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Gene Review

Irak1  -  interleukin-1 receptor-associated kinase 1

Mus musculus

Synonyms: AA408924, IRAK, IRAK-1, IRAK1-S, Il1rak, ...
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Disease relevance of Irak1

  • Thus IRAK-1 plays an important role in the host response to staphylococcal sepsis [1].
  • In contrast to the high mortality and extensive weight loss seen in IL-1R-deficient mice in response to 1 x 10(6) S. aureus, IRAK-1-/- mice are resistant to this low dose of S. aureus [1].
  • Though a critical protective role against Staphylococcus aureus infection has been previously attributed to myeloid differentiation factor 88 (MyD88) and IRAK-4, both also involved in TLR/IL-1/IL-18 signaling, the role of IRAK-1 is unknown [1].
  • WT animals developed severe disease, whereas IRAK1-deficient mice were resistant to experimental autoimmune encephalomyelitis, exhibiting little or no CNS inflammation [2].
  • Deletion of Irak, however, does not affect the ability of mice to develop delayed-type hypersensitivity or clear infection with the intracellular parasite, Listeria monocytogenes [3].

High impact information on Irak1

  • TLRs transduce their signals through MyD88 and the serine/threonine kinase IRAK [4].
  • Here we show by gene-targeting that IRAK-4, an IRAK molecule closely related to the Drosophila Pelle protein, is indispensable for the responses of animals and cultured cells to IL-1 and ligands that stimulate various TLRs [5].
  • Thus, IRAK-M acts as a dominant negative IRAK [6].
  • The kinase activity of IRAK-1 was necessary for transcriptional activation of IRF7 [7].
  • This triggers IRAK-1 phosphorylation and in turn the activation of multiple signaling cascades such as activation of the transcription factor nuclear factor (NF)-kappaB [8].

Chemical compound and disease context of Irak1


Biological context of Irak1


Anatomical context of Irak1

  • Ras participates in CpG oligodeoxynucleotide signaling through association with toll-like receptor 9 and promotion of interleukin-1 receptor-associated kinase/tumor necrosis factor receptor-associated factor 6 complex formation in macrophages [14].
  • IRAK-deficient fibroblasts show diminished activation of NF-kappaB when stimulated with IL-1 [3].
  • Results from these experiments demonstrate that lipopolysaccharides (LPS) activate Toll/IL-1 signaling and IL-1 receptor-associated kinase-1 (IRAK1), a critical pathway intermediate in the heart, indicating that the function of this pathway is not limited to immune system tissues [15].
  • In contrast, ethanol treatment to mice increased expression of IRAK in Kupffer cells 21hrs later and LPS-induced activation of NFkappaB was elevated significantly [16].
  • FliC induced IRAK activation in HeNC2 and GG2EE cells as well as in the human promonocytic cell line THP-1 [17].

Associations of Irak1 with chemical compounds


Physical interactions of Irak1


Enzymatic interactions of Irak1


Regulatory relationships of Irak1

  • Furthermore, macrophages lacking IRAK exhibit impaired LPS-stimulated TNF-alpha production, and IRAK-deficient mice withstand the lethal effects of LPS [22].
  • The role of IRAK in IL-18-induced responses was studied in IRAK-deficient mice [23].
  • In the presence of MyD88s, IRAK-1 is not phosphorylated and neither activates NF-kappaB nor is ubiquitinated [8].
  • In transgene-negative cells, constitutive activation of IL-1-dependent signaling by wild type or kinase-dead IRAK1 stimulated IL-1alpha production independent of Erk [24].

Other interactions of Irak1

  • IRAK-1-S cDNA is shorter than the originally reported IRAK-1 (IRAK-1-W) cDNA by 271 nucleotides, and the subsequent frameshift causes a premature termination of translation after 23 amino acids, which are unique to the IRAK-1-S protein [12].
  • The main transduction pathway responsible for NF-kappaB activation has been established and involves the MyD88, interleukin-1 receptor-associated kinase, tumor necrosis factor receptor-associated factor-6, NF-kappaB-inducing kinase, and inhibitor of kappaB kinase complex [25].
  • Upon stimulation of cells with interleukin-1 (IL-1) the IL-1 receptor type I (IL-1RI) associated kinase-1 (IRAK-1) transiently associates to and dissociates from the IL-1RI and thereafter translocates into the nucleus [21].
  • Interleukin (IL)-1 receptor-associated kinase (IRAK) requirement for optimal induction of multiple IL-1 signaling pathways and IL-6 production [26].
  • Activation of IL-1R-associated kinase-1 (IRAK-1) and IRAK-4 in response to LPS stimulation was inhibited by antioxidants [27].

Analytical, diagnostic and therapeutic context of Irak1


  1. IL-1 receptor-associated kinase 1 mediates protection against Staphylococcus aureus infection. Verdrengh, M., Thomas, J.A., Hultgren, O.H. Microbes Infect. (2004) [Pubmed]
  2. IL-1 receptor-associated kinase 1 regulates susceptibility to organ-specific autoimmunity. Deng, C., Radu, C., Diab, A., Tsen, M.F., Hussain, R., Cowdery, J.S., Racke, M.K., Thomas, J.A. J. Immunol. (2003) [Pubmed]
  3. Impaired cytokine signaling in mice lacking the IL-1 receptor-associated kinase. Thomas, J.A., Allen, J.L., Tsen, M., Dubnicoff, T., Danao, J., Liao, X.C., Cao, Z., Wasserman, S.A. J. Immunol. (1999) [Pubmed]
  4. IRAK-M is a negative regulator of Toll-like receptor signaling. Kobayashi, K., Hernandez, L.D., Galán, J.E., Janeway, C.A., Medzhitov, R., Flavell, R.A. Cell (2002) [Pubmed]
  5. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Suzuki, N., Suzuki, S., Duncan, G.S., Millar, D.G., Wada, T., Mirtsos, C., Takada, H., Wakeham, A., Itie, A., Li, S., Penninger, J.M., Wesche, H., Ohashi, P.S., Mak, T.W., Yeh, W.C. Nature (2002) [Pubmed]
  6. IL-1 receptor-associated kinase M is a central regulator of osteoclast differentiation and activation. Li, H., Cuartas, E., Cui, W., Choi, Y., Crawford, T.D., Ke, H.Z., Kobayashi, K.S., Flavell, R.A., Vignery, A. J. Exp. Med. (2005) [Pubmed]
  7. Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction. Uematsu, S., Sato, S., Yamamoto, M., Hirotani, T., Kato, H., Takeshita, F., Matsuda, M., Coban, C., Ishii, K.J., Kawai, T., Takeuchi, O., Akira, S. J. Exp. Med. (2005) [Pubmed]
  8. Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4. Burns, K., Janssens, S., Brissoni, B., Olivos, N., Beyaert, R., Tschopp, J. J. Exp. Med. (2003) [Pubmed]
  9. Curcumin blocks interleukin-1 (IL-1) signaling by inhibiting the recruitment of the IL-1 receptor-associated kinase IRAK in murine thymoma EL-4 cells. Jurrmann, N., Brigelius-Flohé, R., Böl, G.F. J. Nutr. (2005) [Pubmed]
  10. IRAK contributes to burn-triggered myocardial contractile dysfunction. Thomas, J.A., Tsen, M.F., White, D.J., Horton, J.W. Am. J. Physiol. Heart Circ. Physiol. (2002) [Pubmed]
  11. Phosphorylation of Ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by Mouse Pelle-like kinase/interleukin-1 receptor-associated kinase: cross-talk between inflammatory signaling and insulin signaling that may contribute to insulin resistance. Kim, J.A., Yeh, D.C., Ver, M., Li, Y., Carranza, A., Conrads, T.P., Veenstra, T.D., Harrington, M.A., Quon, M.J. J. Biol. Chem. (2005) [Pubmed]
  12. A novel splice variant of mouse interleukin-1-receptor-associated kinase-1 (IRAK-1) activates nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK). Yanagisawa, K., Tago, K., Hayakawa, M., Ohki, M., Iwahana, H., Tominaga, S. Biochem. J. (2003) [Pubmed]
  13. Interleukin-1 receptor-associated kinase gene Il1rak maps to the mouse X chromosome. Centanni, J.M., de Miguel, M., Gopalan, G., Gilbert, D.J., Copeland, N.G., Jenkins, N.A., Donovan, P.J. Mamm. Genome (1998) [Pubmed]
  14. Ras participates in CpG oligodeoxynucleotide signaling through association with toll-like receptor 9 and promotion of interleukin-1 receptor-associated kinase/tumor necrosis factor receptor-associated factor 6 complex formation in macrophages. Xu, H., An, H., Yu, Y., Zhang, M., Qi, R., Cao, X. J. Biol. Chem. (2003) [Pubmed]
  15. IRAK1 deletion disrupts cardiac Toll/IL-1 signaling and protects against contractile dysfunction. Thomas, J.A., Haudek, S.B., Koroglu, T., Tsen, M.F., Bryant, D.D., White, D.J., Kusewitt, D.F., Horton, J.W., Giroir, B.P. Am. J. Physiol. Heart Circ. Physiol. (2003) [Pubmed]
  16. Ethanol-induced sensitization to endotoxin in Kupffer cells is dependent upon oxidative stress. Yamashina, S., Takei, Y., Ikejima, K., Enomoto, N., Kitamura, T., Sato, N. Alcohol. Clin. Exp. Res. (2005) [Pubmed]
  17. Activation of interleukin-1 receptor-associated kinase by gram-negative flagellin. Moors, M.A., Li, L., Mizel, S.B. Infect. Immun. (2001) [Pubmed]
  18. IRAK1 serves as a novel regulator essential for lipopolysaccharide-induced interleukin-10 gene expression. Huang, Y., Li, T., Sane, D.C., Li, L. J. Biol. Chem. (2004) [Pubmed]
  19. The immunomodulating neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) suppresses LPS-stimulated TLR4 with IRAK-M in macrophages. Taylor, A.W. J. Neuroimmunol. (2005) [Pubmed]
  20. Developmental and tissue-specific expression of mouse pelle-like protein kinase. Trofimova, M., Sprenkle, A.B., Green, M., Sturgill, T.W., Goebl, M.G., Harrington, M.A. J. Biol. Chem. (1996) [Pubmed]
  21. Cellular trafficking of the IL-1RI-associated kinase-1 requires intact kinase activity. Böl, G.F., Jurrmann, N., Brigelius-Flohé, R. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  22. IL-1 receptor-associated kinase modulates host responsiveness to endotoxin. Swantek, J.L., Tsen, M.F., Cobb, M.H., Thomas, J.A. J. Immunol. (2000) [Pubmed]
  23. Defective interleukin (IL)-18-mediated natural killer and T helper cell type 1 responses in IL-1 receptor-associated kinase (IRAK)-deficient mice. Kanakaraj, P., Ngo, K., Wu, Y., Angulo, A., Ghazal, P., Harris, C.A., Siekierka, J.J., Peterson, P.A., Fung-Leung, W.P. J. Exp. Med. (1999) [Pubmed]
  24. Regulation of interleukin-1alpha expression by integrins and epidermal growth factor receptor in keratinocytes from a mouse model of inflammatory skin disease. Hobbs, R.M., Watt, F.M. J. Biol. Chem. (2003) [Pubmed]
  25. Activation of phosphatidylinositol 3-kinase and c-Jun-N-terminal kinase cascades enhances NF-kappaB-dependent gene transcription in BCG-stimulated macrophages through promotion of p65/p300 binding. Darieva, Z., Lasunskaia, E.B., Campos, M.N., Kipnis, T.L., Da Silva, W.D. J. Leukoc. Biol. (2004) [Pubmed]
  26. Interleukin (IL)-1 receptor-associated kinase (IRAK) requirement for optimal induction of multiple IL-1 signaling pathways and IL-6 production. Kanakaraj, P., Schafer, P.H., Cavender, D.E., Wu, Y., Ngo, K., Grealish, P.F., Wadsworth, S.A., Peterson, P.A., Siekierka, J.J., Harris, C.A., Fung-Leung, W.P. J. Exp. Med. (1998) [Pubmed]
  27. Involvement of reactive oxygen species in Toll-like receptor 4-dependent activation of NF-kappa B. Asehnoune, K., Strassheim, D., Mitra, S., Kim, J.Y., Abraham, E. J. Immunol. (2004) [Pubmed]
  28. Zinc inhibits interleukin-1-dependent T cell stimulation. Wellinghausen, N., Martin, M., Rink, L. Eur. J. Immunol. (1997) [Pubmed]
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