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

Wnt/ß-catenin signaling plays important roles in many developmental processes including neural crest-derived melanocyte development and migration. However, the effective contribution of Wnt/ß-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 α-melanocyte-stimulating hormone (α-MSH) induces phosphorylation of ß-catenin-Ser675 and stabilization of ß-catenin protein. Activation of protein kinase A by α-MSH attenuates glycogen synthase kinase-3ß, which regulates ubiquitin-dependent degradation of ß-catenin, suggesting a coordinated mechanism of ß-catenin activity stimulation. Consistent with increased nuclear ß-catenin, cyclic adenosine monophosphate (cAMP) elevation facilitates ß-catenin-dependent transactivation of many Wnt target genes. Moreover, chromatin immunoprecipitation assays demonstrated an increased association of ß-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 ß-catenin could play a key role in the physiological regulation of epidermal melanogenesis.