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J. Biol. Chem., Vol. 280, Issue 17, 16901-16908, April 29, 2005

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Disabled1 Regulates the Intracellular Trafficking of Reelin Receptors^*

Toshifumi Morimura¶||, Mitsuharu Hattori**, Masaharu Ogawa¶, and Katsuhiko Mikoshiba

From the Division of Molecular Neurobiology, Department of Basic Medical Science, the Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato-ku 108-8639, Laboratory for Developmental Neurobiology and ^¶Laboratory for Cell Culture Development, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, ^**Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, 4-1-8 Hon-machi, Saitama 332-0012, and Calcium Oscillation Project, ICORP, Japan Science and Technology Agency, 3 Nibancho, Chiyoda-ku, Tokyo 102-0084, Japan

Reelin is a huge secreted protein that controls proper laminar formation in the developing brain. It is generally believed that tyrosine phosphorylation of Disabled1 (Dab1) by Src family tyrosine kinases is the most critical downstream event in Reelin signaling. The receptors for Reelin belong to the low density lipoprotein receptor family, most of whose members undergo regulated intracellular trafficking. In this study, we propose novel roles for Dab1 in Reelin signaling. We first demonstrated that cell surface expression of Reelin receptors was decreased in Dab1-deficient neurons. In heterologous cells, Dab1 enhanced cell surface expression of Reelin receptors, and this effect was mediated by direct interaction with the receptors. Moreover, Dab1 did not stably associate with the receptors at the plasma membrane in the resting state. When Reelin was added to primary cortical neurons, Dab1 was recruited to the receptors, and its tyrosine residues were phosphorylated. Although Reelin and Dab1 colocalized well shortly after the addition of Reelin, Dab1 was no longer associated with internalized Reelin. When Src family tyrosine kinases were inhibited, internalization of Reelin was severely abrogated, and Reelin colocalized with Dab1 near the plasma membrane for a prolonged period. Taken together, these results indicate that Dab1 regulates both cell surface expression and internalization of Reelin receptors, and these regulations may play a role in correct laminar formation in the developing brain.

Received for publication, August 6, 2004 , and in revised form, February 4, 2005.

^* This work was supported by grants from the Japan Science and Technology Agency (to M. H.) and from the Ministry of Education and Science of Japan (to T. M., M. H., and K. M.). 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.

Present address: Dept. of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1, Tanabe-dori, Mizuho-ku, Nagoya, Aichi, 467-8603, Japan.

^|| To whom correspondence should be addressed: Laboratory for Cell Culture Development, BSI, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan. Tel.: 81-48-467-5594; Fax: 81-48-467-5496; E-mail: morimura{at}brain.riken.jp.

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