期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 283, 期 19, 页码 13252-13260出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M706937200
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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). 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.
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