Role of SHP-2 in fibroblast growth factor receptor-mediated suppression of myogenesis in C2C12 myoblasts.
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.
Kontaridis
Maria I
MI
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, USA.
Liu
Xiangdong
X
Zhang
Lei
L
Bennett
Anton M
AM
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002455:Cell Division; D002460:Cell Line; D004268:DNA-Binding Proteins; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D024510:Muscle Development / Q000235:genetics / Q000502:physiology*; D009132:Muscles / Q000166:cytology* / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017354:Point Mutation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D015398:Signal Transduction; D014157:Transcription Factors; D015533:Transcriptional Activation; D050807:ets-Domain Protein Elk-1
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C494113:Elk1 protein, mouse; C106534:FRS2 protein, human; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D017468:Receptors, Fibroblast Growth Factor; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D016222:Fibroblast Growth Factor 2; D007334:Insulin-Like Growth Factor I; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases