Auto ubiquitination of oligo-TRAF6 bound to p-IRAK2 IRAK2 induces TRAF6 oligomerization Auto phosphorylation of TAK1 bound to p-IRAK2:pUb oligo-TRAF6: free K63 pUb:TAB1:TAB2/TAB3 Activated TRAF6 synthesizes unanchored polyubiquitin chains Activated TRAF6:p-IRAK2 interacts with TAK1 complex PathwayStep6694 PathwayStep6695 PathwayStep6696 PathwayStep6697 PathwayStep6698 IRAK2 mediated activation of TAK1 complex Although IRAK-1 was originally thought to be a key mediator of TRAF6 activation in the IL1R/TLR signaling (Dong W et al. 2006), recent studies showed that IRAK-2, but not IRAK-1, led to TRAF6 polyubiquitination (Keating SE et al 2007). IRAK-2 loss-of-function mutants, with mutated TRAF6-binding motifs, could no longer activate NF-kB and could no longer stimulate TRAF-6 ubiquitination (Keating SE et al 2007). Furthermore, the proxyvirus protein A52 - an inhibitor of all IL-1R/TLR pathways to NF-kB activation, was found to interact with both IRAK-2 and TRAF6, but not IRAK-1. Further work showed that A52 inhibits IRAK-2 functions, whereas association with TRAF6 results in A52-induced MAPK activation. The strong inhibition effect of A52 was also observed on the TLR3-NFkB axis and this observation led to the discovery that IRAK-2 is recruited to TLR3 to activate NF-kB (Keating SE et al 2007). Thus, A52 possibly inhibits MyD88-independent TLR3 pathways to NF-kB via targeting IRAK-2 as it does for other IL-1R/TLR pathways, although it remains unclear how IRAK-2 is involved in TLR3 signaling.<p>IRAK-2 was shown to have two TRAF6 binding motifs that are responsible for initiating TRAF6 signaling transduction (Ye H et al 2002). Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2012-11-06 Pubmed12140561 Pubmed16831874 Pubmed17878161 Pubmed21606490 Reactome Database ID Release 43937042 Reactome, http://www.reactome.org ReactomeREACT_25380 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16