The role of focal-adhesion kinase in cancer — a new therapeutic opportunity

McLean, Gordon W.; Carragher, Neil O.; Avizienyte, Egle; Evans, Jeff; Brunton, Valerie G.; Frame, Margaret C.

doi:10.1038/nrc1647

Cited by 950 publications

(924 citation statements)

References 110 publications

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“…Focal adhesion kinase, a ubiquitously expressed nonreceptor protein tyrosine kinase, has emerged as an important molecule that participates in pathways affecting cell motility and invasion McLean et al, 2005). Ezrin, another member of the ERM family, is reported to participate in Src signaling and to induce FAK activation (Poullet et al, 2001;Srivastava et al, 2005) Although ezrin and merlin have similarities in structure and common interacting partners, such as CD44, NHERF and N-WASP (Bretscher et al, 2000;Morrison et al, 2001;Martin et al, 2003;Manchanda et al, 2005), they possess opposite functions in cell growth and proliferation.…”

Section: Re-expression Of Merlin Attenuates Fak Phosphorylation At Tymentioning

confidence: 99%

“…As increased FAK protein levels and activity are linked to increased cell invasion and migration (Owens et al, 1995;McLean et al, 2005), we tested whether FAK overexpression in MM cells would lead to increased invasiveness. For this purpose, we created Meso17 cells that stably overexpress Flag-tagged FAK, and we used two clones (Meso17-FAK no.…”

Section: Merlin Inhibits Invasiveness Promoted By Focal Adhesion Kinamentioning

confidence: 99%

“…FAK expression and/or activity are reported to be upregulated in a wide range of malignancies, including cancers of the thyroid, prostate, cervix, colon, rectum, oral epithelium, ovary and breast (McLean et al, 2005;Watermann et al, 2005). Ezrin, another member of the ERM family, has been shown to positively regulate FAK activity (Poullet et al, 2001), and merlin itself has been proposed to form a complex with FAK and the Na þ /H þ exchanger regulatory factor, NHERF (James et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

et al. 2006

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The neurofibromatosis type 2 NF2 gene product, merlin, is a tumor suppressor frequently inactivated in malignant mesothelioma (MM). To investigate a possible correlation between merlin inactivation and MM invasiveness, we restored merlin expression in NF2-deficient MM cells. Re-expression of merlin markedly inhibited cell motility, spreading and invasiveness, properties connected with the malignant phenotype of MM cells. To test directly whether merlin inactivation promotes invasion in a nonmalignant system, we used small interfering RNA to silence Nf2 in mouse embryonic fibroblasts (MEFs) and found that downregulation of merlin resulted in enhanced cell spreading and invasion. To delineate signaling events connected with this phenotype, we investigated the effect of merlin expression on focal adhesion kinase (FAK), a key component of cellular pathways affecting migration and invasion. Expression of merlin attenuated FAK phosphorylation at the critical phosphorylation site Tyr397 and disrupted the interaction of FAK with its binding partners Src and p85, the regulatory subunit of phosphatidylinositol-3-kinase. In addition, NF2-null MM cells stably overexpressing FAK showed increased invasiveness, which decreased significantly when merlin expression was restored. Collectively, these findings suggest that merlin inactivation is a critical step in MM pathogenesis and is related, at least in part, with upregulation of FAK activity.

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Section: Re-expression Of Merlin Attenuates Fak Phosphorylation At Tymentioning

confidence: 99%

Section: Merlin Inhibits Invasiveness Promoted By Focal Adhesion Kinamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

et al. 2006

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“…In normal cells, FAK functions as an important regulator of cell motility, proliferation and anchorage-dependent cell survival (Hanks et al, 2003;. In many tumor cells and malignant tissue, FAK expression is elevated (Gabarra-Niecko et al, 2003) and the role of FAK in promoting tumor progression remains an area of active investigation (McLean et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Intrinsic focal adhesion kinase activity controls orthotopic breast carcinoma metastasis via the regulation of urokinase plasminogen activator expression in a syngeneic tumor model

Lim

et al. 2006

Oncogene

105

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Expression of focal adhesion kinase (FAK) is elevated in malignant breast cancer, yet the role of intrinsic FAK activity in promoting tumor progression remains undefined. Here, we have inhibited FAK activity or expression in murine 4T1 breast carcinoma cells via dominantnegative focal adhesion kinase-related non-kinase (FRNK) or anti-FAK short hairpin RNA (shRNA) expression, respectively. Neither FRNK nor FAK shRNA (B80% reduced FAK levels) affected 4T1 proliferation in culture, whereas reduced FAK activity or expression blocked 4T1 cell invasion through Matrigel and resulted in 2-3-fold lower urokinase plasminogen activator (uPA) expression. Control 4T1 cells implanted into mammary fat pads of BALB/c mice exhibited spontaneous metastasis to the lungs, to the peritoneal cavity, and resulted in 90% lethality within 21 days. Whereas FAK shRNAexpressing 4T1 cells formed tumors in mice with low levels of apoptosis, when mammary-injected, these cells did not exhibit lung metastasis after 21 days and caused only 40% lethality up to 60 days. Transient re-expression of wildtype but not kinase-dead FAK in 4T1 FAK shRNA cells promoted uPA production and mammary to lung metastasis within 7 days. In fact, stable human uPA overexpression in 4T1 FAK shRNA cells promoted Matrigel invasion and lung metastasis equal to 4T1 controls. Conversely, treatment with plasminogen activator inhibitor-1 or neutralizing antibody to uPA blocked Matrigel invasion of 4T1 control cells. These studies provide the first direct proof that FAK catalytic activity can facilitate metastatic breast cancer progression by regulating uPA expression.

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“…c-Src phosphorylates Tyr 576 and 577 in the catalytic domain of FAK, which augments its kinase activity and induces the formation of a multimolecular complex, including Shc, JSAP1, and p130 Cas , leading to activate mitogen-activated protein kinases (MAPK) such as extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase [1][2][3][4]. In fact, elevated FAK and c-Src expression and activity has been associated with tumor progression [5].…”

Section: Introductionmentioning

confidence: 99%

MT1-MMP promotes cell growth and ERK activation through c-Src and paxillin in three-dimensional collagen matrix

Takino

Tsuge

Ozawa

et al. 2010

Biochemical and Biophysical Research Communications

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The role of focal-adhesion kinase in cancer — a new therapeutic opportunity

Cited by 950 publications

References 110 publications

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

Intrinsic focal adhesion kinase activity controls orthotopic breast carcinoma metastasis via the regulation of urokinase plasminogen activator expression in a syngeneic tumor model

MT1-MMP promotes cell growth and ERK activation through c-Src and paxillin in three-dimensional collagen matrix

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