Poster presentation, P40

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

Sema4D, the ligand for Plexin B1, is a proliferation and survival factor for normal human melanocytes, and down-regulates the activity of c-Met

Semaphorins are membrane bound or secreted proteins that bind to Plexin receptors, and are implicated in tumor progression in breast, kidney, ovarian and prostate cancer. We recently showed that Plexin B1, the receptor for semaphorin 4D (Sema4D) is a tumor suppression protein for melanoma, in part through its’ ability to suppress activation of the oncogenic c-Met receptor by its ligand, hepatocyte growth factor (HGF). In this report we examined the signaling pathways of Plexin B1 in primary human melanocytes, the expression of Sema4D in the skin, regulation of Plexin B1 by UVR, and effects of Sema4D on c-Met activation. Treatment of melanocytes with recombinant Sema4D induced rapid phosphorylation of Akt and Erk, which was abrogated in Plexin B1-silenced cells. Functional analysis of proliferation (CLICK-IT assay) and apoptosis (TUNEL) in Plexin B1 knockdowns showed markedly increased apoptosis and decreased proliferation, supporting a role for Plexin B1 in melanocyte survival and proliferation. Treatment of melanocytes with Sema4D, which we show is expressed by epidermal keratinocytes in vivio, abrogated UV-dependent apoptosis of melanocytes by 50%, shown by Western blotting for caspase-3. c-Met stimulates melanocyte migration, in part, through down-regulation of E-cadherin expression. Treatment of melanocytes with HGF, in the presence of Sema4D, partially blocked c-Met activation and abrogated the effects of c-Met on E-cadherin expression. Further, Sema4D blocked the stimulatory effects of c-Met on melanocyte migration. Finally, we show that Plexin B1 expression is markedly suppressed by UVB at the mRNA and protein level. These results show that Plexin B1 and its ligand Sema4D are important for melanocyte survival and proliferation, and suggest that Sema4D plays a role in moderating the effects of HGF on c-Met activity in melanocytes. Down-regulation of Plexin B1 by UVB may release inhibitory pressure on the c-Met receptor, promoting melanoma initiation.

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