IRS4, a novel modulator of BMP/Smad and Akt signalling during early muscle differentiation

Abstract Elaborate regulatory networks of the Bone Morphogenetic Protein (BMP) pathways ensure precise signalling outcome during cell differentiation and tissue homeostasis. Here, we identified IRS4 as a novel regulator of BMP signal transduction and provide molecular insights how it integrates into...

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Autores principales:	Gina Dörpholz, Arunima Murgai, Jerome Jatzlau, Daniel Horbelt, Mohammad Poorgholi Belverdi, Christina Heroven, Isabelle Schreiber, Gisela Wendel, Karen Ruschke, Sigmar Stricker, Petra Knaus
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1eb3e5fa24f24e5eb5f151ca67e39838
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spelling	oai:doaj.org-article:1eb3e5fa24f24e5eb5f151ca67e398382021-12-02T16:06:46ZIRS4, a novel modulator of BMP/Smad and Akt signalling during early muscle differentiation10.1038/s41598-017-08676-62045-2322https://doaj.org/article/1eb3e5fa24f24e5eb5f151ca67e398382017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08676-6https://doaj.org/toc/2045-2322Abstract Elaborate regulatory networks of the Bone Morphogenetic Protein (BMP) pathways ensure precise signalling outcome during cell differentiation and tissue homeostasis. Here, we identified IRS4 as a novel regulator of BMP signal transduction and provide molecular insights how it integrates into the signalling pathway. We found that IRS4 interacts with the BMP receptor BMPRII and specifically targets Smad1 for proteasomal degradation consequently leading to repressed BMP/Smad signalling in C2C12 myoblasts while concomitantly activating the PI3K/Akt axis. IRS4 is present in human and primary mouse myoblasts, the expression increases during myogenic differentiation but is downregulated upon final commitment coinciding with Myogenin expression. Functionally, IRS4 promotes myogenesis in C2C12 cells, while IRS4 knockdown inhibits differentiation of myoblasts. We propose that IRS4 is particularly critical in the myoblast stage to serve as a molecular switch between BMP/Smad and Akt signalling and to thereby control cell commitment. These findings provide profound understanding of the role of BMP signalling in early myogenic differentiation and open new ways for targeting the BMP pathway in muscle regeneration.Gina DörpholzArunima MurgaiJerome JatzlauDaniel HorbeltMohammad Poorgholi BelverdiChristina HerovenIsabelle SchreiberGisela WendelKaren RuschkeSigmar StrickerPetra KnausNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-17 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gina Dörpholz Arunima Murgai Jerome Jatzlau Daniel Horbelt Mohammad Poorgholi Belverdi Christina Heroven Isabelle Schreiber Gisela Wendel Karen Ruschke Sigmar Stricker Petra Knaus IRS4, a novel modulator of BMP/Smad and Akt signalling during early muscle differentiation
description	Abstract Elaborate regulatory networks of the Bone Morphogenetic Protein (BMP) pathways ensure precise signalling outcome during cell differentiation and tissue homeostasis. Here, we identified IRS4 as a novel regulator of BMP signal transduction and provide molecular insights how it integrates into the signalling pathway. We found that IRS4 interacts with the BMP receptor BMPRII and specifically targets Smad1 for proteasomal degradation consequently leading to repressed BMP/Smad signalling in C2C12 myoblasts while concomitantly activating the PI3K/Akt axis. IRS4 is present in human and primary mouse myoblasts, the expression increases during myogenic differentiation but is downregulated upon final commitment coinciding with Myogenin expression. Functionally, IRS4 promotes myogenesis in C2C12 cells, while IRS4 knockdown inhibits differentiation of myoblasts. We propose that IRS4 is particularly critical in the myoblast stage to serve as a molecular switch between BMP/Smad and Akt signalling and to thereby control cell commitment. These findings provide profound understanding of the role of BMP signalling in early myogenic differentiation and open new ways for targeting the BMP pathway in muscle regeneration.
format	article
author	Gina Dörpholz Arunima Murgai Jerome Jatzlau Daniel Horbelt Mohammad Poorgholi Belverdi Christina Heroven Isabelle Schreiber Gisela Wendel Karen Ruschke Sigmar Stricker Petra Knaus
author_facet	Gina Dörpholz Arunima Murgai Jerome Jatzlau Daniel Horbelt Mohammad Poorgholi Belverdi Christina Heroven Isabelle Schreiber Gisela Wendel Karen Ruschke Sigmar Stricker Petra Knaus
author_sort	Gina Dörpholz
title	IRS4, a novel modulator of BMP/Smad and Akt signalling during early muscle differentiation
title_short	IRS4, a novel modulator of BMP/Smad and Akt signalling during early muscle differentiation
title_full	IRS4, a novel modulator of BMP/Smad and Akt signalling during early muscle differentiation
title_fullStr	IRS4, a novel modulator of BMP/Smad and Akt signalling during early muscle differentiation
title_full_unstemmed	IRS4, a novel modulator of BMP/Smad and Akt signalling during early muscle differentiation
title_sort	irs4, a novel modulator of bmp/smad and akt signalling during early muscle differentiation
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/1eb3e5fa24f24e5eb5f151ca67e39838
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IRS4, a novel modulator of BMP/Smad and Akt signalling during early muscle differentiation

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