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Gene Review

IRAK1  -  interleukin-1 receptor-associated kinase 1

Homo sapiens

Synonyms: IRAK, IRAK-1, Interleukin-1 receptor-associated kinase 1, pelle
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Disease relevance of IRAK1


High impact information on IRAK1

  • When human embryonic kidney cells (cell line 293) over-expressing IL-1RI or HeLa cells were exposed to IL-1, IRAK rapidly associated with the IL-1RI complex and was phosphorylated [7].
  • A protein kinase designated IRAK (IL-1 receptor-associated kinase) was purified, and its complementary DNA was molecularly cloned [7].
  • The primary amino acid sequence of IRAK shares similarity with that of Pelle, a protein kinase that is essential for the activation of a NF-kappa B homolog in Drosophila [7].
  • Furthermore, recent data imply a role for IRAK-1 in tumor necrosis factor receptor (TNFR) superfamily-induced signaling pathways as well [8].
  • We now demonstrate that signaling by the human Toll receptor employs an adaptor protein, MyD88, and induces activation of NF-kappaB via the Pelle-like kinase IRAK and the TRAF6 protein, similar to IL-1R-mediated NF-kappaB activation [9].

Biological context of IRAK1

  • We also demonstrate that Akt activity is necessary for IL-1-dependent NF-kappaB transactivation, since a kinase-defective mutant of Akt impairs IRAK2- and MyD88-dependent, but not IRAK1-dependent, NF-kappaB activity, as monitored by a gene reporter assay [10].
  • We define sequential phosphorylation steps in IRAK-1, which are, in vitro, autophosphorylation [11].
  • Thus, decreased TLR4-MyD88 complex formation with subsequent impairment of IRAK-1 activity may underlie the LPS-tolerant phenotype [12].
  • Bacterial lipoprotein-induced self-tolerance and cross-tolerance to LPS are associated with reduced IRAK-1 expression and MyD88-IRAK complex formation [13].
  • This mechanism of tolerance induction which serves to mitigate excessive and potentially harmful inflammatory reactions appears to be due partly to fimbria-induced downregulation of the expression of interleukin-1 receptor-associated kinase-1 (IRAK-1), an important signaling intermediate of the TLR pathway [14].

Anatomical context of IRAK1


Associations of IRAK1 with chemical compounds


Physical interactions of IRAK1

  • Formation of the signaling IL-1 receptor complex results in the activation and hyperphosphorylation of IRAK-1, which leads to a pronounced shift of its apparent molecular mass in gel electrophoresis [11].
  • The interleukin-1 receptor-associated kinase 1 (IRAK-1) is an important adapter in the signaling complex of the Toll/interleukin-1 (IL-1) receptor family [11].
  • IL-8-induced NF-kappaB activation is not observed in a cell-permeable peptide that has TRAF6 binding motif-treated cells or IRAK-deficient cells [23].

Enzymatic interactions of IRAK1

  • In addition, we show for the first time that Tollip is a bona fide substrate for IRAK and is phosphorylated by IRAK upon stimulation with lipopolysaccharide or IL-1 [24].
  • The recent characterization of an IL-1 receptor associated kinase (IRAK) and a continuous molecular path between this kinase and that which directly phosphorylates IkappaB would seem to all but close the basic understanding of IL-1 receptor signal transduction [25].
  • IRAK-1 is then subsequently phosphorylated to up-regulate CD86 expression, resulting in subsequent T-cell proliferation [26].

Regulatory relationships of IRAK1

  • These results suggest that acute alcohol attenuates TLR4-induced inflammation via inhibition of IRAK-1 and ERK1/2 kinases and increases in IRAK-monocyte levels in monocytes [27].
  • Taken together, these results indicate a novel regulatory mechanism for IL-1beta signaling and suggest that CaMKK-dependent Akt activation inhibits IL-1beta-induced NF-kappaB activation through interference with the coupling of IRAK1 to MyD88 [28].
  • Truncated IRAK-4 proteins constitutively interacted more strongly with MyD88 and blunted IL-1-induced recruitment of IRAK-1 and MyD88 to the IL-1R [29].
  • Furthermore, MyD88Delta inhibited NE-induced IRAK degradation [30].
  • However, neither TNF-alpha nor IL-1beta induced IRAK degradation or stimulated TNF-alpha or TxB2 production in naive cells [31].

Other interactions of IRAK1

  • In contrast to the interleukin-1 receptor/toll-like receptor-mediated NF-kappaB pathways, the CTAR2-mediated NF-kappaB pathway does not require MyD88, IRAK1, or IRAK4 for TRAF6 engagement [32].
  • Hyperphosphorylation of this region leads to dissociation of IRAK-1 from the upstream adapters MyD88 and Tollip but leaves its interaction with the downstream adapter TRAF6 unaffected [11].
  • LPS induced the association of MyD88 with TLR4 and increased IRAK-1 activity in medium-pretreated cells [12].
  • This is the first example of a CLR protein that antagonizes inflammatory responses initiated by TLR agonists via interference with IRAK-1 activation [33].
  • Concomitant with receptor oligomerization, the IL-1R-associated kinase (IRAK) is recruited to the TLR2 complex [34].

Analytical, diagnostic and therapeutic context of IRAK1


  1. Association of a haplotype (196Phe/532Ser) in the interleukin-1-receptor-associated kinase (IRAK1) gene with low radial bone mineral density in two independent populations. Ishida, R., Emi, M., Ezura, Y., Iwasaki, H., Yoshida, H., Suzuki, T., Hosoi, T., Inoue, S., Shiraki, M., Ito, H., Orimo, H. J. Bone Miner. Res. (2003) [Pubmed]
  2. Interactions of sequence variants in interleukin-1 receptor-associated kinase4 and the toll-like receptor 6-1-10 gene cluster increase prostate cancer risk. Sun, J., Wiklund, F., Hsu, F.C., Bälter, K., Zheng, S.L., Johansson, J.E., Chang, B., Liu, W., Li, T., Turner, A.R., Li, L., Li, G., Adami, H.O., Isaacs, W.B., Xu, J., Grönberg, H. Cancer Epidemiol. Biomarkers Prev. (2006) [Pubmed]
  3. Airway epithelial cell tolerance to Pseudomonas aeruginosa. Wu, Q., Lu, Z., Verghese, M.W., Randell, S.H. Respir. Res. (2005) [Pubmed]
  4. Transcriptional regulator CTCF controls human interleukin 1 receptor-associated kinase 2 promoter. Kuzmin, I., Geil, L., Gibson, L., Cavinato, T., Loukinov, D., Lobanenkov, V., Lerman, M.I. J. Mol. Biol. (2005) [Pubmed]
  5. Variant IRAK-1 haplotype is associated with increased nuclear factor-kappaB activation and worse outcomes in sepsis. Arcaroli, J., Silva, E., Maloney, J.P., He, Q., Svetkauskaite, D., Murphy, J.R., Abraham, E. Am. J. Respir. Crit. Care Med. (2006) [Pubmed]
  6. Expression of interleukin-1 receptor-associated kinase-1 in non-small cell lung carcinoma and preneoplastic lesions. Behrens, C., Feng, L., Kadara, H., Kim, H.J., Lee, J.J., Mehran, R., Hong, W.K., Lotan, R., Wistuba, I.I. Clin. Cancer Res. (2010) [Pubmed]
  7. IRAK: a kinase associated with the interleukin-1 receptor. Cao, Z., Henzel, W.J., Gao, X. Science (1996) [Pubmed]
  8. Functional diversity and regulation of different interleukin-1 receptor-associated kinase (IRAK) family members. Janssens, S., Beyaert, R. Mol. Cell (2003) [Pubmed]
  9. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Medzhitov, R., Preston-Hurlburt, P., Kopp, E., Stadlen, A., Chen, C., Ghosh, S., Janeway, C.A. Mol. Cell (1998) [Pubmed]
  10. Interleukin-1-receptor-associated kinase 2 (IRAK2)-mediated interleukin-1-dependent nuclear factor kappaB transactivation in Saos2 cells requires the Akt/protein kinase B kinase. Cenni, V., Sirri, A., De Pol, A., Maraldi, N.M., Marmiroli, S. Biochem. J. (2003) [Pubmed]
  11. Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adapter in interleukin-1 signaling. Kollewe, C., Mackensen, A.C., Neumann, D., Knop, J., Cao, P., Li, S., Wesche, H., Martin, M.U. J. Biol. Chem. (2004) [Pubmed]
  12. Dysregulation of LPS-induced Toll-like receptor 4-MyD88 complex formation and IL-1 receptor-associated kinase 1 activation in endotoxin-tolerant cells. Medvedev, A.E., Lentschat, A., Wahl, L.M., Golenbock, D.T., Vogel, S.N. J. Immunol. (2002) [Pubmed]
  13. Bacterial lipoprotein-induced self-tolerance and cross-tolerance to LPS are associated with reduced IRAK-1 expression and MyD88-IRAK complex formation. Li, C.H., Wang, J.H., Redmond, H.P. J. Leukoc. Biol. (2006) [Pubmed]
  14. Intracellular signaling and cytokine induction upon interactions of Porphyromonas gingivalis fimbriae with pattern-recognition receptors. Hajishengallis, G., Sojar, H., Genco, R.J., DeNardin, E. Immunol. Invest. (2004) [Pubmed]
  15. A central role for the Hsp90.Cdc37 molecular chaperone module in interleukin-1 receptor-associated-kinase-dependent signaling by toll-like receptors. De Nardo, D., Masendycz, P., Ho, S., Cross, M., Fleetwood, A.J., Reynolds, E.C., Hamilton, J.A., Scholz, G.M. J. Biol. Chem. (2005) [Pubmed]
  16. Nitric oxide activates the expression of IRAK-M via the release of TNF-alpha in human monocytes. del Fresno, C., Gómez-García, L., Caveda, L., Escoll, P., Arnalich, F., Zamora, R., López-Collazo, E. Nitric Oxide (2004) [Pubmed]
  17. Dual receptors and distinct pathways mediate interleukin-1 receptor-associated kinase degradation in response to lipopolysaccharide. Involvement of CD14/TLR4, CR3, and phosphatidylinositol 3-kinase. Noubir, S., Hmama, Z., Reiner, N.E. J. Biol. Chem. (2004) [Pubmed]
  18. Gamma interferon and granulocyte/monocyte colony-stimulating factor prevent endotoxin tolerance in human monocytes by promoting interleukin-1 receptor-associated kinase expression and its association to MyD88 and not by modulating TLR4 expression. Adib-Conquy, M., Cavaillon, J.M. J. Biol. Chem. (2002) [Pubmed]
  19. Divergence of bacterial lipopolysaccharide pro-apoptotic signaling downstream of IRAK-1. Bannerman, D.D., Tupper, J.C., Erwert, R.D., Winn, R.K., Harlan, J.M. J. Biol. Chem. (2002) [Pubmed]
  20. Distinct post-receptor alterations generate gene- and signal-selective adaptation and cross-adaptation of TLR4 and TLR2 in human leukocytes. Li, L., Jacinto, R., Yoza, B., McCall, C.E. J. Endotoxin Res. (2003) [Pubmed]
  21. Ubiquitin activated tumor necrosis factor receptor associated factor-6 (TRAF6) is recycled via deubiquitination. Jensen, L.E., Whitehead, A.S. FEBS Lett. (2003) [Pubmed]
  22. Identification of threonine 66 as a functionally critical residue of the interleukin-1 receptor-associated kinase. Ross, K., Yang, L., Dower, S., Volpe, F., Guesdon, F. J. Biol. Chem. (2002) [Pubmed]
  23. Interleukin-8 induces nuclear transcription factor-kappaB through a TRAF6-dependent pathway. Manna, S.K., Ramesh, G.T. J. Biol. Chem. (2005) [Pubmed]
  24. Negative regulation of toll-like receptor-mediated signaling by Tollip. Zhang, G., Ghosh, S. J. Biol. Chem. (2002) [Pubmed]
  25. The interleukin 1 receptor: ligand interactions and signal transduction. Auron, P.E. Cytokine Growth Factor Rev. (1998) [Pubmed]
  26. Caveolin-1 Triggers T-cell Activation via CD26 in Association with CARMA1. Ohnuma, K., Uchiyama, M., Yamochi, T., Nishibashi, K., Hosono, O., Takahashi, N., Kina, S., Tanaka, H., Lin, X., Dang, N.H., Morimoto, C. J. Biol. Chem. (2007) [Pubmed]
  27. TLR2- and TLR4-mediated signals determine attenuation or augmentation of inflammation by acute alcohol in monocytes. Oak, S., Mandrekar, P., Catalano, D., Kodys, K., Szabo, G. J. Immunol. (2006) [Pubmed]
  28. 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. Chen, B.C., Wu, W.T., Ho, F.M., Lin, W.W. J. Biol. Chem. (2002) [Pubmed]
  29. Cutting edge: expression of IL-1 receptor-associated kinase-4 (IRAK-4) proteins with mutations identified in a patient with recurrent bacterial infections alters normal IRAK-4 interaction with components of the IL-1 receptor complex. Medvedev, A.E., Thomas, K., Awomoyi, A., Kuhns, D.B., Gallin, J.I., Li, X., Vogel, S.N. J. Immunol. (2005) [Pubmed]
  30. Interleukin-8 up-regulation by neutrophil elastase is mediated by MyD88/IRAK/TRAF-6 in human bronchial epithelium. Walsh, D.E., Greene, C.M., Carroll, T.P., Taggart, C.C., Gallagher, P.M., O'Neill, S.J., McElvaney, N.G. J. Biol. Chem. (2001) [Pubmed]
  31. Effect of cross-tolerance between endotoxin and TNF-alpha or IL-1beta on cellular signaling and mediator production. Ferlito, M., Romanenko, O.G., Ashton, S., Squadrito, F., Halushka, P.V., Cook, J.A. J. Leukoc. Biol. (2001) [Pubmed]
  32. The C-terminal activating region 2 of the Epstein-Barr virus-encoded latent membrane protein 1 activates NF-kappaB through TRAF6 and TAK1. Wu, L., Nakano, H., Wu, Z. J. Biol. Chem. (2006) [Pubmed]
  33. The CATERPILLER protein monarch-1 is an antagonist of toll-like receptor-, tumor necrosis factor alpha-, and Mycobacterium tuberculosis-induced pro-inflammatory signals. Williams, K.L., Lich, J.D., Duncan, J.A., Reed, W., Rallabhandi, P., Moore, C., Kurtz, S., Coffield, V.M., Accavitti-Loper, M.A., Su, L., Vogel, S.N., Braunstein, M., Ting, J.P. J. Biol. Chem. (2005) [Pubmed]
  34. Signaling events induced by lipopolysaccharide-activated toll-like receptor 2. Yang, R.B., Mark, M.R., Gurney, A.L., Godowski, P.J. J. Immunol. (1999) [Pubmed]
  35. Interferon gamma accelerates NF-kappaB activation of biliary epithelial cells induced by Toll-like receptor and ligand interaction. Harada, K., Isse, K., Nakanuma, Y. J. Clin. Pathol. (2006) [Pubmed]
  36. Neutrophil-Derived Elastase Induces TGF-beta1 Secretion in Human Airway Smooth Muscle via NF-{kappa}B Pathway. Lee, K.Y., Ho, S.C., Lin, H.C., Lin, S.M., Liu, C.Y., Huang, C.D., Wang, C.H., Chung, K.F., Kuo, H.P. Am. J. Respir. Cell Mol. Biol. (2006) [Pubmed]
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