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FLASH GENE
Symbol IRAK4 contributors: mct/ - updated : 12-07-2018
HGNC name interleukin-1 receptor-associated kinase 4
HGNC id 17967
Corresponding disease
IRAK4D interleukin-1 receptor-associated kinase 4 (IRAK-4) deficiency
Location 12q12      Physical location : 44.152.746 - 44.183.346
Synonym name
  • IRAK-4 mutated form 1
  • NY-REN-64 antigen
  • renal carcinoma antigen NY-REN-64
  • Synonym symbol(s) REN64, NY-REN-64, IRAK-4, IPD1
    EC.number 2.7.11.1
    DNA
    TYPE functioning gene
    STRUCTURE 30.60 kb     12 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    Physical map
    SLC2A13 12p11.23 solute carrier family 2 (facilitated glucose transporter), member 13 DKFZp434H2111 12q12 hypothetical protein DKFZp434H2111 LOC390307 12 similar to submaxillary apomucin MUC19 12q12 mucin 19 CNTN1 12q11.2-q12 contactin 1 DKFZp434B0417 12q12 similar to semaF cytoplasmic domain associated protein 3 LOC283464 12q12 hypothetical protein LOC283464 YAF2 12p11.23 YY1 associated factor 2 LOC283465 12q12 similar to hepatocellular carcinoma autoantigen MADP-1 12q12 MADP-1 protein PPHLN1 12q12 periphilin 1 PRICKLE1 12q12 prickle-like 1 (Drosophila) LOC390308 12 hypothetical gene supported by NM_018464 MRPS36P5 12q12 mitochondrial ribosomal protein S36 pseudogene ADAMTS20 12q12 a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif, 20 LOC387852 12 similar to 52 kDa repressor of the inhibitor of the protein kinase (p58IPK-interacting protein) (58 kDa interferon-induced protein kinase-interacting protein) (P52rIPK) (Death associated protein 4) (THAP domain protein 0) LOC390309 12 similar to elongation factor 1 alpha DKFZP434G1415 12q12 hypothetical protein DKFZp434G1415 IRAK4 12q12 interleukin-1 receptor-associated kinase 4 PTK9 12q12 PTK9 protein tyrosine kinase 9 DKFZp434K2435 12q12 hypothetical protein DKFZp434K2435 ZNF75B 12q13 zinc finger protein 75b NELL2 12q13.1-q13.12 NEL-like 2 (chicken) FKSG42 12q12 FKSG42 LOC51054 12q putative glycolipid transfer protein DKFZp313M0720 12q12-q13.11 hypothetical protein DKFZp313M0720 DKFZp686G052 SFRS2IP 12q12-q14.3 splicing factor, arginine/serine-rich 2, interacting protein SLC38A1 12p11.21 solute carrier family 38, member 1 SLC38A2 12q solute carrier family 38, member 2 LOC387853 12 hypothetical gene supported by BC014370 SLC38A4 12q12-q13 solute carrier family 38, member 4 LOC390310 12 similar to transient receptor protein 6 AMIGO2 12q13.11 amphoterin induced gene 2 MGC16044 12q13.11 hypothetical protein MGC16044 LOC387854 12 LOC387854 LOC387855 12 LOC387855 FLJ21908 12q13.11 hypothetical protein FLJ21908 P11 12q13.1 26 serine protease EPAC 12q13.1 Rap1 guanine-nucleotide-exchange factor directly activated by cAMP
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    12 - 4771 - 336 - 2009 19181383
    13 - 4351 51.4 460 - 2009 19181383
    12 - 4205 37.5 336 - 2009 19181383
    12 - 4303 51.4 460 - 2009 19181383
    11 - 4157 37.5 336 - 2009 19181383
    10 - 3987 37.5 336 - 2009 19181383
    13 - 4525 - 460 - 2009 19181383
    13 - 4544 - 336 - 2009 19181383
    11 - 4245 - 257 - 2009 19181383
    14 - 4408 - 336 - 2009 19181383
    13 - 4360 - 336 - 2009 19181383
    11 - 4061 - 257 - 2009 19181383
    12 - 4190 - 336 - 2009 19181383
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveliver   highly
    Urinarykidney   highly
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N terminal death domain, and N-terminal loop of IRAK4 that plays a critical regulatory role in Myddosome assembly
  • kinase catalytic domain
  • mono polymer heteromer , dimer
    HOMOLOGY
    interspecies ortholog to Drosophila pelle
    Homologene
    FAMILY
  • protein kinase superfamily
  • TKL Ser/Thr protein kinase family
  • Pelle subfamily
  • IRAK family
  • CATEGORY antigen , receptor membrane serine/threonine
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,cytosolic
    text
  • in unstimulated cells endogenous IRAK4 is distributed in the cytosol and the protein kinase activity is inhibited
  • basic FUNCTION
  • central element in the early signal transduction of Toll/IL1R (TIR) upstream of IRAK1
  • required for various responses induced by IL-1R and Toll-like receptor signals
  • required for the optimal transduction of IL1-induced signals, including the activation of IRAK1, NF-kappaB, and JNK, and the maximal induction of inflammatory cytokines
  • plays a critical role in IL1 receptor (IL1R)/TLR7-mediated induction of inflammatory responses
  • initiate a cascade of signaling events eventually leading to induction of inflammatory target gene expression
  • plays an important role in innate and adaptive immune responses
  • its kinase activity is required for IRAK4-dependent signaling in innate and adaptive immunity
  • protein kinases that mediate signaling by Toll/IL1/Plant R (TIR) domain-containing receptors including the IL-1, IL-18, and Toll-like receptors (TLRs)
  • its non-kinase functions are essential in cells, whereas the kinase activity of IRAK4 appears redundant with that of IRAK1
  • having a kinase activity that is critical for development of atherosclerosis
  • has an ability to induce the degradation of IRAK1 in addition to its role as an activator of IRAK1
  • induce the degradation of IRAK1 in a proteosome-independent manner
  • MYD88 and the associated kinases IRAK1 and IRAK4 are essential for activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) survival
  • IRAK4 activation acts normally to regulate microglial activation status and influence amyloid homeostasis in the brain
  • serine/threonine kinase that is a central adaptor protein in TLR signaling
  • unexpected role of IRAK4, AKT1, and MTOR in the regulation of tolerance in human monocytes
  • IRAK4 is recruited to the membrane-proximal adaptor MYD88 through death domain (DD) interactions, forming the oligomeric Myddosome and mediating NFKB1 activation
  • in pericytes, MYD88 and IRAK4 are key regulators of 2 major injury responses: inflammatory and fibrogenic
  • kinase activity of IRAK4 plays a critical role in signalling mediated by the TLRs
  • mediates host defense against infections
  • plays a critical role in innate immune signaling by Toll-like receptors (TLRs), and loss of IRAK4 activity increases susceptibility to bacterial infections and causes defects in TLR and IL1 ligand sensing
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS immunity/defense
    text innate immunity
    PATHWAY
    metabolism
    signaling signal transduction
    part of the IL1R signaling cascade and is capable of transmitting signals both dependent on and independent of its kinase activity
    a component
  • heterodimer with IRAK1, IRAK2
  • essential component of the signal transduction complex downstream of the IL1 and Toll-like receptors
  • MYD88-IRAK4-IRAK2 death domain (DD) complex, which surprisingly reveals a left-handed helical oligomer that consists of 6 MYD88, 4 IRAK4 and 4 IRAK2 DDs
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with IRAK1 and TRAF6 in an IL-1 dependent manner, activating NF-K beta and mitogen-activated protein (MAP) kinase pathway
  • activating PELI1, PELI2, PELI3
  • TIRAP is a substrate for IRAK1 and IRAK4 and is likely an important control mechanism in TLR2 and TLR4 signal transduction
  • IRAK1 catalytic activity is not triggered by a covalent modification but by an allosteric mechanism induced by its interaction with IRAK4
  • IRAK4 kinase activity controls the activation of IRF5, a transcription factor implicated in the pathogenesis of multiple autoimmune diseases
  • IRAK4 activity regulates likely MAP3K7 and IKBKB activation, leading to the nuclear translocation of IRF5 and induction of inflammatory cytokines in human monocytes
  • cell & other
    REGULATION
    inhibited by MYD88 (requires activation of the MyD88-dependent pathway and the death domains of both MyD88 and IRAK4 are important for this downregulation)
    ASSOCIATED DISORDERS
    corresponding disease(s) IRAK4D
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional germinal mutation      
    in pyogenic bacterial infections
    Susceptibility to pyogenic bacterial infections
    Variant & Polymorphism other mutations associated with pyogenic bacterial diseases, including invasive pneumococcal diseases
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cardiovascularatheroma 
    potential therapeutic target in atherogenesis
    miscelleaneoustransplantation 
    elucidation of the role of IRAK4 kinase activity in adaptive immunity might also open new opportunities for future treatment modalities in transplantation
    cancerhemopathy 
    development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumours bearing oncogenic MYD88 mutations
    osteoarticularbone 
    is a potential therapeutic target to inhibit stimulated osteoclastogenesis
    ANIMAL & CELL MODELS
    IRAK4(-/-) animals are severely impaired in their response to viral and bacterial challenges