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.

Semaphorin 7a promotes spreading and dendricity in human melanocytes through beta1-integrins.

Described as secreted and membrane-bound proteins important for neural pathfinding, the class of proteins called Semaphorins are expressed in multiple tissue types and are involved in diverse biologic processes. In this study, we describe the function of Semaphorin 7a, a membrane-bound Semaphorin known to stimulate neurite outgrowth, on human melanocytes. We show that Semaphorin 7a is expressed by human keratinocytes and fibroblasts in vitro and in vivo and that melanocytes express Plexin C1, a receptor for Semaphorin 7a. Upregulation of Semaphorin 7a was observed in fibroblasts treated with UV irradiation, a potent stimulus for melanocyte dendricity. Because of the importance of melanocyte dendrites in cutaneous photoprotection, we performed functional studies examining the effect of Semaphorin 7a in melanocyte dendrite formation. We also examined the contribution of beta1-integrin and Plexin C1 receptor signaling in mediating effects of Semaphorin 7a in melanocytes. We show that Semaphorin 7a induces significant melanocyte spreading and dendricity in human melanocytes. Furthermore, we show that beta1-integrins and Plexin C1 receptors are ligands for Semaphorin 7a, and that signaling by these receptors has opposing effects on Semaphorin 7a-induced dendrite formation.