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J. Biol. Chem., Vol. 280, Issue 18, 18418-18424, May 6, 2005

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Direct Interaction of Rnd1 with FRS2 Regulates Rnd1-induced Down-regulation of RhoA Activity and Is Involved in Fibroblast Growth Factor-induced Neurite Outgrowth in PC12 Cells^*

Amane Harada, Hironori Katoh, and Manabu Negishi

From the Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan

The Rho family of small GTPases has been implicated in the reorganization of the actin cytoskeleton and subsequent morphological changes in various cells. Rnd1, a member of this family, has a low intrinsic GTPase activity and exerts antagonistic effects on RhoA signaling. However, how the activity of Rnd1 is regulated has not yet been elucidated. Here we have demonstrated that Rnd1 directly associates with FRS2 and FRS2, which are docking proteins of fibroblast growth factor (FGF) receptors and play important roles in the intracellular signals induced by FGFs. The interaction of FRS2 with Rnd1 suppresses the inhibitory effect of Rnd1 on RhoA. Rnd1 binds to the COOH-terminal region of FRS2 including tyrosine residues essential for the interaction with Shp2. When FGF receptor 1 is activated, it phosphorylates FRS2, recruits Shp2, and releases Rnd1 from FRS2. The liberated Rnd1 then inhibits RhoA activity. Furthermore, knockdown of Rnd1 by Rnd1-specific short interfering RNAs suppress the FGF-induced neurite outgrowth in PC12 cells. These results suggest that the activity of Rnd1 is regulated by FGF receptor through FRS2 and that Rnd1 plays an important role in the FGF signaling during neurite outgrowth.

Received for publication, October 5, 2004 , and in revised form, February 17, 2005.

^* This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture 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.

To whom correspondence should be addressed. Tel.: 81-75-753-4547; Fax: 81-75-753-7688; E-mail: mnegishi{at}pharm.kyoto-u.ac.jp.

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