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Published online
doi:10.1083/jcb.200807029
The Journal of Cell Biology, Vol. 184, No. 5, 737-750
The Rockefeller University Press, 0021-9525 $30.00
© Hata et al.
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Article

Unc5B associates with LARG to mediate the action of repulsive guidance molecule



Katsuhiko Hata1, Kozo Kaibuchi3, Shinobu Inagaki2, and Toshihide Yamashita1

1 Department of Molecular Neuroscience and 2 Group of Neurobiology, Division of Health Sciences, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
3 Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi 466-8550, Japan

Correspondence to Katsuhiko Hata: hata0731{at}molneu.med.osaka-u.ac.jp; or Toshihide Yamashita: yamashita{at}molneu.med.osaka-u.ac.jp

Neuronal axons are guided by attractive and repulsive cues in their local environment. Because the repulsive guidance molecule A (RGMa) was originally identified as an axon repellent in the visual system, diverse functions in the developing and adult central nervous system have been ascribed to it. RGMa binding to its receptor neogenin induces RhoA activation, leading to inhibitory/repulsive behavior and collapse of the neuronal growth cone. However, the precise mechanisms that regulate RhoA activation are poorly understood. In this study, we show that Unc5B, a member of the netrin receptor family, interacts with neogenin as a coreceptor for RGMa. Moreover, leukemia-associated guanine nucleotide exchange factor (LARG) associates with Unc5B to transduce the RhoA signal. Focal adhesion kinase (FAK) is involved in RGMa-induced tyrosine phosphorylation of LARG as well as RhoA activation. These findings uncover the molecular basis for diverse functions mediated by RGMa.

Abbreviations used in this paper: ANOVA, analysis of variance; CNS, central nervous system; DB, DCC binding; DCC, deleted in colorectal cancer; DD, death domain; ECD, extracellular domain; FRNK, FAK-related nonkinase; GEF, guanine nucleotide exchange factor; GPCR, G protein–coupled receptor; HEK, human embryonic kidney; ICD, intracellular domain; IGF-1, insulin-like growth factor-1; IP, immunoprecipitation; LARG, leukemia-associated GEF; RGM, repulsive guidance molecule; RGS, regulator of G protein signaling; TrkB, tropomyosin-related kinase B; VSV-G, vesicular stomatitis virus G protein.

© 2009 Hata et al.
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