α‐MSH and cAMP signalling in normal human melanocytes

Abstract

Melanocytes are neural crest‐derived skin cells specialized in the synthesis of melanin pigments responsible, in human, for skin and hair colour. The pro‐opiomelanocortin peptide, α‐MSH is a strong melanogenic agent secreted by keratinocytes following UV radiation. α‐MSH through the binding to the MC1R and activation of the cyclic AMP pathway plays a pivotal role in melanocyte differentiation and in the regulation of skin pigmentation. During the last few years, we have elucidated the molecular events linking the cAMP pathway to melanogenesis upregulation. This cascade involves the activation of protein kinase A and CREB transcription factor, leading to the upregulation of the expression of microphthalmia‐associated transcription factor (MITF). MITF binds and activates the melanogenic gene promoters thereby increasing their expression, which results in an increased melanin synthesis. Beyond this simplified scheme, other intracellular signalling pathways are regulated by cAMP and participate to the regulation of melanocyte differentiation. Indeed, cAMP inhibits the phosphatidyl inositol 3‐kinase pathway, leading to the inhibition of AKT and to the activation of GSK3β. This kinase phosphorylates MITF and allows its binding to the target sequence. Such pathways are involved in the upregulation of melanogenesis. α‐MSH and cAMP signalling also regulate melanocyte dendricity, and melanosome transport through the inhibition of the Rho GTPase cascade that function downstream the PI3 kinase. It should be also mentioned that cAMP activates the ERK pathway through a melanocyte‐specific pathway involving Ras and B‐Raf. The activation of ERK and RSK1 leads to the phosphorylation of MITF and target MITF to the proteasome degradation pathway. Interestingly, several proteins involved in melanocyte differentiation by α‐MSH (MC1R, PI3K, B‐Raf and MITF) have also been implicated in the development of melanoma, suggesting that the cAMP pathway could influence melanocyte transformation.