IRAK1

Interleukin-1 receptor-associated kinase 1

Identifiers

IRAK1 ; IRAK; pelle

External IDs

OMIM: 300283 MGI: 107420 HomoloGene: 37496 ChEMBL: 3357 GeneCards: IRAK1 Gene

2.7.11.1

Gene ontology
Molecular function	• protein kinase activity • protein serine/threonine kinase activity • NF-kappaB-inducing kinase activity • ubiquitin-protein transferase activity • interleukin-1 receptor binding • protein binding • ATP binding • kinase activity • heat shock protein binding • protein homodimerization activity • protein heterodimerization activity
Cellular component	• nucleus • cytoplasm • lipid particle • cytosol • plasma membrane • endosome membrane • interleukin-1 receptor complex
Biological process	• activation of MAPK activity • regulation of cytokine-mediated signaling pathway • toll-like receptor signaling pathway • MyD88-dependent toll-like receptor signaling pathway • MyD88-independent toll-like receptor signaling pathway • protein phosphorylation • signal transduction • transmembrane receptor protein serine/threonine kinase signaling pathway • activation of NF-kappaB-inducing kinase activity • JNK cascade • aging • protein ubiquitination • lipopolysaccharide-mediated signaling pathway • negative regulation of NF-kappaB transcription factor activity • response to peptidoglycan • response to lipopolysaccharide • toll-like receptor 2 signaling pathway • toll-like receptor 3 signaling pathway • toll-like receptor 4 signaling pathway • toll-like receptor 5 signaling pathway • toll-like receptor 9 signaling pathway • toll-like receptor 10 signaling pathway • cellular response to heat • intracellular signal transduction • TRIF-dependent toll-like receptor signaling pathway • nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway • toll-like receptor TLR1:TLR2 signaling pathway • toll-like receptor TLR6:TLR2 signaling pathway • negative regulation of apoptotic process • positive regulation of I-kappaB kinase/NF-kappaB signaling • positive regulation of MAP kinase activity • innate immune response • positive regulation of transcription, DNA-templated • protein autophosphorylation • neurotrophin TRK receptor signaling pathway • positive regulation of smooth muscle cell proliferation • positive regulation of NF-kappaB transcription factor activity • protein oligomerization • stress-activated MAPK cascade • nucleotide-binding oligomerization domain containing signaling pathway • interleukin-1-mediated signaling pathway • response to interleukin-1 • cellular response to hypoxia
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr X:
154.01 – 154.02 Mb

Chr X:
74.01 – 74.02 Mb

PubMed search

Interleukin-1 receptor-associated kinase 1 is an enzyme that in humans is encoded by the IRAK1 gene.^[1]^[2]

Function

This gene encodes the interleukin-1 receptor-associated kinase 1, one of two putative serine/threonine kinases that become associated with the interleukin-1 receptor (IL1R) upon stimulation. This gene is partially responsible for IL1-induced upregulation of the transcription factor NF-kappa B. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.^[3]

Signaling pathway of toll-like receptors. Dashed grey lines represent unknown associations

Interactions

IRAK1 has been shown to interact with:

CHUK,^[4]^[5]
IKBKG,^[6]^[4]
IKK2,^[4]^[5]
Myd88,^[7]^[8]^[9]^[10]
TRAF6,^[1]^[8]^[9]^[11]^[12]^[13]^[14]^[15]^[16] and
UBC.^[6]^[4]^[17]^[18]

References

1 2 Muzio M, Ni J, Feng P, Dixit VM (December 1997). "IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling". Science 278 (5343): 1612–5. doi:10.1126/science.278.5343.1612. PMID 9374458.
↑ Cao Z, Henzel WJ, Gao X (April 1996). "IRAK: a kinase associated with the interleukin-1 receptor". Science 271 (5252): 1128–31. doi:10.1126/science.271.5252.1128. PMID 8599092.
↑ "Entrez Gene: IRAK1 interleukin-1 receptor-associated kinase 1".
1 2 3 4 Windheim M, Stafford M, Peggie M, Cohen P (March 2008). "Interleukin-1 (IL-1) induces the Lys63-linked polyubiquitination of IL-1 receptor-associated kinase 1 to facilitate NEMO binding and the activation of IkappaBalpha kinase". Mol. Cell. Biol. 28 (5): 1783–91. doi:10.1128/MCB.02380-06. PMC 2258775. PMID 18180283.
1 2 Vig E, Green M, Liu Y, Yu KY, Kwon HJ, Tian J, Goebl MG, Harrington MA (March 2001). "SIMPL is a tumor necrosis factor-specific regulator of nuclear factor-kappaB activity". J. Biol. Chem. 276 (11): 7859–66. doi:10.1074/jbc.M010399200. PMID 11096118.
1 2 Conze DB, Wu CJ, Thomas JA, Landstrom A, Ashwell JD (May 2008). "Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activation". Mol. Cell. Biol. 28 (10): 3538–47. doi:10.1128/MCB.02098-07. PMC 2423148. PMID 18347055.
↑ Chen BC, Wu WT, Ho FM, Lin WW (July 2002). "Inhibition of interleukin-1beta -induced NF-kappa B activation by calcium/calmodulin-dependent protein kinase kinase occurs through Akt activation associated with interleukin-1 receptor-associated kinase phosphorylation and uncoupling of MyD88". J. Biol. Chem. 277 (27): 24169–79. doi:10.1074/jbc.M106014200. PMID 11976320.
1 2 Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z (July 1999). "IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family". J. Biol. Chem. 274 (27): 19403–10. doi:10.1074/jbc.274.27.19403. PMID 10383454.
1 2 Li S, Strelow A, Fontana EJ, Wesche H (April 2002). "IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase". Proc. Natl. Acad. Sci. U.S.A. 99 (8): 5567–72. doi:10.1073/pnas.082100399. PMC 122810. PMID 11960013.
↑ Fitzgerald KA, Palsson-McDermott EM, Bowie AG, Jefferies CA, Mansell AS, Brady G, Brint E, Dunne A, Gray P, Harte MT, McMurray D, Smith DE, Sims JE, Bird TA, O'Neill LA (September 2001). "Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction". Nature 413 (6851): 78–83. doi:10.1038/35092578. PMID 11544529.
↑ Qian Y, Commane M, Ninomiya-Tsuji J, Matsumoto K, Li X (November 2001). "IRAK-mediated translocation of TRAF6 and TAB2 in the interleukin-1-induced activation of NFkappa B". J. Biol. Chem. 276 (45): 41661–7. doi:10.1074/jbc.M102262200. PMID 11518704.
↑ Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV (October 1996). "TRAF6 is a signal transducer for interleukin-1". Nature 383 (6599): 443–6. doi:10.1038/383443a0. PMID 8837778.
↑ Takatsuna H, Kato H, Gohda J, Akiyama T, Moriya A, Okamoto Y, Yamagata Y, Otsuka M, Umezawa K, Semba K, Inoue J (April 2003). "Identification of TIFA as an adapter protein that links tumor necrosis factor receptor-associated factor 6 (TRAF6) to interleukin-1 (IL-1) receptor-associated kinase-1 (IRAK-1) in IL-1 receptor signaling". J. Biol. Chem. 278 (14): 12144–50. doi:10.1074/jbc.M300720200. PMID 12566447.
↑ Ling L, Goeddel DV (August 2000). "T6BP, a TRAF6-interacting protein involved in IL-1 signaling". Proc. Natl. Acad. Sci. U.S.A. 97 (17): 9567–72. doi:10.1073/pnas.170279097. PMC 16905. PMID 10920205.
↑ Takaesu G, Ninomiya-Tsuji J, Kishida S, Li X, Stark GR, Matsumoto K (April 2001). "Interleukin-1 (IL-1) receptor-associated kinase leads to activation of TAK1 by inducing TAB2 translocation in the IL-1 signaling pathway". Mol. Cell. Biol. 21 (7): 2475–84. doi:10.1128/MCB.21.7.2475-2484.2001. PMC 86880. PMID 11259596.
↑ Chen F, Du Y, Zhang Z, Chen G, Zhang M, Shu HB, Zhai Z, Chen D (April 2008). "Syntenin negatively regulates TRAF6-mediated IL-1R/TLR4 signaling". Cell. Signal. 20 (4): 666–74. doi:10.1016/j.cellsig.2007.12.002. PMID 18234474.
↑ Newton K, Matsumoto ML, Wertz IE, Kirkpatrick DS, Lill JR, Tan J, Dugger D, Gordon N, Sidhu SS, Fellouse FA, Komuves L, French DM, Ferrando RE, Lam C, Compaan D, Yu C, Bosanac I, Hymowitz SG, Kelley RF, Dixit VM (August 2008). "Ubiquitin chain editing revealed by polyubiquitin linkage-specific antibodies". Cell 134 (4): 668–78. doi:10.1016/j.cell.2008.07.039. PMID 18724939.
↑ Xiao H, Qian W, Staschke K, Qian Y, Cui G, Deng L, Ehsani M, Wang X, Qian YW, Chen ZJ, Gilmour R, Jiang Z, Li X (May 2008). "Pellino 3b negatively regulates interleukin-1-induced TAK1-dependent NF kappaB activation". J. Biol. Chem. 283 (21): 14654–64. doi:10.1074/jbc.M706931200. PMC 2386918. PMID 18326498.

Auron PE (1999). "The interleukin 1 receptor: ligand interactions and signal transduction.". Cytokine Growth Factor Rev. 9 (3-4): 221–37. doi:10.1016/S1359-6101(98)00018-5. PMID 9918122.
Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV (1996). "TRAF6 is a signal transducer for interleukin-1.". Nature 383 (6599): 443–6. doi:10.1038/383443a0. PMID 8837778.
Brenner V, Nyakatura G, Rosenthal A, Platzer M (1997). "Genomic organization of two novel genes on human Xq28: compact head to head arrangement of IDH gamma and TRAP delta is conserved in rat and mouse.". Genomics 44 (1): 8–14. doi:10.1006/geno.1997.4822. PMID 9286695.
Huang J, Gao X, Li S, Cao Z (1998). "Recruitment of IRAK to the interleukin 1 receptor complex requires interleukin 1 receptor accessory protein.". Proc. Natl. Acad. Sci. U.S.A. 94 (24): 12829–32. doi:10.1073/pnas.94.24.12829. PMC 24223. PMID 9371760.
Muzio M, Natoli G, Saccani S, Levrero M, Mantovani A (1998). "The human toll signaling pathway: divergence of nuclear factor kappaB and JNK/SAPK activation upstream of tumor necrosis factor receptor-associated factor 6 (TRAF6).". J. Exp. Med. 187 (12): 2097–101. doi:10.1084/jem.187.12.2097. PMC 2212359. PMID 9625770.
Maschera B, Ray K, Burns K, Volpe F (1999). "Overexpression of an enzymically inactive interleukin-1-receptor-associated kinase activates nuclear factor-kappaB.". Biochem. J. 339 (2): 227–31. doi:10.1042/0264-6021:3390227. PMC 1220149. PMID 10191251.
Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z (1999). "IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family.". J. Biol. Chem. 274 (27): 19403–10. doi:10.1074/jbc.274.27.19403. PMID 10383454.
Yang RB, Mark MR, Gurney AL, Godowski PJ (1999). "Signaling events induced by lipopolysaccharide-activated toll-like receptor 2.". J. Immunol. 163 (2): 639–43. PMID 10395652.
Thomas JA, Allen JL, Tsen M, Dubnicoff T, Danao J, Liao XC, Cao Z, Wasserman SA (1999). "Impaired cytokine signaling in mice lacking the IL-1 receptor-associated kinase.". J. Immunol. 163 (2): 978–84. PMID 10395695.
Reichwald K, Thiesen J, Wiehe T, Weitzel J, Poustka WA, Rosenthal A, Platzer M, Strätling WH, Kioschis P (2000). "Comparative sequence analysis of the MECP2-locus in human and mouse reveals new transcribed regions.". Mamm. Genome 11 (3): 182–90. doi:10.1007/s003350010035. PMID 10723722.
Burns K, Clatworthy J, Martin L, Martinon F, Plumpton C, Maschera B, Lewis A, Ray K, Tschopp J, Volpe F (2000). "Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor.". Nat. Cell Biol. 2 (6): 346–51. doi:10.1038/35014038. PMID 10854325.
Böl G, Kreuzer OJ, Brigelius-Flohé R (2000). "Translocation of the interleukin-1 receptor-associated kinase-1 (IRAK-1) into the nucleus.". FEBS Lett. 477 (1-2): 73–8. doi:10.1016/S0014-5793(00)01759-2. PMID 10899313.
Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination.". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
Vig E, Green M, Liu Y, Yu KY, Kwon HJ, Tian J, Goebl MG, Harrington MA (2001). "SIMPL is a tumor necrosis factor-specific regulator of nuclear factor-kappaB activity.". J. Biol. Chem. 276 (11): 7859–66. doi:10.1074/jbc.M010399200. PMID 11096118.
Li X, Commane M, Jiang Z, Stark GR (2001). "IL-1-induced NFkappa B and c-Jun N-terminal kinase (JNK) activation diverge at IL-1 receptor-associated kinase (IRAK).". Proc. Natl. Acad. Sci. U.S.A. 98 (8): 4461–5. doi:10.1073/pnas.071054198. PMC 31857. PMID 11287640.
Jensen LE, Whitehead AS (2001). "IRAK1b, a novel alternative splice variant of interleukin-1 receptor-associated kinase (IRAK), mediates interleukin-1 signaling and has prolonged stability.". J. Biol. Chem. 276 (31): 29037–44. doi:10.1074/jbc.M103815200. PMID 11397809.
Qian Y, Commane M, Ninomiya-Tsuji J, Matsumoto K, Li X (2001). "IRAK-mediated translocation of TRAF6 and TAB2 in the interleukin-1-induced activation of NFkappa B.". J. Biol. Chem. 276 (45): 41661–7. doi:10.1074/jbc.M102262200. PMID 11518704.

Signaling pathway: TLR signaling pathway

Receptor

TLR 4

TLR 1 TLR 2 TLR 6

TLR 5 TLR 10

Other external

Internal

adaptor: MYD88 TRIF TIRAP TRAF6 TOLLIP

IRAK1 IRAK4

IRF3

TLR 3 TLR 7 TLR 8 TLR 9

Kinases: Serine/threonine-specific protein kinases (EC 2.7.11-12)

Serine/threonine-specific protein kinases (EC 2.7.11.1-EC 2.7.11.20)

Non-specific serine/threonine protein kinases (EC 2.7.11.1)	LATS1 LATS2 MAST1 MAST2 STK38 STK38L CIT ROCK1 SGK SGK2 SGK3 Protein kinase B AKT1 AKT2 AKT3 Ataxia telangiectasia mutated Mammalian target of rapamycin EIF-2 kinases PKR HRI EIF2AK3 EIF2AK4 Wee1 WEE1

Pyruvate dehydrogenase kinase (EC 2.7.11.2)	PDK1 PDK2 PDK3

Dephospho-(reductase kinase) kinase (EC 2.7.11.3)	AMP-activated protein kinase α PRKAA1 PRKAA2 β PRKAB1 PRKAB2 γ PRKAG1 PRKAG2 PRKAG3

(3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)) (EC 2.7.11.4)	BCKDK BCKDHA BCKDHB

(isocitrate dehydrogenase (NADP+)) kinase (EC 2.7.11.5)	IDH2 IDH3A IDH3B IDH3G

(tyrosine 3-monooxygenase) kinase (EC 2.7.11.6)	STK4

Myosin-heavy-chain kinase (EC 2.7.11.7)	Aurora kinase Aurora A kinase Aurora B kinase

Fas-activated serine/threonine kinase (EC 2.7.11.8)	FASTK STK10

Goodpasture-antigen-binding protein kinase (EC 2.7.11.9)	-

IκB kinase (EC 2.7.11.10)	CHUK IKK2 TBK1 IKBKE IKBKG IKBKAP

cAMP-dependent protein kinase (EC 2.7.11.11)	Protein kinase A PRKACG PRKACB PRKACA PRKY

cGMP-dependent protein kinase (EC 2.7.11.12)	Protein kinase G PRKG1

Protein kinase C (EC 2.7.11.13)	Protein kinase C Protein kinase Cζ PKC alpha PRKCB1 PRKCD PRKCE PRKCH PRKCG PRKCI PRKCQ Protein kinase N1 PKN2 PKN3

Rhodopsin kinase (EC 2.7.11.14)	Rhodopsin kinase

Beta adrenergic receptor kinase (EC 2.7.11.15)	Beta adrenergic receptor kinase Beta adrenergic receptor kinase-2

G-protein coupled receptor kinases (EC 2.7.11.16)	GRK4 GRK5 GRK6

Ca2+/calmodulin-dependent (EC 2.7.11.17)	BRSK2 CAMK1 CAMK2A CAMK2B CAMK2D CAMK2G CAMK4 MLCK CASK CHEK1 CHEK2 DAPK1 DAPK2 DAPK3 STK11 MAPKAPK2 MAPKAPK3 MAPKAPK5 MARK1 MARK2 MARK3 MARK4 MELK MKNK1 MKNK2 NUAK1 NUAK2 OBSCN PASK PHKG1 PHKG2 PIM1 PIM2 PKD1 PRKD2 PRKD3 PSKH1 SNF1LK2 KIAA0999 STK40 SNF1LK SNRK SPEG TSSK2 Kalirin TRIB1 TRIB2 TRIB3 TRIO Titin DCLK1

Myosin light-chain kinase (EC 2.7.11.18)	MYLK MYLK2 MYLK3 MYLK4

Phosphorylase kinase (EC 2.7.11.19)	PHKA1 PHKA2 PHKB PHKG1 PHKG2

Elongation factor 2 kinase (EC 2.7.11.20)	EEF2K STK19

Polo kinase (EC 2.7.11.21)	PLK1 PLK2 PLK3 PLK4

Serine/threonine-specific protein kinases (EC 2.7.11.21-EC 2.7.11.30)

Polo kinase (EC 2.7.11.21)	PLK1 PLK2 PLK3 PLK4

Cyclin-dependent kinase (EC 2.7.11.22)	CDK1 CDK2 CDKL2 CDK3 CDK4 CDK5 CDKL5 CDK6 CDK7 CDK8 CDK9 CDK10 CDK12 CDC2L5 PCTK1 PCTK2 PCTK3 PFTK1 CDC2L1

(RNA-polymerase)-subunit kinase (EC 2.7.11.23)	RPS6KA5 RPS6KA4 P70S6 kinase P70-S6 Kinase 1 RPS6KB2 RPS6KA2 RPS6KA3 RPS6KA1 RPS6KC1

Mitogen-activated protein kinase (EC 2.7.11.24)	Extracellular signal-regulated MAPK1 MAPK3 MAPK4 MAPK6 MAPK7 MAPK12 MAPK15 C-Jun N-terminal MAPK8 MAPK9 MAPK10 P38 mitogen-activated protein MAPK11 MAPK13 MAPK14

MAP3K (EC 2.7.11.25)	MAP kinase kinase kinases MAP3K1 MAP3K2 MAP3K3 MAP3K4 MAP3K5 MAP3K6 MAP3K7 MAP3K8 RAFs ARAF BRAF KSR1 KSR2 MLKs MAP3K12 MAP3K13 MAP3K9 MAP3K10 MAP3K11 MAP3K7 ZAK CDC7 MAP3K14

Tau-protein kinase (EC 2.7.11.26)	TPK1 TTK GSK-3

(acetyl-CoA carboxylase) kinase (EC 2.7.11.27)	-

Tropomyosin kinase (EC 2.7.11.28)	-

Low-density-lipoprotein receptor kinase (EC 2.7.11.29)	-

Receptor protein serine/threonine kinase (EC 2.7.11.30)	Bone morphogenetic protein receptors BMPR1 BMPR1A BMPR1B BMPR2 ACVR1 ACVR1B ACVR1C ACVR2A ACVR2B ACVRL1 Anti-Müllerian hormone receptor

Dual-specificity kinases (EC 2.7.12)

MAP2K	MAP2K1 MAP2K2 MAP2K3 MAP2K4 MAP2K5 MAP2K6 MAP2K7

Proteins: enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases(list) EC2 Transferases(list) EC3 Hydrolases(list) EC4 Lyases(list) EC5 Isomerases(list) EC6 Ligases(list)

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IRAK1

Function

Interactions

References

Further reading