Mahoganoid and Mahogany Mutations Rectify the Obesity of the Yellow Mouse by Effects on Endosomal Traffic of MC4R Protein

The ubiquitous overexpression of agouti-signaling protein (ASP), a paracrine-signaling molecule that regulates pigment-type switching in the hair follicle of the mouse, is responsible for the obesity and yellow pelage of the Yellow mouse (A(y)). Mahogany (Attractin, Atrn/mg) and mahoganoid (Mahoguni...

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Main Authors: Overton, John D., Leibel, Rudolph L.
Formato: Artigo
Idioma:Inglês
Publicado em: American Society for Biochemistry and Molecular Biology 2011
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Acesso em linha:https://ncbi.nlm.nih.gov/pmc/articles/PMC3099707/
https://ncbi.nlm.nih.gov/pubmed/21460229
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1074/jbc.M111.224592
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spelling pubmed-30997072012-05-27 Mahoganoid and Mahogany Mutations Rectify the Obesity of the Yellow Mouse by Effects on Endosomal Traffic of MC4R Protein Overton, John D. Leibel, Rudolph L. J Biol Chem Molecular Bases of Disease The ubiquitous overexpression of agouti-signaling protein (ASP), a paracrine-signaling molecule that regulates pigment-type switching in the hair follicle of the mouse, is responsible for the obesity and yellow pelage of the Yellow mouse (A(y)). Mahogany (Attractin, Atrn/mg) and mahoganoid (Mahogunin Ring Finger-1, Mgrn1/md) are mutations epistatic to A(y). These mutations have been described as suppressors of ASP action, blocking its antagonizing effects on the melanocortin 1 and 4 receptors (MC1R and MC4R) in the skin and the brain, respectively, via unknown mechanisms. Here, we describe the molecular bases for the md- and mg-dependent rescue of the A(y) phenotype at the MC4R. We show that overexpression of ASP inhibits the rise in cAMP levels in response to α-melanocyte-stimulating hormone, an MC4R agonist, by blocking ligand binding and by directing MC4R trafficking to the lysosome. Loss-of-function of either attractin or MGRN1 blocks ASP-dependent MC4R degradation and promotes increased trafficking of internalized MC4R to the cell surface, but it does not restore α-melanocyte-stimulating hormone-dependent cAMP signaling. We propose that MGRN1 and attractin are components of an evolutionarily conserved receptor trafficking pathway and that the md and mg mutations rescue the A(y) phenotypes by a primarily cAMP-independent mechanism promoting trafficking of MC4R and likely MC1R away from the lysosome toward the cell surface. American Society for Biochemistry and Molecular Biology 2011-05-27 2011-04-01 /pmc/articles/PMC3099707/ /pubmed/21460229 http://dx.doi.org/10.1074/jbc.M111.224592 Text en © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
institution US NLM
collection PubMed Central
language Inglês
format Artigo
topic Molecular Bases of Disease
spellingShingle Molecular Bases of Disease
Overton, John D.
Leibel, Rudolph L.
Mahoganoid and Mahogany Mutations Rectify the Obesity of the Yellow Mouse by Effects on Endosomal Traffic of MC4R Protein
description The ubiquitous overexpression of agouti-signaling protein (ASP), a paracrine-signaling molecule that regulates pigment-type switching in the hair follicle of the mouse, is responsible for the obesity and yellow pelage of the Yellow mouse (A(y)). Mahogany (Attractin, Atrn/mg) and mahoganoid (Mahogunin Ring Finger-1, Mgrn1/md) are mutations epistatic to A(y). These mutations have been described as suppressors of ASP action, blocking its antagonizing effects on the melanocortin 1 and 4 receptors (MC1R and MC4R) in the skin and the brain, respectively, via unknown mechanisms. Here, we describe the molecular bases for the md- and mg-dependent rescue of the A(y) phenotype at the MC4R. We show that overexpression of ASP inhibits the rise in cAMP levels in response to α-melanocyte-stimulating hormone, an MC4R agonist, by blocking ligand binding and by directing MC4R trafficking to the lysosome. Loss-of-function of either attractin or MGRN1 blocks ASP-dependent MC4R degradation and promotes increased trafficking of internalized MC4R to the cell surface, but it does not restore α-melanocyte-stimulating hormone-dependent cAMP signaling. We propose that MGRN1 and attractin are components of an evolutionarily conserved receptor trafficking pathway and that the md and mg mutations rescue the A(y) phenotypes by a primarily cAMP-independent mechanism promoting trafficking of MC4R and likely MC1R away from the lysosome toward the cell surface.
author Overton, John D.
Leibel, Rudolph L.
author_facet Overton, John D.
Leibel, Rudolph L.
author_sort Overton, John D.
title Mahoganoid and Mahogany Mutations Rectify the Obesity of the Yellow Mouse by Effects on Endosomal Traffic of MC4R Protein
title_short Mahoganoid and Mahogany Mutations Rectify the Obesity of the Yellow Mouse by Effects on Endosomal Traffic of MC4R Protein
title_full Mahoganoid and Mahogany Mutations Rectify the Obesity of the Yellow Mouse by Effects on Endosomal Traffic of MC4R Protein
title_fullStr Mahoganoid and Mahogany Mutations Rectify the Obesity of the Yellow Mouse by Effects on Endosomal Traffic of MC4R Protein
title_full_unstemmed Mahoganoid and Mahogany Mutations Rectify the Obesity of the Yellow Mouse by Effects on Endosomal Traffic of MC4R Protein
title_sort mahoganoid and mahogany mutations rectify the obesity of the yellow mouse by effects on endosomal traffic of mc4r protein
publisher American Society for Biochemistry and Molecular Biology
publishDate 2011
url https://ncbi.nlm.nih.gov/pmc/articles/PMC3099707/
https://ncbi.nlm.nih.gov/pubmed/21460229
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1074/jbc.M111.224592
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