| First Author | Motegi H | Year | 2011 |
| Journal | Genes Cells | Volume | 16 |
| Issue | 2 | Pages | 179-89 |
| PubMed ID | 21155952 | Mgi Jnum | J:186969 |
| Mgi Id | MGI:5433832 | Doi | 10.1111/j.1365-2443.2010.01474.x |
| Citation | Motegi H, et al. (2011) TRAF6 negatively regulates the Jak1-Erk pathway in interleukin-2 signaling. Genes Cells 16(2):179-89 |
| abstractText | Tumor necrosis factor receptor-associated factor 6 (TRAF6) plays a critical role in establishing both innate and acquired immune responses by mediating signals from the TNF superfamily, the TLR/IL-1R family, and the T-cell receptor. Here, we report a previously unidentified function of TRAF6 in IL-2 signaling. CD3/CD28 stimulation-induced proliferation and Il2 mRNA expression in Traf6(-/-) CD4(+) T cells were dramatically enhanced. This enhancement is likely due to hyperactive IL-2 signaling, in which activation of the Jak1-Erk pathway was enhanced and the subsequent Fos gene expression was up-regulated. To elucidate the molecular mechanisms of the enhanced activation of Jak1, IL-2 signaling was reconstituted in mouse embryonic fibroblast (MEF) cells to investigate the interaction between TRAF6 and the TRAF6-binding site that overlaps with the Jak1-binding site present in the IL-2R beta-chain. The Jak1-Erk pathway was activated upon IL-2 stimulation in Traf6(-/-) MEF cells, while a beta-chain mutation that inactivates TRAF6 binding but retains Jak1 binding abrogated the TRAF6-dependent reduction in IL-2 signaling. These results indicate that the binding of TRAF6 to the TRAF6-binding site of the beta-chain negatively regulates IL-2-induced Jak1 activation, which is likely to be involved in the proper regulation of T-cell activation and development. |
