Abstract
The cytoplasmic tyrosine phosphatases, SHP1 and SHP2, are implicated in the control of cellular proliferation and survival. Here we demonstrate that both SHP1 and SHP2 associate with the betac subunit of the human 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 this interaction is direct. Competition studies, using phosphotyrosine-containing peptides based on sequences surrounding key tyrosine residues within betac, suggest that phosphorylation of tyrosine 612 is the key event mediating the association of betac with SHP1 and SHP2. However, inhibition of SHP2 binding to betac, did not prevent tyrosine phosphorylation of SHP2. Interestingly, this same phosphopeptide served as a substrate for the tyrosine phosphatase activity of both SHP1 and SHP2. Binding of these protein-tyrosine phosphatases to the IL-3 receptor may regulate IL-3 signal transduction pathways, both through their catalytic activity and through the recruitment of other molecules to the receptor complex.
Highlights
The cytoplasmic tyrosine phosphatases, SHP1 and SHP2, are implicated in the control of cellular proliferation and survival
In this study we have demonstrated that the tyrosine phosphatases SHP1 and SHP2 can both bind inducibly to c following IL-3 stimulation
This association appears to be directly mediated by interactions between the src homology region 2 (SH2) domains of SHP1 and SHP2 and phosphotyrosine residues within c
Summary
The cytoplasmic tyrosine phosphatases, SHP1 and SHP2, are implicated in the control of cellular proliferation and survival. This same phosphopeptide served as a substrate for the tyrosine phosphatase activity of both SHP1 and SHP2 Binding of these protein-tyrosine phosphatases to the IL-3 receptor may regulate IL-3 signal transduction pathways, both through their catalytic activity and through the recruitment of other molecules to the receptor complex. Activation of certain hemopoietic growth factor receptors by their ligands results in the association of SHP1 with the EpoR, via tyrosine 429 [18, 19], c-kit [20], and the murine IL-3 receptor  subunit, Aic2A [17], the sites of interaction with which are not currently known. SHP2 may have an additional function as an adaptor molecule, because following treatment of responsive cells with PDGF, SCF, Epo, or IL-3, Grb, via its SH2 domain, associates with tyrosine-phosphorylated SHP2 [7, 28, 29, 38]. SHP2 itself binds to the PDGFR, c-kit, and EpoR, resulting in the localization of Grb to the membrane and may influence the ras pathway
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