Interleukin-1 family signaling (Homo sapiens)

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Bibliography

1. Sharma S, Kulk N, Nold MF, Gräf R, Kim SH, Reinhardt D, Dinarello CA, Bufler P.; ''The IL-1 family member 7b translocates to the nucleus and down-regulates proinflammatory cytokines.''; PubMed Europe PMC Scholia
2. Wu C, Ghosh S.; ''Differential phosphorylation of the signal-responsive domain of I kappa B alpha and I kappa B beta by I kappa B kinases.''; PubMed Europe PMC Scholia
3. Burns K, Janssens S, Brissoni B, Olivos N, Beyaert R, Tschopp J.; ''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.''; PubMed Europe PMC Scholia
4. Cheng H, Addona T, Keshishian H, Dahlstrand E, Lu C, Dorsch M, Li Z, Wang A, Ocain TD, Li P, Parsons TF, Jaffee B, Xu Y.; ''Regulation of IRAK-4 kinase activity via autophosphorylation within its activation loop.''; PubMed Europe PMC Scholia
5. Goldstein MH, Martel JR, Sall K, Goldberg DF, Abrams M, Rubin J, Sheppard J, Tauber J, Korenfeld M, Agahigian J, Durham TA, Furfine E.; ''Multicenter Study of a Novel Topical Interleukin-1 Receptor Inhibitor, Isunakinra, in Subjects With Moderate to Severe Dry Eye Disease.''; PubMed Europe PMC Scholia
6. Arch RH, Gedrich RW, Thompson CB.; ''Tumor necrosis factor receptor-associated factors (TRAFs)--a family of adapter proteins that regulates life and death.''; PubMed Europe PMC Scholia
7. Towne JE, Garka KE, Renshaw BR, Virca GD, Sims JE.; ''Interleukin (IL)-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-1RAcP to activate the pathway leading to NF-kappaB and MAPKs.''; PubMed Europe PMC Scholia
8. Gilmore TD.; ''Introduction to NF-kappaB: players, pathways, perspectives.''; PubMed Europe PMC Scholia
9. Lamothe B, Besse A, Campos AD, Webster WK, Wu H, Darnay BG.; ''Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation.''; PubMed Europe PMC Scholia
10. Wesche H, Henzel WJ, Shillinglaw W, Li S, Cao Z.; ''MyD88: an adapter that recruits IRAK to the IL-1 receptor complex.''; PubMed Europe PMC Scholia
11. Dower SK, Kronheim SR, Hopp TP, Cantrell M, Deeley M, Gillis S, Henney CS, Urdal DL.; ''The cell surface receptors for interleukin-1 alpha and interleukin-1 beta are identical.''; PubMed Europe PMC Scholia
12. Nold-Petry CA, Lo CY, Rudloff I, Elgass KD, Li S, Gantier MP, Lotz-Havla AS, Gersting SW, Cho SX, Lao JC, Ellisdon AM, Rotter B, Azam T, Mangan NE, Rossello FJ, Whisstock JC, Bufler P, Garlanda C, Mantovani A, Dinarello CA, Nold MF, Nold MF.; ''IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction.''; PubMed Europe PMC Scholia
13. Spencer E, Jiang J, Chen ZJ.; ''Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCP.''; PubMed Europe PMC Scholia
14. Shi P, Zhu S, Lin Y, Liu Y, Liu Y, Chen Z, Shi Y, Qian Y.; ''Persistent stimulation with interleukin-17 desensitizes cells through SCFβ-TrCP-mediated degradation of Act1.''; PubMed Europe PMC Scholia
15. Sims JE, Gayle MA, Slack JL, Alderson MR, Bird TA, Giri JG, Colotta F, Re F, Mantovani A, Shanebeck K.; ''Interleukin 1 signaling occurs exclusively via the type I receptor.''; PubMed Europe PMC Scholia
16. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, Gorman DM, Bazan JF, Kastelein RA.; ''IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines.''; PubMed Europe PMC Scholia
17. Jiang Z, Johnson HJ, Nie H, Qin J, Bird TA, Li X.; ''Pellino 1 is required for interleukin-1 (IL-1)-mediated signaling through its interaction with the IL-1 receptor-associated kinase 4 (IRAK4)-IRAK-tumor necrosis factor receptor-associated factor 6 (TRAF6) complex.''; PubMed Europe PMC Scholia
18. Yaron A, Hatzubai A, Davis M, Lavon I, Amit S, Manning AM, Andersen JS, Mann M, Mercurio F, Ben-Neriah Y.; ''Identification of the receptor component of the IkappaBalpha-ubiquitin ligase.''; PubMed Europe PMC Scholia
19. Born TL, Smith DE, Garka KE, Renshaw BR, Bertles JS, Sims JE.; ''Identification and characterization of two members of a novel class of the interleukin-1 receptor (IL-1R) family. Delineation of a new class of IL-1R-related proteins based on signaling.''; PubMed Europe PMC Scholia
20. Towne JE, Renshaw BR, Douangpanya J, Lipsky BP, Shen M, Gabel CA, Sims JE.; ''Interleukin-36 (IL-36) ligands require processing for full agonist (IL-36α, IL-36β, and IL-36γ) or antagonist (IL-36Ra) activity.''; PubMed Europe PMC Scholia
21. Takaesu G, Kishida S, Hiyama A, Yamaguchi K, Shibuya H, Irie K, Ninomiya-Tsuji J, Matsumoto K.; ''TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway.''; PubMed Europe PMC Scholia
22. Carter DB, Deibel MR, Dunn CJ, Tomich CS, Laborde AL, Slightom JL, Berger AE, Bienkowski MJ, Sun FF, McEwan RN.; ''Purification, cloning, expression and biological characterization of an interleukin-1 receptor antagonist protein.''; PubMed Europe PMC Scholia
23. van de Veerdonk FL, Stoeckman AK, Wu G, Boeckermann AN, Azam T, Netea MG, Joosten LA, van der Meer JW, Hao R, Kalabokis V, Dinarello CA.; ''IL-38 binds to the IL-36 receptor and has biological effects on immune cells similar to IL-36 receptor antagonist.''; PubMed Europe PMC Scholia
24. Palomo J, Dietrich D, Martin P, Palmer G, Gabay C.; ''The interleukin (IL)-1 cytokine family--Balance between agonists and antagonists in inflammatory diseases.''; PubMed Europe PMC Scholia
25. Lingel A, Weiss TM, Niebuhr M, Pan B, Appleton BA, Wiesmann C, Bazan JF, Fairbrother WJ.; ''Structure of IL-33 and its interaction with the ST2 and IL-1RAcP receptors--insight into heterotrimeric IL-1 signaling complexes.''; PubMed Europe PMC Scholia
26. Butler MP, Hanly JA, Moynagh PN.; ''Pellino3 is a novel upstream regulator of p38 MAPK and activates CREB in a p38-dependent manner.''; PubMed Europe PMC Scholia
27. Seckinger P, Klein-Nulend J, Alander C, Thompson RC, Dayer JM, Raisz LG.; ''Natural and recombinant human IL-1 receptor antagonists block the effects of IL-1 on bone resorption and prostaglandin production.''; PubMed Europe PMC Scholia
28. Moynagh PN.; ''The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling.''; PubMed Europe PMC Scholia
29. Gabay C, Towne JE.; ''Regulation and function of interleukin-36 cytokines in homeostasis and pathological conditions.''; PubMed Europe PMC Scholia
30. Lang V, Symons A, Watton SJ, Janzen J, Soneji Y, Beinke S, Howell S, Ley SC.; ''ABIN-2 forms a ternary complex with TPL-2 and NF-kappa B1 p105 and is essential for TPL-2 protein stability.''; PubMed Europe PMC Scholia
31. Bulau AM, Nold MF, Li S, Nold-Petry CA, Fink M, Mansell A, Schwerd T, Hong J, Rubartelli A, Dinarello CA, Bufler P.; ''Role of caspase-1 in nuclear translocation of IL-37, release of the cytokine, and IL-37 inhibition of innate immune responses.''; PubMed Europe PMC Scholia
32. Nold MF, Nold MF, Nold-Petry CA, Zepp JA, Palmer BE, Bufler P, Dinarello CA.; ''IL-37 is a fundamental inhibitor of innate immunity.''; PubMed Europe PMC Scholia
33. Debets R, Timans JC, Homey B, Zurawski S, Sana TR, Lo S, Wagner J, Edwards G, Clifford T, Menon S, Bazan JF, Kastelein RA.; ''Two novel IL-1 family members, IL-1 delta and IL-1 epsilon, function as an antagonist and agonist of NF-kappa B activation through the orphan IL-1 receptor-related protein 2.''; PubMed Europe PMC Scholia
34. Windheim M, Stafford M, Peggie M, Cohen P.; ''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.''; PubMed Europe PMC Scholia
35. Kroll M, Margottin F, Kohl A, Renard P, Durand H, Concordet JP, Bachelerie F, Arenzana-Seisdedos F, Benarous R.; ''Inducible degradation of IkappaBalpha by the proteasome requires interaction with the F-box protein h-betaTrCP.''; PubMed Europe PMC Scholia
36. Nakamura K, Kimple AJ, Siderovski DP, Johnson GL.; ''PB1 domain interaction of p62/sequestosome 1 and MEKK3 regulates NF-kappaB activation.''; PubMed Europe PMC Scholia
37. Dinarello CA, Nold-Petry C, Nold M, Fujita M, Li S, Kim S, Bufler P.; ''Suppression of innate inflammation and immunity by interleukin-37.''; PubMed Europe PMC Scholia
38. Stafford MJ, Morrice NA, Peggie MW, Cohen P.; ''Interleukin-1 stimulated activation of the COT catalytic subunit through the phosphorylation of Thr290 and Ser62.''; PubMed Europe PMC Scholia
39. Smith H, Peggie M, Campbell DG, Vandermoere F, Carrick E, Cohen P.; ''Identification of the phosphorylation sites on the E3 ubiquitin ligase Pellino that are critical for activation by IRAK1 and IRAK4.''; PubMed Europe PMC Scholia
40. Winston JT, Strack P, Beer-Romero P, Chu CY, Elledge SJ, Harper JW.; ''The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro.''; PubMed Europe PMC Scholia
41. Butler MP, Hanly JA, Moynagh PN.; ''Kinase-active interleukin-1 receptor-associated kinases promote polyubiquitination and degradation of the Pellino family: direct evidence for PELLINO proteins being ubiquitin-protein isopeptide ligases.''; PubMed Europe PMC Scholia
42. Novick D, Kim SH, Fantuzzi G, Reznikov LL, Dinarello CA, Rubinstein M.; ''Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response.''; PubMed Europe PMC Scholia
43. Born TL, Thomassen E, Bird TA, Sims JE.; ''Cloning of a novel receptor subunit, AcPL, required for interleukin-18 signaling.''; PubMed Europe PMC Scholia
44. Waterfield MR, Zhang M, Norman LP, Sun SC.; ''NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase.''; PubMed Europe PMC Scholia
45. Huang J, Gao X, Li S, Cao Z.; ''Recruitment of IRAK to the interleukin 1 receptor complex requires interleukin 1 receptor accessory protein.''; PubMed Europe PMC Scholia
46. Luo C, Shu Y, Luo J, Liu D, Huang DS, Han Y, Chen C, Li YC, Zou JM, Qin J, Wang Y, Li D, Wang SS, Zhang GM, Chen J, Feng ZH.; ''Intracellular IL-37b interacts with Smad3 to suppress multiple signaling pathways and the metastatic phenotype of tumor cells.''; PubMed Europe PMC Scholia
47. Dinarello CA.; ''Immunological and inflammatory functions of the interleukin-1 family.''; PubMed Europe PMC Scholia
48. Cao Z, Henzel WJ, Gao X.; ''IRAK: a kinase associated with the interleukin-1 receptor.''; PubMed Europe PMC Scholia
49. Voges D, Zwickl P, Baumeister W.; ''The 26S proteasome: a molecular machine designed for controlled proteolysis.''; PubMed Europe PMC Scholia
50. Rothwarf DM, Zandi E, Natoli G, Karin M.; ''IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex.''; PubMed Europe PMC Scholia
51. Hattori K, Hatakeyama S, Shirane M, Matsumoto M, Nakayama K.; ''Molecular dissection of the interactions among IkappaBalpha, FWD1, and Skp1 required for ubiquitin-mediated proteolysis of IkappaBalpha.''; PubMed Europe PMC Scholia
52. Kishore N, Huynh QK, Mathialagan S, Hall T, Rouw S, Creely D, Lange G, Caroll J, Reitz B, Donnelly A, Boddupalli H, Combs RG, Kretzmer K, Tripp CS.; ''IKK-i and TBK-1 are enzymatically distinct from the homologous enzyme IKK-2: comparative analysis of recombinant human IKK-i, TBK-1, and IKK-2.''; PubMed Europe PMC Scholia
53. Colotta F, Re F, Muzio M, Bertini R, Polentarutti N, Sironi M, Giri JG, Dower SK, Sims JE, Mantovani A.; ''Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4.''; PubMed Europe PMC Scholia
54. Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ.; ''TAK1 is a ubiquitin-dependent kinase of MKK and IKK.''; PubMed Europe PMC Scholia
55. Krappmann D, Hatada EN, Tegethoff S, Li J, Klippel A, Giese K, Baeuerle PA, Scheidereit C.; ''The I kappa B kinase (IKK) complex is tripartite and contains IKK gamma but not IKAP as a regular component.''; PubMed Europe PMC Scholia
56. Pavlowsky A, Zanchi A, Pallotto M, Giustetto M, Chelly J, Sala C, Billuart P.; ''Neuronal JNK pathway activation by IL-1 is mediated through IL1RAPL1, a protein required for development of cognitive functions.''; PubMed Europe PMC Scholia
57. Ordureau A, Smith H, Windheim M, Peggie M, Carrick E, Morrice N, Cohen P.; ''The IRAK-catalysed activation of the E3 ligase function of Pellino isoforms induces the Lys63-linked polyubiquitination of IRAK1.''; PubMed Europe PMC Scholia
58. Cohen S, Achbert-Weiner H, Ciechanover A.; ''Dual effects of IkappaB kinase beta-mediated phosphorylation on p105 Fate: SCF(beta-TrCP)-dependent degradation and SCF(beta-TrCP)-independent processing.''; PubMed Europe PMC Scholia
59. Chen Z, Hagler J, Palombella VJ, Melandri F, Scherer D, Ballard D, Maniatis T.; ''Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway.''; PubMed Europe PMC Scholia
60. Pan G, Risser P, Mao W, Baldwin DT, Zhong AW, Filvaroff E, Yansura D, Lewis L, Eigenbrot C, Henzel WJ, Vandlen R.; ''IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1Rrp.''; PubMed Europe PMC Scholia
61. Strack P, Caligiuri M, Pelletier M, Boisclair M, Theodoras A, Beer-Romero P, Glass S, Parsons T, Copeland RA, Auger KR, Benfield P, Brizuela L, Rolfe M.; ''SCF(beta-TRCP) and phosphorylation dependent ubiquitinationof I kappa B alpha catalyzed by Ubc3 and Ubc4.''; PubMed Europe PMC Scholia
62. Torigoe K, Ushio S, Okura T, Kobayashi S, Taniai M, Kunikata T, Murakami T, Sanou O, Kojima H, Fujii M, Ohta T, Ikeda M, Ikegami H, Kurimoto M.; ''Purification and characterization of the human interleukin-18 receptor.''; PubMed Europe PMC Scholia
63. Chaitidis P, O'Donnell V, Kuban RJ, Bermudez-Fajardo A, Ungethuem U, Kühn H.; ''Gene expression alterations of human peripheral blood monocytes induced by medium-term treatment with the TH2-cytokines interleukin-4 and -13.''; PubMed Europe PMC Scholia
64. Dripps DJ, Brandhuber BJ, Thompson RC, Eisenberg SP.; ''Interleukin-1 (IL-1) receptor antagonist binds to the 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction.''; PubMed Europe PMC Scholia
65. Burns K, Clatworthy J, Martin L, Martinon F, Plumpton C, Maschera B, Lewis A, Ray K, Tschopp J, Volpe F.; ''Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor.''; PubMed Europe PMC Scholia
66. Shi Y, Massagué J.; ''Mechanisms of TGF-beta signaling from cell membrane to the nucleus.''; PubMed Europe PMC Scholia
67. Kishimoto K, Matsumoto K, Ninomiya-Tsuji J.; ''TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop.''; PubMed Europe PMC Scholia
68. Adhikari A, Xu M, Chen ZJ.; ''Ubiquitin-mediated activation of TAK1 and IKK.''; PubMed Europe PMC Scholia
69. Mora J, Schlemmer A, Wittig I, Richter F, Putyrski M, Frank AC, Han Y, Jung M, Ernst A, Weigert A, Brüne B.; ''Interleukin-38 is released from apoptotic cells to limit inflammatory macrophage responses.''; PubMed Europe PMC Scholia
70. Bufler P, Azam T, Gamboni-Robertson F, Reznikov LL, Kumar S, Dinarello CA, Kim SH.; ''A complex of the IL-1 homologue IL-1F7b and IL-18-binding protein reduces IL-18 activity.''; PubMed Europe PMC Scholia
71. Strelow A, Kollewe C, Wesche H.; ''Characterization of Pellino2, a substrate of IRAK1 and IRAK4.''; PubMed Europe PMC Scholia
72. Conze DB, Wu CJ, Thomas JA, Landstrom A, Ashwell JD.; ''Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activation.''; PubMed Europe PMC Scholia
73. Brough D, Rothwell NJ.; ''Caspase-1-dependent processing of pro-interleukin-1beta is cytosolic and precedes cell death.''; PubMed Europe PMC Scholia
74. Kawagoe T, Sato S, Matsushita K, Kato H, Matsui K, Kumagai Y, Saitoh T, Kawai T, Takeuchi O, Akira S.; ''Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2.''; PubMed Europe PMC Scholia
75. Gottipati S, Rao NL, Fung-Leung WP.; ''IRAK1: a critical signaling mediator of innate immunity.''; PubMed Europe PMC Scholia
76. Mercurio F, Zhu H, Murray BW, Shevchenko A, Bennett BL, Li J, Young DB, Barbosa M, Mann M, Manning A, Rao A.; ''IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation.''; PubMed Europe PMC Scholia
77. Kumar S, Hanning CR, Brigham-Burke MR, Rieman DJ, Lehr R, Khandekar S, Kirkpatrick RB, Scott GF, Lee JC, Lynch FJ, Gao W, Gambotto A, Lotze MT.; ''Interleukin-1F7B (IL-1H4/IL-1F7) is processed by caspase-1 and mature IL-1F7B binds to the IL-18 receptor but does not induce IFN-gamma production.''; PubMed Europe PMC Scholia
78. Arend WP, Gabay C.; ''Physiologic role of interleukin-1 receptor antagonist.''; PubMed Europe PMC Scholia
79. Kollewe C, Mackensen AC, Neumann D, Knop J, Cao P, Li S, Wesche H, Martin MU.; ''Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adapter in interleukin-1 signaling.''; PubMed Europe PMC Scholia
80. Cheung PC, Nebreda AR, Cohen P.; ''TAB3, a new binding partner of the protein kinase TAK1.''; PubMed Europe PMC Scholia
81. Belich MP, Salmerón A, Johnston LH, Ley SC.; ''TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105.''; PubMed Europe PMC Scholia
82. Beinke S, Deka J, Lang V, Belich MP, Walker PA, Howell S, Smerdon SJ, Gamblin SJ, Ley SC.; ''NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activity.''; PubMed Europe PMC Scholia
83. Handoyo H, Stafford MJ, McManus E, Baltzis D, Peggie M, Cohen P.; ''IRAK1-independent pathways required for the interleukin-1-stimulated activation of the Tpl2 catalytic subunit and its dissociation from ABIN2.''; PubMed Europe PMC Scholia
84. Cui J, Zhu L, Xia X, Wang HY, Legras X, Hong J, Ji J, Shen P, Zheng S, Chen ZJ, Wang RF.; ''NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways.''; PubMed Europe PMC Scholia
85. McMahan CJ, Slack JL, Mosley B, Cosman D, Lupton SD, Brunton LL, Grubin CE, Wignall JM, Jenkins NA, Brannan CI.; ''A novel IL-1 receptor, cloned from B cells by mammalian expression, is expressed in many cell types.''; PubMed Europe PMC Scholia
86. Cho J, Melnick M, Solidakis GP, Tsichlis PN.; ''Tpl2 (tumor progression locus 2) phosphorylation at Thr290 is induced by lipopolysaccharide via an Ikappa-B Kinase-beta-dependent pathway and is required for Tpl2 activation by external signals.''; PubMed Europe PMC Scholia
87. Muroi M, Tanamoto K.; ''TRAF6 distinctively mediates MyD88- and IRAK-1-induced activation of NF-kappaB.''; PubMed Europe PMC Scholia
88. Thiefes A, Wolter S, Mushinski JF, Hoffmann E, Dittrich-Breiholz O, Graue N, Dörrie A, Schneider H, Wirth D, Luckow B, Resch K, Kracht M.; ''Simultaneous blockade of NFkappaB, JNK, and p38 MAPK by a kinase-inactive mutant of the protein kinase TAK1 sensitizes cells to apoptosis and affects a distinct spectrum of tumor necrosis factor [corrected] target genes.''; PubMed Europe PMC Scholia
89. Wei SJ, Williams JG, Dang H, Darden TA, Betz BL, Humble MM, Chang FM, Trempus CS, Johnson K, Cannon RE, Tennant RW.; ''Identification of a specific motif of the DSS1 protein required for proteasome interaction and p53 protein degradation.''; PubMed Europe PMC Scholia
90. Li S, Strelow A, Fontana EJ, Wesche H.; ''IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase.''; PubMed Europe PMC Scholia
91. Arend WP, Palmer G, Gabay C.; ''IL-1, IL-18, and IL-33 families of cytokines.''; PubMed Europe PMC Scholia
92. Brikos C, Wait R, Begum S, O'Neill LA, Saklatvala J.; ''Mass spectrometric analysis of the endogenous type I interleukin-1 (IL-1) receptor signaling complex formed after IL-1 binding identifies IL-1RAcP, MyD88, and IRAK-4 as the stable components.''; PubMed Europe PMC Scholia
93. Roget K, Ben-Addi A, Mambole-Dema A, Gantke T, Yang HT, Janzen J, Morrice N, Abbott D, Ley SC.; ''IκB kinase 2 regulates TPL-2 activation of extracellular signal-regulated kinases 1 and 2 by direct phosphorylation of TPL-2 serine 400.''; PubMed Europe PMC Scholia
94. Grimsby S, Jaensson H, Dubrovska A, Lomnytska M, Hellman U, Souchelnytskyi S.; ''Proteomics-based identification of proteins interacting with Smad3: SREBP-2 forms a complex with Smad3 and inhibits its transcriptional activity.''; PubMed Europe PMC Scholia
95. Heissmeyer V, Krappmann D, Hatada EN, Scheidereit C.; ''Shared pathways of IkappaB kinase-induced SCF(betaTrCP)-mediated ubiquitination and degradation for the NF-kappaB precursor p105 and IkappaBalpha.''; PubMed Europe PMC Scholia
96. Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV.; ''TRAF6 is a signal transducer for interleukin-1.''; PubMed Europe PMC Scholia
97. Lang V, Janzen J, Fischer GZ, Soneji Y, Beinke S, Salmeron A, Allen H, Hay RT, Ben-Neriah Y, Ley SC.; ''betaTrCP-mediated proteolysis of NF-kappaB1 p105 requires phosphorylation of p105 serines 927 and 932.''; PubMed Europe PMC Scholia
98. Khan JA, Brint EK, O'Neill LA, Tong L.; ''Crystal structure of the Toll/interleukin-1 receptor domain of human IL-1RAPL.''; PubMed Europe PMC Scholia

History

External references

DataNodes

Name	Type	Database reference	Comment
2xMyri-IL1A [extracellular region]	Protein	P01583 (Uniprot-TrEMBL)
3xUb-p-S927,S932-NFKB1(1-968)	Protein	P19838 (Uniprot-TrEMBL)
ADP	Metabolite	CHEBI:16761 (ChEBI)
ATP	Metabolite	CHEBI:15422 (ChEBI)
Activated IKK Complex	Complex	REACT_7826 (Reactome)
Activated TAK complexes	Complex	REACT_23279 (Reactome)
BTRC [cytosol]	Protein	Q9Y297 (Uniprot-TrEMBL)
CHUK [cytosol]	Protein	O15111 (Uniprot-TrEMBL)
CUL1 [cytosol]	Protein	Q13616 (Uniprot-TrEMBL)
IKBKB [cytosol]	Protein	O14920 (Uniprot-TrEMBL)
IKBKG [cytosol]	Protein	Q9Y6K9 (Uniprot-TrEMBL)
IKKA:IKKB:NEMO	Complex	REACT_7693 (Reactome)
IL1 receptor complex- activated IRAK4:TOLLIP:hp-IRAK1	Complex	REACT_23332 (Reactome)
IL1 receptor complex- activated IRAK4:TOLLIP:p-IRAK1	Complex	REACT_23087 (Reactome)
IL1 receptor complex-activated IRAK4:TOLLIP:IRAK1	Complex	REACT_22771 (Reactome)
IL1 receptor complex-activated IRAK4:TOLLIP:hp-IRAK:TRAF6	Complex	REACT_22757 (Reactome)
IL1 receptor complex:TOLLIP	Complex	REACT_23348 (Reactome)
IL1 receptor complex - activated IRAK4:TOLLIP	Complex	REACT_23002 (Reactome)
IL1 receptor complex	Complex	REACT_23029 (Reactome)
IL1:IL1R1:IL1RAP:MYD88 homodimer	Complex	REACT_23167 (Reactome)
IL1B [extracellular region]	Protein	P01584 (Uniprot-TrEMBL)
IL1B	Protein	P01584 (Uniprot-TrEMBL)
IL1R1 [plasma membrane]	Protein	P14778 (Uniprot-TrEMBL)
IL1R1:IL1:IL1RAP	Complex	REACT_22656 (Reactome)
IL1R1	Protein	P14778 (Uniprot-TrEMBL)
IL1R2 [plasma membrane]	Protein	P27930 (Uniprot-TrEMBL)
IL1R2	Protein	P27930 (Uniprot-TrEMBL)
IL1RAP-1 [plasma membrane]	Protein	Q9NPH3-1 (Uniprot-TrEMBL)
IL1RAP-1	Protein	Q9NPH3-1 (Uniprot-TrEMBL)
IL1RN [plasma membrane]	Protein	P18510 (Uniprot-TrEMBL)
IL1RN	Protein	P18510 (Uniprot-TrEMBL)
IRAK1 [cytosol]	Protein	P51617 (Uniprot-TrEMBL)
IRAK1	Protein	P51617 (Uniprot-TrEMBL)
IRAK2	Protein	O43187 (Uniprot-TrEMBL)
IRAK3	Protein	Q9Y616 (Uniprot-TrEMBL)
IRAK4 [cytosol]	Protein	Q9NWZ3 (Uniprot-TrEMBL)
IRAK4	Protein	Q9NWZ3 (Uniprot-TrEMBL)
Interleukin 1 receptor type 2:interleukin 1	Complex	REACT_22786 (Reactome)
Interleukin 1 receptors:IL1RN	Complex	REACT_22878 (Reactome)
Interleukin 1 receptors	Protein	REACT_23342 (Reactome)
Interleukin-1 receptor type 1:Interleukin-1	Complex	REACT_23118 (Reactome)
Interleukin-1	Protein	REACT_22576 (Reactome)
K63polyUb TRAF6 [cytosol]	Protein	Q9Y4K3 (Uniprot-TrEMBL)
K63polyUb-hp-IRAK1 [cytosol]	Protein	P51617 (Uniprot-TrEMBL)
K63polyUb-hp-IRAK1	Complex	P51617 (Uniprot-TrEMBL)
K63polyUb		REACT_21645 (Reactome)
MAP2K6	Protein	P52564 (Uniprot-TrEMBL)
MAP3K3 [cytosol]	Protein	Q99759 (Uniprot-TrEMBL)
MAP3K7 [cytosol]	Protein	O43318 (Uniprot-TrEMBL)
MAP3K8 [cytosol]	Protein	P41279 (Uniprot-TrEMBL)
MAP3K8	Protein	P41279 (Uniprot-TrEMBL)
MDP [cytosol]	Metabolite	CHEBI:59414 (ChEBI)
MEK1, SEK1	Protein	REACT_22657 (Reactome)
MYD88 [cytosol]	Protein	Q99836 (Uniprot-TrEMBL)
MYD88 homodimer	Complex	REACT_14253 (Reactome)
NFKB p105:TPL2:ABIN2	Complex	REACT_22747 (Reactome)
NFKB1(1-968) [cytosol]	Protein	P19838 (Uniprot-TrEMBL)
NFKB1(1-968)	Protein	P19838 (Uniprot-TrEMBL)
NOD1 [cytosol]	Protein	Q9Y239 (Uniprot-TrEMBL)
NOD2 [cytosol]	Protein	Q9HC29 (Uniprot-TrEMBL)
PELI1 [cytosol]	Protein	Q96FA3 (Uniprot-TrEMBL)
PELI2 [cytosol]	Protein	Q9HAT8 (Uniprot-TrEMBL)
PELI3 [cytosol]	Protein	Q8N2H9 (Uniprot-TrEMBL)
Pellino 1,2,3	Protein	REACT_22780 (Reactome)
Phospho-MEK1, phospho-SEK1	Protein	REACT_22945 (Reactome)
Poly-K6-Ub-hp-IRAK1:IKK complex	Complex	REACT_22624 (Reactome)
RBX1 [cytosol]	Protein	P62877 (Uniprot-TrEMBL)
SCF beta-TrCP complex	Complex	REACT_22981 (Reactome)
SCF betaTrCP complex:p-NFKB p105	Complex	REACT_22646 (Reactome)
SKP1 [cytosol]	Protein	P63208 (Uniprot-TrEMBL)
SQSTM1 [cytosol]	Protein	Q13501 (Uniprot-TrEMBL)
TAB1 [cytosol]	Protein	Q15750 (Uniprot-TrEMBL)
TAB2 [cytosol]	Protein	Q9NYJ8 (Uniprot-TrEMBL)
TAB2 [plasma membrane]	Protein	Q9NYJ8 (Uniprot-TrEMBL)
TAB3(1-712) [cytosol]	Protein	Q8N5C8 (Uniprot-TrEMBL)
TAB3(1-712) [plasma membrane]	Protein	Q8N5C8 (Uniprot-TrEMBL)
TAK1 complex	Complex	REACT_22633 (Reactome)
TNIP2 [cytosol]	Protein	Q8NFZ5 (Uniprot-TrEMBL)
TNIP2	Protein	Q8NFZ5 (Uniprot-TrEMBL)
TOLLIP(2-274) [cytosol]	Protein	Q9H0E2 (Uniprot-TrEMBL)
TOLLIP(2-274)	Protein	Q9H0E2 (Uniprot-TrEMBL)
TRAF6 [cytosol]	Protein	Q9Y4K3 (Uniprot-TrEMBL)
TRAF6	Protein	Q9Y4K3 (Uniprot-TrEMBL)
UBE2N [cytosol]	Protein	P61088 (Uniprot-TrEMBL)
UBE2V1 [cytosol]	Protein	Q13404 (Uniprot-TrEMBL)
Ub-209-RIPK2 [cytosol]	Protein	O43353 (Uniprot-TrEMBL)
Ubc13:UBE2V1	Complex	REACT_12995 (Reactome)
hp-IRAK1, IRAK4	Protein	REACT_23241 (Reactome)
hp-IRAK1: p-Pellino-1,2,(3)	Complex	REACT_22866 (Reactome)
hp-IRAK1:K6 poly-Ub oligo-TRAF6	Complex	REACT_23272 (Reactome)
hp-IRAK1:K6-poly-Ub oligo-TRAF6:Activated TAK1 complex	Complex	REACT_23314 (Reactome)
hp-IRAK1:K6-poly-Ub oligo-TRAF6:TAK1 complex	Complex	REACT_22797 (Reactome)
hp-IRAK1:Pellino, IRAK4:Pellino	Complex	REACT_23330 (Reactome)
hp-IRAK1:TRAF6	Complex	REACT_22529 (Reactome)
hp-IRAK1:oligo-TRAF6	Complex	REACT_22793 (Reactome)
hp-IRAK1:p-Pellino, IRAK4:p-Pellino	Complex	REACT_22769 (Reactome)
iE-DAP [cytosol]	Metabolite	CHEBI:59271 (ChEBI)
p-2S,S376,T,T209,T387-IRAK1 [cytosol]	Protein	P51617 (Uniprot-TrEMBL)	This is the hyperphosphorylated, active form of IRAK1. The unknown coordinate phosphorylation events are to symbolize the multiple phosphorylations that likely take place in the ProST domain (aa10-211).
p-IRAK2 [cytosol]	Protein	O43187 (Uniprot-TrEMBL)
p-IRAK2	Protein	O43187 (Uniprot-TrEMBL)
p-Pellino-1,2,(3)	Protein	REACT_22733 (Reactome)
p-S176,S180-CHUK [cytosol]	Protein	O15111 (Uniprot-TrEMBL)
p-S177,S181-IKBKB [cytosol]	Protein	O14920 (Uniprot-TrEMBL)
p-S207,T211-MAP2K6	Protein	P52564 (Uniprot-TrEMBL)
p-S376,T387-IRAK1 [cytosol]	Protein	P51617 (Uniprot-TrEMBL)
p-S927,S932-NFKB1(1-968) [cytosol]	Protein	P19838 (Uniprot-TrEMBL)
p-S927,S932-NFKB1(1-968)	Protein	P19838 (Uniprot-TrEMBL)
p-T184,T187-MAP3K7 [cytosol]	Protein	O43318 (Uniprot-TrEMBL)
p-T342,T345,S346-IRAK4 [cytosol]	Protein	Q9NWZ3 (Uniprot-TrEMBL)
p-T342,T345,S346-IRAK4	Protein	Q9NWZ3 (Uniprot-TrEMBL)
p62:MEKK3:TRAF6	Complex	REACT_23141 (Reactome)
p62:MEKK3	Complex	REACT_23211 (Reactome)

Annotated Interactions

Source	Target	Type	Database reference	Comment
	3xUb-p-S927,S932-NFKB1(1-968)	Arrow	REACT_22407 (Reactome)
	ADP	Arrow	REACT_22125 (Reactome)
	ADP	Arrow	REACT_22162 (Reactome)
	ADP	Arrow	REACT_22190 (Reactome)
	ADP	Arrow	REACT_22271 (Reactome)
	ADP	Arrow	REACT_22325 (Reactome)
	ADP	Arrow	REACT_22405 (Reactome)
	ADP	Arrow	REACT_22418 (Reactome)
	ADP	Arrow	REACT_6935 (Reactome)
ATP			REACT_22125 (Reactome)
ATP			REACT_22162 (Reactome)
ATP			REACT_22190 (Reactome)
ATP			REACT_22271 (Reactome)
ATP			REACT_22325 (Reactome)
ATP			REACT_22405 (Reactome)
ATP			REACT_22418 (Reactome)
ATP			REACT_6935 (Reactome)
	Activated IKK Complex	Arrow	REACT_6935 (Reactome)
Activated IKK Complex		mim-catalysis	REACT_22418 (Reactome)
Activated TAK complexes		mim-catalysis	REACT_6935 (Reactome)
IKKA:IKKB:NEMO			REACT_22256 (Reactome)
IKKA:IKKB:NEMO			REACT_6935 (Reactome)
	IL1 receptor complex- activated IRAK4:TOLLIP:hp-IRAK1	Arrow	REACT_22162 (Reactome)
IL1 receptor complex- activated IRAK4:TOLLIP:hp-IRAK1			REACT_22311 (Reactome)
	IL1 receptor complex- activated IRAK4:TOLLIP:p-IRAK1	Arrow	REACT_22125 (Reactome)
IL1 receptor complex- activated IRAK4:TOLLIP:p-IRAK1			REACT_22162 (Reactome)
IL1 receptor complex- activated IRAK4:TOLLIP:p-IRAK1		mim-catalysis	REACT_22162 (Reactome)
	IL1 receptor complex-activated IRAK4:TOLLIP:IRAK1	Arrow	REACT_22379 (Reactome)
IL1 receptor complex-activated IRAK4:TOLLIP:IRAK1			REACT_22125 (Reactome)
IL1 receptor complex-activated IRAK4:TOLLIP:IRAK1		mim-catalysis	REACT_22125 (Reactome)
	IL1 receptor complex-activated IRAK4:TOLLIP:hp-IRAK:TRAF6	Arrow	REACT_22311 (Reactome)
IL1 receptor complex-activated IRAK4:TOLLIP:hp-IRAK:TRAF6			REACT_22209 (Reactome)
	IL1 receptor complex:TOLLIP	Arrow	REACT_22120 (Reactome)
IL1 receptor complex:TOLLIP			REACT_22405 (Reactome)
	IL1 receptor complex - activated IRAK4:TOLLIP	Arrow	REACT_22405 (Reactome)
IL1 receptor complex - activated IRAK4:TOLLIP			REACT_22379 (Reactome)
IL1 receptor complex - activated IRAK4:TOLLIP			REACT_22435 (Reactome)
	IL1 receptor complex	Arrow	REACT_22326 (Reactome)
IL1 receptor complex			REACT_22120 (Reactome)
	IL1:IL1R1:IL1RAP:MYD88 homodimer	Arrow	REACT_22154 (Reactome)
	IL1:IL1R1:IL1RAP:MYD88 homodimer	Arrow	REACT_22209 (Reactome)
IL1:IL1R1:IL1RAP:MYD88 homodimer			REACT_22326 (Reactome)
IL1B		TBar	REACT_22171 (Reactome)
	IL1R1:IL1:IL1RAP	Arrow	REACT_22382 (Reactome)
IL1R1:IL1:IL1RAP			REACT_22154 (Reactome)
IL1R1			REACT_22375 (Reactome)
IL1R2			REACT_22253 (Reactome)
IL1RAP-1			REACT_22382 (Reactome)
IL1RN			REACT_22331 (Reactome)
IRAK1			REACT_22379 (Reactome)
IRAK2			REACT_22435 (Reactome)
IRAK3		TBar	REACT_22209 (Reactome)
IRAK4			REACT_22326 (Reactome)
	Interleukin 1 receptor type 2:interleukin 1	Arrow	REACT_22253 (Reactome)
	Interleukin 1 receptors:IL1RN	Arrow	REACT_22331 (Reactome)
Interleukin 1 receptors			REACT_22331 (Reactome)
	Interleukin-1 receptor type 1:Interleukin-1	Arrow	REACT_22375 (Reactome)
Interleukin-1 receptor type 1:Interleukin-1			REACT_22382 (Reactome)
Interleukin-1			REACT_22253 (Reactome)
Interleukin-1			REACT_22375 (Reactome)
	K63polyUb-hp-IRAK1	Arrow	REACT_22381 (Reactome)
K63polyUb-hp-IRAK1			REACT_22256 (Reactome)
K63polyUb			REACT_22381 (Reactome)
K63polyUb			REACT_22430 (Reactome)
MAP2K6			REACT_22190 (Reactome)
MAP3K8			REACT_22206 (Reactome)
MAP3K8		mim-catalysis	REACT_22271 (Reactome)
MEK1, SEK1			REACT_22271 (Reactome)
MYD88 homodimer			REACT_22154 (Reactome)
	NFKB p105:TPL2:ABIN2	Arrow	REACT_22206 (Reactome)
NFKB1(1-968)			REACT_22206 (Reactome)
NFKB1(1-968)			REACT_22418 (Reactome)
Pellino 1,2,3			REACT_22286 (Reactome)
	Phospho-MEK1, phospho-SEK1	Arrow	REACT_22271 (Reactome)
	Poly-K6-Ub-hp-IRAK1:IKK complex	Arrow	REACT_22256 (Reactome)
			REACT_22120 (Reactome)	Toll-interacting protein (TOLLIP) binds to IRAK1 and IL-1RAP within the receptor complex. TOLLIP has the capacity to act as an ubiquitin-binding receptor for ubiquitinated IL1R1, linking IL1R to endosomal degradation.
			REACT_22125 (Reactome)	MyD88 recruits unphosphorylated IRAK1 to the signaling complex. IRAK1 is then rapidly activated and autophosphorylates in a region that is outside the kinase domain (Cao et al. 1996). Several pieces of evidence suggest that IRAK4 triggers IRAK1 activation by phosphorylating its kinase activation loop, leading to IRAK1 autophosphorylation (Suzuki et al. 2002): in vitro kinase assays indicate that IRAK1 can be a direct substrate of IRAK4 (Li et al. 2002); IRAK1 phosphorylation by IRAK4 is independent of and precedes IRAK1 activation and autophosphorylation; IRAK1 autophosphorylation is partially inhibited in cells overexpressing a kinase-inactive IRAK4 protein (Li et al. 2002).
			REACT_22154 (Reactome)	MYD88 is a cytoplasmic adaptor protein that is recruited to the intracellular region of the IL1 receptor complex following IL1 stimulation. MYD88 binds to the complex of the two receptor chains and subsequently to IL-1 receptor-associated kinase 4 (IRAK4). This complex is the minimum required for signaling (Brikos et al. 2007).
			REACT_22162 (Reactome)	A series of sequential phosphorylation events lead to full or hyper-phopshorylation of IRAK1. Under in vitro conditions these are all autophosphorylation events. First, Thr-209 is phosphorylated resulting in a conformational change of the kinase domain. Next, Thr-387 in the activation loop is phosphorylated, leading to full enzymatic activity. Several additional residues are phosphorylated in the proline-, serine-, and threonine-rich (ProST) region between the N-terminal death domain and kinase domain. Hyperphosphorylation of this region leads to dissociation of IRAK1 from the upstream adapters MyD88 and Tollip. The significance of these phosphorylation events is not clear; the kinase activity of IRAK1 is dispensable for IL1-induced NFkB and MAP kinase activation (Knop & Martin, 1999), unlike that of IRAK4 (Suzuki et al. 2002; Kozicak-Holbro et al. 2007), so IRAK1 is believed to act primarily as an adaptor for TRAF6 (Conze et al. 2008).
			REACT_22171 (Reactome)	p62, MEKK3 and TRAF6 co-localize in cytoplasmic aggregates that are thought to be centres for organizing TRAF6-regulated NF-kappaB signaling and the assembly of polyubiquinated proteins sorting to sequestosomes and proteasomes. p62/Sequestosome-1 is a scaffold protein involved in the regulation of autophagy, trafficking of proteins to the proteasome and activation of NF-kB. p62 binds the basic region of MEKK3. MEKK3 is known to bind TRAF6 in response to IL1B (Huang et al. 2004). Recently p62 was shown to be required for the association of MEKK3 with TRAF6. RNA knockdown of p62 inhibited IL1B and MEKK3 activation of NF-kB. IL1B stimulation resulted in dissociation of MEKK3 from p62:TRAF6 (Nakamura et al. 2010).
			REACT_22176 (Reactome)	The TAK1 complex consists of the transforming growth factor-? (TGF-beta)-activated kinase (TAK1) and the TAK1-binding proteins TAB1, TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Sakurai H et al 2000; Shibuya H et al 2000). TAB1 promotes autophosphorylation of the TAK1 kinase activation lobe, likely through an allosteric mechanism (Sakurai H et al 2000 ; Kishimoyo K et al 2000). The TAK1 complex is regulated by polyubiquitination. The TAK1 complex consists of the transforming growth factor-? (TGF- ?)-activated kinase (TAK1) and the TAK1-binding proteins TAB1, TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya H et al 1996; Sakurai H et al 2000). TAB1 promotes autophosphorylation of the TAK1 kinase activation lobe, likely through an allosteric mechanism (Brown K et al 2005; Ono K et al 2001). The TAK1 complex is regulated by polyubiquitination. Binding of TAB2 and TAB3 to Lys63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Binding of multiple TAK1 complexes onto the same polyubiquitin chain may promote oligomerization of TAK1, facilitating TAK1 autophosphorylation and subsequent activation of its kinase activity (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that leads to the activation of TAK1. Another possibility is that TAB2/3 may recruit the IKK complex by binding to ubiquitinated NEMO; polyubiquitin chains may function as a scaffold for higher order signaling complexes that allow interaction between TAK1 and IKK (Kanayama et al. 2004).
			REACT_22190 (Reactome)	Within the TAK1 complex (TAK1 plus TAB1 and TAB2/3) activated TAK1 phosphorylates IKKB, MAPK kinase 6 (MKK6) and other MAPKs to activate the NFkappaB and MAPK signaling pathways. TAB2 within the TAK1 complex can be linked to polyubiquitinated TRAF6; current models of IL-1 signaling suggest that the TAK1 complex is linked to TRAF6, itself complexed with polyubiquitinated IRAK1 which is linked via NEMO to the IKK complex. The TAK1 complex is also essential for NOD signaling; NOD receptors bind RIP2 which recruits the TAK1 complex (Hasegawa et al. 2008).
			REACT_22206 (Reactome)	The C-terminal half of NFKB1 p105 forms a high-affinity stoichiometric association with Tpl2 via two distinct interactions (Belich et al. 1999; Beinke et al. 2003). The Tpl2 C-terminus (residues 398-467) binds to a region N-terminal to the p105 ankyrin repeat region (human p105 residues 497-534), whereas the Tpl2 kinase domain interacts with the p105 death domain (Beinke et al. 2003). In unstimulated macrophages, all detectable Tpl2 is associated with p105 (Belich et al. 1999; Lang et al. 2004). Binding to p105 maintains the stability of Tpl2 but inhibits Tpl2 MEK kinase activity by preventing access to MEK (Beinke et al. 2003; Waterfield et al. 2003). Tpl2 phosphorylation at Thr-290 may also play a role in the activation of Tpl2 (Cho & Tsichlis 2005). A20-binding inhibitor of NFkappaB2 (ABIN-2) interacts with Tpl2 and p105 but preferentially forms a ternary complex with both proteins. As ABIN2 is a polyubiquitin binding protein, it has been suggested that it may facilitate recruitment of the p105/Tpl2 complex to the activated IKK complex, allowing IKK2 induced p105 phosphorylation and consequent Tpl2 activation.
			REACT_22209 (Reactome)	MyD88 and Tollip only bind to non-phosphorylated IRAK1 [Wesche et al. 1997) so hyper-phosphorylated IRAK1 is predisposed to release from the receptor complex, a key step in this signaling cascade. It is believed that the interaction of IRAK1 with TRAF6 enables the release of IRAK1:TRAF6 from the receptor (Gottipati et al. 2007). Though released from the receptor complex, IRAK1:TRAF6 remains associated with the membrane, perhaps due to subsequent interaction with the TAK1 complex (Dong et al. 2006).
			REACT_22253 (Reactome)	Interleukin-1 receptor type 2 (IL1R2) binds Interleukin-1 but does not participate in any signaling processes. IL1R2 is thought to be a decoy receptor, removing or neutralizing Interleukin-1 that could otherwise stimulate the type 1 receptor.
			REACT_22256 (Reactome)	NF-kappa-B essential modulator (NEMO, also known as IKKG abbreviated from Inhibitor of nuclear factor kappa-B kinase subunit gamma) is the regulatory subunit of the IKK complex which phosphorylates inhibitors of NF-kappa-B leading to dissociation of the inhibitor/NF-kappa-B complex. NEMO binds to K63-pUb chains (Ea et al. 2006; Wu et al. 2006), linking K63-pUb-hp-IRAK1 with the IKK complex. Models of IL-1R dependent activation of NF-kappaB suggest that the polyubiquitination of both TRAF6 and IRAK1 within a TRAF6:IRAK1 complex and their subsequent interactions with the TAK1 complex and IKK complex respectively brings these complexes into proximity, facilitating the TAK1-catalyzed activation of IKK (Moynagh, 2008).
			REACT_22271 (Reactome)	Tpl2 (also known as Cot) is constitutively bound to NFKB p105 (p105) which inhibits its MEK kinase activity in resting cells. Proteolysis of p105 frees Tpl2 from p105 and allows subsequent phosphorylation and activation of MEK1. Tpl2 can also activate SEK1. Phosphorylation of Tpl-2 is believed to play a role in its activation (Cho et al, 2005; Robinson et al. 2007). Positions of phosphorylations represented here are inferred from general experimental data (Zheng & Guan, 1994).
			REACT_22286 (Reactome)	IRAK1 and 4 interact with Pellino-1 (Jiang et al. 2003), 2 (Strellow et al. 2003) and 3 (Butler et al. 2005, 2007). Pellinos may act as scaffolding proteins, bringing signaling complexes into proximity. They are E3 ubiquitin ligases capable of ubiquitinating IRAK1, believed to mediate IL-1-stimulated formation of K63-polyubiquitinated IRAK1 in cells. Though not clearly demonstrated and therefore not shown here, the current models of IRAK1 involvement suggest it would be within a complex including TRAF6.
			REACT_22311 (Reactome)	Hyperphosphorylated IRAK1, still within the receptor complex, binds TRAF6 through multiple regions including the death domain, the undefined domain and the C-terminal C1 domain (Li et al. 2001). The C-terminal region of IRAK-1 contains three potential TRAF6-binding sites; mutation of the amino acids (Glu544, Glu587, Glu706) in these sites to alanine greatly reduces activation of NFkappaB (Ye et al. 2002).
			REACT_22322 (Reactome)	TAK1-binding protein 2 (TAB2) and/or TAB3, as part of a complex that also contains TAK1 and TAB1, binds polyubiquitinated TRAF6. The TAB2 and TAB3 regulatory subunits of the TAK1 complex contain C-terminal Npl4 zinc finger (NZF) motifs that recognize with Lys63-pUb chains (Kanayama et al. 2004). The recognition mechanism is specific for Lys63-linked ubiquitin chains [Kulathu Y et al 2009]. TAK1 can be activated by unattached Lys63-polyubiquitinated chains when TRAF6 has no detectable polyubiquitination (Xia et al. 2009) and thus the synthesis of these chains by TRAF6 may be the signal transduction mechanism.
			REACT_22325 (Reactome)	IRAK1 and 4 can phosphorylate Pellino-1 and -2 and probably -3. Phosphorylation enhances the E3 ligase activity of Pellino-1 in conjunction with several different E2-conjugating enzymes (Ubc13-Uev1a, UbcH4, or UbcH5a/5b). Phosphorylation at any of several different sites or a combination of other sites leads to full activation of Pellino-1 E3 ubiquitin ligase activity. Though not shown here, the current models of IRAK1 involvement suggest it is part of a complex that includes TRAF6.
			REACT_22326 (Reactome)	MYD88 is a cytoplasmic adaptor protein that is recruited to the intracellular region of the IL1 receptor complex following IL1 stimulation. MYD88 binds to the complex of the two receptor chains and subsequently to IL-1 receptor-associated kinase 4 (IRAK4). This complex is the minimum required for signaling (Brikos et al. 2007).
			REACT_22331 (Reactome)	The interleukin 1 receptor antagonist protein (ILRAP or IL1RN) is a member of the IL1 family that binds to IL1R1 (and with much lower affinity IL1R2) but does not elicit a signaling response. By competing with IL1 for IL1R1 binding ILRAP acts as a natural antagonist, inhibiting the biological actions of both agonist forms of IL1 (IL1 alpha and IL1 beta).
			REACT_22353 (Reactome)	IKK-mediated NFkB p105 phosphorylation generates a binding site for betaTrCP, the receptor subunit of the SCF-type beta-TrCP ubiquitin E3 ligase complex.
			REACT_22375 (Reactome)	Interleukin-1 receptor type 1 (IL1R1) is the receptor responsible for transmitting the inflammatory effects of Interleukin-1 (IL1).
			REACT_22379 (Reactome)	MYD88 recruits unphosphorylated, inactive IRAK1 to the IL1 receptor complex.
			REACT_22381 (Reactome)	IL1 induces the poly-ubiquitination and degradation of IRAK1. This was believed to be K48-linked polyubiquitination, targeting IRAK1 for proteolysis by the proteasome, but recently IL-1R signaling has been shown to lead to K63-linked polyubiquitination of IRAK1 (Windheim et al. 2008; Conze et al. 2008), and demonstrated to have a role in the activation of NF-kappaB. IRAK1 is ubiquitinated on K134 and K180; mutation of these sites impairs IL1R-mediated ubiquitylation of IRAK1 (Conze et al. 2008). Some authors have proposed a role for TRAF6 as the E3 ubiquitin ligase that catalyzes polyubiquitination of IRAK1 (Conze et al. 2008) but this view has been refuted (Windheim et al. 2008; Xiao et al. 2008). There is stronger agreement that Pellino proteins have a role as IRAK1 E3 ubiquitin ligases. Pellino1-3 possess E3 ligase activity and are believed to directly catalyse polyubiquitylation of IRAK1 (Xiao et al. 2008; Butler et al. 2007; Ordureau et al. 2008). They are capable of catalysing the formation of K63- and K48-linked polyubiquitin chains; the type of linkage is controlled by the collaborating E2 enzyme. All the Pellino proteins can combine with the E2 heterodimer UbcH13–Uev1a to catalyze K63-linked ubiquitylation (Ordureau et al. 2008).
			REACT_22382 (Reactome)	Interleukin receptor 1 type 1 when bound to interleukin 1 binds interleukin 1 receptor accessory protein, essential for eliciting a signaling cascade.
			REACT_22405 (Reactome)	IRAK4 is activated by autophosphorylation at 3 positions within the kinase activation loop, Thr-342, Thr-345 and Ser-346.
			REACT_22407 (Reactome)	Beta-TrCP ubiquitinates p105 at several lysine residues within the C-terminal region 660-968. The level of ubiquitination is variable; in this reaction p105 is represented with 3 ubiquitinated lysine residues. Removal of all lysines within this region abolishes subsequent p105 degradation.
			REACT_22416 (Reactome)	TRAF6 oligomerization is induced by IRAK1. The TRAF6 oligomer consists of more than two molecules of TRAF6; thermodynamic data for TRAF2 strongly suggests that it is functionally a trimer (Rawlings et al. 2006). TRAF6 is represented here as a trimer, though the extent and significance of TRAF6 oligomerization is unclear. Oligomerisation may be assisted by TIFA (TRAF-interacting protein with a FHA domain; Takatsuna et al. 2003).
			REACT_22418 (Reactome)	NFkappaB p105 protein (p105) is a precursor of the NFkappaB p50 subunit and an inhibitor of NFkappaB. The IkappaB kinase (IKK) complex phosphorylates p105 on S927 within the PEST region. TNF-alpha-induced p105 proteolysis additionally requires the phosphorylation of S932. Purified IKK (IKK1) or IKKB (IKK2) can phosphorylate both these regulatory serines in vitro.
			REACT_22430 (Reactome)	TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein. In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex.
			REACT_22435 (Reactome)	IRAK2 has been implicated in IL1R and TLR signaling by the observation that IRAK2 can associate with MyD88 and Mal (Muzio et al. 1997). Like IRAK1, IRAK2 is activated downstream of IRAK4 (Kawagoe et al. 2008). It has been suggested that IRAK1 activates IRAK2 (Wesche et al. 1999) but IRAK2 phosphorylation is observed in IRAK1–/– mouse macrophages while IRAK4 deficiency abrogates IRAK2 phosphorylation (Kawagoe et al. 2008), suggesting that activated IRAK4 phosphorylates IRAK2 as it does IRAK1. IL6 production in response to IL1beta is impaired in embryonic fibroblasts from IRAK1 or IRAK2 knockout mice and abrogated in IRAK1/2 dual knockouts (Kawagoe et al. 2007) suggesting that IRAK1 and IRAK2 are both involved in IL1R signaling downstream of IRAK4.
			REACT_6935 (Reactome)	In humans, the IKKs - IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. The IKK complex contains two catalytic subunits, IKK alpha and IKK beta associated with a regulatory subunit, NEMO (IKKgamma). The activation of the IKK complex and the NFkB mediated antiviral response are dependent on the phosphorylation of IKK alpha/beta at its activation loop and the ubiquitination of NEMO [Solt et al 2009; Li et al 2002]. NEMO ubiquitination by TRAF6 is required for optimal activation of IKKalpha/beta; it is unclear if NEMO subunit undergoes K63-linked or linear ubiquitination. This basic trimolecular complex is referred to as the IKK complex. Each catalytic IKK subunit has an N-terminal kinase domain and leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-terminal NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs. IKK beta is the major IKK catalytic subunit for NF-kB activation. Phosphorylation in the activation loop of IKK beta requires Ser177 and Ser181 and thus activates the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.
	SCF beta-TrCP complex	Arrow	REACT_22407 (Reactome)
SCF beta-TrCP complex			REACT_22353 (Reactome)
SCF beta-TrCP complex		mim-catalysis	REACT_22407 (Reactome)
	SCF betaTrCP complex:p-NFKB p105	Arrow	REACT_22353 (Reactome)
SCF betaTrCP complex:p-NFKB p105			REACT_22407 (Reactome)
TAK1 complex			REACT_22322 (Reactome)
TAK1 complex		mim-catalysis	REACT_22190 (Reactome)
TNIP2			REACT_22206 (Reactome)
	TOLLIP(2-274)	Arrow	REACT_22209 (Reactome)
TOLLIP(2-274)			REACT_22120 (Reactome)
TRAF6			REACT_22171 (Reactome)
TRAF6			REACT_22311 (Reactome)
TRAF6			REACT_22416 (Reactome)
	Ubc13:UBE2V1	Arrow	REACT_22381 (Reactome)
	Ubc13:UBE2V1	Arrow	REACT_22430 (Reactome)
Ubc13:UBE2V1			REACT_22381 (Reactome)
Ubc13:UBE2V1			REACT_22430 (Reactome)
hp-IRAK1, IRAK4			REACT_22286 (Reactome)
hp-IRAK1, IRAK4		mim-catalysis	REACT_22325 (Reactome)
hp-IRAK1: p-Pellino-1,2,(3)			REACT_22381 (Reactome)
hp-IRAK1: p-Pellino-1,2,(3)		mim-catalysis	REACT_22381 (Reactome)
	hp-IRAK1:K6 poly-Ub oligo-TRAF6	Arrow	REACT_22430 (Reactome)
hp-IRAK1:K6 poly-Ub oligo-TRAF6			REACT_22322 (Reactome)
	hp-IRAK1:K6-poly-Ub oligo-TRAF6:Activated TAK1 complex	Arrow	REACT_22176 (Reactome)
	hp-IRAK1:K6-poly-Ub oligo-TRAF6:TAK1 complex	Arrow	REACT_22322 (Reactome)
hp-IRAK1:K6-poly-Ub oligo-TRAF6:TAK1 complex			REACT_22176 (Reactome)
	hp-IRAK1:Pellino, IRAK4:Pellino	Arrow	REACT_22286 (Reactome)
hp-IRAK1:Pellino, IRAK4:Pellino			REACT_22325 (Reactome)
	hp-IRAK1:TRAF6	Arrow	REACT_22209 (Reactome)
hp-IRAK1:TRAF6			REACT_22416 (Reactome)
	hp-IRAK1:oligo-TRAF6	Arrow	REACT_22416 (Reactome)
hp-IRAK1:oligo-TRAF6			REACT_22430 (Reactome)
hp-IRAK1:oligo-TRAF6		mim-catalysis	REACT_22430 (Reactome)
	hp-IRAK1:p-Pellino, IRAK4:p-Pellino	Arrow	REACT_22325 (Reactome)
	p-IRAK2	Arrow	REACT_22435 (Reactome)
	p-Pellino-1,2,(3)	Arrow	REACT_22381 (Reactome)
	p-S207,T211-MAP2K6	Arrow	REACT_22190 (Reactome)
	p-S927,S932-NFKB1(1-968)	Arrow	REACT_22418 (Reactome)
p-S927,S932-NFKB1(1-968)			REACT_22353 (Reactome)
	p-T342,T345,S346-IRAK4	Arrow	REACT_22209 (Reactome)
	p62:MEKK3:TRAF6	Arrow	REACT_22171 (Reactome)
p62:MEKK3			REACT_22171 (Reactome)