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TRAF6 negatively regulates the Jak1‐Erk pathway in interleukin‐2 signaling
Author(s) -
Motegi Hidehiko,
Shimo Yusuke,
Akiyama Taishin,
Inoue Junichiro
Publication year - 2011
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2010.01474.x
Subject(s) - biology , microbiology and biotechnology , signal transduction , mapk/erk pathway , co stimulation , receptor , tumor necrosis factor alpha , t cell , cd28 , immune system , immunology , biochemistry
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.