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J. Biol. Chem., Vol. 280, Issue 8, 6761-6765, February 25, 2005

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Direct Binding of Lgl2 to LGN during Mitosis and Its Requirement for Normal Cell Division^*

Masato Yasumi, Toshiaki Sakisaka, Takashi Hoshino, Toshihiro Kimura, Yasuhisa Sakamoto, Tomoyuki Yamanaka¶, Shigeo Ohno¶, and Yoshimi Takai||

From the Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, and the ^¶Department of Molecular Biology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan

The Drosophila tumor suppressor protein lethal (2) giant larvae (l(2)gl) is involved in asymmetric cell division during development and epithelial cell polarity through interaction with the aPKC·Par-6 complex. We showed here that Lgl2, a mammalian homolog of l(2)gl, directly bound to LGN, a mammalian homolog of Partner of inscuteable in HEK293 cells. The C-terminal tail of Lgl2 bound to LGN with a K_d value of about 56 nM. Endogenous Lgl2 formed a complex with aPKC, Par-6, and LGN. This complex formation was enhanced in metaphase of the synchronized cells by treatment with thymidine and nocodazole. Immunofluorescence staining of the complex was the strongest at the cell periphery of the metaphase cells. Overexpression of the C-terminal tail of Lgl2 induced mis-localization of the nuclear mitotic apparatus protein NuMA and disorganization of the mitotic spindle during mitosis, eventually causing formation of multiple micronuclei. Knockdown of endogenous Lgl (Lgl1 and Lgl2) also induced disorganization of the mitotic spindle, thereby causing formation of multiple micronuclei. The binding between Lgl2 and LGN played a role in the mitotic spindle organization through regulating formation of the LGN·NuMA complex. These results indicate that Lgl2 forms a Lgl2·Par-6·aPKC·LGN complex, which responds to mitotic signaling to establish normal cell division.

Received for publication, September 20, 2004 , and in revised form, December 14, 2004.

^* This work was supported by grants-in-aid for Scientific Research and for Cancer Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (2003, 2004). 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.

Recipient of Human Frontier Science Program Career Development Award 2003–2005.

^|| To whom correspondence should be addressed. Tel.: 81-6-6879-3410; Fax: 81-6-6879-3419; E-mail: ytakai{at}molbio.med.osaka-u.ac.jp.

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