Extracellular Matrix Survival Signals Transduced by Focal Adhesion Kinase Suppress p53-mediated Apoptosis

doi:10.1083/jcb.143.2.547

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J. Cell Biol., Volume 143, Number 2, October 19, 1998 547-560

Extracellular Matrix Survival Signals Transduced by Focal Adhesion Kinase Suppress p53-mediated Apoptosis

Du $s$ ko Ili $c'$ ,^* Eduardo A.C. Almeida,^* David D. Schlaepfer,^§ Paul Dazin, Shinichi Aizawa, and Caroline H. Damsky^*

^* Departments of Stomatology and Anatomy, Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California 94143-0512; ^§ The Scripps Research Institute, Department of Immunology, La Jolla, California 92037; and Department of Morphogenesis, Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Kumamoto 860, Japan

In many malignant cells, both the anchorage requirement for survival and the function of the p53 tumor suppressor gene aresubverted. These effects are consistent with the hypothesis thatsurvival signals from extracellular matrix (ECM) suppress a p53-regulatedcell death pathway. We report that survival signals from fibronectinare transduced by the focal adhesion kinase (FAK). If FAK or thecorrect ECM is absent, cells enter apoptosis through a p53-dependentpathway activated by protein kinase C $lambda$ / $iota$ and cytosolic phospholipaseA₂. This pathway is suppressible by dominant-negative p53 andBcl2 but not CrmA. Upon inactivation of p53, cells survive evenif they lack matrix signals or FAK. This is the first report thatp53 monitors survival signals from ECM/FAK in anchorage- dependentcells.

Key words: fibronectin; survival; FAK; p53; apoptosis

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Weyant, M. J., Carothers, A. M., Dannenberg, A. J., Bertagnolli, M. M. (2001). (+)-Catechin Inhibits Intestinal Tumor Formation and Suppresses Focal Adhesion Kinase Activation in the Min/+ Mouse. Cancer Res. 61: 118-125 [Abstract] [Full Text]
Jones, C. B., McIntosh, J., Huang, H., Graytock, A., Hoyt, D. G. (2001). Regulation of Bleomycin-Induced DNA Breakage and Chromatin Structure in Lung Endothelial Cells by Integrins and Poly(ADP-Ribose) Polymerase. Mol. Pharmacol. 59: 69-75 [Abstract] [Full Text]
Komarova, S. V., Ataullakhanov, F. I., Globus, R. K. (2000). Bioenergetics and mitochondrial transmembrane potential during differentiation of cultured osteoblasts. Am. J. Physiol. Cell Physiol. 279: C1220-C1229 [Abstract] [Full Text]
Cummings, B. S., McHowat, J., Schnellmann, R. G. (2000). Phospholipase A2s in Cell Injury and Death. J. Pharmacol. Exp. Ther. 294: 793-799 [Abstract] [Full Text]
Fincham, V. J., Brunton, V. G., Frame, M. C. (2000). The SH3 Domain Directs Acto-Myosin-Dependent Targeting of v-Src to Focal Adhesions via Phosphatidylinositol 3-Kinase. Mol. Cell. Biol. 20: 6518-6536 [Abstract] [Full Text]
Fornaro, M., Steger, C. A., Bennett, A. M., Wu, J. J., Languino, L. R. (2000). Differential Role of beta 1C and beta 1A Integrin Cytoplasmic Variants in Modulating Focal Adhesion Kinase, Protein Kinase B/AKT, and Ras/Mitogen-activated Protein Kinase Pathways. Mol. Biol. Cell 11: 2235-2249 [Abstract] [Full Text]
Zachary, I., Mathur, A., Yla-Herttuala, S., Martin, J. (2000). Vascular Protection : A Novel Nonangiogenic Cardiovascular Role for Vascular Endothelial Growth Factor. Arterioscler. Thromb. Vasc. Bio. 20: 1512-1520 [Abstract] [Full Text]
Cance, W. G., Harris, J. E., Iacocca, M. V., Roche, E., Yang, X., Chang, J., Simkins, S., Xu, L. (2000). Immunohistochemical Analyses of Focal Adhesion Kinase Expression in Benign and Malignant Human Breast and Colon Tissues: Correlation with Preinvasive and Invasive Phenotypes. Clin. Cancer Res. 6: 2417-2423 [Abstract] [Full Text]
Sonoda, Y., Matsumoto, Y., Funakoshi, M., Yamamoto, D., Hanks, S. K., Kasahara, T. (2000). Anti-apoptotic Role of Focal Adhesion Kinase (FAK). INDUCTION OF INHIBITOR-OF-APOPTOSIS PROTEINS AND APOPTOSIS SUPPRESSION BY THE OVEREXPRESSION OF FAK IN A HUMAN LEUKEMIC CELL LINE, HL-60. J. Biol. Chem. 275: 16309-16315 [Abstract] [Full Text]
Almeida, E. A.C., Ili, D., Han, Q., Hauck, C. R., Jin, F., Kawakatsu, H., Schlaepfer, D. D., Damsky, C. H. (2000). Matrix Survival Signaling: From Fibronectin via Focal Adhesion Kinase to c-Jun NH2-terminal Kinase. J. Cell Biol. 149: 741-754 [Abstract] [Full Text]
Gilmore, A. P., Metcalfe, A. D., Romer, L. H., Streuli, C. H. (2000). Integrin-mediated Survival Signals Regulate the Apoptotic Function of Bax through Its Conformation and Subcellular Localization. J. Cell Biol. 149: 431-446 [Abstract] [Full Text]
Cho, S. Y., Klemke, R. L. (2000). Extracellular-regulated Kinase Activation and CAS/Crk Coupling Regulate Cell Migration and Suppress Apoptosis during Invasion of the Extracellular Matrix. J. Cell Biol. 149: 223-236 [Abstract] [Full Text]