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Molecular and Cellular Biology, December 2006, p. 9016-9034, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.01383-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Interaction between ROCK II and Nucleophosmin/B23 in the Regulation of Centrosome Duplication{triangledown}

Zhiyong Ma,1 Masayuki Kanai,1 Kenji Kawamura,1,2 Kozo Kaibuchi,3 Keqiang Ye,4 and Kenji Fukasawa1*

Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0521,1 Department of Urology, Kanazawa Medical University, 1-1 Daigaku Uchinada, Ishikawa, 920-0293, Japan,2 Nagoya University Graduate School of Medicine, Showa, Nagoya, Aichi 466-8500, Japan,3 Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Georgia 303224

Received 27 July 2006/ Returned for modification 1 September 2006/ Accepted 13 September 2006

Nucleophosmin (NPM)/B23 has been implicated in the regulation of centrosome duplication. NPM/B23 localizes between two centrioles in the unduplicated centrosome. Upon phosphorylation on Thr199 by cyclin-dependent kinase 2 (CDK2)/cyclin E, the majority of centrosomal NPM/B23 dissociates from centrosomes, but some NPM/B23 phosphorylated on Thr199 remains at centrosomes. It has been shown that Thr199 phosphorylation of NPM/B23 is critical for the physical separation of the paired centrioles, an initial event of the centrosome duplication process. Here, we identified ROCK II kinase, an effector of Rho small GTPase, as a protein that localizes to centrosomes and physically interacts with NPM/B23. Expression of the constitutively active form of ROCK II promotes centrosome duplication, while down-regulation of ROCK II expression results in the suppression of centrosome duplication, especially delaying the initiation of centrosome duplication during the cell cycle. Moreover, ROCK II regulates centrosome duplication in its kinase and centrosome localization activity-dependent manner. We further found that ROCK II kinase activity is significantly enhanced by binding to NPM/B23 and that NPM/B23 acquires a higher binding affinity to ROCK II upon phosphorylation on Thr199. Moreover, physical interaction between ROCK II and NPM/B23 in vivo occurs in association with CDK2/cyclin E activation and the emergence of Thr199-phosphorylated NPM/B23. All these findings point to ROCK II as the effector of the CDK2/cyclin E-NPM/B23 pathway in the regulation of centrosome duplication.

* Corresponding author. Mailing address: Department of Cell Biology, University of Cincinnati College of Medicine, P.O. Box 670521 (3125 Eden Ave.), Cincinnati, OH 45267-0521. Phone: (513) 558-4939. Fax: (513) 558-4454. E-mail: Kenji.Fukasawa{at}uc.edu.

{triangledown} Published ahead of print on 2 October 2006.

Molecular and Cellular Biology, December 2006, p. 9016-9034, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.01383-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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