reported that the PTEN gene is required for patterning of the cephalic and caudal regions of the embryo and for placental development. However, these results suggest that the PTEN gene may act in normal tissues to guide the development of cellular interactions such that cells, tissues, and organs are properly formed with respect to one another. Furthermore, PTEN gene heterozygous mice develop hyperplastic changes in the prostate, skin, and colon (24) and in the endometrium, liver, prostate, gastrointestinal tract, thyroid, and thymus (27) or T-cell lymphoma, teratocarcinoma, and prostatic cancer (26). Molecular examination of these tumors revealed that the wild-type PTEN allele had been lost in many cases, confirming the role of the PTEN gene as a tumor suppressor (26,27). It remains unknown whether PTEN gene mutation is the only cause of development of hamartomas and cancer in patients with Cowden disease and in PTEN gene heterozygous mice. It should also be noted that the patterns of tumor formation, as well as the effects on embryonic development, differ in the different mouse PTEN gene knockout models described to date, suggesting that genetic background can substantially modify the effects of PTEN gene deletion.
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 steps—at 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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PTEN is the first tumor suppressor gene that has phosphatase activity. However, it is not surprising that the loss of a phosphatase should contribute to oncogenesis because it functions as a regulatory molecule that acts in opposition to kinases. Mutations of the PTEN gene are observed in a wide variety of cancers, suggesting that the PTEN gene plays a critical role in oncogenesis in many tissues. Recent studies have elucidated PTEN's tumor-suppressive function, affecting growth apoptosis, invasion, and the cytoskeleton. PTEN consequently has complex but important effects on signaling and cell biologic processes. Elucidation of these novel regulatory pathways may lead to fresh, new approaches to cancer therapy.
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REFERENCES |
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TopAbstractIntroductionThe Tumor Suppressor Gene...Integrin SignalingRoles of Integrins in...PTEN and FAK in...PTEN and Cell GrowthReferences |
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1 Bishop JM. Molecular themes in oncogenesis. Cell 1991;64:235-48.[CrossRef][ISI][Medline]cancerlit;91105844
2 Frisch SM, Ruoslahti E. Integrins and anoikis. Curr Opin Cell Biol 1997;9:701-6.[CrossRef][ISI][Medline]
3
Schwartz MA. Integrins, oncogenes, and anchorage
independence. J Cell Biol 1997;139:575-8.
4 Schwartz MA, Ingber DE. Integrating with integrins. Mol Biol Cell 1994;5:389-93.[Abstract]cancerlit;94331779
5
Giancotti FG, Ruoslahti E. Integrin signaling. Science 1999;285:1028-32.
6
Clark EA, Brugge JS. Integrins and signal transduction pathways:
the road taken. Science 1995;268:233-9.
7 Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 1992;69:11-25.[CrossRef][ISI][Medline]
8 Yamada KM, Miyamoto S. Integrin transmembrane signaling and cytoskeletal control. Curr Opin Cell Biol 1995;7:681-9.[CrossRef][ISI][Medline]
9 Yamada KM. Integrin signaling. Matrix Biol1997;16:137-41.[CrossRef][ISI][Medline]
10 Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759-67.[CrossRef][ISI][Medline]cancerlit;90263101
11 Cho KR, Vogelstein B. Genetic alterations in the adenoma-carcinoma sequence. Cancer 1992;70(6 suppl):1727-31.[CrossRef][ISI][Medline]
12 Louis DN, Gusella JF. A tiger behind many doors: multiple genetic pathways to malignant glioma. Trends Genet 1995;11:412-5.[CrossRef][ISI][Medline]cancerlit;96033652
13 Rasheed BK, McLendon RE, Friedman HS, Friedman AH, Fuchs HE, Bigner DD, et al. Chromosome 10 deletion mapping in human gliomas: a common deletion region in 10q25. Oncogene 1995;10:2243-6.[ISI][Medline]cancerlit;95303488
14
Gray IC, Phillips SM, Lee SJ, Neoptolemos JP, Weissenbach J,
Spurr NK. Loss of the chromosomal region 10q23-25 in prostate cancer. Cancer Res 1995;55:4800-3.
15
Ittmann M. Allelic loss on chromosome 10 in prostate
adenocarcinoma. Cancer Res 1996;56:2143-7.
16
Fults D, Pedone CA, Thomas GA, White R. Allelotype of human
malignant astrocytoma. Cancer Res 1990;50:5784-9.
17
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al.
PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate
cancer. Science 1997;275:1943-7.
18 Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997;15:356-62.[CrossRef][ISI][Medline]cancerlit;97245711
19
Li DM, Sun H. TEP1, encoded by a candidate tumor suppressor
locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res 1997;57:2124-9.
20
Myers MP, Stolarov JP, Eng C, Li J, Wang SI, Wigler MH, et
al. P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity
phosphatase. Proc Natl Acad Sci U S A 1997;94:9052-7.
21
Li L, Ernsting BR, Wishart MJ, Lohse DL, Dixon JE. A family
of putative tumor suppressors is structurally and functionally conserved in humans and yeast. J Biol Chem 1997;272:29403-6.
22
Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1,
dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J
Biol Chem 1998;273:13375-8.
23
Davis S, Lu ML, Lo SH, Lin S, Butler JA, Druker BJ, et al.
Presence of an SH2 domain in the actin-binding protein tensin. Science 1991;252:712-5.
24 Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP. Pten is essential for embryonic development and tumour suppression. Nat Genet 1998;19:348-55.[CrossRef][ISI][Medline]cancerlit;98361160
25 Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 1998;95:29-39.[CrossRef][ISI][Medline]cancerlit;98449694
26 Suzuki A, de la Pompa JL, Stambolic V, Elia AJ, Sasaki T, del Barco Barrantes IB, et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol 1998;8:1169-78.[CrossRef][ISI][Medline]cancerlit;99018257
27
Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M,
Yamada KM, et al. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci U S A 1999;96:1563-8.
28
Sakai A, Thieblemont C, Wellmann A, Jaffe ES, Raffeld M.
PTEN gene alterations in lymphoid neoplasms. Blood 1998;92:3410-5.
29
Teng DH, Hu R, Lin H, Davis T, Iliev D, Frye C, et al.
MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res 1997;57:5221-5.
30
Tashiro H, Blazes MS, Wu R, Cho KR, Bose S, Wang SI, et al.
Mutations in PTEN are frequent in endometrial carcinoma but rare in other common
gynecological malignancies. Cancer Res 1997;57:3935-40.
31
Okami K, Wu L, Riggins G, Cairns P, Goggins M, Evron E, et
al. Analysis of PTEN/MMAC1 alterations in aerodigestive tract tumors. Cancer Res1998
;58:509-11.
32 Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 1997;16:64-7.[CrossRef][ISI][Medline]cancerlit;97285123
33 Marsh DJ, Dahia PL, Zheng Z, Liaw D, Parsons R, Gorlin RJ, et al. Germline mutations in PTEN are present in Bannayan-Zonana syndrome. Nat Genet 1997;16:333-4.[CrossRef][ISI][Medline]cancerlit;97385233
34 Ali IU, Shrimi L, Dean M. Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. J Natl Cancer Inst. In press 1999.
35
Rasheed BK, Stenzel TT, McLendon RE, Parsons R, Friedman
AH, Friedman HS, et al. PTEN gene mutations are seen in high-grade but not in low-grade
gliomas. Cancer Res 1997;57:4187-90.
36 Duerr EM, Rollbrocker B, Hayashi Y, Peters N, Meyer-Puttlitz B, Louis DN, et al. PTEN mutations in gliomas and glioneuronal tumors. Oncogene1998 ;16:2259-64.[CrossRef][ISI][Medline]
37 Cairns P, Evron E, Okami K, Halachmi N, Esteller M, Herman JG, et al. Point mutation and homozygous deletion of PTEN/MMAC1 in primary bladder cancers.Oncogene 1998;16:3215-8.[CrossRef][ISI][Medline]cancerlit;98334477
38 Tohma Y, Gratas C, Biernat W, Peraud A, Fukuda M, Yonekawa Y, et al. PTEN (MMAC1) mutations are frequent in primary glioblastomas (de novo) but not in secondary glioblastomas. J Neuropathol Exp Neurol 1998;57:684-9.[ISI][Medline]cancerlit;98352982
39
Cairns P, Okami K, Halachmi S, Halachmi N, Esteller M,
Herman JG, et al. Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res 1997;57:4997-5000.
40
Suzuki H, Freije D, Nusskern DR, Okami K, Cairns P, Sidransky
D, et al. Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic
prostate cancer tissues. Cancer Res 1998;58:204-9.
41
Vlietstra RJ, van Alewijk DC, Hermans KG, van Steenbrugge
GJ, Trapman J. Frequent inactivation of PTEN in prostate cancer cell lines and xenografts. Cancer Res 1998;58:2720-3.
42
Whang YE, Wu X, Suzuki H, Reiter RE, Tran C, Vessella RL,
et al. Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer
through loss of expression. Proc Natl Acad Sci U S A 1998;95:5246-50.
43 Parsons R. Phosphatases and tumorigenesis. Curr Opin Oncol 1998;10:88-91.[Medline]cancerlit;98125966
44 Hunter T. Anti-phosphatases take the stage. Nat Genet 1998;18:303-5.[CrossRef][ISI][Medline]
45
Miyamoto S, Teramoto H, Coso OA, Gutkind JS, Burbelo PD,
Akiyama SK, et al. Integrin function: molecular hierarchies of cytoskeletal and signaling
molecules. J Cell Biol 1995;131:791-805.
46 Yamada KM, Geiger B. Molecular interactions in cell adhesion complexes. Curr Opin Cell Biol 1997;9:76-85.[CrossRef][ISI][Medline]
47
Miyamoto S, Akiyama SK, Yamada KM. Synergistic roles for
receptor occupancy and aggregation in integrin transmembrane function. Science 1995;267:883-5.
48 Guan JL, Shalloway D. Regulation of focal adhesion-associated protein tyrosine kinase by both cellular adhesion and oncogenic transformation. Nature 1992;358:690-2.[CrossRef][Medline]cancerlit;92357148
49
Kornberg L, Earp HS, Parsons JT, Schaller M, Juliano RL. Cell
adhesion or integrin clustering increases phosphorylation of a focal adhesion-associated tyrosine
kinase. J Biol Chem 1992;267:23439-42.
50 Kaplan KB, Bibbins KB, Swedlow JR, Arnaud M, Morgan DO, Varmus HE. Association of the amino-terminal half of c-Src with focal adhesions alters their properties and is regulated by phosphorylation of tyrosine 527. EMBO J 1994;13:4745-56.[ISI][Medline]cancerlit;95045365
51
Otey CA, Pavalko FM, Burridge K. An interaction between
-actinin and the ß1 integrin subunit in vitro. J Cell Biol 1990;111:721-9.
52
Pavalko FM, LaRoche SM. Activation of human neutrophils
induces an interaction between the integrin ß2-subunit (CD18) and the actin binding protein
-actinin. J Immunol 1993;151:3795-807.[Abstract]
53 Rees DJ, Ades SE, Singer SJ, Hynes RO. Sequence and domain structure of talin. Nature 1990;347:685-9.[CrossRef][Medline]
54
Burridge K, Turner CE, Romer LH. Tyrosine phosphorylation of
paxillin and pp125FAK accompanies cell adhesion to extracellular matrix: a role in
cytoskeletal assembly. J Cell Biol 1992;119:893-903.
55
Nojima Y, Morino N, Mimura T, Hamasaki K, Furuya H, Sakai
R, et al. Integrin-mediated cell adhesion promotes tyrosine phosphorylation of p130Cas, a Src homology 3-containing molecule having multiple Src homology 2-binding motifs. J Biol Chem 1995;270:15398-402.
56 Petch LA, Bockholt SM, Bouton A, Parsons JT, Burridge K. Adhesion-induced tyrosine phosphorylation of the p130 src substrate. J Cell Sci 1995;108:1371-9.[Abstract]cancerlit;95340667
57 Vuori K, Hirai H, Aizawa S, Ruoslahti E. Introduction of p130cas signaling complex formation upon integrin-mediated cell adhesion: a role for Src family kinases. Mol Cell Biol 1996;16:2606-13.[Abstract]
58
Miyamoto S, Teramoto H, Gutkind JS, Yamada KM. Integrins
can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP
kinase activation: roles of integrin aggregation and occupancy of receptors. J Cell Biol 1996;135:1633-42.
59
Schneller M, Vuori K, Ruoslahti E. vß3 integrin
associates with activated insulin and PDGFß receptors and potentiates the biological activity
of PDGF. EMBO J 1997;16:5600-7.[CrossRef][ISI][Medline]
60 Plopper GE, McNamee HP, Dike LE, Bojanowski K, Ingber DE. Convergence of integrin and growth factor receptor signaling pathways within the focal adhesion complex. Mol Biol Cell 1995;6:1349-65.[Abstract]cancerlit;96117049
61
Morino N, Mimura T, Hamasaki K, Tobe K, Ueki K, Kikuchi K,
et al. Matrix/integrin interaction activates the mitogen-activated protein kinase, p44erk-1 and
p42erk-2. J Biol Chem 1995;270:269-73.
62 Schlaepfer DD, Hanks SK, Hunter T, van der Geer P. Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature 1994;372:786-91.[Medline]cancerlit;95089819
63
Chen Q, Kinch MS, Lin TH, Burridge K, Juliano RL.
Integrin-mediated cell adhesion activates mitogen-activated protein kinases. J Biol Chem 1994;269:26602-5.
64
Kapron-Bras C, Fitz-Gibbon L, Jeevaratnam P, Wilkins J,
Dedhar S. Stimulation of tyrosine phosphorylation and accumulation of GTP-bound p21ras upon
antibody-mediated 2ß1 integrin activation in T-lymphoblastic cells. J Biol Chem 1993;268:20701-4.
65
Yebra M, Filardo EJ, Bayna EM, Kawahara E, Becker JC,
Cheresh DA. Induction of carcinoma cell migration on vitronectin by NF-B-dependent gene
expression. Mol Biol Cell 1995;6:841-50.[Abstract]cancerlit;96086497
66
Chen HC, Guan JL. Association of focal adhesion kinase with its
potential substrate phosphatidylinositol 3-kinase. Proc Natl Acad Sci U S A 1994;91:10148-52.
67
Woods A, Couchman JR. Protein kinase C involvement in focal
adhesion formation. J Cell Sci 1992;101:277-90.
68
Vuori K, Ruoslahti E. Activation of protein kinase C precedes
5ß1 integrin-mediated cell spreading on fibronectin. J Biol Chem 1993;268:21459-62.
69
Vuori K, Ruoslahti E. Association of insulin receptor substrate-1
with integrins. Science 1994;266:1576-8.
70 Wary KK, Mariotti A, Zurzolo C, Giancotti FG. A requirement for caveolin-1 and associated kinase Fyn in integrin signaling and anchorage-dependent cell growth. Cell 1998;94:625-34.[CrossRef][ISI][Medline]cancerlit;98412658
71
Frisch SM, Vuori K, Kelaita D, Sicks S. A role for
Jun-N-terminal kinase in anoikis; suppression by bcl-2 and crmA. J Cell Biol 1996;135:1377-82.
72
McNamee HP, Ingber DE, Schwartz MA. Adhesion to
fibronectin stimulates inositol lipid synthesis and enhances PDGF-induced inositol lipid
breakdown. J Cell Biol 1993;121:673-8.
73
Arora PD, Ma J, Min W, Cruz T, McCulloch CA.
Interleukin-1-induced calcium flux in human fibroblasts is mediated through focal adhesions. J Biol Chem 1995;270:6042-9.
74 Renshaw MW, Ren XD, Schwartz MA. Growth factor activation of MAP kinase requires cell adhesion. EMBO J 1997;16:5592-9.[CrossRef][ISI][Medline]cancerlit;97459945
75 Damsky CH, Werb Z. Signal transduction by integrin receptors for extracellular matrix: cooperative processing of extracellular information. Curr Opin Cell Biol 1992;4:772-81.[CrossRef][Medline]
76 Juliano RL, Varner JA. Adhesion molecules in cancer: the role of integrins. Curr Opin Cell Biol 1993;5:812-8.[CrossRef][Medline]cancerlit;94059574
77 Sastry SK, Horwitz AF. Integrin cytoplasmic domains: mediators of cytoskeletal linkages and extra- and intracellular initiated transmembrane signaling. Curr Opin Cell Biol 1993;5:819-31.[CrossRef][Medline]
78 Boudreau N, Bissell MJ. Extracellular matrix signaling: integration of form and function in normal and malignant cells. Curr Opin Cell Biol 1998;10:640-6.[CrossRef][ISI][Medline]cancerlit;99035564
79 Lukashev ME, Werb Z. ECM signalling: orchestrating cell behaviour and misbehaviour. Trends Cell Biol 1998;8:437-41.[CrossRef][ISI][Medline]
80 Porter JC, Hogg N. Integrins take partners: cross-talk between integrins and other membrane receptors. Trends Cell Biol 1998;8:390-6.[CrossRef][ISI][Medline]
81 Keely P, Parise L, Juliano R. Integrins and GTPases in tumour cell growth, motility and invasion. Trends Cell Biol 1998;8:101-6.[CrossRef][ISI][Medline]cancerlit;98360931
82 Hart IR, Saini A. Biology of tumour metastasis. Lancet 1992;339:1453-7.[CrossRef][ISI][Medline]cancerlit;92292771
83 Fidler IJ. The biology of cancer metastasis or, ‘you cannot fix it if you do not know how it works'. Bioessays 1991;13:551-4.[CrossRef][ISI][Medline]cancerlit;92095945
84 Honn KV, Tang DG. Adhesion molecules and tumor cell interaction with endothelium and subendothelial matrix. Cancer Metastasis Rev 1992;11:353-75.[CrossRef][ISI][Medline]cancerlit;93046916
85 Varner JA, Cheresh DA. Integrins and cancer. Curr Opin Cell Biol 1996;8:724-30.[CrossRef][ISI][Medline]cancerlit;97094586
86 Yamada KM. Cell surface interactions with extracellular materials. Annu Rev Biochem 1983;52:761-99.[CrossRef][ISI][Medline]
87 Mosher DF, editor. Fibronectin. San Diego (CA): Academic Press; 1989.
88 Hynes RO. Fibronectins. Berlin (Germany): Springer-Verlag; 1990.
89
Schreiner C, Fisher M, Hussein S, Juliano RL. Increased
tumorigenicity of fibronectin receptor deficient Chinese hamster ovary cell variants. Cancer
Res 1991;51:1738-40.
90
Giancotti FG, Ruoslahti E. Elevated levels of the 5ß1
fibronectin receptor suppress the transformed phenotype of Chinese hamster ovary cells. Cell 1990;60:849-59.[CrossRef][ISI][Medline]cancerlit;90182673
91
Felding-Habermann B, Mueller BM, Romerdahl CA, Cheresh
DA. Involvement of integrin V gene expression in human melanoma tumorigenicity. J
Clin Invest 1992;89:2018-22.cancerlit;92291323
92
Albelda SM, Mette SA, Elder DE, Stewart R, Damjanovich L,
Herlyn M, et al. Integrin distribution in malignant melanoma: association of the ß3 subunit
with tumor progression. Cancer Res 1990;50:6757-64.
93
Varner JA, Emerson DA, Juliano RL. Integrin 5 ß1
expression negatively regulates cell growth: reversal by attachment to fibronectin. Mol Biol
Cell 1995;6:725-40.[Abstract]cancerlit;96059483
94 Lafrenie RM, Yamada KM. Integrin-dependent signal transduction. J Cell Biochem 1996;61:543-53.[CrossRef][ISI][Medline]
95
Roskelley CD, Desprez PY, Bissell MJ. Extracellular
matrix-dependent tissue-specific gene expression in mammary epithelial cells requires both
physical and biochemical signal transduction. Proc Natl Acad Sci U S A 1994;91:12378-82.
96
Qwarnstrom EE, Ostberg CO, Turk GL, Richardson CA,
Bomsztyk K. Fibronectin attachment activates the NF-B p50/p65 heterodimer in fibroblasts
and smooth muscle cells. J Biol Chem 1994;269:30765-8.
97
Guadagno TM, Ohtsubo M, Roberts JM, Assoian RK. A link
between cyclin A expression and adhesion-dependent cell cycle progression [published
erratum appears in Science 1994;263:455]. Science 1993;262:1572-5.
98 Fang F, Orend G, Watanabe N, Hunter T, Ruoslahti E. Dependence of cyclin E-CDK2 kinase activity on cell anchorage. Science 1996;271:499-502.[Abstract]cancerlit;96152368
99
Zhu X, Ohtsubo M, Bohmer RM, Roberts JM, Assoian RK.
Adhesion-dependent cell cycle progression linked to the expression of cyclin D1, activation of
cyclin E-cdk2, and phosphorylation of the retinoblastoma protein. J Cell Biol 1996;133:391-403.
100 Gilmore AP, Romer LH. Inhibition of focal adhesion kinase (FAK) signaling in focal adhesions decreases cell motility and proliferation. Mol Biol Cell 1996;7:1209-24.[Abstract]
101
Zhao JH, Reiske H, Guan JL. Regulation of the cell cycle by
focal adhesion kinase. J Cell Biol 1998;143:1997-2008.
102
Frisch SM, Vuori K, Ruoslahti E, Chan-Hui PY. Control of
adhesion-dependent cell survival by focal adhesion kinase. J Cell Biol 1996;134:793-9.
103 Wary KK, Mainiero F, Isakoff SJ, Marcantonio EE, Giancotti FG. The adaptor protein Shc couples a class of integrins to the control of cell cycle progression. Cell 1996;87:733-43.[CrossRef][ISI][Medline]
104
Owens LV, Xu L, Craven RJ, Dent GA, Weiner TM, Kornberg
L, et al. Overexpression of the focal adhesion kinase (p125FAK) in invasive human
tumors. Cancer Res 1995;55:2752-5.
105 Tremblay L, Hauck W, Nguyen LT, Allard P, Landry F, Chapdelaine A, et al. Regulation and activation of focal adhesion kinase and paxillin during the adhesion, proliferation, and differentiation of prostatic epithelial cells in vitro and in vivo. Mol Endocrinol 1996;10:1010-20.[Abstract]
106 Weiner TM, Liu ET, Craven RJ, Cance WG. Expression of focal adhesion kinase gene and invasive cancer. Lancet 1993;342:1024-5.[CrossRef][ISI][Medline]cancerlit;94018208
107
Hungerford JE, Compton MT, Matter ML, Hoffstrom BG,
Otey CA. Inhibition of pp125FAK in cultured fibroblasts results in apoptosis. J Cell Biol 1996;135:1383-90.
108 Kulik G, Weber MJ. Akt-dependent and -independent survival signaling pathways utilized by insulin-like growth factor I. Mol Cell Biol 1998;18:6711-8.