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

Sci Rep. 2017 Aug 18;7(1):8778. doi: 10.1038/s41598-017-08676-6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Biomarkers
  • Bone Morphogenetic Protein Receptors, Type II / chemistry
  • Bone Morphogenetic Protein Receptors, Type II / metabolism
  • Bone Morphogenetic Proteins / chemistry
  • Bone Morphogenetic Proteins / metabolism*
  • Cell Differentiation / genetics*
  • Cell Line
  • Cell Membrane / metabolism
  • Gene Knockdown Techniques
  • Insulin Receptor Substrate Proteins / chemistry
  • Insulin Receptor Substrate Proteins / genetics*
  • Insulin Receptor Substrate Proteins / metabolism*
  • Ligands
  • Mice
  • Models, Biological
  • Muscle Development
  • Myoblasts / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Proteolysis
  • Proto-Oncogene Proteins c-akt / chemistry
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats
  • Signal Transduction*
  • Smad Proteins / chemistry
  • Smad Proteins / metabolism*
  • Ubiquitination

Substances

  • Biomarkers
  • Bone Morphogenetic Proteins
  • Insulin Receptor Substrate Proteins
  • Irs4 protein, mouse
  • Ligands
  • Smad Proteins
  • Proto-Oncogene Proteins c-akt
  • Bmpr2 protein, mouse
  • Bone Morphogenetic Protein Receptors, Type II
  • Proteasome Endopeptidase Complex