title: MC1R signaling. Intracellular partners and pathophysiological implications.
abstract: The melanocortin-1 receptor (MC1R) preferentially expressed in melanocytes is best known as a key regulator of the synthesis of epidermal melanin pigments. Its paracrine stimulation by keratinocyte-derived melanocortins also activates DNA repair pathways and antioxidant defenses to build a complex, multifaceted photoprotective response. Many MC1R actions rely on cAMP-dependent activation of two transcription factors, MITF and PGC1α, but pleiotropic MC1R signaling also involves activation of mitogen-activated kinases and AKT. MC1R partners such as β-arrestins, PTEN and the E3 ubiquitin ligase MGRN1 differentially regulate these pathways. The MC1R gene is complex and polymorphic, with frequent variants associated with skin phenotypes and increased cancer risk. We review current knowledge of signaling from canonical MC1R, its splice isoforms and natural polymorphic variants. Recently discovered intracellular targets and partners are also discussed, to highlight the diversity of mechanisms that may contribute to normal and pathological variation of pigmentation and sensitivity to solar radiation-induced damage. This article is part of a Special Issue entitled: Melanocortin Receptors - edited by Ya-Xiong Tao.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Murcia and Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 El Palmar, Murcia, Spain.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Herraiz
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Murcia and Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 El Palmar, Murcia, Spain. Electronic address: gborron@um.es.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Garcia-Borron
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Murcia and Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 El Palmar, Murcia, Spain.
authors.forename: Celia
authors.initials: C
authors.lastname: Jiménez-Cervantes
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Murcia and Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 El Palmar, Murcia, Spain.
authors.forename: Conchi
authors.initials: C
authors.lastname: Olivares
mesh_terms: D000818:Animals; D004260:DNA Repair; D006801:Humans; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D011110:Polymorphism, Genetic; D060066:Protein Interaction Maps; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D044102:Receptor, Melanocortin, Type 1
keywords: Melanocortin 1 receptor; Melanocytes; Melanoma; Photoprotection; Pigmentation; Signaling