Interleukin-1 family signaling (Homo sapiens)

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4, 713225, 23211911, 36251, 1431293818, 26, 326, 12, 3410128, 15, 20, 24, 255, 35171162, 3514393283720, 33279Interleukin 1 receptorsIL1RN Interleukin-1 Interleukin-1 IL1 receptor complex - activated IRAK4TOLLIP SCF beta-TrCP complex hp-IRAK1TRAF6 TAB2/3 hp-IRAK1oligo-TRAF6 Interleukin-1 IKKAIKKBNEMO IL1R1IL1IL1RAP IL1R1IL1IL1RAP IL1R1IL1IL1RAP IL1 receptor complex-activated IRAK4TOLLIPhp-IRAKTRAF6 IL1 receptor complex - activated IRAK4TOLLIP Interleukin-1 receptor type 1Interleukin-1 hp-IRAK1K6-poly-Ub oligo-TRAF6Activated TAK1 complex IL1 receptor complex-activated IRAK4TOLLIPIRAK1 NFKB p105TPL2ABIN2 IL1 receptor complex - activated IRAK4TOLLIP IL1R1IL1IL1RAP p62MEKK3TRAF6 hp-IRAK1K6 poly-Ub oligo-TRAF6 Interleukin-1 IL1R1IL1IL1RAP cytosolInterleukin-1 Interleukin 1 receptors Interleukin 1 receptor type 2interleukin 1 hp-IRAK1K6-polyUb TRAF6 hp-IRAK1K6-polyUb TRAF6 MYD88 homodimer Interleukin-1 receptor type 1Interleukin-1 Interleukin-1 IL1 receptor complexTOLLIP Interleukin-1 receptor type 1Interleukin-1 Interleukin-1 IL1IL1R1IL1RAPMYD88 homodimer TAB2/3 hp-IRAK1K6 poly-Ub oligo-TRAF6 MYD88 homodimer TAK1 complex IKKAIKKBNEMO Interleukin-1 IL1IL1R1IL1RAPMYD88 homodimer hp-IRAK1TRAF6 IL1 receptor complex- activated IRAK4TOLLIPhp-IRAK1 Interleukin-1 receptor type 1Interleukin-1 IL1R1IL1IL1RAP IL1 receptor complex- activated IRAK4TOLLIPhp-IRAK1 MYD88 homodimer hp-IRAK1K6 poly-Ub oligo-TRAF6 Poly-K6-Ub-hp-IRAK1IKK complex MYD88 homodimer Interleukin-1 Interleukin-1 MYD88 homodimer MYD88 homodimer IL1R1IL1IL1RAP MYD88 homodimer Ubc13UBE2V1 Interleukin-1 receptor type 1Interleukin-1 Interleukin-1 receptor type 1Interleukin-1 IL1 receptor complex - activated IRAK4TOLLIP SCF betaTrCP complexp-NFKB p105 hp-IRAK1 p-Pellino-1,2,IL1 receptor complex- activated IRAK4TOLLIPp-IRAK1 IL1 receptor complex - activated IRAK4TOLLIP Interleukin-1 receptor type 1Interleukin-1 IL1R1IL1IL1RAP IL1R1IL1IL1RAP MYD88 homodimer SCF beta-TrCP complex Interleukin-1 receptor type 1Interleukin-1 hp-IRAK1K6-polyUb TRAF6 MYD88 homodimer p62MEKK3 IL1 receptor complex Interleukin-1 hp-IRAK1K6-poly-Ub oligo-TRAF6TAK1 complex TAK1 complex TAK1 complex IL1 receptor complex TAB2/3 Interleukin-1 receptor type 1Interleukin-1 p62MEKK3 Interleukin-1 receptor type 1Interleukin-1 IL1IL1R1IL1RAPMYD88 homodimer Activated IKK Complex TAB2 NFKB1IKBKB IL1RAP-1 TRAF6 p-S207,T211-MAP2K6IL1R1IL1IL1RAPIL1RAP-1 TOLLIPK63polyUb TRAF6 MAP3K8 ADP2xMyri-IL1A IL1R1 hp-IRAK1oligo-TRAF6IL1R1 TRAF6 Ubc13UBE2V1TOLLIPIL1R1 UBE2N 3xUb-p-S927,S932-NFKB1Interleukin-1IL1RAP-1 SCF betaTrCP complexp-NFKB p105hp-IRAK1 p-Pellino-1,2,ATPhp-IRAK1TRAF6IL1R1SKP1 p-T342,T345,S346-IRAK4 p-T342,T345,S346-IRAK4 IL1 receptor complex-activated IRAK4TOLLIPhp-IRAKTRAF62xMyri-IL1A IL1RAP-1K63polyUb-hp-IRAK1 TAB3TNIP2MAP3K3 MAP3K7 IL1R2IL1B Interleukin 1 receptorsIL1RNSQSTM1 2xMyri-IL1A p-2S,S376,T,T209,T387-IRAK1 MYD88 K63polyUbATPTRAF6 Interleukin 1 receptorsIL1B ADP2xMyri-IL1A ATP2xMyri-IL1A MYD88 2xMyri-IL1A 2xMyri-IL1A p-S376,T387-IRAK1 IL1RAP-1 IL1IL1R1IL1RAPMYD88 homodimerp62MEKK3SKP1 TRAF6ADPK63polyUb-hp-IRAK1IKBKG K63polyUb TRAF6 p-S176,S180-CHUK IL1RNIL1B CUL1 IRAK4 Pellino 1,2,3p-Pellino-1,2,Activated IKK ComplexPoly-K6-Ub-hp-IRAK1IKK complexTRAF6 IL1RN p-T342,T345,S346-IRAK4 IL1B IL1RAP-1 IL1 receptor complexIKBKG K63polyUb TRAF6 RBX1 TOLLIPIKBKB IRAK1 CHUK IL1B BTRC 2xMyri-IL1A TOLLIPp62MEKK3TRAF6MYD88 ADPTAK1 complexTOLLIPCUL1 hp-IRAK1p-Pellino, IRAK4p-PellinoTAB3TAB1 ATPTAB1 IL1 receptor complex- activated IRAK4TOLLIPp-IRAK1p-IRAK2ATPp-2S,S376,T,T209,T387-IRAK1 SCF beta-TrCP complexp-S177,S181-IKBKB IL1R1 Interleukin-1 receptor type 1Interleukin-1p-S927,S932-NFKB1MYD88 homodimerMAP2K6SQSTM1 UBE2V1 ADP2xMyri-IL1A TAB3IL1 receptor complex-activated IRAK4TOLLIPIRAK1MYD88 hp-IRAK1K6 poly-Ub oligo-TRAF6p-2S,S376,T,T209,T387-IRAK1 p-2S,S376,T,T209,T387-IRAK1 TAB1 hp-IRAK1, IRAK4IRAK4Phospho-MEK1, phospho-SEK1p-2S,S376,T,T209,T387-IRAK1 IL1R1 hp-IRAK1K6-poly-Ub oligo-TRAF6Activated TAK1 complexIKBKG p-2S,S376,T,T209,T387-IRAK1 IL1B CHUK IL1R1 IRAK4 IL1B p-S927,S932-NFKB1IL1RAP-1 hp-IRAK1Pellino, IRAK4PellinoIL1B IL1B IL1RAP-1 IL1R2 IL1R1 2xMyri-IL1A IL1 receptor complex - activated IRAK4TOLLIPMYD88 ADPIL1 receptor complex- activated IRAK4TOLLIPhp-IRAK1MYD88 2xMyri-IL1A IRAK1ADPTOLLIPIL1BIKKAIKKBNEMOIL1R1 Activated TAK complexesMAP3K3 IL1R1 MAP3K8MYD88 TNIP2 BTRC IL1RAP-1 IL1B ATPIL1R1 ATPIL1R2 IRAK2RBX1 TAB2 IL1RAP-1 p-2S,S376,T,T209,T387-IRAK1 hp-IRAK1K6-poly-Ub oligo-TRAF6TAK1 complexp-T342,T345,S346-IRAK4 IL1 receptor complexTOLLIPIL1B MEK1, SEK1MAP3K7 p-T342,T345,S346-IRAK4 IRAK3TOLLIPMAP3K7 NFKB1p-T342,T345,S346-IRAK4TAB2 Interleukin 1 receptor type 2interleukin 1IL1R1 ATPMYD88 ADPNFKB p105TPL2ABIN2p-2S,S376,T,T209,T387-IRAK1 MYD88 3031313130


Description

Interleukin 1 (IL1) signals via Interleukin 1 receptor 1 (IL1R1), the only signaling-capable IL1 receptor. This is a single chain type 1 transmembrane protein comprising an extracellular ligand binding domain and an intracellular region called the Toll/Interleukin-1 receptor (TIR) domain that is structurally conserved and shared by other members of the two families of receptors (Xu et al. 2000). This domain is also shared by the downstream adapter molecule MyD88. IL1 binding to IL1R1 leads to the recruitment of a second receptor chain termed the IL1 receptor accessory protein (IL1RAP or IL1RAcP) enabling the formation of a high-affinity ligand-receptor complex that is capable of signal transduction. Intracellular signaling is initiated by the recruitment of MyD88 to the IL-1R1/IL1RAP complex. IL1RAP is only recruited to IL1R1 when IL1 is present; it is believed that a TIR domain signaling complex is formed between the receptor and the adapter TIR domains. The recruitment of MyD88 leads to the recruitment of Interleukin-1 receptor-associated kinase (IRAK)-1 and -4, probably via their death domains. IRAK4 then activates IRAK1, allowing IRAK1 to autophosphorylate. Both IRAK1 and IRAK4 then dissociate from MyD88 (Brikos et al. 2007) which remains stably complexed with IL-1R1 and IL1RAP. They in turn interact with Tumor Necrosis Factor Receptor (TNFR)-Associated Factor 6 (TRAF6), which is an E3 ubiquitin ligase (Deng et al. 2000). TRAF6 is then thought to auto-ubiquinate, attaching K63-polyubiquitin to itself with the assistance of the E2 conjugating complex Ubc13/Uev1a. K63-pUb-TRAF6 recruits Transforming Growth Factor (TGF) beta-activated protein kinase 1 (TAK1) in a complex with TAK1-binding protein 2 (TAB2) and TAB3, which both contain nuclear zinc finger motifs that interact with K63-polyubiquitin chains (Ninomiya-Tsuji et al. 1999). This activates TAK1, which then activates inhibitor of NF-kappaB (IkappaB) kinase 2 (IKK2 or IKKB) within the IKK complex, the kinase responsible for phosphorylation of IkappaB. The IKK complex also contains the scaffold protein NF-kappa B essential modulator (NEMO). TAK1 also couples to the upstream kinases for p38 and c-jun N-terminal kinase (JNK). IRAK1 undergoes K63-linked polyubiquination; Pellino E3 ligases are important in this process. (Butler et al. 2007; Ordureau et al. 2008). The activity of these proteins is greatly enhanced by IRAK phosphorylation (Schauvliege et al. 2006), leading to K63-linked polyubiquitination of IRAK1. This recruits NEMO to IRAK1, with NEMO binding to polyubiquitin (Conze et al. 2008).

TAK1 activates IKKB (and IKK), resulting in phosphorylation of the inhibitory IkB proteins and enabling translocation of NFkB to the nucleus; IKKB also phosphorylates NFkB p105, leading to its degradation and the subsequent release of active TPL2 that triggers the extracellular-signal regulated kinase (ERK)1/2 MAPK cascade. TAK1 can also trigger the p38 and JNK MAPK pathways via activating the upstream MKKs3, 4 and 6. The MAPK pathways activate a number of downstream kinases and transcription factors that co-operate with NFkB to induce the expression of a range of TLR/IL-1R-responsive genes. There are reports suggesting that IL1 stimulation increases nuclear localization of IRAK1 (Bol et al. 2000) and that nuclear IRAK1 binds to the promoter of NFkB-regulated gene and IkBa, enhancing binding of the NFkB p65 subunit to NFkB responsive elements within the IkBa promoter. IRAK1 is required for IL1-induced Ser-10 phosphorylation of histone H3 in vivo (Liu et al. 2008). However, details of this aspect of IRAK1 signaling mechanisms remain unclear. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=446652

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  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

View all...
CompareRevisionActionTimeUserComment
114671view16:14, 25 January 2021ReactomeTeamReactome version 75
113118view11:18, 2 November 2020ReactomeTeamReactome version 74
112352view15:28, 9 October 2020ReactomeTeamReactome version 73
101253view11:14, 1 November 2018ReactomeTeamreactome version 66
100792view20:42, 31 October 2018ReactomeTeamreactome version 65
100334view19:19, 31 October 2018ReactomeTeamreactome version 64
99879view16:02, 31 October 2018ReactomeTeamreactome version 63
99436view14:37, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99023view13:07, 24 October 2018DeSlOntology Term : 'signaling pathway' added !
99022view13:06, 24 October 2018DeSlOntology Term : 'kinase mediated signaling pathway' added !
94504view09:20, 14 September 2017Mkutmonreactome version 61
86604view09:22, 11 July 2016ReactomeTeamreactome version 56
83129view10:03, 18 November 2015ReactomeTeamVersion54
81471view13:00, 21 August 2015ReactomeTeamVersion53
76943view08:21, 17 July 2014ReactomeTeamFixed remaining interactions
76648view12:02, 16 July 2014ReactomeTeamFixed remaining interactions
75978view10:03, 11 June 2014ReactomeTeamRe-fixing comment source
75681view11:01, 10 June 2014ReactomeTeamReactome 48 Update
75036view13:54, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74838view10:06, 30 April 2014ReactomeTeamReactome46
74680view08:45, 30 April 2014ReactomeTeamReactome46
44873view10:01, 6 October 2011MartijnVanIerselOntology Term : 'interleukin-1 signaling pathway' added !
44872view10:00, 6 October 2011MartijnVanIerselOntology Term : 'PW:0000512' removed !
44869view09:59, 6 October 2011MartijnVanIerselOntology Term : 'Interleukin mediated signaling pathway' added !
42058view21:53, 4 March 2011MaintBotAutomatic update
39865view05:53, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2xMyri-IL1A ProteinP01583 (Uniprot-TrEMBL)
3xUb-p-S927,S932-NFKB1ProteinP19838 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated IKK ComplexComplexREACT_7826 (Reactome)
Activated TAK complexesComplexREACT_23279 (Reactome)
BTRC ProteinQ9Y297 (Uniprot-TrEMBL)
CHUK ProteinO15111 (Uniprot-TrEMBL)
CUL1 ProteinQ13616 (Uniprot-TrEMBL)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IKKA

IKKB

NEMO		ComplexREACT_7693 (Reactome)
IL1

IL1R1 IL1RAP

MYD88 homodimer		ComplexREACT_23167 (Reactome)
IL1 receptor complex TOLLIPComplexREACT_23348 (Reactome)
IL1 receptor complex - activated IRAK4 TOLLIPComplexREACT_23002 (Reactome)
IL1 receptor complex- activated IRAK4

TOLLIP

hp-IRAK1		ComplexREACT_23332 (Reactome)
IL1 receptor complex- activated IRAK4

TOLLIP

p-IRAK1		ComplexREACT_23087 (Reactome)
IL1 receptor complex-activated IRAK4

TOLLIP

IRAK1		ComplexREACT_22771 (Reactome)
IL1 receptor complex-activated IRAK4

TOLLIP hp-IRAK

TRAF6		ComplexREACT_22757 (Reactome)
IL1 receptor complexComplexREACT_23029 (Reactome)
IL1B ProteinP01584 (Uniprot-TrEMBL)
IL1BProteinP01584 (Uniprot-TrEMBL)
IL1R1

IL1

IL1RAP		ComplexREACT_22656 (Reactome)
IL1R1 ProteinP14778 (Uniprot-TrEMBL)
IL1R1ProteinP14778 (Uniprot-TrEMBL)
IL1R2 ProteinP27930 (Uniprot-TrEMBL)
IL1R2ProteinP27930 (Uniprot-TrEMBL)
IL1RAP-1 ProteinQ9NPH3-1 (Uniprot-TrEMBL)
IL1RAP-1ProteinQ9NPH3-1 (Uniprot-TrEMBL)
IL1RN ProteinP18510 (Uniprot-TrEMBL)
IL1RNProteinP18510 (Uniprot-TrEMBL)
IRAK1 ProteinP51617 (Uniprot-TrEMBL)
IRAK1ProteinP51617 (Uniprot-TrEMBL)
IRAK2ProteinO43187 (Uniprot-TrEMBL)
IRAK3ProteinQ9Y616 (Uniprot-TrEMBL)
IRAK4 ProteinQ9NWZ3 (Uniprot-TrEMBL)
IRAK4ProteinQ9NWZ3 (Uniprot-TrEMBL)
Interleukin 1 receptor type 2 interleukin 1ComplexREACT_22786 (Reactome)
Interleukin 1 receptors IL1RNComplexREACT_22878 (Reactome)
Interleukin 1 receptorsProteinREACT_23342 (Reactome)
Interleukin-1 receptor type 1 Interleukin-1ComplexREACT_23118 (Reactome)
Interleukin-1ProteinREACT_22576 (Reactome)
K63polyUb TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
K63polyUb-hp-IRAK1 ProteinP51617 (Uniprot-TrEMBL)
K63polyUb-hp-IRAK1ComplexP51617 (Uniprot-TrEMBL)
K63polyUbREACT_21645 (Reactome)
MAP2K6ProteinP52564 (Uniprot-TrEMBL)
MAP3K3 ProteinQ99759 (Uniprot-TrEMBL)
MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
MAP3K8 ProteinP41279 (Uniprot-TrEMBL)
MAP3K8ProteinP41279 (Uniprot-TrEMBL)
MEK1, SEK1ProteinREACT_22657 (Reactome)
MYD88 ProteinQ99836 (Uniprot-TrEMBL)
MYD88 homodimerComplexREACT_14253 (Reactome)
NFKB p105

TPL2

ABIN2		ComplexREACT_22747 (Reactome)
NFKB1ProteinP19838 (Uniprot-TrEMBL)
Pellino 1,2,3ProteinREACT_22780 (Reactome)
Phospho-MEK1, phospho-SEK1ProteinREACT_22945 (Reactome)
Poly-K6-Ub-hp-IRAK1 IKK complexComplexREACT_22624 (Reactome)
RBX1 ProteinP62877 (Uniprot-TrEMBL)
SCF beta-TrCP complexComplexREACT_22981 (Reactome)
SCF betaTrCP complex p-NFKB p105ComplexREACT_22646 (Reactome)
SKP1 ProteinP63208 (Uniprot-TrEMBL)
SQSTM1 ProteinQ13501 (Uniprot-TrEMBL)
TAB1 ProteinQ15750 (Uniprot-TrEMBL)
TAB2 ProteinQ9NYJ8 (Uniprot-TrEMBL)
TAB3ProteinQ8N5C8 (Uniprot-TrEMBL)
TAK1 complexComplexREACT_22633 (Reactome)
TNIP2 ProteinQ8NFZ5 (Uniprot-TrEMBL)
TNIP2ProteinQ8NFZ5 (Uniprot-TrEMBL)
TOLLIPProteinQ9H0E2 (Uniprot-TrEMBL)
TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRAF6ProteinQ9Y4K3 (Uniprot-TrEMBL)
UBE2N ProteinP61088 (Uniprot-TrEMBL)
UBE2V1 ProteinQ13404 (Uniprot-TrEMBL)
Ubc13 UBE2V1ComplexREACT_12995 (Reactome)
hp-IRAK1 p-Pellino-1,2,ComplexREACT_22866 (Reactome)
hp-IRAK1 K6 poly-Ub oligo-TRAF6ComplexREACT_23272 (Reactome)
hp-IRAK1

K6-poly-Ub oligo-TRAF6

Activated TAK1 complex		ComplexREACT_23314 (Reactome)
hp-IRAK1

K6-poly-Ub oligo-TRAF6

TAK1 complex		ComplexREACT_22797 (Reactome)
hp-IRAK1

Pellino, IRAK4

Pellino		ComplexREACT_23330 (Reactome)
hp-IRAK1 TRAF6ComplexREACT_22529 (Reactome)
hp-IRAK1 oligo-TRAF6ComplexREACT_22793 (Reactome)
hp-IRAK1

p-Pellino, IRAK4

p-Pellino		ComplexREACT_22769 (Reactome)
hp-IRAK1, IRAK4ProteinREACT_23241 (Reactome)
p-2S,S376,T,T209,T387-IRAK1 ProteinP51617 (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-IRAK2ProteinO43187 (Uniprot-TrEMBL)
p-Pellino-1,2,ProteinREACT_22733 (Reactome)
p-S176,S180-CHUK ProteinO15111 (Uniprot-TrEMBL)
p-S177,S181-IKBKB ProteinO14920 (Uniprot-TrEMBL)
p-S207,T211-MAP2K6ProteinP52564 (Uniprot-TrEMBL)
p-S376,T387-IRAK1 ProteinP51617 (Uniprot-TrEMBL)
p-S927,S932-NFKB1ProteinP19838 (Uniprot-TrEMBL)
p-T342,T345,S346-IRAK4 ProteinQ9NWZ3 (Uniprot-TrEMBL)
p-T342,T345,S346-IRAK4ProteinQ9NWZ3 (Uniprot-TrEMBL)
p62

MEKK3

TRAF6		ComplexREACT_23141 (Reactome)
p62 MEKK3ComplexREACT_23211 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
3xUb-p-S927,S932-NFKB1ArrowREACT_22407 (Reactome)
ADPArrowREACT_22125 (Reactome)
ADPArrowREACT_22162 (Reactome)
ADPArrowREACT_22190 (Reactome)
ADPArrowREACT_22271 (Reactome)
ADPArrowREACT_22325 (Reactome)
ADPArrowREACT_22405 (Reactome)
ADPArrowREACT_22418 (Reactome)
ADPArrowREACT_6935 (Reactome)
ATPREACT_22125 (Reactome)
ATPREACT_22162 (Reactome)
ATPREACT_22190 (Reactome)
ATPREACT_22271 (Reactome)
ATPREACT_22325 (Reactome)
ATPREACT_22405 (Reactome)
ATPREACT_22418 (Reactome)
ATPREACT_6935 (Reactome)
Activated IKK ComplexArrowREACT_6935 (Reactome)
Activated IKK ComplexREACT_22418 (Reactome)
Activated TAK complexesREACT_6935 (Reactome)
IKKA

IKKB

NEMO		REACT_22256 (Reactome)
IKKA

IKKB

NEMO		REACT_6935 (Reactome)
IL1

IL1R1 IL1RAP

MYD88 homodimer		ArrowREACT_22209 (Reactome)
IL1

IL1R1 IL1RAP

MYD88 homodimer		REACT_22326 (Reactome)
IL1 receptor complex TOLLIPREACT_22405 (Reactome)
IL1 receptor complex - activated IRAK4 TOLLIPArrowREACT_22405 (Reactome)
IL1 receptor complex - activated IRAK4 TOLLIPREACT_22379 (Reactome)
IL1 receptor complex - activated IRAK4 TOLLIPREACT_22435 (Reactome)
IL1 receptor complex- activated IRAK4

TOLLIP

hp-IRAK1		ArrowREACT_22162 (Reactome)
IL1 receptor complex- activated IRAK4

TOLLIP

hp-IRAK1		REACT_22311 (Reactome)
IL1 receptor complex- activated IRAK4

TOLLIP

p-IRAK1		ArrowREACT_22125 (Reactome)
IL1 receptor complex- activated IRAK4

TOLLIP

p-IRAK1		REACT_22162 (Reactome)
IL1 receptor complex-activated IRAK4

TOLLIP

IRAK1		REACT_22125 (Reactome)
IL1 receptor complexREACT_22120 (Reactome)
IL1BTBarREACT_22171 (Reactome)
IL1R1

IL1

IL1RAP		REACT_22154 (Reactome)
IL1R1REACT_22375 (Reactome)
IL1R2REACT_22253 (Reactome)
IL1RAP-1REACT_22382 (Reactome)
IL1RNREACT_22331 (Reactome)
IRAK1REACT_22379 (Reactome)
IRAK2REACT_22435 (Reactome)
IRAK3TBarREACT_22209 (Reactome)
IRAK4REACT_22326 (Reactome)
Interleukin 1 receptorsREACT_22331 (Reactome)
Interleukin-1 receptor type 1 Interleukin-1REACT_22382 (Reactome)
Interleukin-1REACT_22253 (Reactome)
Interleukin-1REACT_22375 (Reactome)
K63polyUb-hp-IRAK1ArrowREACT_22381 (Reactome)
K63polyUb-hp-IRAK1REACT_22256 (Reactome)
K63polyUbREACT_22381 (Reactome)
K63polyUbREACT_22430 (Reactome)
MAP2K6REACT_22190 (Reactome)
MAP3K8REACT_22206 (Reactome)
MAP3K8REACT_22271 (Reactome)
MEK1, SEK1REACT_22271 (Reactome)
MYD88 homodimerREACT_22154 (Reactome)
NFKB1REACT_22206 (Reactome)
NFKB1REACT_22418 (Reactome)
Pellino 1,2,3REACT_22286 (Reactome)
Phospho-MEK1, phospho-SEK1ArrowREACT_22271 (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 complexArrowREACT_22407 (Reactome)
SCF beta-TrCP complexREACT_22353 (Reactome)
SCF beta-TrCP complexREACT_22407 (Reactome)
TAK1 complexREACT_22190 (Reactome)
TAK1 complexREACT_22322 (Reactome)
TNIP2REACT_22206 (Reactome)
TOLLIPArrowREACT_22209 (Reactome)
TOLLIPREACT_22120 (Reactome)
TRAF6REACT_22171 (Reactome)
TRAF6REACT_22311 (Reactome)
TRAF6REACT_22416 (Reactome)
Ubc13 UBE2V1ArrowREACT_22381 (Reactome)
Ubc13 UBE2V1ArrowREACT_22430 (Reactome)
Ubc13 UBE2V1REACT_22381 (Reactome)
Ubc13 UBE2V1REACT_22430 (Reactome)
hp-IRAK1 p-Pellino-1,2,REACT_22381 (Reactome)
hp-IRAK1 K6 poly-Ub oligo-TRAF6ArrowREACT_22430 (Reactome)
hp-IRAK1 K6 poly-Ub oligo-TRAF6REACT_22322 (Reactome)
hp-IRAK1

Pellino, IRAK4

Pellino		REACT_22325 (Reactome)
hp-IRAK1 TRAF6ArrowREACT_22209 (Reactome)
hp-IRAK1 TRAF6REACT_22416 (Reactome)
hp-IRAK1 oligo-TRAF6REACT_22430 (Reactome)
hp-IRAK1

p-Pellino, IRAK4

p-Pellino		ArrowREACT_22325 (Reactome)
hp-IRAK1, IRAK4REACT_22286 (Reactome)
hp-IRAK1, IRAK4REACT_22325 (Reactome)
p-Pellino-1,2,ArrowREACT_22381 (Reactome)
p-S207,T211-MAP2K6ArrowREACT_22190 (Reactome)
p-S927,S932-NFKB1ArrowREACT_22418 (Reactome)
p-S927,S932-NFKB1REACT_22353 (Reactome)
p-T342,T345,S346-IRAK4ArrowREACT_22209 (Reactome)
p62 MEKK3REACT_22171 (Reactome)
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