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J. Biol. Chem., Vol. 277, Issue 48, 46687-46695, November 29, 2002

This Article Full Text Full Text (PDF) All Versions of this Article: 277/48/46687    most recent M209643200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lu, H. Articles by Fantus, I. G. Search for Related Content PubMed PubMed Citation Articles by Lu, H. Articles by Fantus, I. G. Social Bookmarking                      What's this?

The Differentiation of Skeletal Muscle Cells Involves a Protein-tyrosine Phosphatase--mediated C-Src Signaling Pathway^*

Huogen Lu, Poonam Shah^§, David Ennis^¶, Gail Shinder, Jan Sap, Hoang Le-Tien, and I. George Fantus^**

From the  Departments of Medicine and Physiology, Mount Sinai Hospital and The University Health Network and the Banting and Best Diabetes Center, University of Toronto, Toronto, Ontario M5G 1X5, Canada and the  Department of Pharmacology and Kaplan Cancer Center, New York University, School of Medicine, New York, New York 10016

Protein-tyrosine phosphatase- (PTP) plays an important role in various cellular signaling events, including proliferation and differentiation. In this study, we established L6 cell lines either underexpressing or overexpressing PTP by stable transfection of cells with antisense PTP or with full-length wild-type human or mouse or double catalytic site Cys  Ala mutant (DM8) PTP cDNA. Expression of PTP in these cell lines was determined by immunoblotting and immunofluorescence. Cells harboring antisense PTP exhibited a significantly reduced growth rate and thymidine incorporation when compared with the wild-type L6 cells. In contrast, cells overexpressing PTP showed more rapid (2-fold) proliferation. Myoblasts with diminished PTP failed to undergo fusion and did not form myotubes in reduced serum whereas overexpression of PTP promoted myogenesis 2 days earlier than wild-type L6 cells. Overexpression of phosphatase-inactive mutant PTP recapitulated the phenotype of the antisense cells. The different myogenic activities of these cell lines were correlated with the expression of myogenin and creatine kinase activity. Consistent with previous reports, PTP positively regulated the activity of the protein-tyrosine kinase Src. Treatment of L6 cells with PP2 or SU6656, specific inhibitors of Src family kinases, and transient transfection of dominant-inhibitory Src inhibited the formation of myotubes and expression of myogenin. Moreover, enhanced expression of PTP and activation of Src was detected during myogenesis. Together, these data indicate that PTP is involved in the regulation of L6 myoblast growth and skeletal muscle cell differentiation via an Src-mediated signaling pathway.

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