Disease relevance of TRAF6

• We concluded that Syk is required for the IL-1-induced chemokine production through the association with TRAF-6 in fibroblasts of nasal polyps [1].
• H. pylori activates NF-kappaB through a signaling pathway involving IkappaB kinases, NF-kappaB-inducing kinase, TRAF2, and TRAF6 in gastric cancer cells [2].
• TRAF6-deficient mice display hypohidrotic ectodermal dysplasia [3].
• Activation of TRAF5 and TRAF6 signal cascades negatively regulates the latent replication origin of Epstein-Barr virus through p38 mitogen-activated protein kinase [4].
• MyD88 and TNF receptor-associated factor 6 are critical signal transducers in Helicobacter pylori-infected human epithelial cells [5].
• Activation of NF-kappaB, JNK, and p38, but not IRF3, was impaired in TRAF6-deficient mouse embryo fibroblasts in response to vesicular stomatitis virus and poly(I:C) [6].

High impact information on TRAF6

• We find that TRAF6, a RING domain protein, functions together with Ubc13/Uev1A to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (K63) of ubiquitin [7].
• When it binds to its cell-surface receptor, IL-1 initiates a signalling cascade that leads to activation of the transcription factor NF-kappaB and is relayed through the protein TRAF6 and a succession of kinase enzymes, including NF-kappaB-inducing kinase (NIK) and I kappaB kinases (IKKs) [8].
• Here we report the identification of a new TRAF family member, designated TRAF6 [9].
• Mutation of K485 to R blocked TRAF6 and NGF-dependent polyubiquitination of TrkA, resulting in retention of the receptor on the membrane and an absence in activation of specific signaling pathways [10].
• TAK1 is in turn activated by TRAF6, a RING domain ubiquitin ligase that facilitates the synthesis of lysine 63-linked polyubiquitin chains [11].

Chemical compound and disease context of TRAF6

• Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a crucial signaling transducer that regulates a diverse array of physiological and pathological processes and is essential for activating NF-kappaB signaling pathway in response to bacterial lipopolysaccharide (LPS) [12].

Biological context of TRAF6

• These observations provide novel insight into the mechanisms of CD40 signaling and the multiple roles played by TRAF6 in signal transduction [13].
• Coexpression of TRAF2 with p75(NTR) enhanced cell death, whereas coexpression of TRAF6 was cytoprotective [14].
• The TRAF6 binding site demonstrated more amino acid sequence flexibility and could be optimized [15].
• We produced and stably expressed in mouse B cell lines a human CD40 molecule with two cytoplasmic domain point mutations (hCD40EEAA); this mutant fails to bind TRAF6, while showing normal association with TRAFs 2 and 3 [16].
• Cigarette smoke causes subsequently a concentration-dependent phosphorylation of IRAK and degradation of TRAF6 [17].

Anatomical context of TRAF6

• Likewise, introduction of a dominant-negative TRAF6 into a wild-type (CD40(+)) macrophage cell line resulted in abrogation of CD40-mediated induction of inflammatory cytokine synthesis [18].
• Thus, we examined the role of TRAF6 in CD40-mediated B lymphocyte effector functions using two approaches [16].
• Finally, treatment of monocytes with a cell-permeable peptide corresponding to the TRAF6-binding motif of CD40 inhibited CD40 activation of ERK1/2, IKK, and inflammatory cytokine production [18].
• Moreover, using vectors expressing dominant-negative forms of MyD88 and TRAF6, we established that LPS-induced activation of respiratory epithelial cells is largely dependent on TLR4 signaling intermediates [19].
• We analyzed macrophages from TRAF6-deficient mice and made the following observations [20].

Associations of TRAF6 with chemical compounds

• Tumor necrosis factor receptor-activated factor 6 (TRAF6) and the nuclear factor kappaB (NF-kappaB)-inducing kinase (NIK) are both involved in subsequent steps of NF-kappaB activation [21].
• Conversely, a dominant negative version of TRAF6 failed to block hToll-induced activation of stress-activated protein kinase/c-Jun NH2-terminal kinases, thus suggesting an early divergence of the two pathways [21].
• Lipopolysaccharide initiates a TRAF6-mediated endothelial survival signal [22].
• TRAF6, in turn, enhances the kinase activity of c-Src leading to tyrosine phosphorylation of downstream signaling molecules such as c-Cbl [23].
• Here, we demonstrate that TRANCE activates the antiapoptotic serine/threonine kinase Akt/PKB through a signaling complex involving c-Src and TRAF6 [23].
• We examined the role of the ZF domains in interleukin-1, lipopolysaccharide, and RANKL signaling by reconstitution of TRAF6-deficient cells with point mutations or deletions of these ZF motifs [24].

Physical interactions of TRAF6

• However, single aa substitution of Glu-235 in cyt-N of human CD40 with Ala abolishes the binding of TRAF6 to cyt-N and NFkappaB activation by cyt-N [25].
• We also inducibly expressed in B cells a transfected "dominant-negative" TRAF6 molecule which contains only the C-terminal TRAF-binding domain of TRAF6 [16].
• IL-8-induced NF-kappaB activation is not observed in a cell-permeable peptide that has TRAF6 binding motif-treated cells or IRAK-deficient cells [26].
• Co-immunoprecipitation studies indicated that TRAF6 was able to interact with both Cezanne and TRABID [27].
• Moreover, A20 was shown to directly interact with TRAF6 [28].
• We found that Mal and TRAF6 directly interact in response to TLR2 and TLR4 stimulation, although membrane localization is not necessary to facilitate interaction [29].

Regulatory relationships of TRAF6

• Furthermore, NFkappaB activation by cyt-C is inhibited by a kinase-negative form of NFkappaB-inducing kinase more efficiently than that by cyt-N, consistent with the result that NFkappaB activation by TRAF2 and TRAF5 is inhibited by a kinase-negative form of NFkappaB-inducing kinase more efficiently than that by TRAF6 [25].
• Interleukin-8 induces nuclear transcription factor-kappaB through a TRAF6-dependent pathway [26].
• In contrast, a higher degree of CD40 multimerization was necessary for maximal signaling in a cell line expressing a mutated CD40 (T254A) that signaled only through TRAF6 [30].
• TIFA activates IkappaB kinase (IKK) by promoting oligomerization and ubiquitination of TRAF6 [31].
• These results identify a specific role for Mal in TLR-mediated signaling in regulating NF-kappaB-dependent gene transcription via its interaction with TRAF6 [32].

Other interactions of TRAF6

• These results suggest that CD40 activates ERK by both a Ras-dependent pathway and a Ras-independent pathway in which TRAF6 could be involved [33].
• Furthermore, whereas poly(I.C)-induced NF-kappaB activation is completely abolished inTRAF6-/- MEFs, the signal-induced activation of IRF3 is TRAF6 independent [34].
• Active RasVHa associated with IRAK, IRAK2, and TRAF6, but not MyD88 [35].
• The site also binds TRAF2 and TRAF5, but not TRAF6 [36].
• Second, a truncated version of A52R, which interacted with IRAK2 and not TRAF6, was unable to activate p38 [37].

Analytical, diagnostic and therapeutic context of TRAF6

• TRAF6 is a signal transducer for interleukin-1 [9].
• Similar to A20, ZNF216 interacted with IKKgamma, RIP, and TRAF6 in co-immunoprecipitation experiments [38].
• However, ligation of a CD40 mutant lacking a functional TRAF6 binding site did not initiate inflammatory cytokine production, and this mutant was found to be defective in CD40-mediated activation of ERK1/2, as well as IkappaB kinase (IKK) and NF-kappaB [18].
• Gene targeting experiments have identified several indispensable physiological functions of TRAF6, and structural and biochemical studies have revealed the potential mechanisms of its action [39].
• The binding of TRAF6 was localized to the juxtamembrane region of p75 by co-immunoprecipitation and Western blotting [40].

References