Activated TLR2/4 interacts with MAL(TIRAP)

Stable Identifier
R-HSA-2201316
Type
Reaction [binding]
Species
Homo sapiens
Related Species
Neisseria meningitidis serogroup B, Chlamydia trachomatis
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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].

Literature References
PubMed ID Title Journal Year
12447441 Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4

Yamamoto, M, Sato, S, Hemmi, H, Sanjo, H, Uematsu, S, Kaisho, T, Hoshino, K, Takeuchi, O, Kobayashi, M, Fujita, T, Takeda, K, Akira, S

Nature 2002
17726518 A dimer of the Toll-like receptor 4 cytoplasmic domain provides a specific scaffold for the recruitment of signalling adaptor proteins

Núñez Miguel, R, Wong, J, Westoll, JF, Brooks, HJ, O'Neill, LA, Gay, NJ, Bryant, CE, Monie, TP

PLoS One 2007
12447442 The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors

Horng, T, Barton, GM, Flavell, RA, Medzhitov, R

Nature 2002
19592497 MyD88 adapter-like (Mal)/TIRAP interaction with TRAF6 is critical for TLR2- and TLR4-mediated NF-kappaB proinflammatory responses

Verstak, B, Nagpal, K, Bottomley, SP, Golenbock, DT, Hertzog, PJ, Mansell, A

J. Biol. Chem. 2009
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