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J. Biol. Chem., Vol. 283, Issue 19, 13252-13260, May 9, 2008

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Calmodulin Binding and Cdk5 Phosphorylation of p35 Regulate Its Effect on Microtubules^*

From the Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China

In the nervous system, Cdk5 and its neuronal activator p35 are involved in the control of various activities, including neuronal differentiation and migration. Recently, we have reported that p35 is a microtubule-associated protein that regulates microtubule dynamics ( Hou, Z., Li, Q., He, L., Lim, H. Y., Fu, X., Cheung, N. S., Qi, D. X., and Qi, R. Z. (2007) J. Biol. Chem. 282, 18666-18670[Abstract/Free Full Text] ). Here we present two regulatory modes of p35 function as a microtubule-associated protein. First, p35 is Ca²⁺-dependent calmodulin (CaM)-binding protein. The CaM- and microtubule binding domains are localized to overlapping regions at the N terminus of p35. Within the CaM-binding region, Ala substitution for Trp-52 abolishes the CaM-binding activity, corroborating specific CaM-binding of p35. Furthermore, CaM blocks p35 association with microtubules in a Ca²⁺-specific manner, suggesting that p35 may be involved in the Ca²⁺/CaM-mediated inhibition of microtubule assembly. Second, p35 phosphorylation by Cdk5 interferes with the microtubule-binding and polymerizing activities of p35. Using a mutational approach, we found that only phosphorylation at Thr-138, one of the two residues primarily phosphorylated in vivo, inhibits the polymerizing activity. In PC12 cells, expression of p35 promotes nerve growth factor-induced neurite outgrowth under a Cdk5 inhibitory condition. Such p35 activity is impaired by the phosphomimetic mutation of Thr-138. These data suggest that Thr-138 phosphorylation plays a critical role in the control of the p35 functions in microtubule assembly and neurite outgrowth.

Received for publication, August 20, 2007 , and in revised form, January 8, 2008.

^* This work was supported by an Earmarked Research Grant from the Research Grants Council and Area of Excellence Scheme under the University Grants Committee of Hong Kong. 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: Dept. of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. Tel.: 852-2358-7273; Fax: 852-2358-1552; E-mail: qirz{at}ust.hk.

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