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J. Biol. Chem., Vol. 279, Issue 19, 20049-20057, May 7, 2004

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NEK2A Interacts with MAD1 and Possibly Functions as a Novel Integrator of the Spindle Checkpoint Signaling^*

Yang Lou, Jianhui Yao, Arzhang Zereshki¶, Zhen Dou, Kashif Ahmed, Hongmei Wang, Junbin Hu, Yuzhen Wang, and Xuebiao Yao, GCC Distinguished Cancer Research Scholar¶||**

From the School of Life Sciences, University of Science & Technology of China, Hefei 230027, China, the ^¶Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, and the ^||Department of Physiology, Morehouse School of Medicine, Atlanta, Georgia 30310

Chromosome segregation in mitosis is orchestrated by protein kinase signaling cascades. A biochemical cascade named spindle checkpoint ensures the spatial and temporal order of chromosome segregation during mitosis. Here we report that spindle checkpoint protein MAD1 interacts with NEK2A, a human orthologue of the Aspergillus nidulans NIMA kinase. MAD1 interacts with NEK2A in vitro and in vivo via a leucine zipper-containing domain located at the C terminus of MAD1. Like MAD1, NEK2A is localized to HeLa cell kinetochore of mitotic cells. Elimination of NEK2A by small interfering RNA does not arrest cells in mitosis but causes aberrant premature chromosome segregation. NEK2A is required for MAD2 but not MAD1, BUB1, and HEC1 to associate with kinetochores. These NEK2A-eliminated or -suppressed cells display a chromosome bridge phenotype with sister chromatid inter-connected. Moreover, loss of NEK2A impairs mitotic checkpoint signaling in response to spindle damage by nocodazole, which affected mitotic escape and led to generation of cells with multiple nuclei. Our data demonstrate that NEK2A is a kinetochore-associated protein kinase essential for faithful chromosome segregation. We hypothesize that NEK2A links MAD2 molecular dynamics to spindle checkpoint signaling.

Received for publication, December 28, 2003 , and in revised form, February 2, 2004.

^* This work was supported by Chinese Natural Science Foundation Grants 39925018 and 30121001, Chinese Academy of Science Grant KSCX2-2-01, Chinese 973 Project 2002CB713700, and American Cancer Society Grant RSG99-173-01 (to X. Y.). 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.

These authors contributed equally to this work.

^** To whom correspondence should be addressed: Laboratory of Cell Dynamics, University of Science & Technology of China, Hefei 230027, China. E-mail: yaoxb{at}ustc.edu.cn.

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