title: Agouti protein, mahogunin, and attractin in pheomelanogenesis and melanoblast-like alteration of melanocytes: a cAMP-independent pathway.
abstract: Melanocortin-1 receptor (MC1R) and its ligands, alpha-melanocyte stimulating hormone (alphaMSH) and agouti signaling protein (ASIP), regulate switching between eumelanin and pheomelanin synthesis in melanocytes. Here we investigated biological effects and signaling pathways of ASIP. Melan-a non agouti (a/a) mouse melanocytes produce mainly eumelanin, but ASIP combined with phenylthiourea and extra cysteine could induce over 200-fold increases in the pheomelanin to eumelanin ratio, and a tan-yellow color in pelletted cells. Moreover, ASIP-treated cells showed reduced proliferation and a melanoblast-like appearance, seen also in melanocyte lines from yellow (A(y)/a and Mc1r(e)/ Mc1r(e)) mice. However ASIP-YY, a C-terminal fragment of ASIP, induced neither biological nor pigmentary changes. As, like ASIP, ASIP-YY inhibited the cAMP rise induced by alphaMSH analog NDP-MSH, and reduced cAMP level without added MSH, the morphological changes and depigmentation seemed independent of cAMP signaling. Melanocytes genetically null for ASIP mediators attractin or mahogunin (Atrn(mg-3J/mg-3J) or Mgrn1(md-nc/md-nc)) also responded to both ASIP and ASIP-YY in cAMP level, while only ASIP altered their proliferation and (in part) shape. Thus, ASIP-MC1R signaling includes a cAMP-independent pathway through attractin and mahogunin, while the known cAMP-dependent component requires neither attractin nor mahogunin.
authors.affiliation: Division of Basic Medical Sciences, St. George's, University of London, Cranmer Terrace, London, UK.
authors.forename: Tokimasa
authors.initials: T
authors.lastname: Hida
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Wakamatsu
authors.forename: Elena V
authors.initials: EV
authors.lastname: Sviderskaya
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Donkin
authors.forename: Lluis
authors.initials: L
authors.lastname: Montoliu
authors.forename: M
authors.initials: M
authors.lastname: Lynn Lamoreux
authors.forename: Bin
authors.initials: B
authors.lastname: Yu
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Millhauser
authors.forename: Shosuke
authors.initials: S
authors.lastname: Ito
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Barsh
authors.forename: Kowichi
authors.initials: K
authors.lastname: Jimbow
authors.forename: Dorothy C
authors.initials: DC
authors.lastname: Bennett
mesh_terms: D054366:Agouti Signaling Protein / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D048430:Cell Shape; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D006200:Hair Color / Q000502:physiology; D008543:Melanins / Q000096:biosynthesis* / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010858:Pigmentation / Q000502:physiology; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D054366:Agouti Signaling Protein; C117928:Atrn protein, mouse; D008543:Melanins; D008565:Membrane Proteins; D044102:Receptor, Melanocortin, Type 1; C018362:pheomelanin; C041877:eumelanin; D000242:Cyclic AMP; C470689:Mgrn1 protein, mouse; D044767:Ubiquitin-Protein Ligases