In mammals, adrenocorticotropic hormone and α-melanocyte-stimulating hormone regulate melanogenesis, and thus skin pigmentation, by activating the adenosine 3′,5′ monophosphate (cAMP) pathway through the melanocortin type 1 receptor. One limb of this pathway involves a protein kinase A (PKA)-dependent stimulation in the expression of the micropthalmia-associated transcription factor (MITF). MITF, in turn, stimulates expression of tyrosinase, the rate-limiting enzyme in melanogenesis. Khaled et al. report an alternative pathway whereby cAMP stimulates melanogenesis through a PKA-independent mechanism. Using Western analysis and in vitro assays on immunoprecipitates of proteins transfected into a melanoma cell line, the authors demonstrated that either elevating cAMP or inhibiting phosphatidylinositol 3-kinase (PI3K) reduced phosphorylation and activity of the serine-threonine kinase AKT. Elevated cAMP decreased phosphorylation of glycogen synthase kinase-3β (GSK-3β), a substrate of AKT, and stimulated GSK-3β activity. Pharmacological analyses indicated that the effects of cAMP on AKT and GSK-3β were independent of both PKA and the Ras to extracellular signal-regulated kinase (ERK) pathways and were mediated through a PI3K-dependent mechanism. GSK-3β overexpression had no effect on basal or cAMP-induced transcription of MITF, but dramatically enhanced MITF stimulation of a reporter gene containing the tyrosinase promoter. Gel shift assays indicated that cAMP stimulated MITF binding to the M box, a target sequence found in the tyrosinase promoter, suggesting that GSK-3β promotes melanogenesis by increasing MITF binding to the tyrosinase promoter. The PKA-independent pathway should thus be able to effectively cooperate with the previously described PKA-dependent pathway, which stimulates MITF synthesis, to enhance melanogenesis.
M. Khaled, L. Larribere, K. Bille, E. Aberdam, J.-P. Ortonne, R. Ballotti, C. Bertolotto, Glycogen synthase kinase 3β is activated by cAMP and plays an active role in the regulation of melanogenesis. J. Biol. Chem. 277, 33690-33697 (2002). [Abstract] [Full Text]