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Published online 15 May 2006. doi:10.1083/jcb.200508204
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 173, Number 4, 601-613
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Article

 Semaphorin 4D/Plexin-B1–mediated R-Ras GAP activity inhibits cell migration by regulating ß1 integrin activity

Izumi Oinuma, Hironori Katoh, and Manabu Negishi

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

Correspondence to Manabu Negishi: mnegishi{at}pharm.kyoto-u.ac.jp

Plexins are cell surface receptors for semaphorins and regulate cell migration in many cell types. We recently reported that the semaphorin 4D (Sema4D) receptor Plexin-B1 functions as a GTPase-activating protein (GAP) for R-Ras, a member of Ras family GTPases implicated in regulation of integrin activity and cell migration (Oinuma, I., Y. Ishikawa, H. Katoh, and M. Negishi. 2004. Science. 305:862–865). We characterized the role of R-Ras downstream of Sema4D/Plexin-B1 in cell migration. Activation of Plexin-B1 by Sema4D suppressed the ECM-dependent R-Ras activation, R-Ras–mediated phosphatydylinositol 3-kinase activation, and ß1 integrin activation through its R-Ras GAP domain, leading to inhibition of cell migration. In addition, inactivation of R-Ras by overexpression of the R-Ras–specific GAP or knockdown of R-Ras by RNA interference was sufficient for suppressing ß1 integrin activation and cell migration in response to the ECM stimulation. Thus, we conclude that R-Ras activity is critical for ECM-mediated ß1 integrin activation and cell migration and that inactivation of R-Ras by Sema4D/Plexin-B1–mediated R-Ras GAP activity controls cell migration by modulating the activity of ß1 integrins.

Abbreviations used in this paper: GAP, GTPase-activating protein; HS, horse serum; PE, phycoerythrin; PI3-K, phosphatydylinositol 3-kinase; WT, wild type.


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