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

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 p56lck. Many members of the cytokine receptor superfamily 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 P13 kinase response to IL-7 in human T cells. We show that IL-7 receptor-mediated 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 signal and also occurs in the absence of Src family kinase activity. JAK3 is found associated with the p85 subunit of P13 kinase in an IL-7-responsive manner in T cells and appears to regulate IL-7-induced P13 kinase activation by mediating tyrosine phosphorylation of the p85 subunit. Specific inhibition of IL-7-induced JAK kinase activity ablates p85 tyrosine phosphorylation, subsequent P13 kinase activation, and, ultimately, proliferation. The ability to regulate P13 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.