Regulation of GDF-8 signaling by the p38 MAPK

Cell Signal. 2005 Mar;17(3):365-75. doi: 10.1016/j.cellsig.2004.08.003.

Abstract

Growth differentiation factor-8 (GDF-8), a member of the TGF-beta superfamily, is a negative regulator of skeletal muscle growth, which functions through activation of the Smad proteins. We found that GDF-8 can activate the p38 mitogen-activated protein kinase (MAPK) through the TGF-beta-activated kinase 1 (TAK1), and this appeared to be independent of Smad signaling. GDF-8-induced transcriptional activation was inhibited by expression of dominant negative MKK6 or treatment with the p38 inhibitor SB203580, while overexpression of wild-type forms of either MKK6 or p38 augmented GDF-8-induced transcriptional activity. In addition, ATF-2, a known transcription factor target of p38, was found to be phosphorylated on GDF-8 stimulation and was detected in a complex with Smad3/Smad4 upon GDF-8 treatment. Furthermore, we found that the p38 MAPK played an important role in GDF-8-induced inhibition of proliferation and upregulation of the cyclin kinase inhibitor p21. Together, these results highlight a functional link between the p38 MAPK and GDF-8-activated Smad pathways, and identify a critical role for the p38 MAPK in GDF-8's function as a negative regulator of muscle growth.

MeSH terms

  • Activating Transcription Factor 2
  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • DNA-Binding Proteins / metabolism
  • Enzyme Activation
  • Humans
  • Imidazoles / pharmacology
  • MAP Kinase Kinase 6 / metabolism
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • Muscle Cells / metabolism*
  • Myostatin
  • Pyridines / pharmacology
  • Signal Transduction
  • Smad Proteins
  • Smad3 Protein
  • Smad4 Protein
  • Trans-Activators / metabolism
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Transforming Growth Factor beta / physiology*
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • ATF2 protein, human
  • Activating Transcription Factor 2
  • Atf2 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • Imidazoles
  • MSTN protein, human
  • Mstn protein, mouse
  • Myostatin
  • Pyridines
  • SMAD3 protein, human
  • SMAD4 protein, human
  • Smad Proteins
  • Smad3 Protein
  • Smad3 protein, mouse
  • Smad4 Protein
  • Trans-Activators
  • Transcription Factors
  • Transforming Growth Factor beta
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • MAP Kinase Kinase 6
  • SB 203580