TRAF6 binds MEKK1 Dissociation of hp-IRAK1:TRAF6 or IRAK2:TRAF6-oligomer from the activated TLR5 or 10:oligo-Myd88:p-IRAK4 complex IRAK4 autophosphorylation within the complex activated TLR:MyD88 IRAK4 binds to MyD88 bound to the activated TLR5 or 10 receptor Phosphorylation of IRAK2 bound to the activated IRAK4:MyD88 oligomerl:activated TLR5 or 10 complex IRAK1/or IRAK2 binds to the activated IRAK4 :oligo MyD88:activated TLR5 or 10 complex MyD88 oligomerization within the complex of activated TLR:MyD88 MyD88 forms a complex with the activated TLR receptor First phosphorylation of IRAK1 by IRAK4 bound to MyD88:activated TLR Second phosphorylation of IRAK1 by IRAK4 bound to MyD88:activated TLR complex Multiple IRAK1 autophosphorylation within the complex p-IRAK4:oligo MyD88:activated TLR TRAF6 binds to hp- IRAK1 or p-IRAK2 PathwayStep6680 PathwayStep6686 PathwayStep6685 PathwayStep6688 PathwayStep6687 PathwayStep6682 PathwayStep6681 PathwayStep6684 PathwayStep6683 PathwayStep6678 PathwayStep6679 PathwayStep6693 PathwayStep6699 PathwayStep6700 MAP kinase activation in TLR cascade TAK1 activates NFkB by phosphorylation and activation of IKKs complex IRAK2 mediated activation of TAK1 complex IRAK1 recruits IKK complex MyD88 cascade initiated on plasma membrane Authored: Shamovsky, V, 2010-10-06 Edited: Shamovsky, V, 2011-08-12 GENE ONTOLOGYGO:0002755 Mammalian myeloid differentiation factor 88 (MyD88) is Toll/interleukin (IL)-1 (TIR)-domain containing adapter protein which plays crucial role in TLR signaling. All TLRs, with only one exception of TLR3, can initiate downstream signaling trough MyD88. In the MyD88 - dependent pathway, once the adaptor is bound to TLR it leads to recruitment of IL1 receptor associated kinase family – IRAK which is followed by activation of tumour necrosis factor receptor-associated factor 6 (TRAF6) . TRAF6 is an ubiquitin E3 ligase which in turn induces TGF-beta activating kinase 1 (TAK1) auto phosphorylation. Once activated TAK1 can ultimately mediate the induction of the transcription factor NF-kB or the mitogen-activated protein kinases (MAPK), such as JNK, p38 and ERK. This results in the translocation of the activated NF-kB and MAPKs to the nucleus and the initiation of appropriate gene transcription leading to the production of many proinflammatory cytokines and antimicrobial peptides. Pubmed10435584 Pubmed15728506 Pubmed16239509 Pubmed9430229 Reactome Database ID Release 43975871 Reactome, http://www.reactome.org ReactomeREACT_27215 Reviewed: Gillespie, ME, 2011-02-10 Reviewed: Li, L, 2011-08-04 PathwayStep3439 PathwayStep3485