JAK3 PROTEIN-TYROSINE KINASE MEDIATES INTERLEUKIN-7-INDUCED ACTIVATION OF PHOSPHATIDYLINOSITOL-3' KINASE

The interleukin-7 (IL-7) receptor is expressed throughout T-cell diffe rentiation and, although lacking a tyrosine kinase domain, mediates ty rosine phosphorylation in T cells. We have identified IL-7-induced act ivation of three cyoplasmic tyrosine kinases in T cells, Jak1, Jak3, a nd the src-like kinase p56lck. Many members of the cytokine receptor s uperfamily activate the Jak protein tyrosine kinase family, with resul tant phosphorylation of the Stat transcriptional activator factors. We describe here a novel function of the Jak kinases, because Jak kinase activity is not only required for Stat activation but also for P13 ki nase response to IL-7 in human T cells. We show that IL-7 receptor-med iated Jak activation can occur independently of p56lck activity. IL-7- induced P13 kinase activation, mediated by tyrosine phosphorylation of the P13 kinase p85 subunit, is essential to the IL-7 proliferative si gnal and also occurs in the absence of src family kinase activity. Jak 3 is found associated with the p85 subunit of P13 kinase in an IL-7-re sponsive manner in T cells and appears to regulate IL-7-induced P13 ki nase activation by mediating tyrosine phosphorylation of the p85 subun it. Specific inhibition of IL-7-induced Jak kinase activity ablates p8 5 tyrosine phosphorylation, subsequent P13 kinase activation, and, ult imately, proliferation. The ability to regulate P13 kinase activity in dicates a more generalized role for the Jak family than activation of gene transcription via the Stat family in cytokine receptor signal tra nsduction. (C) 1995 by The American Society of Hematology.