Regulation of myogenesis by fibroblast growth factors requires beta-gamma subunits of pertussis toxin-sensitive G proteins

Mol Cell Biol. 1998 Oct;18(10):5780-7. doi: 10.1128/MCB.18.10.5780.

Abstract

Terminal differentiation of skeletal muscle cells in culture is inhibited by a number of different growth factors whose subsequent intracellular signaling events are poorly understood. In this study, we have investigated the role of heterotrimeric G proteins in mediating fibroblast growth factor (FGF)-dependent signals that regulate myogenic differentiation. Pertussis toxin, which ADP-ribosylates and inactivates susceptible G proteins, promotes terminal differentiation in the presence of FGF-2, suggesting that Galpha or Gbeta gamma subunits or both are involved in transducing the FGF-dependent signal(s) that inhibits myogenesis. We found that Gbetagamma subunits are likely to be involved since the expression of the C terminus of beta-adrenergic receptor kinase 1, a Gbetagamma subunit-sequestering agent, promotes differentiation in the presence of FGF-2, and expression of the free Gbeta gamma dimer can replace FGF-2, rescuing cells from pertussis toxin-induced differentiation. Addition of pertussis toxin also blocked FGF-2-mediated activation of mitogen-activated protein kinases (MAPKs). Ectopic expression of dominant active mutants in the Ras/MAPK pathway rescued cells from pertussis toxin-induced terminal differentiation, suggesting that the Gbeta gamma subunits act upstream of the Ras/MAPK pathway. It is unlikely that the pertussis toxin-sensitive pathway is activated by other, as yet unidentified FGF receptors since PDGF (platelet-derived growth factor)-stimulated MM14 cells expressing a chimeric receptor containing the FGF receptor-1 intracellular domain and the PDGF receptor extracellular domain were sensitive to pertussis toxin. Our data suggest that FGF-mediated signals involved in repression of myogenic differentiation are transduced by a pertussis toxin-sensitive G-protein-coupled mechanism. This signaling pathway requires the action of Gbeta gamma subunits and activation of MAPKs to repress skeletal muscle differentiation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Line
  • Cholera Toxin / pharmacology
  • Colforsin / pharmacology
  • Fibroblast Growth Factors / metabolism*
  • GTP-Binding Proteins / metabolism*
  • Mice
  • Muscle, Skeletal / cytology*
  • Pertussis Toxin*
  • Receptors, Fibroblast Growth Factor / metabolism
  • Signal Transduction*
  • Virulence Factors, Bordetella / pharmacology*

Substances

  • Receptors, Fibroblast Growth Factor
  • Virulence Factors, Bordetella
  • Colforsin
  • Fibroblast Growth Factors
  • Cholera Toxin
  • Pertussis Toxin
  • GTP-Binding Proteins