SHP-2 complex formation with the SHP-2 substrate-1 during C2C12 myogenesis.
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(1/2) 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.
Kontaridis
M I
MI
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8066, USA.
Liu
X
X
Zhang
L
L
Bennett
A M
AM
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation; D002454:Cell Differentiation; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008970:Molecular Weight; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D017570:MyoD Protein / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1; D019006:Neural Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011971:Receptors, Immunologic; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D015398:Signal Transduction / Q000187:drug effects; D013002:Somatomedins / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; C490897:Gab1 protein, mouse; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D017570:MyoD Protein; D039842:Neural Cell Adhesion Molecule L1; D019006:Neural Cell Adhesion Molecules; D010750:Phosphoproteins; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic; D013002:Somatomedins; D019000:Phosphotyrosine; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases