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J. Biol. Chem., Vol. 277, Issue 8, 5816-5822, February 22, 2002

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Nuclear Localization of Duplin, a -Catenin-binding Protein, Is Essential for Its Inhibitory Activity on the Wnt Signaling Pathway^*

Masashi Kobayashi^§, Shosei Kishida^¶, Akimasa Fukui, Tatsuo Michiue^**, Yoichi Miyamoto, Tetsuji Okamoto^§, Yoshihiro Yoneda, Makoto Asashima^**, and Akira Kikuchi^§§

From the  Department of Biochemistry, Faculty of Medicine, and ^§ Molecular Oral Medicine and Maxillofacial Surgery, Faculty of Dentistry, Hiroshima University 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551, Japan, ^¶ PRESTO, Japan Science and Technology Corporation, Hiroshima, Japan, the  Department of Life Science (Biology) and ^** Crest Project, University of Tokyo, 3-8-1, Komaba, Meguro-ku, Tokyo 153-8902, Japan, and the  Department of Cell Biology and Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan

Duplin binds to -catenin and inhibits the Wnt signaling pathway, thereby leading to repression of the -catenin-mediated transactivation and Xenopus axis formation. To find an additional function of Duplin, yeast two-hybrid screening was carried out. Importin  was isolated as a binding protein of Duplin. Importin  bound directly to basic amino acid clusters of Duplin. Although Duplin was present in the nucleus, deletion of the basic amino acid clusters (Duplin^500-584) retained Duplin in the cytoplasm. Duplin^500-584 bound to -catenin as efficiently as wild-type Duplin, but it neither repressed Wnt-dependent Tcf transcriptional activation in mammalian cells nor showed ventralization in Xenopus embryos. The Duplin mutant without a -catenin-binding region lost the ability to inhibit the Wnt-dependent Tcf activation, but retained its ventralizing activity. Furthermore, Duplin not only suppressed -catenin-dependent axis duplication and expression of siamois, a Wnt-regulated gene, but also inhibited siamois-dependent axis duplication. These results indicate that Duplin is translocated to the nucleus by interacting with importin , and that nuclear localization is essential for the function of Duplin. Moreover, Duplin has an additional activity of inhibiting the Wnt signaling pathway by affecting the downstream -catenin target genes.

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