title: Essential biphasic role for JAK3 catalytic activity in IL-2 receptor signaling.
abstract: To drive lymphocyte proliferation and differentiation, common γ-chain (γc) cytokine receptors require hours to days of sustained stimulation. JAK1 and JAK3 kinases are found together in all γc-receptor complexes, but how their respective catalytic activities contribute to signaling over time is not known. Here we dissect the temporal requirements for JAK3 kinase activity with a selective covalent inhibitor (JAK3i). By monitoring phosphorylation of the transcription factor STAT5 over 20 h in CD4(+) T cells stimulated with interleukin 2 (IL-2), we document a second wave of signaling that is much more sensitive to JAK3i than the first wave. Selective inhibition of this second wave is sufficient to block cyclin expression and entry to S phase. An inhibitor-resistant JAK3 mutant (C905S) rescued all effects of JAK3i in isolated T cells and in mice. Our chemical genetic toolkit elucidates a biphasic requirement for JAK3 kinase activity in IL-2-driven T cell proliferation and will find broad utility in studies of γc-receptor signaling.
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA.|Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Geoffrey A
authors.identifier: http://orcid.org/0000-0002-1638-4219
authors.initials: GA
authors.lastname: Smith
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Kenji
authors.initials: K
authors.lastname: Uchida
authors.affiliation: Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.|Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Weiss
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Taunton
mesh_terms: D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D007371:Interferon-gamma; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D053616:Janus Kinase 3 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D007371:Interferon-gamma; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3