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J. Biol. Chem., Vol. 281, Issue 33, 23611-23619, August 18, 2006

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Physical and Functional Interaction of Fyn Tyrosine Kinase with a Brain-enriched Rho GTPase-activating Protein TCGAP^*

From the Division of Oncology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan

Fyn, a member of the Src family of tyrosine kinases, is implicated in both brain development and adult brain function. In the present study, we identified a Rho GTPase-activating protein (GAP), TCGAP (Tc10/Cdc42 GTPase-activating protein), as a novel Fyn substrate. TCGAP interacted with Fyn and was phosphorylated by Fyn, with Tyr-406 in the GAP domain as a major Fyn-mediated phosphorylation site. Fyn suppressed the GAP activity of wild-type TCGAP but not the Y406F mutant of TCGAP in a phosphorylation-dependent manner, suggesting that Fyn-mediated Tyr-406 phosphorylation negatively regulated the TCGAP activity. In situ hybridization analyses showed that TCGAP mRNA was expressed prominently in both immature and adult mouse brain, with high levels in cortex, corpus striatum, hippocampus, and olfactory bulb. Overexpression of wild-type TCGAP in PC12 cells suppressed nerve growth factor-induced neurite outgrowth, whereas a GAP-defective mutant of TCGAP enhanced the neurite outgrowth. Nerve growth factor enhanced tyrosine phosphorylation of TCGAP through activation of Src family kinases. These results suggest that TCGAP is involved in Fyn-mediated regulation of axon and dendrite outgrowth.

Received for publication, October 14, 2005 , and in revised form, June 12, 2006.

^* This work was supported by Grants-in-Aid for scientific research and the National Project on Protein Structural and Functional Analyses from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 81-3-5449-5301; Fax: 81-3-5449-5413; E-mail: tyamamot{at}ims.u-tokyo.ac.jp.

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