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J. Biol. Chem., Vol. 281, Issue 50, 38951-38965, December 15, 2006

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Mouse Disabled1 (DAB1) Is a Nucleocytoplasmic Shuttling Protein^*

Takao Honda and Kazunori Nakajima¹

From the Department of Anatomy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan and the Department of Molecular Neurobiology, Institute of DNA Medicine, Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan

Disabled1 (DAB1) is an intracellular mediator of the Reelin-signaling pathway and essential for correct neuronal positioning during brain development. So far, DAB1 has been considered a cytoplasmic protein. Here, we show that DAB1 is subject to nucleocytoplasmic shuttling. In its steady state, DAB1 is mainly located in the cytoplasm. However, treatment with leptomycine B, a specific inhibitor of the CRM1 (chromosomal region maintenance 1)-RanGTP-dependent nuclear export, resulted in nuclear accumulation of DAB1. By using deletion or substitutional mutants of DAB1 fused with enhanced green fluorescent protein, we have mapped a bipartite nuclear localization signal and two CRM1-dependent nuclear export signals. These targeting signals were functional in both Neuro2a cells and primary cerebral cortical neurons. Using purified recombinant proteins, we have shown that CRM1 binds to DAB1 directly in a RanGTP-dependent manner. We also show that tyrosine phosphorylation of DAB1, which is indispensable for the layer formation of the brain, by Fyn tyrosine kinase or Reelin stimulation did not affect the subcellular localization of DAB1 in vitro. These results suggest that DAB1 is a nucleocytoplasmic shuttling protein and raise the possibility that DAB1 plays a role in the nucleus as well as in the cytoplasm.

Received for publication, September 25, 2006 , and in revised form, October 23, 2006.

^* This work was supported by the Japan Society for the Promotion of Science, the Ministry of Education, Culture, Sports, and Science, and Technology of Japan, a grant-in-aid for the 21st Century Centers of Excellence Program, the Keio Gijuku Fukuzawa Memorial Fund for the Advancement of Education and Research, the Keio Health Counseling Center, a Keio University grant-in-aid for encouragement of young medical scientists, Keio Gijuku academic development funds, Keio University special grant-in-aid for innovative collaborative research projects, the Casio Science Promotion Foundation, the Okawa Foundation, and the Japan Brain Foundation. 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.

¹ To whom correspondence should be addressed: Dept. of Anatomy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. Tel.: 81-03-3353-1211; Fax: 81-03-5379-1977; E-mail: kazunori{at}sc.itc.keio.ac.jp.

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