Phosphorylation of IRAK2 bound to the activated IRAK4:MyD88 oligomer:Mal:activated TLR complex Second phosphorylation of IRAK1 by IRAK4 bound to activated TLR:MyD88:Mal First phosphorylation of IRAK1 by IRAK4 bound to activated TLR:MyD88:Mal TRAF6 binds to hp- IRAK1 Multiple IRAK1 autophosphorylation steps Dissociation of hp-IRAK1:TRAF6 from the activated TLR:oligo-Myd88:Mal:p-IRAK4 complex TRAF6 binds to p-IRAK2 Dissociation of p-IRAK2:TRAF6 from the activated TLR:oligo-Myd88:Mal:p-IRAK4 complex MyD88 forms a complex with MAL:activated TLR2/4 MAL is phosphorylated by BTK Activated TLR2/4:MAL interacts with BTK Activated TLR2/4 interacts with MAL(TIRAP) IRAK1 or IRAK2 binds to the activated IRAK4 :activated TLR:MyD88:Mal complex IRAK4 autophosphorylation in the complex with activated TLR:MyD88:Mal IRAK4 binds to the activated TLR receptor:Mal:MyD88 complex MyD88 oligomerization within the complex of activated TLR:Mal:MyD88 TRAF6 binds MEKK1 PathwayStep6781 PathwayStep6780 PathwayStep6783 PathwayStep6782 PathwayStep6785 PathwayStep6784 PathwayStep6787 PathwayStep6786 PathwayStep6788 PathwayStep6789 PathwayStep6795 PathwayStep6794 PathwayStep6793 PathwayStep6792 PathwayStep6791 PathwayStep6790 PathwayStep6693 PathwayStep6699 PathwayStep6700 MAP kinase activation in TLR cascade TAK1 activates NFkB by phosphorylation and activation of IKKs complex MyD88:Mal cascade initiated on plasma membrane Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2012-11-05 GENE ONTOLOGYGO:0002755 Pubmed15276183 Reactome Database ID Release 43166058 Reactome, http://www.reactome.org ReactomeREACT_6788 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 The first known downstream component of TLR4 and TLR2 signaling is the adaptor MyD88. Another adapter MyD88-adaptor-like (Mal; also known as TIR-domain-containing adaptor protein or TIRAP) has also been described for TLR4 and TLR2 signaling. MyD88 comprises an N-terminal Death Domain (DD) and a C-terminal TIR, whereas Mal lacks the DD. The TIR homotypic interactions bring adapters into contact with the activated TLRs, whereas the DD modules recruit serine/threonine kinases such as interleukin-1-receptor-associated kinase (IRAK). Recruitment of these protein kinases is accompanied by phosphorylation, which in turn results in the interaction of IRAKs with TNF-receptor-associated factor 6 (TRAF6). The oligomerization of TRAF6 activates TAK1, a member of the MAP3-kinase family, and this leads to the activation of the IkB kinases. These kinases, in turn, phosphorylate IkB, leading to its proteolytic degradation and the translocation of NF-kB to the nucleus. Concomitantly, members of the activator protein-1 (AP-1) transcription factor family, Jun and Fos, are activated, and both AP-1 transcription factors and NF-kB are required for cytokine production, which in turn produces downstream inflammatory effects. IRAK2 mediated activation of TAK1 complex IRAK1 recruits IKK complex PathwayStep3439 PathwayStep3485