JAK3 protein tyrosine kinase mediates interleukin-7-induced activation of phosphatidylinositol-3′ kinase

Abstract

The interleukin-7 (IL-7) receptor is expressed throughout T-cell differentiation and, although lacking a tyrosine kinase domain, mediates tyrosine phosphorylation in T cells. We have identified IL-7-induced activation of three cyoplasmic tyrosine kinases in T cells, Jak1, Jak3, and the src-like kinase p56Ick. Many members of the cytokine receptor super-family activate the Jak protein tyrosine kinase family, with resultant 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 PI3 kinase response to IL-7 in human T cells. We show that IL-7 receptor-mediated Jak activation can occur independently of p56Ick activity. IL-7-induced PI3 kinase activation, mediated by tyrosine phosphorylation of the PI3 kinase p85 subunit, is essential to the IL-7 proliferative signal and also occurs in the absence of src family kinase activity. Jak3 is found associated with the p85 subunit of PI3 kinase in an IL-7-responsive manner in T cells and appears to regulate IL-7-induced PI3 kinase activation by mediating tyrosine phosphorylation of the p85 subunit. Specific inhibition of IL-7-induced Jak kinase activity ablates p85 tyrosine phosphorylation, subsequent PI3 kinase activation, and, ultimately, proliferation. The ability to regulate PI3 kinase activity indicates a more generalized role for the Jak family than activation of gene transcription via the Stat family in cytokine receptor signal transduction. © 7995 by The American Society of Hematology.