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J. Biol. Chem. 286 (7): 5157-5165

© 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

Neogenin, a Receptor for Bone Morphogenetic Proteins*

Meiko Hagihara{ddagger}, Mitsuharu Endo{ddagger}, Katsuhiko Hata{ddagger}, Chikahisa Higuchi§, Kunio Takaoka, Hideki Yoshikawa§, , and Toshihide Yamashita{ddagger}||1

From the Departments of {ddagger}Molecular Neuroscience and
§Orthopedic Surgery, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan,
the Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, Osaka 545-8585, Japan, and
||JST, CREST, 5, Sanbancho, Chiyoda-ku, Tokyo 102-0075, Japan

ABSTRACT Back to Top

Abstract: Bone morphogenetic proteins (BMPs) regulate many mammalian physiologic and pathophysiologic processes. These proteins bind with the kinase receptors BMPR-I and BMPR-II, thereby activating Smad transcription factor. In this study, we demonstrate that neogenin, a receptor for netrins and proteins of the repulsive guidance molecule family, is a receptor for BMPs and modulates Smad signal transduction. Neogenin was found to bind directly with BMP-2, BMP-4, BMP-6, and BMP-7. Knockdown of neogenin in C2C12 cells resulted in the enhancement of the BMP-2-induced processes of osteoblastic differentiation and phosphorylation of Smad1, Smad5, and Smad8. Conversely, overexpression of neogenin in C2C12 cells suppressed these processes. Our results also indicated that BMP-induced activation of RhoA was mediated by neogenin. Inhibition of RhoA promoted BMP-2-induced processes of osteoblastic differentiation and phosphorylation of Smad1/5/8. However, treatment with Y-27632, an inhibitor of Rho-associated protein kinase, did not modulate BMP-induced phosphorylation of Smad1/5/8. Taken together, our findings suggest that neogenin negatively regulates the functions of BMP and that this effect of neogenin is mediated by the activation of RhoA.

Key Words: Bone Morphogenetic Protein (BMP) • Differentiation • Rho • Signal Transduction • SMAD Transcription Factor

Received for publication September 1, 2010. Revision received November 5, 2010.

1 To whom correspondence should be addressed: Dept. of Molecular Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel.: 81-6-68793661; Fax: 81-6-68793669; E-mail: yamashita{at}

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