title: Sema4D, the ligand for Plexin B1, suppresses c-Met activation and migration and promotes melanocyte survival and growth.
abstract: Semaphorins are secreted and membrane-bound proteins involved in neural pathfinding, organogenesis, and tumor progression, through Plexin and neuropilin receptors. We recently reported that Plexin B1, the Semaphorin 4D (Sema4D) receptor, is a tumor-suppressor protein for melanoma, which functions, in part, through inhibition of the oncogenic c-Met tyrosine kinase receptor. In this report, we show that Sema4D is a protective paracrine factor for normal human melanocyte survival in response to UV irradiation, and that it stimulates proliferation and regulates the activity of the c-Met receptor. c-Met receptor signaling stimulates melanocyte migration, partly through downregulation of the cell adhesion molecule E-cadherin. Sema4D suppressed activation of c-Met in response to its ligand, hepatocyte growth factor (HGF), and partially blocked the suppressive effects of HGF on E-cadherin expression in melanocytes and HGF-dependent migration. These data demonstrate a role for Plexin B1 in maintenance of melanocyte survival and proliferation in the skin, and suggest that Sema4D and Plexin B1 act cooperatively with HGF and c-Met to regulate c-Met-dependent effects in human melanocytes. Because our data show that Plexin B1 is profoundly downregulated by UVB in melanocytes, loss of Plexin B1 may accentuate HGF-dependent effects on melanocytes, including melanocyte migration.
authors.affiliation: Department of Pathology, University of Rochester School of Medicine, Rochester, New York 14618, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Soong
authors.forename: Yulin
authors.initials: Y
authors.lastname: Chen
authors.forename: Elina M
authors.initials: EM
authors.lastname: Shustef
authors.forename: Glynis A
authors.initials: GA
authors.lastname: Scott
mesh_terms: D015703:Antigens, CD / Q000502:physiology*; D015820:Cadherins / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology / Q000528:radiation effects; D002478:Cells, Cultured; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000166:cytology* / Q000502:physiology / Q000528:radiation effects; D008545:Melanoma / Q000209:etiology / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D039961:Semaphorins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000503:physiopathology
chemical_list: D015703:Antigens, CD; C093224:CD100 antigen; D015820:Cadherins; D009419:Nerve Tissue Proteins; C492119:PLXNB1 protein, human; D011956:Receptors, Cell Surface; D039961:Semaphorins; D019859:Proto-Oncogene Proteins c-met