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

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