Plexin C1, a receptor for semaphorin 7a, inactivates cofilin and is a potential tumor suppressor for melanoma progression.
Melanocytes are progenitor cells for melanoma, which arises through step-wise progression from dysplastic to invasive, to metastatic tumor. Our previous data showed that semaphorin 7A (Sema7A), a protein involved in axon guidance, stimulates melanocyte adhesion and dendricity through opposing actions of beta1-integrin and Plexin C1 receptors. We now show that Plexin C1 is diminished or absent in human melanoma cell lines; analysis of tissue microarrays of nevi, melanoma, and metastatic melanoma showed a decrease in Plexin C1 expression in metastatic melanoma, and an inverse correlation of Plexin C1 expression with depth of invasion. We examined the signaling intermediates of Sema7A and downstream targets of Plexin C1 in human melanocytes. Sema7A activated mitogen-activated protein kinase and inactivated cofilin, an actin-binding protein involved in cell migration. When Plexin C1 expression was silenced, Sema7A failed to phosphorylate cofilin, indicating that cofilin is downstream of Plexin C1. Further, Lim kinase II, a protein that phosphorylates cofilin, is upregulated by Sema7A in a Plexin C1-dependent manner. These data identify Plexin C1 as a potential tumor suppressor protein in melanoma progression, and suggest that loss of Plexin C1 expression may promote melanoma invasion and metastasis through loss of inhibitory signaling on cofilin activation.
Scott
Glynis A
GA
Department of Dermatology, School of Medicine, University of Rochester, Rochester, New York, USA. Glynis_Scott@urmc.rochester.edu
McClelland
Lindy A
LA
Fricke
Alex F
AF
Fender
Anne
A
D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D015703:Antigens, CD / Q000494:pharmacology*; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D058851:GPI-Linked Proteins; D006801:Humans; D054461:Lim Kinases / Q000032:analysis; D008545:Melanoma / Q000737:chemistry / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D039961:Semaphorins / Q000494:pharmacology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D051339:Actin Depolymerizing Factors; D015703:Antigens, CD; D058851:GPI-Linked Proteins; D009419:Nerve Tissue Proteins; C492119:PLXNB1 protein, human; D011956:Receptors, Cell Surface; C118753:SEMA7A protein, human; D039961:Semaphorins; D025521:Tumor Suppressor Proteins; D051416:Focal Adhesion Protein-Tyrosine Kinases; D054461:Lim Kinases; D048049:Extracellular Signal-Regulated MAP Kinases