PathwayStep6796 PathwayStep6730 Activated TLR4 signalling Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2012-11-06 GENE ONTOLOGYGO:0034142 Pubmed14556004 Pubmed15276183 Pubmed15588429 Pubmed15596121 Pubmed15845500 Pubmed18222170 Pubmed18297073 Pubmed22078883 Reactome Database ID Release 43166054 Reactome, http://www.reactome.org ReactomeREACT_6890 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 TLR4 is unique among the TLR family in its ability to recruit four adapters to activate two distinct signaling pathways. One pathway is activated by the pair of the adapters Mal or TIRAP (Toll/interleukin-1-receptor (TIR)-domain-containing adapter protein) and MyD88, which leads to the NFkB activation and the induction of pro-inflammatory cytokines. The second pathway is activated by the adapters TRIF (TIR-domain-containing adapter protein inducing interferon-beta) and TRAM (TRIF-related adapter molecule). The combined use of TRIF and TRAM adapters is specific for TLR4 signaling pathway and leads to the induction of type I interferons and delayed activation of NFkB.<p>The previous model of TLR4 signaling pathway described the simultaneous activation of these two signaling pathways at the plasma membrane, however the later studies suggested that upon activation TLR4 first induces TIRAP-MyD88 signaling at the plasma membrane and is then endocytosed and activates TRAM-TRIF signaling from the early endosome [Kagan JC et al 2008; Tanimura N et al 2008; Zanoni I et al 2011]. MyD88:Mal cascade initiated on plasma membrane MyD88-independent cascade