Wnt/β-catenin signaling is stimulated by α-melanocyte-stimulating hormone in melanoma and melanocyte cells: implication in cell differentiation

P>Wnt/beta-catenin signaling plays important roles in many developmental processes including neural crest-derived melanocyte development and migration. However, the effective contribution of Wnt/beta-catenin pathway in melanogenesis in adult human melanocytes has not been fully elucidated. Here, we report that in melanoma cells and in normal human melanocytes, melanogenesis stimulation by alpha-melanocyte-stimulating hormone (alpha-MSH) induces phosphorylation of beta-catenin-Ser675 and stabilization of beta-catenin protein. Activation of protein kinase A by alpha-MSH attenuates glycogen synthase kinase-3 beta, which regulates ubiquitin-dependent degradation of beta-catenin, suggesting a coordinated mechanism of beta-catenin activity stimulation. Consistent with increased nuclear beta-catenin, cyclic adenosine monophosphate (cAMP) elevation facilitates beta-catenin-dependent transactivation of many Wnt target genes. Moreover, chromatin immunoprecipitation assays demonstrated an increased association of beta-catenin with the proximal promoter of microphthalmia-associated transcription factor, the master regulator of pigmentation. These results demonstrate the existence of cross talk between the cAMP and Wnt pathways in melanocytes, suggesting that beta-catenin could play a key role in the physiological regulation of epidermal melanogenesis.