| First Author | Smith GA | Year | 2016 |
| Journal | Nat Chem Biol | Volume | 12 |
| Issue | 5 | Pages | 373-9 |
| PubMed ID | 27018889 | Mgi Jnum | J:327791 |
| Mgi Id | MGI:6875337 | Doi | 10.1038/nchembio.2056 |
| Citation | Smith GA, et al. (2016) Essential biphasic role for JAK3 catalytic activity in IL-2 receptor signaling. Nat Chem Biol 12(5):373-9 |
| abstractText | To drive lymphocyte proliferation and differentiation, common gamma-chain (gammac) cytokine receptors require hours to days of sustained stimulation. JAK1 and JAK3 kinases are found together in all gammac-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 gammac-receptor signaling. |
