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Published online 2 October 2006. doi:10.1083/jcb.200602029
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 175, Number 1, 87-97
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Article

SHP-2 activates signaling of the nuclear factor of activated T cells to promote skeletal muscle growth



Mara Fornaro1, Peter M. Burch1, Wentian Yang3, Lei Zhang1, Claire E. Hamilton1, Jung H. Kim2, Benjamin G. Neel3, and Anton M. Bennett1

1 Department of Pharmacology and 2 Department of Pathology, Yale University School of Medicine, New Haven, CT 06520
3 Division of Hematology and Oncology, Department of Medicine, Cancer Biology Program, Beth Israel Deaconess Center, Boston, MA 02115

Correspondence to Anton M. Bennett: anton.bennett{at}yale.edu

The formation of multinucleated myofibers is essential for the growth of skeletal muscle. The nuclear factor of activated T cells (NFAT) promotes skeletal muscle growth. How NFAT responds to changes in extracellular cues to regulate skeletal muscle growth remains to be fully defined. In this study, we demonstrate that mice containing a skeletal muscle–specific deletion of the tyrosine phosphatase SHP-2 (muscle creatine kinase [MCK]–SHP-2 null) exhibited a reduction in both myofiber size and type I slow myofiber number. We found that interleukin-4, an NFAT-regulated cytokine known to stimulate myofiber growth, was reduced in its expression in skeletal muscles of MCK–SHP-2–null mice. When SHP-2 was deleted during the differentiation of primary myoblasts, NFAT transcriptional activity and myotube multinucleation were impaired. Finally, SHP-2 coupled myotube multinucleation to an integrin-dependent pathway and activated NFAT by stimulating c-Src. Thus, SHP-2 transduces extracellular matrix stimuli to intracellular signaling pathways to promote skeletal muscle growth.

M. Fornaro and P.M. Burch contributed equally to this paper.

M. Fornaro's present address is Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland.

Abbreviations used in this paper: CSA, cross-sectional area; CSK, C-terminal Src kinase; DM, differentiation medium; DN, dominant negative; Erk, extracellular-regulated kinase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GM, growth medium; IL, interleukin; MCK, muscle creatine kinase; MHC, myosin heavy chain; NFAT, nuclear factor of activated T cells; NGS, normal goat serum; PTP, protein tyrosine phosphatase; SFK, Src family kinase; SIRP-1{alpha}, signal regulatory protein-1{alpha}; TA, tibialis anterior; WT, wild type.


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