INTERLEUKIN (IL)-3 AND GRANULOCYTE MACROPHAGE COLONY-STIMULATING FACTOR, BUT NOT IL-4, INDUCE TYROSINE PHOSPHORYLATION, ACTIVATION, AND ASSOCIATION OF SHPTP2 WITH GRB2 AND PHOSPHATIDYLINOSITOL 3'-KINASE/

Binding of interleukin (IL)-3 and granulocyte/macrophage colony stimul ating factor (GM-CSF) to their high affinity cell surface receptors in duces tyrosine phosphorylation of a similar set of protein substrates. We have identified one of these common substrates (p70) as the protei n-tyrosine phosphatase SHPTP2. The Src homology 2 (SH2) domain of the adaptor protein Grb2 bound with high affinity to tyrosinephosphorylate d SHPTP2 following treatment of cells with IL-3 or GM-CSF, but not IL- 4. This interaction was inhibited by two phosphotyrosine peptides, bas ed on sequences within SHPTP2, which conform to the postulated consens us sequence for Grb2 SH2 recognition. Following treatment with IL-3 or GM-CSF, but not IL-4, SHPTP2 co-immunoprecipitated with antibodies di rected against the p85 subunit of PI 3'-kinase. This was partially blo cked by the same phosphopeptides that blocked Grb2-SH2 binding to SRPT P2. Importantly treatment with IL-3 resulted in a 2-3-fold increase in SHPTP2 phosphatase activity. These results suggest that SHPTP2 may pl ay an important role in integrating signals from the IL-3 and GM-CSF r eceptors to both Ras and PI 3'-kinase.