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FLASH GENE
Symbol TIRAP contributors: mct/npt - updated : 23-05-2017
HGNC name toll-interleukin 1 receptor (TIR) domain containing adaptor protein
HGNC id 17192
Corresponding disease
TIRAPD TIRAP deficiency
Location 11q24.2      Physical location : 126.152.981 - 126.164.828
Synonym name
  • MyD88 adapter-like protein
  • TIR domain-containing adapter protein
  • toll-like receptor adaptor protein
  • adapter protein wyatt
  • Synonym symbol(s) MAL, TIRA, wyatt, FLJ42305, BACTS1, MyD88-2
    DNA
    TYPE functioning gene
    SPECIAL FEATURE gene in gene
    STRUCTURE 13.67 kb     6 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    Physical map
    SPA17 11q24.2 sperm autoantigenic protein 17 NRGN 11q24 neurogranin (protein kinase C substrate, RC3) CTXL 11q24 cortical thymocyte receptor (X. laevis CTX) like ESAM 11q24.2 cortical thymocyte receptor (X. laevis CTX) like FLJ23342 11q24.2 hypothetical protein FLJ23342 RBIG1 11q24.2 retinoblastoma inhibiting gene 1 ROBO4 11q24.2 roundabout homolog 4, magic roundabout (Drosophila) FLJ25530 11q24.2 hypothetical protein FLJ25530 FLJ13215 11q24.2 hypothetical protein FLJ13215 LOC387816 11 similar to hypothetical protein SLC37A2 11q24.2 solute carrier family 37 (glycerol-3-phosphate transporter), member 2 LOC219854 11q24.2 hypothetical protein LOC219854 LOC390276 11 hypothetical gene supported by AK128036 LOC387817 11 LOC387817 PKNOX2 11q24 PBX/knotted 1 homeobox 2 FLJ30719 11q24.2 hypothetical protein FLJ30719 FEZ1 11q23.3-q24.2 fasciculation and elongation protein zeta 1 (zygin I) EI24 11q23-q24 etoposide induced 2.4 mRNA ITM1 11q23.3-q24.2 integral membrane protein 1 CHEK1 11q24 CHK1 checkpoint homolog (S. pombe) ACRV1 11p12-q13 acrosomal vesicle protein 1 PATE 11q24.2 acrosomal vesicle protein 1 FLJ32915 11q24.2 hypothetical protein FLJ32915 FKSG32 11q24.2 hypothetical protein FKSG32 DDX25 11q24 DEAD (Asp-Glu-Ala-Asp) box polypeptide 25 LOC338667 11q24.2 hypothetical protein LOC338667 CDON 11q23-q24 cell adhesion molecule-related/down-regulated by oncogenes LOC387818 11 similar to Nucleosome assembly protein 1-like 1 (NAP-1 related protein) (hNRP) LOC387819 11 LOC387819 FLJ14494 11q24.2 hypothetical protein FLJ14494 FLJ21103 11q24.2 hypothetical protein FLJ21103 SRPR 11q24.1 signal recognition particle receptor ('docking protein') H17 11q24.2 hypothetical protein H17 TIRAP 11q24.2 toll-interleukin 1 receptor (TIR) domain containing adaptor protein DCPS 11q24.2 mRNA decapping enzyme SIAT4C 11q23-q24 sialyltransferase 4C (beta-galactoside alpha-2,3-sialyltransferase) KIRREL3 11q24 kin of IRRE like 3 (Drosophila) FLJ40224 11q24.2 hypothetical protein FLJ40224
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    6 splicing 2348 23.8 221 - 2017 28235196
    5 splicing 1219 25.3 235 - 2017 28235196
    4 - 1050 25.3 235 - 2017 28235196
    - - 2195 23.8 221 - 2017 28235196
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart    
    Digestiveintestinelarge intestinecolon  
     liver   highly
     salivary gland   highly
    Lymphoid/Immunelymph node   highly
    Urinarykidney    
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / Hematopoieticbone marrow   
    Muscularstriatumskeletal  
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticleukocyte
    Blood/Hematopoieticmonocyte
    Lymphoid/Immunemacrophage
    cell lineage
    cell lines hepatocellular carcinoma cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES Hydrophobic
    STRUCTURE
    motifs/domains
  • a phosphoinositide (PI)-binding motif (PBM) mediating the membrane recruitment of TIRAP
  • C terminal region lacking a DEATH domain
  • one C terminal TIR domain, a Toll/interleukin-1 receptor domain
  • mono polymer homomer , heteromer , dimer
    HOMOLOGY
    interspecies ortholog to murine Tirap
    Homologene
    FAMILY
    CATEGORY adaptor , signaling
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,cytosolic
    basic FUNCTION
  • adapter involved in the TLR4 signaling pathway in the innate immune response, exercing a crucial role in MYD88 dependent signaling cascade shared by TLR2, TLR4
  • playing a role in mediating LPS-induced NF-kappaB activation and apoptosis in endothelial cells
  • having an essential role in a key signaling pathway of the infectious agents
  • key role of its phosphorylation on tyrosine during signaling by TLR2 and TLR4 identifying a novel function for BTK as the kinase involved (Gray 2006)
  • involved in the signaling pathways of Toll-like receptors (TLR) 2 and 4, which are important innate immune receptors for the recognition of a broad range of pathogenic Gram-negative and Gram-positive bacteria (Ferwerda 2009)
  • with MYD88, are adaptor molecules critically involved in the Toll-like receptor (TLR) 4 signaling pathway
  • new role for TIRAP as a key upstream regulator of CREB1 and as a contributor to the expression of both pro- and anti-inflammatory genes
  • TIRAP-signaling is therefore beneficial to the integrity of the intestinal barrier during infection
  • in response to natural activators of innate immunity, the sorting adaptor TIRAP regulates TLR signaling from the plasma membrane and endosomes
  • TIRAP plays the crucial role of activating the MYD88-dependent pathway, which in turn controls the immune response (innate and adaptive) to Helicobacter pylori
  • play likely a crucial role in the TLR2-and TLR4-mediated
  • and MYD88-dependent pathways as an adaptor between
    these two TLRs and MYD88
    CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS immunity/defense
    PATHWAY
    metabolism
    signaling signal transduction
    NF-kappa B, MAPK1, MAPK3, JNK pathway
    a component
  • dimer with MYD88
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • TLR4 and IRAK2 via the TIR domain
  • TLR2 or TLR4 recruits TIRAP, which recruits MYD88
  • to the receptor complex through TIR domain interactions
  • interaction with CASP1 (inhibitory, rather than an activating role for CASP1 in TIRAP regulation, and the caspase-1 cleavage site in TIRAP is part of a TIR-domain interaction site)
  • substrate for IRAK1 and IRAK4 with phosphorylation promoting ubiquitination and degradation of TIRAP (process that may serve to negatively regulate signaling by TLR2 and TLR4)
  • by controlling TIRAP recruitment, PTEN regulates TLR5-induced inflammatory responses
  • TIRAP and MYD88 are adaptor proteins for Toll-like receptors-2 and -4 (TLR2/4) which are engaged in transducing the signal to downstream molecules
  • TLR2, TLR4 interact with the TIR domain-containing adaptor protein (TIRAP), across the plasma membrane, triggering a signaling cascade that leads to innate immune responses
  • cell & other
    REGULATION
    activated by BTK (phosphorylation of TIRAP1 by Bruton's tyrosine kinase, is required for TIRAP activation) (
    Other tyrosine phosphorylation is required for adapter signaling, regulates TIRAP interactions with TLR4 and receptor signaling, and is inhibited in endotoxin tolerance (Piao 2008)
    directly phosphorylated by IRAK1, IRAK4
    ASSOCIATED DISORDERS
    corresponding disease(s) TIRAPD
    Susceptibility
  • to tuberculosis
  • to septic shock
  • to severe malaria and mortality
  • Variant & Polymorphism other
  • S180L polymorphism associated to lower risk of tuberculosis
  • TIRAP S180L heterozygous individuals have a distinctive phenotype compared with the TIRAP S180 homozygous bearers, with the 180L allele associated with a more pronounced inflammatory response and a lower risk of developing septic shock (Ferwerda 2009)
  • SNP at coding region of TIRAP (S180L) has been reported to influence TLRs signaling, and S180L heterozygous mutation may protect patients against severe malaria and mortality
  • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • Tirap(-/-) deficient mice, defects in cytokine production and in activation of NF-kappa B and MAP kinase in response to LPS, a ligand for TLR4 and also to ligands for TLR2, TLR1, TLR6
  • Mal-deficient mice displayed increased susceptibility to oral but not intraperitoneal infection with Salmonella Typhimurium
  • Tirap-deficient mouse macrophages display impaired activation, of NFKB1 in response to the stimulation of TLR2 and TLR4 by MALP2, PGN