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J. Biol. Chem., Vol. 279, Issue 31, 32716-32727, July 30, 2004

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Nucleolar Nek11 Is a Novel Target of Nek2A in G₁/S-arrested Cells^*

Kohji Noguchi, Hidesuke Fukazawa, Yuko Murakami, and Yoshimasa Uehara

From the Department of Bioactive Molecules, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan

We previously reported that Nek11, a member of the NIMA (never-in-mitosis A) family of kinases, is activated in G₁/S-arrested cells. We provide herein several lines of evidence for a novel interaction between Nek11 and Nek2A. Both Nek11 and Nek2A, but not Nek2B, were detected at nucleoli, and the Nek2A-specific C-terminal end (amino acids 399-445) was responsible for nucleolar localization. Endogenous Nek11 coimmunoprecipitated with endogenous Nek2A, and non-catalytic regions of each kinase were involved in the complex formation. Nek11L interacted with phosphorylated Nek2A but barely with the kinase-inactive Nek2A (K37R) mutant. In addition, both Nek2A autophosphorylation activity and the Nek11L-Nek2A complex formation increased in G₁/S-arrested cells. These results indicate that autophosphorylation of Nek2A could stimulate its interaction with Nek11L at the nucleolus. Moreover, Nek2 directly phosphorylated Nek11 in the C-terminal non-catalytic region and elevated Nek11 kinase activity. The non-catalytic region of Nek11 showed autoinhibitory activity through intramolecular interaction with its N-terminal catalytic domain. Nek2 dissociated this autoinhibitory interaction. Altogether, our studies demonstrate a unique mechanism of Nek11 activation by Nek2A in G₁/S-arrested cells and suggest a novel possibility for nucleolar function of the NIMA family.

Received for publication, April 13, 2004

^* This work was supported by a grant-in-aid for Young Scientists (B) (to K. N.) and grants for Cancer Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to Y. U.) and by the Japan Health Sciences Foundation for Research on Health Sciences Focusing on Drug Innovation (to K. N.). 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.

To whom correspondence should be addressed. Tel.: 81-3-5285-1111 (ext. 2301); Fax: 81-3-5285-1175; E-mail: yuehara{at}nih.go.jp.

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