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J. Biol. Chem., Vol. 282, Issue 14, 10398-10404, April 6, 2007

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Focal Adhesion Kinase Is Negatively Regulated by Phosphorylation at Tyrosine 407^*

Yangmi Lim¹, Haein Park¹, Jihyun Jeon, Innoc Han, Jinsook Kim, Eek-Hoon Jho^¶, and Eok-Soo Oh²

From the Department of Life Sciences, Division of Molecular Life Sciences and Center for Cell Signaling Research, Ewha Womans University, Seoul 120-750, the College of Medicine, Department of Physiology and Biophysics, Inha University, Incheon 402-751, and the ^¶Department of Life Science, University of Seoul, Seoul 130-743, Korea

Focal adhesion kinase (FAK) mediates signal transduction in response to multiple extracellular inputs via tyrosine phosphorylation at specific residues. Although several tyrosine phosphorylation events have been linked to FAK activation and downstream signal transduction, the function of FAK phosphorylation at Tyr⁴⁰⁷ was previously unknown. Here, we show for the first time that phosphorylation of FAK Tyr⁴⁰⁷ increases during serum starvation, contact inhibition, and cell cycle arrest, all conditions under which activating FAK Tyr³⁹⁷ phosphorylation decreases. Transfection of NIH3T3 cells with a phosphorylation-mimicking FAK 407E mutant decreased autophosphorylation at Tyr³⁹⁷ and inhibited both FAK kinase activity in vitro and FAK-mediated functions such as cell adhesion, spreading, proliferation, and migration. The opposite effects were observed in cells transfected with nonphosphorylatable mutant FAK 407F. Taken together, these data suggest the novel concept that FAK Tyr⁴⁰⁷ phosphorylation negatively regulates the enzymatic and biological activities of FAK.

Received for publication, October 2, 2006 , and in revised form, January 26, 2007.

^* This work was supported by Molecular and Cellular BioDiscovery Research Program Grant CBM-01B-2-1 (to E.-S. O.) and in part by Ministry of Ministry of Health & Welfare Research Grant 02-PJ1-PG3-20905-0012 (to E.-S. O.). 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 These authors contributed equally to this study.

² To whom correspondence should be addressed: Center for Cell Signaling Research, Ewha Womans University, Daehyun-dong, Seodaemoon-Gu, Seoul 120-750, Korea. Tel.: 82-2-3277-3761; Fax: 82-2-3277-3760; E-mail: OhES{at}ewha.ac.kr.

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