Filippo Giancotti: Focal Adhesion Kinase Signaling in Tumorigenesis

The non-receptor tyrosine kinase FAK is a major mediator of integrin signaling. Engagement of β1 and αv integrins — but not that of β4 — induces FAK localization to matrix adhesions and activation. Upon autophosphorylation at Tyr 397, FAK combines with Src or another Src Family Kinase (SFK). The SFK in turn phosphorylates FAK and FAK-associated focal adhesion proteins, such as p130Cas, paxillin and p190-Rho-GEF, on tyrosine residues. In addition, FAK can combine with PI-3K and Grb7 and activate the tyrosine kinase Etk/BMX. Through this plethora of effectors, FAK regulates focal adhesion dynamics during cell migration and activates prosurvival and mitogenic signaling pathways.

To examine the role of FAK in mammary tumorigenesis, Yuliya Pylayeva introduced a mammary gland-specific deletion of FAK in MMTV-PyMT mice. These mice develop mammary carcinomas following Middle T oncoprotein-mediated activation of Ras and PI-3K. Yuliya discovered that genetic ablation of FAK completely protects these mice from mammary tumorigenesis. Through genetic experiments in cell culture and mouse models, Yuliya found that FAK supports malignant transformation by promoting mammary tumor cell proliferation, survival, and invasion. Mutational analysis indicated that FAK coordinates these core cellular functions through its interaction with Cas proteins. Interestingly, she also found that the remarkable effects of FAK on mammary oncogenesis are not limited to mouse cells transformed by the Middle T oncoprotein. Upon acute silencing of FAK, Ras-transformed cells lost their invasive ability and became senescent, whereas Neu-transformed cells underwent growth arrest and apoptosis. Human breast cancer cells of diverse origins and carrying distinct oncogenic mutations underwent a similar demise. These results reveal that breast cancer cells are addicted to integrin signaling, identifying a novel vulnerability that can be exploited therapeutically.

Current efforts by Kelly Gillen are directed at elucidating the signaling mechanisms by which FAK promotes tumor cell hyperproliferation and suppresses anoikis. In addition, since we have observed that the gene encoding FAK is amplified in a significant fraction of human breast cancers, we are examining the hypothesis that FAK is an oncogene.

Oktay M, Wary KK, Dans M, Birge RB, Giancotti FG. Integrin-mediated activation of focal adhesion kinase is required for signaling to Jun NH2-terminal kinase and progression through the G1 phase of the cell cycle. J Cell Biol. 1999, 28;145(7):1461-9.

Sumitomo M, Shen R, Walburg M, Dai J, Geng Y, Navarro D, Boileau G, Papandreou CN, Giancotti FG, Knudsen B, Nanus DM. Neutral endopeptidase inhibits prostate cancer cell migration by blocking focal adhesion kinase signaling. J Clin Invest. 2000, 106(11):1399-407.

Barberis L, Wary KK, Fiucci G, Liu F, Hirsch E, Brancaccio M, Altruda F, Tarone G, Giancotti FG. Distinct roles of the adaptor protein Shc and focal adhesion kinase in integrin signaling to ERK. J Biol Chem. 2000, 24;275(47):36532-40.

Mettouchi A, Klein S, Guo W, Lopez-Lago M, Lemichez E, Westwick JK, Giancotti FG. Integrin-specific activation of Rac controls progression through the G(1) phase of the cell cycle. Mol Cell. 2001, 8(1):115-27. [Previews by Ridley, A.J. in Dev. Cell 1(2):160-161, 2001; Research Roundup by Powledge, T.M. in J. Cell Biol. 154:677, 2001; Must Read F1000].

Hirsch E, Barberis L, Brancaccio M, Azzolino O, Xu D, Kyriakis JM, Silengo L, Giancotti FG, Tarone G, Fässler R, Altruda F. Defective Rac-mediated proliferation and survival after targeted mutation of the β1 integrin cytodomain. J Cell Biol. 2002, 157(3):481-92 [Must Read F1000].

Klein S, de Fougerolles AR, Blaikie P, Khan L, Pepe A, Green CD, Koteliansky V, Giancotti FG. α5β1 integrin activates an NF-kappa B-dependent program of gene expression important for angiogenesis and inflammation. Mol Cell Biol. 2002, 22(16):5912-22.

Pylayeva Y, Gillen KM, Gerald W, Beggs HE, Reichardt LF, Giancotti FG. Ras- and PI3K-dependent breast tumorigenesis in mice and humans requires focal adhesion kinase signaling. J Clin Invest. 2009, 119(2):252-66. doi: 10.1172/JCI37160.

Rossi F, Yozgat Y, de Stanchina E, Veach D, Clarkson B, Manova K, Giancotti FG, Antonescu CR, Besmer P. Imatinib upregulates compensatory integrin signaling in a mouse model of gastrointestinal stromal tumor and is more effective when combined with dasatinib. Mol Cancer Res. 2010, 8(9):1271-83.

Baranwal S, Wang Y, Rathinam R, Lee J, Jin L, McGoey R, Pylayeva Y, Giancotti FG, Blobe G, Alahary SK. Nischarin suppresses breast cancer progression through integrin alpha5-FAK-mediated signaling events. J. Natl. Cancer Inst. 2011 in press.