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J. Biol. Chem., Vol. 279, Issue 10, 9565-9576, March 5, 2004

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Focal Adhesion Kinase Regulation of N-WASP Subcellular Localization and Function^*

Xiaoyang Wu, Shiro Suetsugu, Lee Ann Cooper, Tadaomi Takenawa, and Jun-Lin Guan¶

From the Department of Molecular Medicine, Cornell University, Ithaca, New York 14853 and the Department of Biochemistry, University of Tokyo, Tokyo 108-8639, Japan

N-WASP is a member of the WASP family of proteins that regulate actin cytoskeleton remodeling. FAK is a cytoplasmic tyrosine kinase implicated in integrin signaling during cell migration. Here we identify a direct interaction between N-WASP and FAK and show that N-WASP is phosphorylated by FAK at a conserved tyrosine residue, Tyr²⁵⁶. We found that phosphorylation of Tyr²⁵⁶ affected N-WASP nuclear localization, suggesting that phosphorylation of N-WASP by FAK may regulate its activity in vivo by altering its subcellular localization. We also showed that the nuclear localization of N-WASP is dependent on its being in the open conformation either after its activation by Cdc42 or the truncation of the C-terminal VCA domain. Phosphorylation of Tyr²⁵⁶ of N-WASP could reduce its interaction with nuclear importin NPI-1, which might be responsible for its decreased nuclear localization. Lastly, we show that phosphorylation of Tyr²⁵⁶ plays an important role in promoting cell migration. Together, these results suggest a novel regulatory mechanism of N-WASP by tyrosine phosphorylation and subcellular localization and its potential role in the regulation of cell migration.

Received for publication, September 29, 2003 , and in revised form, December 10, 2003.

^* This research was supported by National Institutes of Health grants (to J.-L. G.). 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.

^¶ To whom correspondence should be addressed. Tel.: 607-253-3586; Fax: 607-253-3708; E-mail: jg19{at}cornell.edu.

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