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

Autor:	Petra Knaus, Gina Dörpholz, Christina Heroven, Gisela Wendel, Mohammad Poorgholi Belverdi, Arunima Murgai, Jerome Jatzlau, Sigmar Stricker, Isabelle Schreiber, Daniel Horbelt, Karen Ruschke
Jazyk:	angličtina
Rok vydání:	2017
Předmět:	0301 basic medicine Cellular differentiation Smad Proteins SMAD Ligands Muscle Development Myoblasts Mice Tissue homeostasis Multidisciplinary Myogenesis Cell Differentiation musculoskeletal system Cell biology Gene Knockdown Techniques embryonic structures Bone Morphogenetic Proteins Medicine C2C12 Protein Binding Signal Transduction medicine.medical_specialty Proteasome Endopeptidase Complex Science Kinases Biology Bone morphogenetic protein Bone Morphogenetic Protein Receptors Type II Models Biological Article Cell Line 03 medical and health sciences Internal medicine medicine Animals PI3K/AKT/mTOR pathway Binding Sites 030102 biochemistry & molecular biology Cell Membrane Ubiquitination Growth factor signalling BMPR2 Rats 030104 developmental biology Endocrinology Proteolysis Insulin Receptor Substrate Proteins Proto-Oncogene Proteins c-akt Biomarkers
Zdroj:	Scientific Reports, Vol 7, Iss 1, Pp 1-17 (2017) Scientific Reports
ISSN:	2045-2322
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5ecaa649c711e0ef956f3beecc1753e2 https://doaj.org/article/1eb3e5fa24f24e5eb5f151ca67e39838 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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