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J. Biol. Chem., Vol. 282, Issue 14, 10370-10379, April 6, 2007

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Preferential Phosphorylation of Focal Adhesion Kinase Tyrosine 861 Is Critical for Mediating an Anti-apoptotic Response to Hyperosmotic Stress^*

From the Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, UCLA-CURE, Digestive Diseases Research Center and Molecular Biology Institute, UCLA, Los Angeles, California 90095

The results presented here demonstrate that focal adhesion kinase (FAK) Tyr-861 is the predominant tyrosine phosphorylation site stimulated by hyperosmotic stress in a variety of cell types, including epithelial cell lines (ileum-derived IEC-18, colon-derived Caco2, and stomach-derived NCI-N87), FAK null fibroblasts re-expressing FAK, and Src family kinase triple null fibroblasts (SYF cells) in which c-Src has been restored (YF cells). We show that hyperosmotic stress-stimulated FAK phosphorylation in epithelial cells is inhibited by Src family kinase inhibitors PP2 and SU6656 and that it does not occur in SYF cells. Unexpectedly, hyperosmotic stress-induced phosphorylation of FAK at Tyr-397, Tyr-576, and most dramatically at Tyr-861 was completely insensitive to the F-actin-disrupting agents, latrunculin A and cytochalasin D. Finally, we show that in FAK null cells exposed to hyperosmotic stress or growth factor withdrawal, re-expression of wild type FAK restored cell survival, whereas re-expression of FAK mutated from tyrosine to phenylalanine at position 861 (FAKY861F) did not. Our results indicate that FAK Tyr-861 phosphorylation is required for mammalian cell survival of hyperosmotic stress. Furthermore, the results suggest that FAK is an upstream regulator (rather than downstream effector) of F-actin reorganization in response to hyperosmotic stress. We propose that FAK/c-Src bipartite enzyme is a sensor of cytoplasmic shrinkage, and that the phosphorylation on FAK Tyr-861 by Src and subsequent reorganization of F-actin can initiate an anti-apoptotic signaling pathway that protects cells from hyperosmotic stress.

Received for publication, August 15, 2006 , and in revised form, January 11, 2007.

^* This work was supported in part by National Institutes of Health Grants DK 56930, DK 55003, and P30 DK41301 (to E. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by NCI Mentored Career Development Award K08CA104039-01.

² To whom correspondence should be addressed: Ronald S. Hirshberg Professor of Pancreatic Cancer Research, 900 Veteran Ave., Warren Hall Rm. 11-124, Dept. of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095-178622. Tel.: 310-794-6610; Fax: 310-167-2399; E-mail: erozengurt{at}mednet.ucla.edu.

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