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Distinct amino acid–sensing mTOR pathways regulate skeletal myogenesis
Signaling through the mammalian target of rapamycin (mTOR) in response to amino acid availability controls many cellular and developmental processes. mTOR is a master regulator of myogenic differentiation, but the pathways mediating amino acid signals in this process are not known. Here we examine t...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3843001/ https://www.ncbi.nlm.nih.gov/pubmed/24068326 http://dx.doi.org/10.1091/mbc.E13-06-0353 |
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author | Yoon, Mee-Sup Chen, Jie |
author_facet | Yoon, Mee-Sup Chen, Jie |
author_sort | Yoon, Mee-Sup |
collection | PubMed |
description | Signaling through the mammalian target of rapamycin (mTOR) in response to amino acid availability controls many cellular and developmental processes. mTOR is a master regulator of myogenic differentiation, but the pathways mediating amino acid signals in this process are not known. Here we examine the Rag GTPases and the class III phosphoinositide 3-kinase (PI3K) Vps34, two mediators of amino acid signals upstream of mTOR complex 1 (mTORC1) in cell growth regulation, for their potential involvement in myogenesis. We find that, although both Rag and Vps34 mediate amino acid activation of mTORC1 in C2C12 myoblasts, they have opposing functions in myogenic differentiation. Knockdown of RagA/B enhances, whereas overexpression of active RagB/C mutants impairs, differentiation, and this inhibitory function of Rag is mediated by mTORC1 suppression of the IRS1-PI3K-Akt pathway. On the other hand, Vps34 is required for myogenic differentiation. Amino acids activate a Vps34-phospholipase D1 (PLD1) pathway that controls the production of insulin-like growth factor II, an autocrine inducer of differentiation, through the Igf2 muscle enhancer. The product of PLD, phosphatidic acid, activates the enhancer in a rapamycin-sensitive but mTOR kinase–independent manner. Our results uncover amino acid–sensing mechanisms controlling the homeostasis of myogenesis and underline the versatility and context dependence of mTOR signaling. |
format | Online Article Text |
id | pubmed-3843001 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-38430012014-02-16 Distinct amino acid–sensing mTOR pathways regulate skeletal myogenesis Yoon, Mee-Sup Chen, Jie Mol Biol Cell Articles Signaling through the mammalian target of rapamycin (mTOR) in response to amino acid availability controls many cellular and developmental processes. mTOR is a master regulator of myogenic differentiation, but the pathways mediating amino acid signals in this process are not known. Here we examine the Rag GTPases and the class III phosphoinositide 3-kinase (PI3K) Vps34, two mediators of amino acid signals upstream of mTOR complex 1 (mTORC1) in cell growth regulation, for their potential involvement in myogenesis. We find that, although both Rag and Vps34 mediate amino acid activation of mTORC1 in C2C12 myoblasts, they have opposing functions in myogenic differentiation. Knockdown of RagA/B enhances, whereas overexpression of active RagB/C mutants impairs, differentiation, and this inhibitory function of Rag is mediated by mTORC1 suppression of the IRS1-PI3K-Akt pathway. On the other hand, Vps34 is required for myogenic differentiation. Amino acids activate a Vps34-phospholipase D1 (PLD1) pathway that controls the production of insulin-like growth factor II, an autocrine inducer of differentiation, through the Igf2 muscle enhancer. The product of PLD, phosphatidic acid, activates the enhancer in a rapamycin-sensitive but mTOR kinase–independent manner. Our results uncover amino acid–sensing mechanisms controlling the homeostasis of myogenesis and underline the versatility and context dependence of mTOR signaling. The American Society for Cell Biology 2013-12-01 /pmc/articles/PMC3843001/ /pubmed/24068326 http://dx.doi.org/10.1091/mbc.E13-06-0353 Text en © 2013 Yoon and Chen. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology. |
spellingShingle | Articles Yoon, Mee-Sup Chen, Jie Distinct amino acid–sensing mTOR pathways regulate skeletal myogenesis |
title | Distinct amino acid–sensing mTOR pathways regulate skeletal myogenesis |
title_full | Distinct amino acid–sensing mTOR pathways regulate skeletal myogenesis |
title_fullStr | Distinct amino acid–sensing mTOR pathways regulate skeletal myogenesis |
title_full_unstemmed | Distinct amino acid–sensing mTOR pathways regulate skeletal myogenesis |
title_short | Distinct amino acid–sensing mTOR pathways regulate skeletal myogenesis |
title_sort | distinct amino acid–sensing mtor pathways regulate skeletal myogenesis |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3843001/ https://www.ncbi.nlm.nih.gov/pubmed/24068326 http://dx.doi.org/10.1091/mbc.E13-06-0353 |
work_keys_str_mv | AT yoonmeesup distinctaminoacidsensingmtorpathwaysregulateskeletalmyogenesis AT chenjie distinctaminoacidsensingmtorpathwaysregulateskeletalmyogenesis |