Open AccessIRS4, a novel modulator of BMP/Smad and Akt signalling during early muscle differentiation
Author(s) -
Gina Dörpholz,
Arunima Murgai,
Jerome Jatzlau,
Daniel Horbelt,
Mohammad Poorgholi Belverdi,
Christina Heroven,
Isabelle Schreiber,
Gisela Wendel,
Karen Ruschke,
Sigmar Stricker,
Petra Knaus
Publication year - 2017
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/s41598-017-08676-6
Subject(s) - c2c12 , myogenesis , smad , microbiology and biotechnology , pi3k/akt/mtor pathway , myocyte , bone morphogenetic protein , protein kinase b , bone morphogenetic protein 2 , signal transduction , bmpr2 , myogenin , biology , chemistry , genetics , gene , in vitro
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.