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Molecular and Cellular Biology, June 2002, p. 3875-3891, Vol. 22, No. 11
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.11.3875-3891.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Role of SHP-2 in Fibroblast Growth Factor Receptor-Mediated Suppression of Myogenesis in C2C12 Myoblasts

Maria I. Kontaridis, Xiangdong Liu,,{dagger} Lei Zhang, and Anton M. Bennett*

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066

Received 24 August 2001/ Returned for modification 22 October 2001/ Accepted 27 February 2002

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.

* Corresponding author. Mailing address: Yale University School of Medicine, Department of Pharmacology, SHM B230, 333 Cedar St., New Haven, CT 06520-8066. Phone: (203) 737-2441. Fax: (203) 785-7670. E-mail: anton.bennett{at}yale.edu.

{dagger} Present address: Curagen Corporation, Branford, CT 06405.

Molecular and Cellular Biology, June 2002, p. 3875-3891, Vol. 22, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.11.3875-3891.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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