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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...

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Autores principales: Yoon, Mee-Sup, Chen, Jie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2013
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.
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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
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