SHP-2 positively regulates myogenesis by coupling to the Rho GTPase signaling pathway

Kontaridis, M. I., Eminaga, S., Fornaro, M., Zito, C. I., Sordella, R., Settleman, J., Bennett, A. M. (June 2004) SHP-2 positively regulates myogenesis by coupling to the Rho GTPase signaling pathway. Molecular and Cellular Biology, 24 (12). pp. 5340-52. ISSN 0270-7306

URL: http://www.ncbi.nlm.nih.gov/pubmed/15169898
DOI: 10.1128/MCB.24.12.5340-5352.2004

Abstract

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.

Item Type: Paper
Uncontrolled Keywords: Animals Base Sequence Cell Line DNA Complementary genetics DNA-Binding Proteins GTPase-Activating Proteins Gene Expression Regulation Developmental Guanine Nucleotide Exchange Factors chemistry metabolism Intracellular Signaling Peptides and Proteins Mice Mice Knockout Models Biological Muscle Development genetics physiology Mutagenesis Site-Directed Myoblasts cytology metabolism Nuclear Proteins chemistry metabolism Phosphorylation Protein Tyrosine Phosphatase Non-Receptor Type 11 Protein Tyrosine Phosphatases deficiency genetics metabolism RNA Interference Repressor Proteins Signal Transduction Tyrosine chemistry rho GTP-Binding Proteins metabolism rhoA GTP-Binding Protein metabolism
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > GTPase
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > protein tyrosine phosphatase
CSHL Authors:
Communities: CSHL labs > Sordella lab
Depositing User: CSHL Librarian
Date: June 2004
Date Deposited: 01 Feb 2012 17:59
Last Modified: 13 Mar 2013 16:07
PMCID: PMC419889
Related URLs:
URI: http://repository.cshl.edu/id/eprint/22414

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