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J. Biol. Chem., Vol. 282, Issue 28, 20544-20552, July 13, 2007

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The Extremely Conserved C-terminal Region of Reelin Is Not Necessary for Secretion but Is Required for Efficient Activation of Downstream Signaling^*

Yoshimi Nakano, Takao Kohno, Terumasa Hibi, Shiori Kohno, Atsushi Baba, Katsuhiko Mikoshiba^¶, Kazunori Nakajima^||**, and Mitsuharu Hattori¹

From the Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 467-8603, the Division of Molecular Neurobiology, Institute of Medical Science, University of Tokyo, 108-8639, the ^¶Laboratory for Developmental Neuroscience, Brain Science Institute, RIKEN, Wako, Saitama 351-0198, the ^||Department of Anatomy, Keio University School of Medicine, Tokyo 160-8582, and the ^**Department of Molecular Neurobiology, Institute of DNA Medicine, Jikei University School of Medicine, Tokyo 105-8641, Japan

Reelin is a very large secreted glycoprotein essential for correct development of the mammalian brain. It is also implicated in higher functions and diseases of human brain. However, whether or not secretion of Reelin is regulated and how Reelin transmits signals remain largely unknown. Reelin protein is composed of an N-terminal F-spondin-like domain, Reelin repeats, and a short and highly basic C-terminal region (CTR). The primary sequence of CTR is almost completely conserved among vertebrates except fishes, indicating its importance. A prevailing idea regarding the function of CTR is that it is required for the secretion of Reelin, although this remains unproven. Here we aimed to clarify the function of Reelin CTR. Neither deleting most of CTR nor replacing CTR with unrelated amino acids affected secretion efficiency, indicating that CTR is not absolutely required for the secretion of Reelin. We also found that Reelin mutants without CTR were less potent in activating the downstream signaling in cortical neurons. Although these mutants were able to bind to the Reelin receptor ectodomain as efficiently as wild-type Reelin, quite interestingly, their ability to bind to the isolated cell membrane bearing Reelin receptors or receptor-expressing cells (including cortical neurons) was much weaker than that of wild-type Reelin. Therefore, it is concluded that the CTR of Reelin is not essential for its secretion but is required for efficient activation of downstream signaling events, presumably via binding to an unidentified "co-receptor" molecule(s) on the cell membrane.

Received for publication, March 16, 2007 , and in revised form, May 2, 2007.

^* This work was supported by Grants-in-aids from the Ministry of Education, Science and Technology, the Takeda Science Foundation, and the Kato Memorial Bioscience Foundation (to M. H.). 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 supplemental Figs. S1–S3.

¹ To whom correspondence should be addressed: Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan. Tel./Fax: 81-52-836-3465; E-mail: mhattori{at}phar.nagoya-cu.ac.jp.

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