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J. Biol. Chem., Vol. 282, Issue 3, 1687-1694, January 19, 2007

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Suppression of Calpain-dependent Cleavage of the CDK5 Activator p35 to p25 by Site-specific Phosphorylation^*

Hirotsugu Kamei, Taro Saito, Mirai Ozawa, Yuichi Fujita, Akiko Asada, James A. Bibb, Takaomi C. Saido^¶, Hiroyuki Sorimachi^||, and Shin-ichi Hisanaga¹

From the Department of Biological Sciences, Graduate School of Science, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachiohji, Tokyo 192-0397, Japan, the Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, the ^¶Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan, and the ^||Enzymatic Regulation for Cell Functions, The Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan

Cdk5 is a proline-directed Ser/Thr protein kinase predominantly expressed in postmitotic neurons together with its activator, p35. N-terminal truncation of p35 to p25 by calpain results in deregulation of Cdk5 and contributes to neuronal cell death associated with several neurodegenerative diseases. Previously we reported that p35 occurred as a phosphoprotein, phospho-p35 levels changed with neuronal maturation, and that phosphorylation of p35 affected its vulnerability to calpain cleavage. Here, we identify the p35 residues Ser⁸ and Thr¹³⁸ as the major sites of phosphorylation by Cdk5. Mutagenesis of these sites to unphosphorylatable Ala increased susceptibility to calpain in cultured cells and neurons while changing them to phosphomimetic glutamate-attenuated cleavage. Furthermore, phosphorylation state-specific antibodies to these sites revealed that Thr¹³⁸ was dephosphorylated in adult rat, although both Ser⁸ and Thr¹³⁸ were phosphorylated in prenatal brains. In cultured neurons, inhibition of protein phosphatases converted phosho-Ser⁸ p35 to dual phospho-Ser⁸/Thr¹³⁸ p35 and conferred resistance to calpain cleavage. These results suggest phosphorylation of Thr¹³⁸ predominantly defines the susceptibility of p35 to calpain-dependent cleavage and that dephosphorylation of this site is a critical determinant of Cdk5-p25-induced cell death associated with neurodegeneration.

Received for publication, November 13, 2006

^* This work was supported in part by grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports and Science and Technology, of Japan (to S. H.) and the National Institute of Drug Abuse (to J. A. B.). 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.: 81-42-677-2577; Fax: 81-42-677-2559; E-mail: hisanaga-shinichi{at}c.metro-u.ac.jp.

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