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_7 label "Selventa" provenance.
large_corpus.bel title "BEL Framework Large Corpus Document" provenance.
large_corpus.bel description "Approximately 61,000 statements." provenance.
large_corpus.bel version "1.4" provenance.
large_corpus.bel authoredBy _7 provenance.
assertion wasDerivedFrom large_corpus.bel provenance.
assertion wasDerivedFrom _6 provenance.
assertion hadPrimarySource 15229469 provenance.
_6 wasQuotedFrom 15229469 provenance.
_6 value "In IRAK1-deficient mice, cytokine production in response to IL-1 and LPS was diminished but not abolished25-27, whereas IRAK4-deficient mice showed virtually no response to IL-1, LPS or other bacterial components, demonstrating that IRAK4 has an important role in IL-1R/TLR signalling28. Recently, patients with an inherited IRAK4 deficiency have been identified29. These patients failed to respond to IL-1, to IL-18 or to stimulation of each of five TLRs (TLR2, TLR3, TLR4, TLR5 and TLR9). Together, these results show that IRAK4 and its kinase activity are required for TLR signalling and that IRAK4 functions upstream of IRAK1. TRAF6. TRAFs constitute a family of evolutionarily conserved adaptor proteins30. So far, six members of the TRAF family have been identified in mammals, and they are characterized by the presence of an N-terminal coiled-coil domain (known as TRAF-N) and a conserved C-terminal domain (known as TRAF-C). The N-terminal portion of most TRAF proteins contains a RING (really interesting new gene)-finger/zinc-finger region, which is essential for downstream signalling events, whereas the TRAF-C domain mediates self-association and interactions with upstream receptors and signalling proteins. TRAF6 functions as a signalling mediator for both the TNF-receptor superfamily and the TLR/IL-1R superfamily, interacting directly with members of the TNF-receptor superfamily (CD40 and TNF-related activation-induced cytokine receptor, TRANCER) or being coupled indirectly to TLR/IL-1R superfamily members through its association with IRAKs. The consensus sequence for the TRAF6-binding domain has been identified as P-X-E-X-X-(D/E/F/W/Y)31. This motif is found in CD40, TRANCER, and the IRAKs; three of these TRAF6-binding motifs are found in IRAK1, two in IRAK2 and one in IRAK-M. TAK1 and TABs. The activation by TRAF6 of the transcription factors NF-kB and activator protein 1 (AP1) involves TAK1 and two adaptor proteins TAB1 and TAB2. TAK1 is a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family32, which has been shown to be essential for both IL-1/LPS- and TNF-induced NF-kB activation33. Two TAK1-binding proteins, TAB1 and TAB2, have been identified34, 35. When co-expressed ectopically, TAB1 enhances the kinase activity of TAK1, indicating that TAB1 functions as an activator of TAK134. By contrast, TAB2 functions as an adaptor, linking TAK1 to TRAF6 and thereby facilitating TAK1 activation35. However, embryonic fibroblasts obtained from TAB2-deficient mice show no impairment in either IL-1/LPS- or TNF-induced activation of NF-kB36. Furthermore, a new TAB2-like molecule, TAB3, has been identified recently, and similar to TAB2, it has been shown to associate with TAK1 and activate NF-kB37. Co-transfection of SMALL INTERFERING RNAS (siRNAs) directed against both TAB2 and TAB3 inhibited both IL-1- and TNF-induced activation of TAK1 and NF-kB, indicating that TAB2 and TAB3 function redundantly as mediators of TAK1 activation. It has been shown that UBIQUITYLATION has an important role in TAK1 activation and that TRAF6 functions as an E3 ubiquitin ligase38. TRAF6 can interact through its RING-finger domain with ubiquitin-conjugating enzyme 13 (UBC13), and this UBC13-TRAF6 complex triggers TAK1 activation through the assembly of a lysine63-linked polyubiquitin chain39. NF-kB. The NF-kB family of transcription factors is composed of five members - p65 (REL-A), REL-B, cytoplasmic (c) REL, p50 and p52 - which function as homo- and heterodimers. NF-kB dimers are usually sequestered in the cytoplasm in an inactive form by molecules of the inhibitor of NF-kB (IB) family. Activation of NF-kB involves the phosphorylation and proteolysis of the IB proteins and the concomitant release and nuclear translocation of the NF-kB factors. This acute activation process is mediated by the IB kinase (IKK) complex, which comprises two catalytic subunits - IKK- and IKK- (also kn..." provenance.