Signaling from the Human Melanocortin 1 Receptor to ERK1 and ERK2 Mitogen-Activated Protein Kinases Involves Transactivation of cKIT

Abstract

Melanocortin 1 receptor (MC1R), a Gs protein-coupled receptor expressed in melanocytes, is a major determinant of skin pigmentation, phototype and cancer risk. Upon stimulation by αMSH, MC1R triggers the cAMP and ERK1/ERK2 MAPK pathways. In mouse melanocytes, ERK activation by αMSH binding to Mc1r depends on cAMP, and melanocytes are considered a paradigm for cAMP-dependent ERK activation. However, human MC1R variants associated with red hair, fair skin [red hair color (RHC) phenotype], and increased skin cancer risk display reduced cAMP signaling but activate ERKs as efficiently as wild type in heterologous cells, suggesting independent signaling to ERKs and cAMP in human melanocytes. We show that MC1R signaling activated the ERK pathway in normal human melanocytes and melanoma cells expressing physiological levels of endogenous RHC variants. ERK activation was comparable for wild-type and mutant MC1R and was independent on cAMP because it was neither triggered by stimulation of cAMP synthesis with forskolin nor blocked by the adenylyl cyclase inhibitor 2',5'-dideoxyadenosine. Stimulation of MC1R with αMSH did not lead to protein kinase C activation and ERK activation was unaffected by protein kinase C inhibitors. Conversely, pharmacological interference, small interfering RNA studies, expression profiles, and functional reconstitution experiments showed that αMSH-induced ERK activation resulted from Src tyrosine kinase-mediated transactivation of the stem cell factor receptor, a receptor tyrosine kinase essential for proliferation, differentiation, and survival of melanocyte precursors, thus demonstrating a functional link between the stem cell factor receptor and MC1R. Moreover, this transactivation phenomenon is unique because it is unaffected by natural mutations impairing canonical MC1R signaling through the cAMP pathway.

Differential and competitive regulation of human melanocortin 1 receptor signaling by β-arrestin isoforms

“…Notably, ARRB2 did not impair MC1R functional coupling to the ERK pathway. We have shown that activation of the ERKs by human MC1R relies on the cAMP-independent transactivation of the cKIT receptor tyrosine kinase (Herraiz et al, 2011a). We have also shown that many natural or artificial MC1R mutations decrease MC1R coupling to the cAMP pathway without effects on ERK activation (Herraiz et al, 2012).…”

“…MC1R is a Gprotein-coupled receptor (GPCR) whose activation triggers the cAMP pathway leading to cAMP-dependent transcriptional activation of microphthalmia transcription factor (Levy et al, 2006). In human melanocytic cells, MC1R also activates the extracellular signal regulated kinases (ERK) 1 and 2 independently of cAMP Herraiz et al, 2011a). Active ERKs phosphorylate Microphthalmia to increase its activity (Hemesath et al, 1998), thereby stimulating transcription of genes encoding for melanogenic proteins.…”

α-MSH stimulation contributes to TGF-β1 production via MC1R-MITF signaling pathway in melanoma cell

“…MITF is the target of MAPK pathway at various levels including its transcription and its protein turnover and function 15,20,21) , which is essential for melanocyte differentiation 25) , and importantly related to malignant progression 31) .…”

“…Thus, MC1R is considered as a key factor that plays important roles in the melanocyte transformation process in pathological conditions such as ultraviolet radiation 14) . In melanoma, MC1R is overexpressed on the cell surface of the majority of human melanomas, and correlated with melanoma initiation, progression and metastasis 15) .…”

Melanocortins: Anti-Inflammatory and Neuroprotective Peptides

“…MC3R has been shown to induce inositol phosphate signaling (Konda et al, 1994) and MC5R was reported to activate the Janus kinase/signal transducer and activator of transcription (Jak/STAT) pathway in B cells (Buggy, 1998). Stimulation of all MCRs leads to activation of mitogen-activated protein kinases (MAPK) ERK-1/2 Chai et al, 2007;Herraiz et al, 2011;Patten et al, 2007, Rodrigues et al, 2009Roy et al, 2011). Depending on the cell type this effect may involve phosphoinositol 3 kinase activation (Rodrigues et al, 2009;Vongs et al, 2004).…”