SHP1 AND SHP2 PROTEIN-TYROSINE PHOSPHATASES ASSOCIATE WITH BETA-C AFTER INTERLEUKIN-3-INDUCED RECEPTOR TYROSINE PHOSPHORYLATION - IDENTIFICATION OF POTENTIAL BINDING-SITES AND SUBSTRATES

The cytoplasmic tyrosine phosphatases, SHP1 and SHP2, are implicated i n the control of cellular proliferation and survival. Here we demonstr ate that both SHP1 and SHP2 associate with the beta c subunit of the h uman interleukin-3 (IL-3) receptor following IL-3 stimulation and that the src homology region 2 (SH2) domains of these phosphatases mediate this interaction. Sequential immunoprecipitation analyses suggest thi s interaction is direct. Competition studies, using phosphotyrosine-co ntaining peptides based on sequences surrounding key tyrosine residues within beta c, suggest that phosphorylation of tyrosine 612 is the ke y event mediating the association of beta c with SHP1 and SHP2. Howeve r, inhibition of SHP2 binding to beta c, did not prevent tyrosine phos phorylation of SHP2. interestingly, this same phosphopeptide served as a substrate for the tyrosine phosphatase activity of both SHP1 and SH P2. Binding of these protein-tyrosine phosphatases to the IL-3 recepto r may regulate IL-3 signal transduction pathways, both through their c atalytic activity and through the recruitment of other molecules to th e receptor complex.