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All rights reserved. http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/dc/elements/1.1/title BEL Framework Large Corpus Document http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/pav/authoredBy http://www.tkuhn.ch/bel2nanopub/RAbHsmXiAN7ORc-yfRHjvBa6N9JjU_q9clROKL5XqcJAU#_7 http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/pav/version 1.4 http://www.tkuhn.ch/bel2nanopub/RAbHsmXiAN7ORc-yfRHjvBa6N9JjU_q9clROKL5XqcJAU#_6 http://www.w3.org/ns/prov#value MyD88 also interacts directly with AKT, and a dominant-negative mutant of AKT causes a defect in MyD88-dependent NF-kB transcriptional activity. However, the binding of NF-kB to DNA is not affected by inhibiting AKT, indicating that AKT might be involved in the phosphorylation of the p65 transactivation domain. A dominant-negative mutant of MyD88 was shown to block the kinase activity of AKT generated in response to LPS and IL-1, and a dominant-negative mutant of p85 inhibited the NF-kB activity elicited by LPS and IL-1 but not that elicited by TNF85. These findings indicate that PI3K is a positive mediator of the signalling induced by LPS and IL-1 that leads to NF-kB activation. However, recent studies using mice that lack the p85 regulatory subunit showed an increased production of IL-12 by DCs, possibly because of enhanced activation of the p38 MAPK, indicating that PI3K might have a negative role in TLR signalling in DCs86. ECSIT. ECSIT has no homology with any known protein and was cloned as a TRAF6-interacting protein by yeast two-hybrid screening87. ECSIT interacts with the conserved TRAF domain of TRAF6. A Drosophila homologue of ECSIT has been identified, and the interaction between TRAF6 and ECSIT is also conserved in Drosophila. ECSIT also interacts with MEKK1 (MAPK/ERK (extracellular signal-regulated kinase) kinase kinase 1), which can phosphorylate and activate the IKK complex. Expression of a dominant-negative mutant of ECSIT blocks signalling through TLR4, indicating that ECSIT might transduce TLR signals by bridging TRAF6 and the IKK complex. Furthermore, the inhibition of ECSIT expression, using siRNA in a macrophage cell line, resulted in impaired LPS-induced, but not TNF-induced, NF-kB activation88. The physiological function of ECSIT was studied by generating ECSIT-deficient mice, which were found to die on about embryonic day 7.5 (Ref. 88). Further characterization showed that ECSIT is an obligatory intermediate in bone morphogenetic protein (BMP) signalling, and therefore ECSIT is an essential component in both the TLR- and BMP-signalling pathways. SRC family of tyrosine kinases. Bruton's tyrosine kinase (BTK) is a member of the SRC-related TEC-family of protein tyrosine kinases and has an essential role in B-cell development and B-cell receptor (BCR)-mediated signalling. Macrophages from X-linked-immunodeficient mice that lack BTK show reduced responses to LPS, and BTK has also been found to associate with the TIR domain of TLR4,TLR6, TLR8 and TLR9 (Ref. 89). It has also been shown to associate with MyD88, TIRAP and IRAK1, and to be tyrosine phosphorylated in response to LPS, whereas a dominant-negative form of BTK inhibits LPS-induced activation of NF-kB, indicating that BTK is involved in the TLR-mediated signalling pathway. During BCR-mediated signalling, BTK interacts with and is activated by the SRC family of tyrosine kinases, such as FYN, LYN and haematopoietic-cell kinase, HCK; however, SRC-family kinases have only a minor role in LPS signalling90. Therefore, the involvement of BTK in TLR signalling needs to be further investigated. MAPKKK. Members of the MAPKKK family - such as TAK1, MEKK1, MEKK2, MEKK3, TPL2 (tumour-progression locus 2; also known as cancer Osaka thyroid, COT) and NIK - are implicated in IKK-NF-kB and MAPK activation. Among these members, MEKK3 has been shown to be involved in signalling through TLR4 but not through TLR9 (Ref. 91): in response to stimulation with a TLR4 ligand but not a TLR9 ligand, embryonic fibroblasts from MEKK3-deficient mice were shown to have impaired IL-6 production and defective activation of NF-kB, JNK and the p38 MAPK. Stimulation of TLR4 also induced association of MEKK3 with TRAF6. So, MEKK3 is involved in the TLR4-mediated signalling pathway. Another member of the MKKK family, TPL2 has been shown to be involved in the TLR4-mediated activation of ERK92. 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