IRF3/ IRF7 activated TLR3/4:TRIF:K63-poly-Ub-TRAF3:p-TBK1/p-IKKE:IRF3/IRF7 activated TLR3/4:TRIF:K63-poly-Ub-TRAF3:p-TBK1/p-IKK epsilon IRF3/IRF7 recruitment to p-TBK1/p-IKK epsilon bound to the activated TLR Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2011-08-12 Pubmed11070172 Pubmed14517278 Pubmed14703513 Pubmed15210742 Pubmed17157040 Pubmed9566918 Reactome Database ID Release 43166271 Reactome, http://www.reactome.org ReactomeREACT_6917 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 SH2-containing protein tyrosine phosphatase 2 (SHP-2) has been shown to inhibit the TRIF-dependent production of proin?ammatory cytokines and type I interferon in LPS or poly(I-C)-stimulated mouse peritoneal macrophages. SHP-2 overexpression also inhibited TRIF-induced IFN-? luciferase reporter gene expression in human embryonic kidney HEK293 cells. Experiments with truncated SHP-2 or truncated TBK1 mutants revealed that C-terminal domain of SHP-2 associates with N-terminal domain of TBK1 when coexpressed in HEK293 cells. Furthermore, SHP-2 is thought to prevent TBK1-mediated downstream substrate phosphorylation in tyrosine phosphatase activity independent manner by binding to kinase domain of TBK1 [An H et al 2006]. Two members of the interferon regulatory factor (IRF) family IRF-3 and IRF-7 are the major modulators of IFN gene expression. Activation of IRF-3 and IRF-7, which is mediated by TBK1/IKK protein kinases, promotes IFN gene expression and the production of IFN developing an effective antiviral immune response.<p>Irf-3 deficient mice were found to be more vulnerable to virus infection. Mouse cells defective in IRF-3 and IRF-7 expression totally fail to induce IFN genes in response to viral infection. It was shown on mice and mouse cells that both IRF-3 and IRF-7 have non redundant and distinct roles. IRF-3 is expressed at a basal level in normally growing cells and is a major factor in the early induction phase of IFN-alpha/beta production, while the IRF-7 gene expression is induced upon IFNs stimulation and IRF-7 is involved in the late induction phase.<br> has a Stoichiometric coefficient of 2