Cargando…
Trim32 reduces PI3K–Akt–FoxO signaling in muscle atrophy by promoting plakoglobin–PI3K dissociation
Activation of the PI3K–Akt–FoxO pathway induces cell growth, whereas its inhibition reduces cell survival and, in muscle, causes atrophy. Here, we report a novel mechanism that suppresses PI3K–Akt–FoxO signaling. Although skeletal muscle lacks desmosomes, it contains multiple desmosomal components,...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941042/ https://www.ncbi.nlm.nih.gov/pubmed/24567360 http://dx.doi.org/10.1083/jcb.201304167 |
_version_ | 1782305858643820544 |
---|---|
author | Cohen, Shenhav Lee, Donghoon Zhai, Bo Gygi, Steven P. Goldberg, Alfred L. |
author_facet | Cohen, Shenhav Lee, Donghoon Zhai, Bo Gygi, Steven P. Goldberg, Alfred L. |
author_sort | Cohen, Shenhav |
collection | PubMed |
description | Activation of the PI3K–Akt–FoxO pathway induces cell growth, whereas its inhibition reduces cell survival and, in muscle, causes atrophy. Here, we report a novel mechanism that suppresses PI3K–Akt–FoxO signaling. Although skeletal muscle lacks desmosomes, it contains multiple desmosomal components, including plakoglobin. In normal muscle plakoglobin binds the insulin receptor and PI3K subunit p85 and promotes PI3K–Akt–FoxO signaling. During atrophy, however, its interaction with PI3K–p85 is reduced by the ubiquitin ligase Trim32 (tripartite motif containing protein 32). Inhibition of Trim32 enhanced plakoglobin binding to PI3K–p85 and promoted PI3K–Akt–FoxO signaling. Surprisingly, plakoglobin overexpression alone enhanced PI3K–Akt–FoxO signaling. Furthermore, Trim32 inhibition in normal muscle increased PI3K–Akt–FoxO signaling, enhanced glucose uptake, and induced fiber growth, whereas plakoglobin down-regulation reduced PI3K–Akt–FoxO signaling, decreased glucose uptake, and caused atrophy. Thus, by promoting plakoglobin–PI3K dissociation, Trim32 reduces PI3K–Akt–FoxO signaling in normal and atrophying muscle. This mechanism probably contributes to insulin resistance during fasting and catabolic diseases and perhaps to the myopathies and cardiomyopathies seen with Trim32 and plakoglobin mutations. |
format | Online Article Text |
id | pubmed-3941042 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-39410422014-09-03 Trim32 reduces PI3K–Akt–FoxO signaling in muscle atrophy by promoting plakoglobin–PI3K dissociation Cohen, Shenhav Lee, Donghoon Zhai, Bo Gygi, Steven P. Goldberg, Alfred L. J Cell Biol Research Articles Activation of the PI3K–Akt–FoxO pathway induces cell growth, whereas its inhibition reduces cell survival and, in muscle, causes atrophy. Here, we report a novel mechanism that suppresses PI3K–Akt–FoxO signaling. Although skeletal muscle lacks desmosomes, it contains multiple desmosomal components, including plakoglobin. In normal muscle plakoglobin binds the insulin receptor and PI3K subunit p85 and promotes PI3K–Akt–FoxO signaling. During atrophy, however, its interaction with PI3K–p85 is reduced by the ubiquitin ligase Trim32 (tripartite motif containing protein 32). Inhibition of Trim32 enhanced plakoglobin binding to PI3K–p85 and promoted PI3K–Akt–FoxO signaling. Surprisingly, plakoglobin overexpression alone enhanced PI3K–Akt–FoxO signaling. Furthermore, Trim32 inhibition in normal muscle increased PI3K–Akt–FoxO signaling, enhanced glucose uptake, and induced fiber growth, whereas plakoglobin down-regulation reduced PI3K–Akt–FoxO signaling, decreased glucose uptake, and caused atrophy. Thus, by promoting plakoglobin–PI3K dissociation, Trim32 reduces PI3K–Akt–FoxO signaling in normal and atrophying muscle. This mechanism probably contributes to insulin resistance during fasting and catabolic diseases and perhaps to the myopathies and cardiomyopathies seen with Trim32 and plakoglobin mutations. The Rockefeller University Press 2014-03-03 /pmc/articles/PMC3941042/ /pubmed/24567360 http://dx.doi.org/10.1083/jcb.201304167 Text en © 2014 Cohen et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Research Articles Cohen, Shenhav Lee, Donghoon Zhai, Bo Gygi, Steven P. Goldberg, Alfred L. Trim32 reduces PI3K–Akt–FoxO signaling in muscle atrophy by promoting plakoglobin–PI3K dissociation |
title | Trim32 reduces PI3K–Akt–FoxO signaling in muscle atrophy by promoting plakoglobin–PI3K dissociation |
title_full | Trim32 reduces PI3K–Akt–FoxO signaling in muscle atrophy by promoting plakoglobin–PI3K dissociation |
title_fullStr | Trim32 reduces PI3K–Akt–FoxO signaling in muscle atrophy by promoting plakoglobin–PI3K dissociation |
title_full_unstemmed | Trim32 reduces PI3K–Akt–FoxO signaling in muscle atrophy by promoting plakoglobin–PI3K dissociation |
title_short | Trim32 reduces PI3K–Akt–FoxO signaling in muscle atrophy by promoting plakoglobin–PI3K dissociation |
title_sort | trim32 reduces pi3k–akt–foxo signaling in muscle atrophy by promoting plakoglobin–pi3k dissociation |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941042/ https://www.ncbi.nlm.nih.gov/pubmed/24567360 http://dx.doi.org/10.1083/jcb.201304167 |
work_keys_str_mv | AT cohenshenhav trim32reducespi3kaktfoxosignalinginmuscleatrophybypromotingplakoglobinpi3kdissociation AT leedonghoon trim32reducespi3kaktfoxosignalinginmuscleatrophybypromotingplakoglobinpi3kdissociation AT zhaibo trim32reducespi3kaktfoxosignalinginmuscleatrophybypromotingplakoglobinpi3kdissociation AT gygistevenp trim32reducespi3kaktfoxosignalinginmuscleatrophybypromotingplakoglobinpi3kdissociation AT goldbergalfredl trim32reducespi3kaktfoxosignalinginmuscleatrophybypromotingplakoglobinpi3kdissociation |