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J. Biol. Chem., Vol. 278, Issue 37, 34897-34909, September 12, 2003

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A Mitotic Cascade of NIMA Family Kinases

Nercc1/Nek9 ACTIVATES THE Nek6 AND Nek7 KINASES^*

Christopher Belham   ¶, Joan Roig  ¶ ||, Jennifer A. Caldwell **, Yumi Aoyama , Bruce E. Kemp  , Michael Comb ¶¶ and Joseph Avruch  ||||

From the Department of Molecular Biology and Medical Services, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, Pharmacia Italia S.p.A./Biology Department, 20014 Milan, Italy, ^**MDS Proteomics, Charlottesville, Virginia 22911, St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia, and ^¶¶Cell Signaling Technologies, Beverly, Massachusetts 01915

The Nek family of protein kinases in humans is composed of 11 members that share an amino-terminal catalytic domain related to NIMA, an Aspergillus kinase involved in the control of several aspects of mitosis, and divergent carboxyl-terminal tails of varying length. Nek6 (314AA) and Nek7 (303AA), 76% identical, have little noncatalytic sequence but bind to the carboxyl-terminal noncatalytic tail of Nercc1/Nek9, a NIMA family protein kinase that is activated in mitosis. Microinjection of anti-Nercc1 antibodies leads to spindle abnormalities and prometaphase arrest or chromosome missegregation. Herein we show that Nek6 is increased in abundance and activity during mitosis; activation requires the phosphorylation of Ser²⁰⁶ on the Nek6 activation loop. This phosphorylation and the activity of recombinant Nek6 is stimulated by coexpression with an activated mutant of Nercc1. Moreover, Nercc1 catalyzes the direct phosphorylation of prokaryotic recombinant Nek6 at Ser²⁰⁶ in vitro concomitant with 20–25-fold activation of Nek6 activity; Nercc1 activates Nek7 in vitro in a similar manner. Nercc1/Nek9 is likely to be responsible for the activation of Nek6 during mitosis and probably participates in the regulation of Nek7 as well. These findings support the conclusion that Nercc1/Nek9 and Nek6 represent a novel cascade of mitotic NIMA family protein kinases whose combined function is important for mitotic progression.

Received for publication, April 8, 2003 , and in revised form, June 29, 2003.

^* This work was supported in part by National Institutes of Health Grant DK17776. 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 two authors contributed equally to this work.

^|| Supported in part by the Fund for Medical Discovery from Massachusetts General Hospital and the Leukemia and Lymphoma Society.

A National Health and Medical Research Council Fellow and supported by the Australian Research Council.

^|||| To whom correspondence should be addressed. E-mail: avruch{at}helix.mgh.harvard.edu.

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