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 factor receptor (EGFR), ErbB2, ErbB3, and ErbB4 mediate the actions of a family of bioactive polypeptides. EGF signals through EGFR, whereas heregulin (HRG) signaling is initiated through binding to either ErbB3 or ErbB4. In this report we studied the role of protein-tyrosine phosphatase SHP-2 in ErbB-mediated activation of mitogen-activated protein kinase (MAPK) by overexpressing SHP-2 mutants in COS-7 cells. We demonstrate that enzymatic activity and both NH2- and COOH-terminal SH2 domains of SHP-2 are required for EGF-induced MAPK activation, but not for c-Jun amino-terminal kinase stimulation or MAPK activation which occurred in response to myristoylated son of sevenless, activated Ras, or phorbol ester. Dominant-negative forms of SHP-2 had no effect on EGF-stimulated interaction of GRB2 with EGFR or SHC, nor did they influence phosphorylation of SHC and SHC/EGFR association. The same mutant SHP-2 structures that inhibited EGF-mediated stimulation of MAPK also blocked 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 demonstrate that SHP-2 performs a common and essential function(s) in ligand-stimulated MAPK activation by the ErbB family of receptors.
Deb
T B
TB
Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
Wong
L
L
Salomon
D S
DS
Zhou
G
G
Dixon
J E
JE
Gutkind
J S
JS
Thompson
S A
SA
Johnson
G R
GR
D000818:Animals; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002384:Catalysis; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000378:metabolism*; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D018909:src Homology Domains
D047908:Intracellular Signaling Peptides and Proteins; D066246:ErbB Receptors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases