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CUTTING EDGE |
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Lymphocyte Cell Biology Section, Arthritis and Rheumatism Branch, National Institute of Arthritis Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Division of Cytokine Biology, Bethesda, MD 20814
Binding of IL-2 to its receptor activates several biochemical pathways, but precisely how these pathways are linked is incompletely understood. Here, we report that SHP-2, an SH2-domain containing tyrosine phosphatase, associates with different molecules of the IL-2 signaling cascade. Upon IL-2 stimulation, SHP-2 was coimmunoprecipitated with Grb2 and the p85 subunit of phosphatidylinositol 3-kinase. In contrast, SHP-2 was constitutively associated with JAK1 and JAK3. Finally, SHP-2 expression amplified STAT-dependent transcriptional activation whereas a dominant negative allele inhibited transactivation and the IL-2-induced activation of MAPK (mitogen-activated protein kinase). These results demonstrate the involvement of SHP-2 in multiple pathways of the IL-2 signaling cascade and provide evidence for its positive regulatory role.
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