title: TRAF6 negatively regulates the Jak1-Erk pathway in interleukin-2 signaling.
abstract: 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 β-chain. The Jak1-Erk pathway was activated upon IL-2 stimulation in Traf6(-/-) MEF cells, while a β-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 β-chain negatively regulates IL-2-induced Jak1 activation, which is likely to be involved in the proper regulation of T-cell activation and development.
authors.affiliation: Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Motegi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shimo
authors.forename: Taishin
authors.initials: T
authors.lastname: Akiyama
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Inoue
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D018014:Gene Transfer Techniques; D057809:HEK293 Cells; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism*; D053646:Interleukin-2 Receptor beta Subunit / Q000378:metabolism*; D053613:Janus Kinase 1 / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008817:Mice, Mutant Strains; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D007376:Interleukin-2; D053646:Interleukin-2 Receptor beta Subunit; D011948:Receptors, Antigen, T-Cell; D048029:TNF Receptor-Associated Factor 6; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D048049:Extracellular Signal-Regulated MAP Kinases