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SHP-2 complex formation with the SHP-2 substrate-1 during C2C12 myogenesis

Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8066, USA

*Author for correspondence (e-mail: anton.Bennett{at}yale.edu)

Accepted March 13, 2001

Myogenesis is a highly ordered process that involves the expression of muscle-specific genes, cell-cell recognition and multinucleated myotube formation. Although protein tyrosine kinases have figured prominently in myogenesis, the involvement of tyrosine phosphatases in this process is unknown. SHP-2 is an SH2 domain-containing tyrosine phosphatase, which positively regulates growth and differentiation. We show that in C2C12 myoblasts, SHP-2 becomes upregulated early on during myogenesis and associates with a 120 kDa tyrosyl-phosphorylated complex. We have identified that the 120 kDa complex consists of the SHP-2 substrate-1 (SHPS-1) and the Grb2-associated binder-1 (Gab-1). SHPS-1, but not Gab-1, undergoes tyrosyl phosphorylation and association with SHP-2 during myogenesis, the kinetics of which correlate with the expression of MyoD. Either constitutive expression or inducible activation of MyoD in 10T fibroblasts promotes SHPS-1 tyrosyl phosphorylation and its association with SHP-2. It has been shown that p38 mitogen-activated protein kinase (MAPK) activity is required for the expression/activation of MyoD and MyoD-responsive genes. Inhibition of p38 MAPK by SB203580 in differentiating C2C12 myoblasts blocks MyoD expression, SHPS-1 tyrosyl phosphorylation and the association of SHPS-1 with SHP-2. These data suggest that SHPS-1/SHP-2 complex formation is an integral signaling component of skeletal muscle differentiation.

Key words: SHP-2, Tyrosine phosphatase, Myogenesis, Signalling, Myoblast, SHPS-1

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