Abstract
Ligand activation of the fibroblast growth factor receptor (FGFR) represses myogenesis and promotes activation of extracellular signal-regulated kinases 1 and 2 (Erks). The precise mechanism through which the FGFR transmits both of these signals in myoblasts remains unclear. The SH2 domain-containing protein tyrosine phosphatase, SHP-2, has been shown to participate in the regulation of FGFR signaling. However, no role for SHP-2 in FGFR myogenic signaling is known. In this study, we show that stimulation of C2C12 myoblasts with FGF-2 induces SHP-2 complex formation with tyrosyl-phosphorylated FGFR substrate 2 alpha (FRS-2 alpha). Both the catalytic activity and, to a much lesser extent, the Grb2 binding-tyrosyl phosphorylation sites of SHP-2 are required for maximal FGF-2-induced Erk activity and Elk-1 transactivation. When overexpressed in C2C12 myoblasts, wild-type SHP-2, but not a catalytically inactive SHP-2 mutant, potentiates the suppressive effects of FGF-2 on muscle-specific gene expression. In addition, expression of a constitutively active mutant of SHP-2 is sufficient to prevent myogenesis. The constitutively active mutant of SHP-2 induces hyper-tyrosyl phosphorylation of FRS-2 alpha but fails to stimulate or potentiate either FGF-2-induced Erk activation or Elk-1 transactivation. These data suggest that in myoblasts, SHP-2 represses myogenesis via a pathway that is independent of the Erks. We propose that SHP-2 plays a pivotal role in FGFR signaling in myoblasts via both Erk-dependent and Erk-independent pathways.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Cell Division
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Cell Line
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DNA-Binding Proteins*
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Fibroblast Growth Factor 2 / metabolism
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Fibroblast Growth Factor 2 / pharmacology
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Insulin / pharmacology
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Insulin-Like Growth Factor I / pharmacology
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Intracellular Signaling Peptides and Proteins
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Ligands
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Membrane Proteins / metabolism
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Mice
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism
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Muscle Development / genetics
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Muscle Development / physiology*
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Muscles / cytology*
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Muscles / metabolism*
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Phosphoproteins / metabolism
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Phosphorylation
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Point Mutation
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism*
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Proto-Oncogene Proteins / genetics
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Receptors, Fibroblast Growth Factor / metabolism*
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SH2 Domain-Containing Protein Tyrosine Phosphatases
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Signal Transduction
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Transcription Factors*
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Transcriptional Activation
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ets-Domain Protein Elk-1
Substances
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Adaptor Proteins, Signal Transducing
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DNA-Binding Proteins
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Elk1 protein, mouse
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FRS2 protein, human
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Insulin
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Intracellular Signaling Peptides and Proteins
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Ligands
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Membrane Proteins
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Phosphoproteins
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Proto-Oncogene Proteins
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Receptors, Fibroblast Growth Factor
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Transcription Factors
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ets-Domain Protein Elk-1
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Fibroblast Growth Factor 2
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Insulin-Like Growth Factor I
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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PTPN11 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatases
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Ptpn11 protein, mouse
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SH2 Domain-Containing Protein Tyrosine Phosphatases