title: Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling.
abstract: The cytokines IL-1 and TNF induce expression of a series of genes that regulate inflammation through activation of NF-kappaB signal transduction pathways. TAK1, a MAPKKK, is critical for both IL-1- and TNF-induced activation of the NF-kappaB pathway. TAB2, a TAK1-binding protein, is involved in IL-1-induced NF-kappaB activation by physically linking TAK1 to TRAF6. However, IL-1-induced activation of NF-kappaB is not impaired in TAB2-deficient embryonic fibroblasts. Here we report the identification and characterization of a novel protein designated TAB3, a TAB2-like molecule that associates with TAK1 and can activate NF-kappaB similar to TAB2. Endogenous TAB3 interacts with TRAF6 and TRAF2 in an IL-1- and a TNF-dependent manner, respectively. Further more, IL-1 signaling leads to the ubiquitination of TAB2 and TAB3 through TRAF6. Cotransfection of siRNAs directed against both TAB2 and TAB3 inhibit both IL-1- and TNF-induced activation of TAK1 and NF-kappaB. These results suggest that TAB2 and TAB3 function redundantly as mediators of TAK1 activation in IL-1 and TNF signal transduction.
authors.affiliation: Department of Molecular Biology, Graduate School of Science, Institute for Advanced Research, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Ishitani
authors.forename: Giichi
authors.initials: G
authors.lastname: Takaesu
authors.forename: Jun
authors.initials: J
authors.lastname: Ninomiya-Tsuji
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shibuya
authors.forename: Richard B
authors.initials: RB
authors.lastname: Gaynor
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Matsumoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000502:physiology*; D003001:Cloning, Molecular; D017931:DNA Primers; D004330:Drosophila / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000517:prevention & control; D007375:Interleukin-1 / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011506:Proteins / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D017931:DNA Primers; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D011506:Proteins; D011994:Recombinant Proteins; C410585:TAB2 protein, human; C481053:TAB3 protein, human; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha