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J. Biol. Chem., Vol. 280, Issue 25, 24212-24220, June 24, 2005

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G Protein-coupled Receptor Activation Rapidly Stimulates Focal Adhesion Kinase Phosphorylation at Ser-843

MEDIATION BY Ca²⁺, CALMODULIN, AND Ca²⁺/CALMODULIN-DEPENDENT KINASE II^*

Robert S. Fan, Rodrigo O. Jácamo, Xiaohua Jiang, James Sinnett-Smith, and Enrique Rozengurt

From the Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, Center for Ulcer Research and Education, Digestive Diseases Research Center and Molecular Biology Institute, University of California, Los Angeles, California

A rapid increase in the tyrosine phosphorylation of focal adhesion kinase (FAK) has been extensively documented in cells stimulated by multiple signaling molecules, but little is known about the regulation of FAK phosphorylation at serine residues. Stimulation of Swiss 3T3 cells with the G protein-coupled receptor agonists bombesin, vasopressin, or bradykinin induced an extremely rapid (within 5 s) increase in FAK phosphorylation at Ser-843. The phosphorylation of this residue preceded FAK phosphorylation at Tyr-397, the major autophosphorylation site, and FAK phosphorylation at Ser-910. Treatment of intact cells with ionomycin stimulated a rapid increase in FAK phosphorylation at Ser-843, indicating that an increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i) is a potential pathway leading to FAK-Ser-843 phosphorylation. Indeed, treatment with agents that prevent an agonist-induced increase in [Ca²⁺]_i (e.g. thapsigargin or BAPTA (1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid)), interfere with calmodulin function (e.g. trifluoperazine, W13, and W7), or block Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) activation (KN93) or expression (small interfering RNA) abrogated the rapid FAK phosphorylation at Ser-843 induced by bombesin, bradykinin, or vasopressin. Furthermore, activated CaMKII directly phosphorylated the recombinant COOH-terminal region of FAK at a residue equivalent to Ser-843. Thus, our results demonstrate that G protein-coupled receptor activation induces rapid FAK phosphorylation at Ser-843 through Ca²⁺, calmodulin, and CaMKII.

Received for publication, January 20, 2005 , and in revised form, April 19, 2005.

^* This work was supported by National Institutes of Health Grants DK 56930 and DK 55003 and NCI, National Institutes of Health Grant P50 CA90388. 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.

A Ronald S. Hirshberg Professor of Pancreatic Cancer Research. To whom correspondence should be addressed: 900 Veteran Ave. Warren Hall, Rm. 11-124, Dept. of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-178622; Tel.: 310-794-6610; Fax: 310-267-2399; E-mail: erozengurt{at}mednet.ucla.edu.

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