The
melanocortin 1 receptor (MC1R), a key regulator of melanogenesis, is known to control
inflammation, acting in concert with the MC1R
ligand α-
melanocyte-stimulating hormone. Although cell migration is a key event in
inflammation, few studies have addressed the function of MC1R in this context. Using highly motile
melanoma cells, we found that the expression level of MC1R was associated with the extent of migration of mouse
melanoma cells, suggesting that MC1R plays a functional role in controlling this migration. Overexpression of MC1R enhanced
melanoma cell migration, whereas the opposite was true when MC1R levels were knocked down using small inhibitory RNAs. Interestingly, MC1R expression enhanced the synthesis of
syndecan-2, a cell surface
heparan sulfate proteoglycan known to be involved in
melanoma cell migration. Knockdown of
syndecan-2 expression decreased MC1R-mediated cell migration. Further, MC1R inhibited the activation of
p38 MAPK, subsequently enhancing expression of sydnecan-2, in parallel with an increase in the extent of cell migration. Consistently, activation of p38 by H(2)O(2) inhibited
syndecan-2 expression and cell migration, whereas inhibition of p38 activation enhanced
syndecan-2 expression and cell migration. Finally, we found that α-
melanocyte-stimulating hormone inhibited MC1R-mediated cell migration via activation of p38 and inhibition of
syndecan-2 expression. Together, the data strongly suggest that MC1R regulates
melanoma cell migration via inhibition of
syndecan-2 expression.