MAL:PI(4,5)P2 Activated TLR1:2 or TLR 2:6 heterodimers or TLR4 homodimer MAL:activated TLR2/4 Activated TLR2/4 interacts with MAL(TIRAP) Authored: Shamovsky, V, 2012-04-19 Edited: Shamovsky, V, 2012-11-06 Pubmed12447441 Pubmed12447442 Pubmed17726518 Pubmed19592497 Reactome Database ID Release 432201316 Reactome, http://www.reactome.org ReactomeREACT_121383 Reviewed: D'Eustachio, P, 2012-05-25 Reviewed: Napetschnig, Johanna, 2012-11-16 TIRAP/Mal-deficient mice showed normal responses to the TLR3, TLR5, TLR7, and TLR9 ligands, but were defective in TLR4 and TLR2 ligand-induced proinflammatory cytokine production (Horng et al. 2002,Yamamoto et al. 2002). In contrast, TLR4 ligand-induced activation of IRF-3 and expression of IFN-inducible genes were not impaired in TIRAP/Mal knockout macrophages or in mice lacking both MyD88 and TIRAP/Mal (Horng et al. 2002,Yamamoto et al. 2002). Thus, TIRAP/Mal is an essential adapter that is involved in the MyD88-dependent pathway via TLR4 and TLR2, but not in the MyD88-independent pathway. Mal contains a phosphatidylinositol 4,5-bisphosphate-binding domain required for retention in the plasma membrane. The intracellular TIR domains of TLR2 or 4 associate with Mal at the cytoplasmic side of the plasma membrane, which in turn facilitates the binding of MyD88 to the activated TLR, leading to NF-kB and MAPK activation [Nunez Miguel et al 2007]. has a Stoichiometric coefficient of 2