PHOSPHOTYROSINE-1173 MEDIATES BINDING OF THE PROTEIN-TYROSINE-PHOSPHATASE SHP-1 TO THE EPIDERMAL GROWTH-FACTOR RECEPTOR AND ATTENUATION OF RECEPTOR SIGNALING

The protein-tyrosine phosphatase SHP-1 binds to and dephosphorylates t he epidermal growth factor receptor (EGFR), and both SH2 domains of SH P-1 are important for this interaction (Tenev, T., Keilhack, H., Tomic , S., Stoyanov, B., Stein-Gerlach, M., Lammers, R., Krivtsov, A. V., U llrich, A., and Bohmer, F. D. (1997) J. Biol, Chem. 272, 5966-5973). W e mapped the EGFR phosphotyrosine 1173 as the major binding site for S HP-1 by a combination of phosphopeptide activation, phosphopeptide com petition, and receptor YF mutant analysis. Mutational conversion of th e EGFR sequence 1171-1176 AEY-LRV into the high affinity SHP-1 binding sequence LEY-LYL of the erythropoietin receptor (EpoR) led to a highl y elevated SHP-1 binding to the mutant EGFR (EGFR(1171-1176EpoR)) and in torn to an enhanced dephosphorylation of the receptor. SHP-1 expres sion interfered with EGF-dependent mitogen-activated protein kinase st imulation, and this effect was more pronounced in case of EGFR(1171-11 76EpoR). Reduced SHP-1 binding to the EGFR Y1173F mutant resulted in a reduced receptor dephosphorylation by coexpressed SHP-1 and less inte rference with EGF-dependent mitogen-activated protein kinase stimulati on. The effects of receptor mutations on SHP-1 binding were, however, stronger than those on receptor dephosphorylation by SHP-1. Therefore, receptor dephosphorylation may be the result of the combined activity of receptor-bound SHP-1 and SHP-1 bound to an auxiliary docking prote in.