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J. Biol. Chem., Vol. 280, Issue 31, 28721-28730, August 5, 2005

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Tyrosine Phosphorylation Regulates the Proteolytic Activation of Protein Kinase C in Dopaminergic Neuronal Cells^*

Siddharth Kaul, Vellareddy Anantharam, Yongjie Yang, Christopher J. Choi, Arthi Kanthasamy, and Anumantha G. Kanthasamy

From the Parkinson's Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011

Oxidative stress is a key apoptotic stimulus in neuronal cell death and has been implicated in the pathogenesis of many neurodegenerative disorders, including Parkinson disease (PD). Recently, we demonstrated that protein kinase C- (PKC) is an oxidative stress-sensitive kinase that can be activated by caspase-3-dependent proteolytic cleavage to induce apoptotic cell death in cell culture models of Parkinson disease (Kaul, S., Kanthasamy, A., Kitazawa, M., Anantharam, V., and Kanthasamy, A. G. (2003) Eur. J. Neurosci. 18, 1387-1401 and Kanthasamy, A. G., Kitazawa, M., Kanthasamy, A., and Anantharam, V. (2003) Antioxid. Redox. Signal. 5, 609-620). Here we showed that the phosphorylation of a tyrosine residue in PKC can regulate the proteolytic activation of the kinase during oxidative stress, which consequently influences the apoptotic cell death in dopaminergic neuronal cells. Exposure of a mesencephalic dopaminergic neuronal cell line (N27 cells) to H₂O₂(0-300 µM) induced a dose-dependent increase in cytotoxicity, caspase-3 activation and PKC cleavage. H₂O₂-induced proteolytic activation of PKC was mediated by the activation of caspase-3. Most interestingly, both the general Src tyrosine kinase inhibitor genistein (25 µM) and the p60^Src tyrosine-specific kinase inhibitor (TSKI; 5 µM) dramatically inhibited H₂O₂ and the Parkinsonian toxin 1-methyl-4-phenylpyridinium-induced PKC cleavage, kinase activation, and apoptotic cell death. H₂O₂ treatment also increased phosphorylation of PKC at tyrosine site 311, which was effectively blocked by co-treatment with TSKI. Furthermore, N27 cells overexpressing a PKC^Y311F mutant protein exhibited resistance to H₂O₂-induced PKC cleavage, caspase activation, and apoptosis. To our knowledge, these data demonstrate for the first time that phosphorylation of Tyr-311 on PKC can regulate the proteolytic activation and proapoptotic function of the kinase in dopaminergic neuronal cells.

Received for publication, January 31, 2005 , and in revised form, June 15, 2005.

^* This work was supported by National Institutes of Health Grants NS38644, ES10586, and NS45133. 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 Figs. 1 and 2.

To whom correspondence should be addressed: Dept. of Biomedical Sciences, 2062 Veterinary Medicine Bldg., Iowa State University, Ames, IA 50011. Tel.: 515-294-2516; Fax: 515-294-2315; E-mail: akanthas{at}iastate.edu.

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