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The FGF receptor-1 tyrosine kinase domain regulates myogenesis but is not sufficient to stimulate proliferation
A J Kudla1, N C Jones, R S Rosenthal
1Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
Abstract:
Ligand-stimulated activation of FGF receptors (FGFRs) in skeletal muscle cells represses terminal myogenic differentiation. Skeletal muscle cell lines and subsets of primary cells are dependent on FGFs to repress myogenesis and maintain growth. To understand the intracellular events that transduce these signals, MM14 skeletal muscle cells were transfected with expression vectors encoding chimeric receptors. The chimeras are comprised of the PDGF beta receptor (PDGFbetaR) extracellular domain, the FGFR-1 intracellular domain, and either the PDGFbetaR or FGFR-1 transmembrane domain. The chimeric receptors were autophosphorylated upon PDGF-BB stimulation and are capable of stimulating mitogen-activated protein kinase activity. Activation of the tyrosine kinase domain of either chimera repressed myogenesis, suggesting intracellular responses regulating skeletal muscle differentiation are transduced by activation of the FGFR-1 tyrosine kinase. Unexpectedly, we found that activation of either chimeric receptor failed to stimulate cellular proliferation. Thus, it appears that regulation of skeletal muscle differentiation by FGFs requires only activation of the FGFR tyrosine kinase. In contrast, stimulation of proliferation may require additional, as yet unidentified, signals involving the receptor ectodomain, the FGF ligand, and heparan sulfate either alone, or in combination.
Insights
Fibroblast Growth Factor Receptors (FGFRs) activation in muscle cells inhibits differentiation. This study shows FGFR-1 tyrosine kinase activation alone represses myogenesis, while proliferation requires additional signals.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Fibroblast Growth Factor Receptors (FGFRs) play a crucial role in regulating skeletal muscle cell growth and differentiation.
- Ligand-stimulated FGFR activation is known to repress terminal myogenic differentiation in skeletal muscle cells.
Purpose of the Study:
- To elucidate the intracellular events mediating FGF signaling in skeletal muscle cells.
- To determine the specific role of FGFR-1 tyrosine kinase activation in regulating myogenesis and proliferation.
Main Methods:
- Transfection of MM14 skeletal muscle cells with chimeric receptors combining PDGFbetaR and FGFR-1 domains.
- Stimulation with PDGF-BB to activate chimeric receptors.
- Analysis of autophosphorylation, mitogen-activated protein kinase (MAPK) activity, myogenesis repression, and cellular proliferation.
Main Results:
- Chimeric receptors activated by PDGF-BB showed autophosphorylation and stimulated MAPK activity.
- Activation of the FGFR-1 tyrosine kinase domain in either chimera effectively repressed myogenesis.
- Unexpectedly, chimeric receptor activation did not stimulate cellular proliferation.
Conclusions:
- Intracellular signals regulating skeletal muscle differentiation are transduced by FGFR-1 tyrosine kinase activation.
- FGF-mediated regulation of skeletal muscle differentiation relies solely on FGFR tyrosine kinase activation.
- Stimulation of proliferation by FGFs may involve additional signals including the receptor ectodomain, FGF ligand, and heparan sulfate.