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Molecular and Cellular Biology, October 1998, p. 5780-5787, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Regulation of Myogenesis by Fibroblast Growth Factors Requires Beta-Gamma Subunits of Pertussis Toxin-Sensitive G Proteins

Yuri V. Fedorov,1,2 Nathan C. Jones,1 and Bradley B. Olwin1,2,*

Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80309,1 and Walther Cancer Institute, Indianapolis, Indiana 472382

Received 9 April 1998/Returned for modification 18 June 1998/Accepted 4 July 1998

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 Gbeta gamma subunits are likely to be involved since the expression of the C terminus of beta -adrenergic receptor kinase 1, a Gbeta gamma 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.

* Corresponding author. Mailing address: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309. Phone: (303) 492-6816. Fax: (303) 492-1587. E-mail: Bradley.Olwin{at}colorado.edu.

Molecular and Cellular Biology, October 1998, p. 5780-5787, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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