Agouti protein, mahogunin, and attractin in pheomelanogenesis and melanoblast-like alteration of melanocytes: a cAMP-independent pathway.
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.
Hida
Tokimasa
T
Division of Basic Medical Sciences, St. George's, University of London, Cranmer Terrace, London, UK.
Wakamatsu
Kazumasa
K
Sviderskaya
Elena V
EV
Donkin
Andrew J
AJ
Montoliu
Lluis
L
Lynn Lamoreux
M
M
Yu
Bin
B
Millhauser
Glenn L
GL
Ito
Shosuke
S
Barsh
Gregory S
GS
Jimbow
Kowichi
K
Bennett
Dorothy C
DC
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*
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