title: Unc5B associates with LARG to mediate the action of repulsive guidance molecule.
abstract: 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.
authors.affiliation: Department of Molecular Neuroscience, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan. hata0731@molneu.med.osaka-u.ac.jp
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Hata
authors.forename: Kozo
authors.initials: K
authors.lastname: Kaibuchi
authors.forename: Shinobu
authors.initials: S
authors.lastname: Inagaki
authors.forename: Toshihide
authors.initials: T
authors.lastname: Yamashita
mesh_terms: D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D058851:GPI-Linked Proteins; D020439:Growth Cones / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009420:Nervous System / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism; D000075386:Netrin Receptors; D055495:Neurogenesis / Q000235:genetics; D010766:Phosphorylation; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction / Q000235:genetics; D014443:Tyrosine / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C577222:ARHGEF12 protein, human; D058851:GPI-Linked Proteins; D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000075386:Netrin Receptors; C522183:RGMA protein, human; D011956:Receptors, Cell Surface; D064067:Rho Guanine Nucleotide Exchange Factors; C532445:UNC5B protein, human; C091279:neogenin; D014443:Tyrosine; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D020742:rhoA GTP-Binding Protein