title: Semaphorin 4D/Plexin-B1-mediated R-Ras GAP activity inhibits cell migration by regulating beta(1) integrin activity.
abstract: Plexins are cell surface receptors for semaphorins and regulate cell migration in many cell types. We recently reported that the semaphorin 4D (Sema4D) receptor Plexin-B1 functions as a GTPase-activating protein (GAP) for R-Ras, a member of Ras family GTPases implicated in regulation of integrin activity and cell migration. We characterized the role of R-Ras downstream of Sema4D/Plexin-B1 in cell migration. Activation of Plexin-B1 by Sema4D suppressed the ECM-dependent R-Ras activation, R-Ras-mediated phosphatydylinositol 3-kinase activation, and beta(1) integrin activation through its R-Ras GAP domain, leading to inhibition of cell migration. In addition, inactivation of R-Ras by overexpression of the R-Ras-specific GAP or knockdown of R-Ras by RNA interference was sufficient for suppressing beta(1) integrin activation and cell migration in response to the ECM stimulation. Thus, we conclude that R-Ras activity is critical for ECM-mediated beta(1) integrin activation and cell migration and that inactivation of R-Ras by Sema4D/Plexin-B1-mediated R-Ras GAP activity controls cell migration by modulating the activity of beta(1) integrins.
authors.affiliation: Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Oinuma
authors.forename: Hironori
authors.initials: H
authors.lastname: Katoh
authors.forename: Manabu
authors.initials: M
authors.lastname: Negishi
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism* / Q000494:pharmacology; D019556:COS Cells; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002522:Chlorocebus aethiops; D003094:Collagen / Q000378:metabolism / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives; D019012:Integrin beta1 / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism*; D039961:Semaphorins / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D003094:Collagen; D020558:GTP Phosphohydrolases; D020690:GTPase-Activating Proteins; D005998:Glycine; D019012:Integrin beta1; D019869:Phosphatidylinositol 3-Kinases; D011956:Receptors, Cell Surface; D039961:Semaphorins; D018631:ras Proteins; C093224:CD100 antigen; C488752:Plxnb1 protein, rat; C084257:PC 12 ester