Control of adhesion-dependent cell survival by focal adhesion kinase.

Frisch, Steven M.; Vuori, Kristiina; Ruoslahti, Erkki; Chan-Hui, Po-Ying

doi:10.1083/jcb.134.3.793

Cited by 1,013 publications

(703 citation statements)

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“…FAK functions in integrin-signaling pathways, [3][4][5][6] cellular motility, 7 and apoptosis. [8][9][10] The avian FAK homologue was originally identified through its association with the v-Src oncogene protein, 11 suggesting a role for FAK in tumorigenesis. In our lab, human FAK was subsequently identified in high-grade sarcomas 12 and breast tumors.…”

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High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype

et al. 2005

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Focal adhesion kinase (FAK) is a protein tyrosine kinase expressed in invasive breast cancer that regulates antiapoptotic signaling. We have examined FAK expression by immunohistochemistry using anti-FAK 4.47 in breast tumor samples from a large population-based, case-control study of women participating in the University of North Carolina Breast Specialized Programs of Research Excellence (SPORE), Carolina Breast Cancer Study. In this population, 629 formalin-fixed, paraffin-embedded tissue sections were stained for FAK and scored as high (3 þ or 4 þ intensity and Z90% positive cells) or otherwise. High FAK expression was associated with poor prognostic indicators including high mitotic index (410 mitoses per 10 consecutive highpower fields), nuclear grade 3, architectural grade 3, estrogen and progesterone receptor negative, and HER-2/ neu overexpressed using CB11 antibody. The association of high FAK expression with HER-2/neu overexpression lends further support that HER-2/neu and FAK collaborate to promote tumorigenesis. The presence of strong FAK expression in many high grade, estrogen-and progesterone-negative breast carcinomas indicates that FAK may be an attractive target for therapeutic intervention.

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High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype

et al. 2005

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“…In normal cells, FAK is the major tyrosine-phosphorylated protein present in cells upon activation of the integrin receptors (Guan et al, 1991). FAK is involved in integrin-signalling pathways (Kornberg et al, 1992;Lipfert et al, 1992;Schlaepfer et al, 1994), cellular motility (Cary et al, 1996;Guan, 1997), and apoptosis (Frisch et al, 1996;Hungerford et al, 1996;Xu et al, 1996). Cells derived from pp125 FAK À/À mouse embryos exhibit reduced migration as a result of impaired adhesion turnover (Ilic et al, 1995(Ilic et al, , 1996.…”

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FAK overexpression is correlated with tumour invasiveness and lymph node metastasis in oesophageal squamous cell carcinoma

et al. 2003

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Focal adhesion kinase (p125 FAK ; 'FAK') is a tyrosine kinase that is localised to cellular focal adhesions and is associated with a number of other proteins, such as integrin adhesion receptors. We performed an immunohistochemical analysis of FAK protein expression to determine the relationship between FAK overexpression and clinicopathological factors in oesophageal squamous cell carcinoma (ESCC). We examined tissue specimens that had been removed from 91 patients with thoracic oesophageal cancer who had undergone surgery between 1983 and 2001. Immunohistochemical staining was performed by the standard streptavidin -biotin method. Seven human ESCC cell lines -TE-1, TE-2, TE-8, TE-13, TE-15, TT, and TTn -and one immortalized human keratinocyte cell line -HaCaT -were used in Western blot analysis. Immunostaining of FAK was seen in the cytoplasm of cancer cells, particularly in cells located in the invasive fronts of cancer nests. FAK overexpression was detected in 54 of the 91 patients (59.3%). Significant correlations were observed between FAK overexpression and cell differentiation (P ¼ 0.0057), depth of tumour invasion (P ¼ 0.0023), presence of regional lymph node metastasis (P ¼ 0.0097), number of lymph node metastases (P ¼ 0.0026), and disease stage (P ¼ 0.012). The survival rates of patients with FAK-overexpressing cancer were significantly lower than those of patients without FAK-overexpression cancer (P ¼ 0.006). The 5-year survival rate of patients without FAK overexpression was 69%, whereas that of patients with FAK overexpression was 38%. On Western blot analysis, FAK was expressed at a high level in TE-1, TE-8, TE-15, and TT cells, at a moderate level in TE-2 and TTn cells, and at a low level in TE13 and HaCaT cells. FAK phosphorylation at tyrosine 397 was demonstrated in proportion to the intensity of FAK in all cell lines except TE15 and HaCaT. In conclusion, FAK overexpression of ESCC was related to cell differentiation, tumour invasiveness, and lymph node metastasis. Consequently, patients with ESCC who had FAK overexpression had a poor prognosis.

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“…When epithelial cells are completely deprived of integrin-mediated anchorage to extracellular matrix, they undergo a form of apoptosis that has been termed "anoikis" (Frisch and Ruoslahti, 1997). Several signal transduction components have been implicated in the underlying mechanism of anoikis, including focal adhesion kinase (FAK) (Frisch et al, 1996b), phosphatidylinositol 3-kinase (PI-3-kinase) , and possibly c-Jun kinase (Frisch et al, 1996a;. In addition to anoikis attributable to a general loss of cellmatrix contact, it is also clear that perturbation of specific integrins can contribute to programmed cell death.…”

Section: Introductionmentioning

confidence: 99%

“…Signaling molecules known thus far that promote cell survival include FAK (Frisch et al, 1996b), MAPK (Berra et al, 1998), nuclear factor B (Van Antwerp et al, 1998;Wang et al, 1998), Bcl-2 and Bcl-2-like proteins (Gajewski and Thompson, 1998), and PI-3-kinase and protein kinase B (PKB)/Akt (Downward, 1998). Conversely, proapoptotic signaling and effector molecules include c-Jun kinase (Ichijo et al, 1997;Yang et al, 1997) and p38 kinase (Berra et al, 1998), Bad and Bad-like proteins (Gajewski and Thompson, 1998), and the caspase family of proteases (Green and Kroemer, 1998;Slee et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

α5β1 Integrin Protects Intestinal Epithelial Cells from Apoptosis through a Phosphatidylinositol 3-Kinase and Protein Kinase B–dependent Pathway

Lee

Juliano

2000

MBoC

152

106

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Renewal of the gastrointestinal epithelium involves a coordinated process of terminal differentiation and programmed cell death. Integrins have been implicated in the control of apoptotic processes in various cell types. Here we examine the role of integrins in the regulation of apoptosis in gastrointestinal epithelial cells with the use of a rat small intestinal epithelial cell line (RIE1) as a model. Overexpression of the integrin ␣5 subunit in RIE1 cells conferred protection against several proapoptotic stimuli. In contrast, overexpression of the integrin ␣2 subunit had no effect on cell survival. The antiapoptotic effect of the ␣5 subunit was partially retained by a mutated version that had a truncation of the cytoplasmic domain. The antiapoptotic effects of the fulllength or truncated ␣5 subunit were reversed upon treatment with inhibitors of phosphatidylinositol 3-kinase (PI-3-kinase), suggesting that the ␣5␤1 integrin might interact with the PI-3-kinase/ Akt survival pathway. When cells overexpressing ␣5 were allowed to adhere to fibronectin, there was a moderate activation of protein kinase B (PKB)/Akt, whereas no such effect was seen in ␣2-overexpressing cells adhering to collagen. Furthermore, in cells overexpressing ␣5 and adhering to fibronectin, there was a dramatic enhancement of the ability of growth factors to stimulate PKB/Akt; again, this was not seen in cells overexpressing ␣2 subunit and adhering to collagen or fibronectin. Expression of a dominant negative version of PKB/Akt in RIE cells blocked to ability of ␣5 to enhance cell survival. Thus, the ␣5␤1 integrin seems to protect intestinal epithelial cells against proapoptotic stimuli by selectively enhancing the activity of the PI-3-kinase/Akt survival pathway. INTRODUCTIONIntegrin-mediated interactions with extracellular matrix components play crucial roles in many fundamental aspects of growth and differentiation (Aplin et al., 1998;Giancotti and Ruoslahti, 1999). For example, integrins are key regulators of the coordinated differentiation of many epithelial tissues. The functions of the ␤1 subfamily of integrins are particularly well understood in mammary development (Faraldo et al., 1998;Bissell et al., 1999) and in the differentiation of the epidermis (Watt, 1998;Zhu et al., 1999). However, integrins clearly play a role in other epithelia as well. The self-renewing cellular lining of the gastrointestinal tract is an interesting and important model for epithelial differentiation. Both in the small intestine and in the colon, epithelial renewal is accompanied by directed migration of differentiating cells away from the stem cell-rich crypts and ultimately results in apoptosis and shedding of terminally differentiated cells into the lumen of the gut (Stappenbeck et al., 1998;Karam, 1999). A variety of factors, including soluble hormones and cytokines, interactions with mesenchymal cells, and interactions with extracellular matrix, have been implicated in growth control mechanisms in the gastrointestinal tract (Burgess, 1998;Kedinger et al....

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Control of adhesion-dependent cell survival by focal adhesion kinase.

Cited by 1,013 publications

References 29 publications

High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype

High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype

FAK overexpression is correlated with tumour invasiveness and lymph node metastasis in oesophageal squamous cell carcinoma

α5β1 Integrin Protects Intestinal Epithelial Cells from Apoptosis through a Phosphatidylinositol 3-Kinase and Protein Kinase B–dependent Pathway

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