20038579

pubmed:Citation

8

Transforming growth factor-beta-activated kinase 1 (TAK1) plays an essential role in the tumor necrosis factor alpha (TNFalpha)- and interleukin-1beta (IL-1beta)-induced IkappaB kinase (IKK)/nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK)/activator protein 1 (AP-1) activation. Here we report that TNFalpha and IL-1beta induce Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue within the kinase domain. Tumor necrosis factor receptor-associated factors 2 and 6 (TRAF2 and -6) act as the ubiquitin E3 ligases to mediate Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue in vivo and in vitro. Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue is required for TAK1-mediated IKK complex recruitment. Reconstitution of TAK1-deficient mouse embryo fibroblast cells with TAK1 wild type or a TAK1 mutant containing a K158R mutation revealed the importance of this site in TNFalpha and IL-1beta-mediated IKK/NF-kappaB and JNK/AP-1 activation as well as IL-6 gene expression. Our findings demonstrate that Lys(63)-linked polyubiquitination of TAK1 at Lys(158) is essential for its own kinase activation and its ability to mediate its downstream signal transduction pathways in response to TNFalpha and IL-1beta stimulation.

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http://linkedlifedata.com/resource/pubmed/journal/2985121R

http://linkedlifedata.com/resource/pubmed/chemical/I-kappa B Kinase, http://linkedlifedata.com/resource/pubmed/chemical/IL6 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-1beta, http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-6, http://linkedlifedata.com/resource/pubmed/chemical/JNK Mitogen-Activated Protein..., http://linkedlifedata.com/resource/pubmed/chemical/Lysine, http://linkedlifedata.com/resource/pubmed/chemical/MAP Kinase Kinase Kinases, http://linkedlifedata.com/resource/pubmed/chemical/MAP kinase kinase kinase 7, http://linkedlifedata.com/resource/pubmed/chemical/NF-kappa B, http://linkedlifedata.com/resource/pubmed/chemical/TNF Receptor-Associated Factor 2, http://linkedlifedata.com/resource/pubmed/chemical/TNF Receptor-Associated Factor 6, http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factor AP-1, http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha, http://linkedlifedata.com/resource/pubmed/chemical/Ubiquitin-Protein Ligases

Feb

pubmed-author:VigPP, pubmed-author:JinS GSG, pubmed-author:ToyP HPH, pubmed-author:ZhangHongH, pubmed-author:SchneiderMichael DMD, pubmed-author:YangYuY, pubmed-author:FuSongbinS, pubmed-author:ChangAlexA, pubmed-author:GeNinglingN