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.
Sharfe
N
N
Division of Immunology and Allergy, Hospital for Sick Children, University of Toronto, Ontario, Canada.
Dadi
H K
HK
Roifman
C M
CM
D000595:Amino Acid Sequence; D002648:Child; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015851:Interleukin-7 / Q000494:pharmacology*; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D008969:Molecular Sequence Data; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology; D020032:Tyrphostins
D015851:Interleukin-7; D009570:Nitriles; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)