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J. Biol. Chem., Vol. 283, Issue 36, 24690-24697, September 5, 2008

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The Role of Kalirin9 in p75/Nogo Receptor-mediated RhoA Activation in Cerebellar Granule Neurons^*

Anthony W. Harrington, Qi Ming Li^¶, Chhavy Tep, Jong Bae Park^||, Zhigang He^**, and Sung Ok Yoon¹

From the Department of Molecular and Cellular Biochemistry, Center for Molecular Neurobiology, the Biochemistry Program, and the ^¶Molecular, Cellular, and Developmental Biology Program, The Ohio State University, Columbus, Ohio 43210, the ^**Division of Neuroscience, Children's Hospital Harvard Medical School, Boston, Massachusetts 02115, and the ^||Neuro-Oncology Branch, National Cancer Center, 410-769 Goyang Si, Korea

p75 and the Nogo receptor form a signaling unit for myelin inhibitory molecules, with p75 being responsible for RhoA activation. Because p75 lacks the GDP/GTP exchange factor domain, it has remained unclear how p75 activates RhoA. Here, we report that Kalirin9, a dual RhoGEF, binds p75 directly and regulates p75-Nogo receptor-dependent RhoA activation and neurite inhibition in response to myelin-associated glycoprotein. The region of p75 that Kalirin9 binds includes its mastoparan-like fifth helix, which was shown to recruit RhoGDI-RhoA. As predicted from the presence of a shared binding site, we found that Kalirin9 competes with RhoGDI for p75 binding in a dose-dependent manner in vitro. In line with these data, myelin-associated glycoprotein addition to cerebellar granule neurons resulted in a reduction in the association of Kalirin9 with p75, and a simultaneous increase in the binding of RhoGDI to p75. These results reveal a mechanism by which the fifth helix of p75 regulates RhoA activation.

Received for publication, March 19, 2008 , and in revised form, June 23, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants NS 39472 (to S. O. Y.) and NS045758. This work was also supported by the Christopher and Dana Reeve Paralysis Foundation. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Center for Molecular Neurobiology, 184 Rightmire Hall, Ohio State University, 1060 Carmack Rd., Columbus, OH 43210. Tel.: 614-292-8542; Fax: 614-292-5379; E-mail: Yoon.84{at}osu.edu.

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