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Essential biphasic role for JAK3 catalytic activity in IL-2 receptor signaling.

ABSTRACT: To drive lymphocyte proliferation and differentiation, common ?-chain (?c) cytokine receptors require hours to days of sustained stimulation. JAK1 and JAK3 kinases are found together in all ?c-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 ?c-receptor signaling.

PROVIDER: S-EPMC4837022 | BioStudies |

REPOSITORIES: biostudies

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