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J. Biol. Chem., Vol. 282, Issue 26, 19259-19271, June 29, 2007

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Lats2 Is an Essential Mitotic Regulator Required for the Coordination of Cell Division^*

Norikazu Yabuta, Nobuhiro Okada, Akihiko Ito, Toshiya Hosomi, Souichi Nishihara, Yuya Sasayama, Azumi Fujimori, Daisuke Okuzaki, Hanjun Zhao, Masahito Ikawa^¶, Masaru Okabe^¶, and Hiroshi Nojima¹

From the Department of Molecular Genetics, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita City, Osaka 565-0871, Japan, the Division of Surgical Pathology, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan, and the ^¶Genome Information Research Center, Osaka University, 3-1 Yamadaoka, Suita City, Osaka 565-0871, Japan

Tumor suppressor Lats2 is a member of the conserved Dbf2 kinase family. It localizes to the centrosome and has been implicated in regulation of the cell cycle and apoptosis. However, the in vivo function of this kinase remains unclear. Here, we show that complete disruption of the gene encoding Lats2 in mice causes developmental defects in the nervous system and embryonic lethality. Furthermore, mutant cells derived from total LATS2-knock-out embryos exhibit mitotic defects including centrosome fragmentation and cytokinesis defects, followed by nuclear enlargement and multinucleation. We show that the Mob1 family, a regulator of mitotic exit, associates with Lats2 to induce its activation. We also show that the complete LATS2-knock-out cells exhibit an acceleration of exit from mitosis and marked down-regulation of critical mitotic regulators. These results suggest that Lats2 plays an essential mitotic role in coordinating accurate cytokinesis completion, governing the stabilization of other mitotic regulators.

Received for publication, September 5, 2006 , and in revised form, May 1, 2007.

^* This work was supported in part by Grants-In-Aid from Innovation Plaza Osaka of Japan Science and Technology Agency (JST), the Bio-Medical Cluster Project In Saito, and Scientific Research on Priority Areas, Scientific Research (S), Exploratory Research and Science, and the Technology Incubation Program in Advanced Regions of the Ministry of Education, Science, Sports and Culture, Japan. 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 detailed experimental procedures, Figs. S1-S11, Tables S1-S3, and Movies S1 and S2.

¹ To whom correspondence should be addressed: Dept. of Molecular Genetics, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita City, Osaka 565-0871, Japan. Tel.: 81-6-6875-3980; Fax: 81-6-6875-5192; E-mail: snj-0212{at}biken.osaka-u.ac.jp.

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