Inhibition of pp125FAK in cultured fibroblasts results in apoptosis

doi:10.1083/jcb.135.5.1383

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Inhibition of pp125FAK in cultured fibroblasts results in apoptosis

JE Hungerford, MT Compton, ML Matter, BG Hoffstrom and CA Otey
Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville 22908, USA.

The tyrosine kinase called pp125FAK is believed to play an important role in integrin-mediated signal transduction. pp125FAK is associated both functionally and spatially with integrins, which are the cell surface receptors for extracellular matrix components. Although the precise function of pp125FAK is not known, two possibilities have been proposed: pp125FAK may regulate the assembly of focal adhesions in spreading or migrating cells, or pp125FAK may participate in a signal transduction cascade to inform the nucleus that the cell is anchored. To test these models in living cells, a peptide representing the focal adhesion kinase (FAK)-binding site of the beta 1 tail was coupled to carrier protein and injected into cultured cells to competitively inhibit the binding of pp125FAK to endogenous integrin, thus inhibiting activation of pp125FAK on a cell-by-cell basis. In addition, an antibody directed against an epitope adjacent to the focal adhesion targeting sequence on pp125FAK was microinjected, as an alternative means of inhibiting pp125FAK activation. It was observed that when rounded cells were injected with either the integrin peptide or the anti-FAK antibody, the cells rapidly began to apoptose, within 4 h after injection. These results indicate that pp125FAK may play a critical role in suppressing apoptosis in fibroblasts.
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Ilic, D., Almeida, E. A.C., Schlaepfer, D. D., Dazin, P., Aizawa, S., Damsky, C. H. (1998). Extracellular Matrix Survival Signals Transduced by Focal Adhesion Kinase Suppress p53-mediated Apoptosis. JCB 143: 547-560 [Abstract] [Full Text]
Chen, H.-C., Chan, P.-C., Tang, M.-J., Cheng, C.-H., Chang, T.-J. (1998). Tyrosine Phosphorylation of Focal Adhesion Kinase Stimulated by Hepatocyte Growth Factor Leads to Mitogen-activated Protein Kinase Activation. J. Biol. Chem. 273: 25777-25782 [Abstract] [Full Text]
Pozzi, A., Wary, K. K., Giancotti, F. G., Gardner, H. A. (1998). Integrin {alpha}1{beta}1 Mediates a Unique Collagen-dependent Proliferation Pathway In Vivo. JCB 142: 587-594 [Abstract] [Full Text]
Rodriguez-Fernandez, J. L., Rozengurt, E. (1998). Bombesin, Vasopressin, Lysophosphatidic Acid, and Sphingosylphosphorylcholine Induce Focal Adhesion Kinase Activation in Intact Swiss 3T3 Cells. J. Biol. Chem. 273: 19321-19328 [Abstract] [Full Text]
Gervais, F. G., Thornberry, N. A., Ruffolo, S. C., Nicholson, D. W., Roy, S. (1998). Caspases Cleave Focal Adhesion Kinase during Apoptosis to Generate a FRNK-like Polypeptide. J. Biol. Chem. 273: 17102-17108 [Abstract] [Full Text]
Law, S. F., Zhang, Y.-Z., Klein-Szanto, A. J.�P., Golemis, E. A. (1998). Cell Cycle-Regulated Processing of HEF1 to Multiple Protein Forms Differentially Targeted to Multiple Subcellular Compartments. Mol. Cell. Biol. 18: 3540-3551 [Abstract] [Full Text]
Claesson-Welsh, L., Welsh, M., Ito, N., Anand-Apte, B., Soker, S., Zetter, B., O'Reilly, M., Folkman, J. (1998). Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrin-binding motif RGD. Proc. Natl. Acad. Sci. USA 95: 5579-5583 [Abstract] [Full Text]
Altun-Gultekin, Z. F., Chandriani, S., Bougeret, C., Ishizaki, T., Narumiya, S., de Graaf, P., Van Bergen en Henegouwen, P., Hanafusa, H., Wagner, J. A., Birge, R. B. (1998). Activation of Rho-Dependent Cell Spreading and Focal Adhesion Biogenesis by the v-Crk Adaptor Protein. Mol. Cell. Biol. 18: 3044-3058 [Abstract] [Full Text]
Yokota, T., Oritani, K., Mitsui, H., Aoyama, K., Ishikawa, J., Sugahara, H., Matsumura, I., Tsai, S., Tomiyama, Y., Kanakura, Y., Matsuzawa, Y. (1998). Growth-Supporting Activities of Fibronectin on Hematopoietic Stem/Progenitor Cells In Vitro and In Vivo: Structural Requirement for Fibronectin Activities of CS1 and Cell-Binding Domains. Blood 91: 3263-3272 [Abstract] [Full Text]
Shen, Y., Schneider, G., Cloutier, J.-F., Veillette, A., Schaller, M. D. (1998). Direct Association of Protein-tyrosine Phosphatase PTP-PEST with Paxillin. J. Biol. Chem. 273: 6474-6481 [Abstract] [Full Text]
Levkau, B., Herren, B., Koyama, H., Ross, R., Raines, E. W. (1998). Caspase-mediated Cleavage of Focal Adhesion Kinase pp125FAK and Disassembly of Focal Adhesions in Human Endothelial Cell Apoptosis. JEM 187: 579-586 [Abstract] [Full Text]