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Molecular and Cellular Biology, June 2004, p. 5340-5352, Vol. 24, No. 12
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.12.5340-5352.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

SHP-2 Positively Regulates Myogenesis by Coupling to the Rho GTPase Signaling Pathway

Maria I. Kontaridis,1,{dagger} Seda Eminaga,1 Mara Fornaro,1 Christina Ivins Zito,1 Raffaella Sordella,2 Jeffrey Settleman,2 and Anton M. Bennett1*

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520,1 Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 021292

Received 19 November 2003/ Returned for modification 30 December 2003/ Accepted 18 March 2004

Myogenesis is an intricate process that coordinately engages multiple intracellular signaling cascades. The Rho family GTPase RhoA is known to promote myogenesis, however, the mechanisms controlling its regulation in myoblasts have yet to be fully elucidated. We show here that the SH2-containing protein tyrosine phosphatase, SHP-2, functions as an early modulator of myogenesis by regulating RhoA. When MyoD was expressed in fibroblasts lacking functional SHP-2, muscle-specific gene activity was impaired and abolition of SHP-2 expression by RNA interference inhibited muscle differentiation. By using SHP-2 substrate-trapping mutants, we identified p190-B RhoGAP as a SHP-2 substrate. When dephosphorylated, p190-B RhoGAP has been shown to stimulate the activation of RhoA. During myogenesis, p190-B RhoGAP was tyrosyl dephosphorylated concomitant with the stimulation of SHP-2's phosphatase activity. Moreover, overexpression of a catalytically inactive mutant of SHP-2 inhibited p190-B RhoGAP tyrosyl dephosphorylation, RhoA activity, and myogenesis. These observations strongly suggest that SHP-2 dephosphorylates p190-B RhoGAP, leading to the activation of RhoA. Collectively, these data provide a mechanistic basis for RhoA activation in myoblasts and demonstrate that myogenesis is critically regulated by the actions of SHP-2 on the p190-B Rho GAP/RhoA pathway.

* Corresponding author. Mailing address: Yale University School of Medicine, Department of Pharmacology, SHM-B226D, 333 Cedar St., New Haven, CT 06520-8066. Phone: (203) 737-2441. Fax: (203) 737-2738. E-mail: anton.bennett{at}yale.edu.

{dagger} Present address: Beth Israel Deaconess Hospital, Boston, MA 02215.

Molecular and Cellular Biology, June 2004, p. 5340-5352, Vol. 24, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.12.5340-5352.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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