Wnt/beta-catenin signaling is stimulated by alpha-Melanocyte-Stimulating Hormone in melanoma and melanocyte cells: implication in cell differentiation.
Wnt/?-catenin signaling plays important roles in many developmental processes including neural crest-derived melanocyte development and migration....
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Wnt/?-catenin signaling plays important roles in many developmental processes including neural crest-derived melanocyte development and migration. However, the effective contribution of Wnt/?-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 ?-MSH induces phosphorylation of ?-catenin-Ser675 and stabilization of ?-catenin protein. Activation of PKA by ?-MSH attenuates glycogen synthase kinase-3?, which regulates ubiquitin-dependent degradation of ?-catenin, suggesting a coordinated mechanism of ?-catenin activity stimulation. Consistent with increased nuclear ?-catenin, cAMP elevation facilitates ?-catenin-dependent transactivation of many Wnt target genes. Moreover, chromatin immunoprecipitation assays demonstrated an increased association of ?-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 ?-catenin could play a key role in the physiological regulation of epidermal melanogenesis.
