A COMMON REQUIREMENT FOR THE CATALYTIC ACTIVITY AND BOTH SH2 DOMAINS OF SHP-2 IN MITOGEN-ACTIVATED PROTEIN (MAP) KINASE ACTIVATION BY THE ERBB FAMILY OF RECEPTORS - A SPECIFIC ROLE FOR SHP-2 IN MAP, BUT NOT C-JUN AMINO-TERMINAL KINASE ACTIVATION

The ErbB family of receptors, which include the epidermal growth facto r receptor (EGFR), ErbB2, ErbB3, and ErbB4 mediate the actions of a fa mily of bioactive polypeptides. EGF signals through EGFR, whereas here gulin (HRG) signaling is initiated through binding to either ErbB3 or ErbB4. In this report we studied the role of protein-tyrosine phosphat ase SHP-2 in ErbB-mediated activation of mitogen-activated protein kin ase (MAPK) by overexpressing SHP-2 mutants in COS-7 cells. We demonstr ate that enzymatic activity and both NH2- and COOH-terminal SH2 domain s of SHP-2 are required for EGF-induced MAPK activation, but not for c -Jun amino-terminal kinase stimulation or MAPK activation which occurr ed in response to myristoylated son of sevenless, activated Ras, or ph orbol ester. Dominant-negative forms of SHP-2 had no effect on EGF-sti mulated interaction of GRB2 with EGFR or SHC, nor did they influence p hosphorylation of SHC and SHC/EGFR association. The same mutant SHP-2 structures that inhibited EGF-mediated stimulation of MAPK also blocke d HRG alpha/beta-induced MAPK activation. EGF or HRG beta caused SHP-2 SH2 domains to engage multiple phosphotyrosine proteins, and mutation of either domain disrupted these associations. These results demonstr ate that SHP-2 performs a common and essential function(s) in ligand-s timulated MAPK activation by the ErbB family of receptors.