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J. Biol. Chem., Vol. 282, Issue 1, 303-318, January 5, 2007

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R-Ras Controls Axon Specification Upstream of Glycogen Synthase Kinase-3 through Integrin-linked Kinase^*

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

The initial event in establishing a polarized neuron is the specification of a single axon. Spatially regulated glycogen synthase kinase-3 (GSK-3) activity is critical for specifying axon-dendrite fate; however, the upstream signaling of GSK-3 in the determination of neuronal polarity still remains obscure. Here, we found that, in cultured hippocampal neurons, the small GTPase R-Ras selectively localized in a single neurite of stage 2 neurons and that its activity increased after plating and peaked between stages 2 and 3. Ectopic expression of R-Ras induced global inactivation of GSK-3 and formation of multiple axons, whereas knockdown of endogenous R-Ras by RNA interference blocked GSK-3 inactivation and axon formation. GSK-3 inactivation and axon formation by R-Ras required integrin-linked kinase (ILK), and subcellular localization of ILK was strictly regulated by R-Ras-mediated phosphatidylinositol 3-kinase activity. In addition, membrane targeting of ILK was sufficient to inactivate GSK-3 and to form multiple axons. Our study demonstrates a novel role of R-Ras and ILK upstream of GSK-3 in the regulation of neuronal polarity.

Received for publication, August 21, 2006 , and in revised form, November 7, 2006.

^* This work was supported in part 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.

¹ 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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