Toll Interleukin 1 Receptor Domain Containing Adaptor Protein (TIRAP)

Mal; Wyatt; MyD88 Adapter-Like; Adaptor protein Wyatt

SPN	L068
HGNC	17192
MGI	2152213
PubMed	21829704
RGD	1595496
UniProt	P58753
Wiki	TIRAP

TIRAP is a TIR adaptor protein involved in the TLR4 signaling pathway of the immune system. It activates NF-kappa-B, MAPK1, MAPK3 and JNK, which then results in cytokine secretion and the inflammatory response. Alternative splicing of this gene results in several transcript variants; however, not all variants have been fully described. MAL, unlike MYD88, does not interact with IRAK1 and is not inhibited by the dominant-negative N-terminal region of IRAK1; however, like MYD88, MAL does, through its TIR domain, interact with and is inhibited in NFKB activation by the dominant-negative form of IRAK2. A dominant-negative form of MAL inhibits TLR4 or lipopolysaccharide activation of NFKB, but not NFKB activation by IL1R1 or IL18R. Immunoprecipitation analysis showed that TLR4 and MAL are constitutively associated.

Reference

"Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction."
Nature 413:78-83(2001) [PubMed] [Europe PMC] [Abstract]

"TIRAP: an adapter molecule in the Toll signaling pathway."
Nat. Immunol. 2:835-841(2001) [PubMed] [Europe PMC] [Abstract]

"Natural selection in the TLR-related genes in the course of primate evolution."
Immunogenetics 60:727-735(2008) [PubMed] [Europe PMC] [Abstract]

"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]

"Human chromosome 11 DNA sequence and analysis including novel gene identification."
Nature 440:497-500(2006) [PubMed] [Europe PMC] [Abstract]

"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]

"Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling."
J. Immunol. 171:4304-4310(2003) [PubMed] [Europe PMC] [Abstract]

"Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation."
Nat. Immunol. 7:148-155(2006) [PubMed] [Europe PMC] [Abstract]

"Etk/BMX, a Btk family tyrosine kinase, and Mal contribute to the cross-talk between MyD88 and FAK pathways."
J. Immunol. 180:3485-3491(2008) [PubMed] [Europe PMC] [Abstract]

"A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP results in loss of MyD88 binding and reduced TLR2/TLR4 signaling."
J. Biol. Chem. 284:25742-25748(2009) [PubMed] [Europe PMC] [Abstract]

"AIP1 functions as Arf6-GAP to negatively regulate TLR4 signaling."
J. Biol. Chem. 285:3750-3757(2010) [PubMed] [Europe PMC] [Abstract]

"IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and degradation of MyD88 adaptor-like (Mal)."
J. Biol. Chem. 285:18276-18282(2010) [PubMed] [Europe PMC] [Abstract]

"Crystal structure of Toll-like receptor adaptor MAL/TIRAP reveals the molecular basis for signal transduction and disease protection."
Proc. Natl. Acad. Sci. U.S.A. 108:14879-14884(2011) [PubMed] [Europe PMC] [Abstract]

"A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis."
Nat. Genet. 39:523-528(2007) [PubMed] [Europe PMC] [Abstract]

"Low frequency of the TIRAP S180L polymorphism in Africa, and its potential role in malaria, sepsis, and leprosy."
BMC Med. Genet. 10:65-65(2009) [PubMed] [Europe PMC] [Abstract]