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J. Biol. Chem., Vol. 282, Issue 32, 23482-23490, August 10, 2007

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Regulation of c-Src Activity in Glutamate-induced Neurodegeneration^*

From the Laboratory of Molecular Medicine, Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus, Ohio 43210

c-Src is heavily expressed in the brain and in human neural tissues. Our pursuit for characterization of the neuroprotective mechanisms of tocotrienols led to the first evidence demonstrating that rapid c-Src activation plays a central role in executing glutamate-induced neurodegeneration. It is now known that Src deficiency or blockade of Src activity in mice provides cerebral protection following stroke. Here, we sought to examine the mechanisms that regulate inducible c-Src activity in glutamate-challenged HT4 neural cells and primary cortical neurons. Knockdown of c-Src protected cells against glutamate-induced loss of viability. Consistently, microinjection of siRNA against c-Src protected cells against glutamate. Using overexpression and knockdown approaches, we noted that SHP-1 may be implicated in glutamate-induced c-Src activation. Following such activation, Cbp and caveolin-1 were phosphorylated and associated with Csk. Csk was translocated to the membrane where it down-regulated glutamate-induced c-Src activity by catalyzing the inhibitory phosphorylation of a tyrosine residue in c-Src. Findings of this study present a new paradigm that addresses the regulation of c-Src under neurodegenerative conditions.

Received for publication, December 8, 2006 , and in revised form, June 13, 2007.

^* This work was supported in part by National Institutes of Health Grant RO1NS42617. 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: 512 Davis Heart & Lung Research Institute, 473 West 12th Ave., The Ohio State University Medical Center, Columbus, OH 43210. Tel.: 614-247-7658; Fax: 614-247-7818; E-mail: Chandan.Sen{at}osumc.edu.

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