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J. Biol. Chem., Vol. 281, Issue 51, 39014-39021, December 22, 2006

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Identification of Nuclear Import Mechanisms for the Neuronal Cdk5 Activator^*

Xinrong Fu, Yuk-Kwan Choi, Dianbo Qu, Yan Yu, Nam Sang Cheung^¶, and Robert Z. Qi¹

From the Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China, the Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, and the ^¶Department of Biochemistry, National University of Singapore, 8 Medical Drive, Singapore 117597

The activation of Cdk5 by p35 plays a pivotal role in a multitude of nervous system activities ranging from neuronal differentiation to degeneration. A fraction of Cdk5 and p35 localizes in the nucleus where Cdk5-p35 exerts its functions via protein phosphorylation, and p35 displays a dynamic localization between the cytoplasm and the nucleus. Here, we examined the nuclear import properties of p35. In nuclear import assays, p35 was actively transported into the nuclei of digitonin-permeabilized HeLa cells and cortical neurons by cytoplasmic carrier-mediated mechanisms. Importin-, importin-5, and importin-7 were identified to import p35 into the nuclei via a direct interaction with it. An N-terminal region of p35 was defined to interact with the above importins, serving as a nuclear localization signal. Finally, we show that the nuclear localization of p35 does not require the association of Cdk5. Furthermore, Cdk5 and importin-/5/7 are mutually exclusive in binding to p35. These results suggest that p35 employs pathways distinct from that used by Cdk5 for transport to the nucleus.

Received for publication, November 28, 2005 , and in revised form, September 5, 2006.

^* This work was supported by the Research Grants Council (HKUST6414/05M) and the University Grants Committee (AoE/B-15/01) 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

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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