Interleukin-1 family signaling (Homo sapiens)

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12, 29920, 2624138, 267, 11, 178, 1934103028132214725153531, 3236162, 3, 6, 18, 335, 627cytosolMAP3K3 p-PELI2 TAK1 complexIL1B 2xMyri-IL1A TAB1 IL1R1 p-T342,T345,S346-IRAK4 IKKA TRAF6 p-PELI3 NOD1 IKBKG p-PELI2 MDP 2xMyri-IL1A p-T342,T345,S346-IRAK4 K63polyUb-hp-IRAK1 MYD88 Poly-K6-Ub-hp-IRAK1:IKK complexp-2S,S376,T,T209,T387-IRAK1 ADPATPIL1B ADPADPIL1B PELI1 K63polyUb-hp-IRAK1UBE2N TAB3 IL1R1 TAB1 p-2S,S376,T,T209,T387-IRAK1 IRAK1 p-PELI2 IRAK4 IL1B p-2S,S376,T,T209,T387-IRAK1 MAP2K6p-2S,S376,T,T209,T387-IRAK1 hp-IRAK1:p-Pellino,IRAK4:p-Pellinop-T342,T345,S346-IRAK4 IL1B ATPInterleukin 1receptor type2:interleukin 1IL1RAP-1 2xMyri-IL1A 2xMyri-IL1A IRAK2p-PELI1 IKBKB p-2S,S376,T,T209,T387-IRAK1 TAB3 p-Pellino-1,2,(3)ADPInterleukin-1TRAF6 p-S207,T211-MAP2K6IL1R2 p-2S,S376,T,T209,T387-IRAK1 IL1 receptorcomplex:TOLLIPIL1RAP-1 IKBKG MYD88 MYD88 MYD88 IL1B PELI2 2xMyri-IL1A IRAK1p-T184,T187-MAP3K7 hp-IRAK1:K6 poly-Uboligo-TRAF6p-2S,S376,T,T209,T387-IRAK1 IL1R1 K63polyUb TRAF6 IKBKG IRAK4 Ub-209-RIPK2 2xMyri-IL1A NOD2 IRAK3K63polyUbIKBKB hp-IRAK1:K6-poly-Uboligo-TRAF6:Activated TAK1 complexTAB1 IL1B MYD88 IRAK4 MYD88 homodimerIL1R1 hp-IRAK1:K6-poly-Uboligo-TRAF6:TAK1complexTRAF6 TAB2 ATPp-IRAK2 IL1:IL1R1:IL1RAP:MYD88 homodimerTAB3 IL1B TAB2 PELI1 IL1B IL1RN TOLLIP 2xMyri-IL1A p-2S,S376,T,T209,T387-IRAK1 2xMyri-IL1A MAP3K7 IL1B PELI3 Ubc13:UBE2V1TOLLIP SQSTM1 ATPIL1RAP-1 MYD88 IL1 receptorcomplex-activatedIRAK4:TOLLIP:IRAK1IL1RAP-1 IL1receptorcomplex-activatedIRAK4:TOLLIP:hp-IRAK:TRAF6Pellino 1,2,3MAP3K7 Activated IKKComplexIL1 receptor complex- activatedIRAK4:TOLLIPPELI2 MAP3K7 p-PELI3 MYD88 p-IRAK2TOLLIP MAP3K8(TPL2)-dependentMAPK1/3 activationp-T342,T345,S346-IRAK4 p62:MEKK3:TRAF6IKKA IL1B IL1R1 TRAF6UBE2V1 MAP3K3 p-S177,S181-IKBKB p-T342,T345,S346-IRAK4TRAF6 Interleukin-1receptor type1:Interleukin-1p-PELI1 p-2S,S376,T,T209,T387-IRAK1 IL1RAP-1 SQSTM1 MAP3K7 TOLLIP 2xMyri-IL1A K63polyUb TRAF6 IL1RAP-1 ADPInterleukin 1receptors2xMyri-IL1A K63polyUb TRAF6 IRAK4 TAB2 IL1 receptor complexhp-IRAK1:oligo-TRAF6TOLLIP IRAK4TAB3 TOLLIPiE-DAP IL1R1 IL1R1 IL1receptorcomplex-activatedIRAK4:TOLLIP:p-IRAK1TAB1 ADPIL1R2 IL1R2K63polyUb p-S176,S180-IKKA 2xMyri-IL1A IL1R1:IL1:IL1RAPIL1B ATPp-2S,S376,T,T209,T387-IRAK1 IL1R1 TAB2 p-S376,T387-IRAK1 p-2S,S376,T,T209,T387-IRAK1 ATPIL1R1IRAK4 PELI3 IL1R1 Interleukin 1receptors:IL1RNK63polyUb TRAF6 TAB3 IL1RAP-1IL1R1 hp-IRAK1:Pellino,IRAK4:Pellinop-T342,T345,S346-IRAK4 IL1R2 p-PELI3 MYD88 K63polyUb-hp-IRAK1 MYD88 2xMyri-IL1A IL1RNIL1RAP-1 hp-IRAK1:p-Pellino-1,2,(3)IL1B(117-269)IL1RAP-1 IL1RAP-1 IL1R1 p62:MEKK3hp-IRAK1, IRAK4IKKA:IKBKB:IKBKGIL1receptorcomplex-activatedIRAK4:TOLLIP:hp-IRAK1IKBKG hp-IRAK1:TRAF6p-2S,S376,T,T209,T387-IRAK1 TOLLIP Activated TAKcomplexesTAB2 p-PELI1 IL1R1 521, 234165516416416


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. View original pathway at:Reactome.

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  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)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated IKK ComplexComplexR-HSA-177663 (Reactome)
Activated TAK complexesComplexR-HSA-772536 (Reactome)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IKKA ProteinO15111 (Uniprot-TrEMBL)
IKKA:IKBKB:IKBKGComplexR-HSA-168113 (Reactome)
IL1

receptor complex- activated

IRAK4:TOLLIP:hp-IRAK1		ComplexR-HSA-446696 (Reactome)
IL1

receptor complex- activated

IRAK4:TOLLIP:p-IRAK1		ComplexR-HSA-446689 (Reactome)
IL1

receptor complex-activated

IRAK4:TOLLIP:hp-IRAK:TRAF6		ComplexR-HSA-446864 (Reactome)
IL1 receptor

complex-activated

IRAK4:TOLLIP:IRAK1		ComplexR-HSA-446693 (Reactome)
IL1 receptor complex:TOLLIPComplexR-HSA-446888 (Reactome)
IL1 receptor complex

- activated

IRAK4:TOLLIP		ComplexR-HSA-446643 (Reactome)
IL1 receptor complexComplexR-HSA-446637 (Reactome)
IL1:IL1R1:IL1RAP:MYD88 homodimerComplexR-HSA-450120 (Reactome)
IL1B ProteinP01584 (Uniprot-TrEMBL)
IL1B(117-269)ProteinP01584 (Uniprot-TrEMBL)
IL1R1 ProteinP14778 (Uniprot-TrEMBL)
IL1R1:IL1:IL1RAPComplexR-HSA-445758 (Reactome)
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 1		ComplexR-HSA-446125 (Reactome)
Interleukin 1 receptors:IL1RNComplexR-HSA-445751 (Reactome)
Interleukin 1 receptorsComplexR-HSA-445750 (Reactome)
Interleukin-1

receptor type

1:Interleukin-1		ComplexR-HSA-445755 (Reactome)
Interleukin-1ComplexR-HSA-445744 (Reactome)
K63polyUb R-HSA-450152 (Reactome)
K63polyUb TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
K63polyUb-hp-IRAK1 ProteinP51617 (Uniprot-TrEMBL)
K63polyUb-hp-IRAK1ComplexR-HSA-P51617 (Uniprot-TrEMBL)
K63polyUbR-HSA-450152 (Reactome)
MAP2K6ProteinP52564 (Uniprot-TrEMBL)
MAP3K3 ProteinQ99759 (Uniprot-TrEMBL)
MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
MAP3K8

(TPL2)-dependent

MAPK1/3 activation		PathwayR-HSA-5684264 (Reactome) Tumor progression locus-2 (TPL2, also known as COT and MAP3K8) functions as a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) in various stress-responsive signaling cascades. MAP3K8 (TPL2) mediates phosphorylation of MAP2Ks (MEK1/2) which in turn phosphorylate MAPK (ERK1/2) (Gantke T et al., 2011).

In the absence of extra-cellular signals, cytosolic MAP3K8 (TPL2) is held inactive in the complex with ABIN2 (TNIP2) and NFkB p105 (NFKB1) (Beinke S et al., 2003; Waterfield MR et al., 2003; Lang V et al., 2004). This interaction stabilizes MAP3K8 (TPL2) but also prevents MAP3K8 and NFkB from activating their downstream signaling cascades by inhibiting the kinase activity of MAP3K8 and the proteolysis of NFkB precursor protein p105. Upon activation of MAP3K8 by various stimuli (such as LPS, TNF-alpha, and IL-1 beta), IKBKB phosphorylates NFkB p105 (NFKB1) at Ser927 and Ser932, which trigger p105 proteasomal degradation and releases MAP3K8 from the complex (Beinke S et al., 2003, 2004; Roget K et al., 2012). Simultaneously, MAP3K8 is activated by auto- and/or transphosphorylation (Gantke T et al. 2011; Yang HT et al. 2012). The released active MAP3K8 phosphorylates its substrates, MAP2Ks. The free MAP3K8, however, is also unstable and is targeted for proteasome-mediated degradation, thus restricting prolonged activation of MAP3K8 (TPL2) and its downstream signaling pathways (Waterfield MR et al. 2003; Cho J et al., 2005). Furthermore, partially degraded NFkB p105 (NFKB1) into p50 can dimerize with other NFkB family members to regulate the transcription of target genes.

MAP3K8 activity is thought to regulate the dynamics of transcription factors that control an expression of diverse genes involved in growth, differentiation, and inflammation. Suppressing the MAP3K8 kinase activity with selective inhibitors, such as C8-chloronaphthyridine-3-carbonitrile, caused a significant reduction in TNFalpha production in LPS- and IL-1beta-induced both primary human monocytes and human blood (Hall JP et al. 2007). Similar results have been reported for mouse LPS-stimulated RAW264.7 cells (Hirata K et al. 2010). Moreover, LPS-stimulated macrophages derived from Map3k8 knockout mice secreted lower levels of pro-inflammatory cytokines such as TNFalpha, Cox2, Pge2 and CXCL1 (Dumitru CD et al. 2000; Eliopoulos AG et al. 2002). Additionally, bone marrow-derived dendritic cells (BMDCs) and macrophages from Map3k8 knockout mice showed significantly lower expression of IL-1beta in response to LPS, poly IC and LPS/MDP (Mielke et al., 2009). However, several other studies seem to contradict these findings and Map3k8 deficiency in mice has been also reported to enhance pro-inflammatory profiles. Map3k8 deficiency in LPS-stimulated macrophages was associated with an increase in nitric oxide synthase 2 (NOS2) expression (López-Peláez et al., 2011). Similarly, expression of IRAK-M, whose function is to compete with IL-1R-associated kinase (IRAK) family of kinases, was decreased in Map3k8-/- macrophages while levels of TNF and IL6 were elevated (Zacharioudaki et al., 2009). Moreover, significantly higher inflammation level was observed in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated Map3k8-/- mouse skin compared to WT skin (DeCicco-Skinner K. et al., 2011). Additionally, MAP3K8 activity is associated with NFkB inflammatory pathway. High levels of active p65 NFkB were observed in the nucleus of Map3k8 -/- mouse keratinocytes that dramatically increased within 15-30 minutes of TPA treatment. Similarly, increased p65 NFkB was observed in Map3k8-deficient BMDC both basally and after stimulation with LPS when compared to wild type controls (Mielke et al., 2009). The data opposes the findings that Map3k8-deficient mouse embryo fibroblasts and human Jurkat T cells with kinase domain-deficient protein have a reduction in NFkB activation but only when certain stimuli are administered (Lin et al., 1999; Das S et al., 2005). Thus, it is possible that whether MAP3K8 serves more of a pro-inflammatory or anti-inflammatory role may depend on cell- or tissue type and on stimuli (LPS vs. TPA, etc.) (Mielke et al., 2009; DeCicco-Skinner K. et al., 2012).

MAP3K8 has been also studied in the context of carcinogenesis, however the physiological role of MAP3K8 in the etiology of human cancers is also convoluted (Vougioukalaki M et al., 2011; DeCicco-Skinner K. et al., 2012).

MDP MetaboliteCHEBI:59414 (ChEBI)
MYD88 ProteinQ99836 (Uniprot-TrEMBL)
MYD88 homodimerComplexR-HSA-193932 (Reactome)
NOD1 ProteinQ9Y239 (Uniprot-TrEMBL)
NOD2 ProteinQ9HC29 (Uniprot-TrEMBL)
PELI1 ProteinQ96FA3 (Uniprot-TrEMBL)
PELI2 ProteinQ9HAT8 (Uniprot-TrEMBL)
PELI3 ProteinQ8N2H9 (Uniprot-TrEMBL)
Pellino 1,2,3ComplexR-HSA-450814 (Reactome)
Poly-K6-Ub-hp-IRAK1:IKK complexComplexR-HSA-451560 (Reactome)
SQSTM1 ProteinQ13501 (Uniprot-TrEMBL)
TAB1 ProteinQ15750 (Uniprot-TrEMBL)
TAB2 ProteinQ9NYJ8 (Uniprot-TrEMBL)
TAB3 ProteinQ8N5C8 (Uniprot-TrEMBL)
TAK1 complexComplexR-HSA-446878 (Reactome)
TOLLIP ProteinQ9H0E2 (Uniprot-TrEMBL)
TOLLIPProteinQ9H0E2 (Uniprot-TrEMBL)
TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRAF6ProteinQ9Y4K3 (Uniprot-TrEMBL)
UBE2N ProteinP61088 (Uniprot-TrEMBL)
UBE2V1 ProteinQ13404 (Uniprot-TrEMBL)
Ub-209-RIPK2 ProteinO43353 (Uniprot-TrEMBL)
Ubc13:UBE2V1ComplexR-HSA-202463 (Reactome)
hp-IRAK1, IRAK4ComplexR-HSA-450810 (Reactome)
hp-IRAK1: p-Pellino-1,2,(3)ComplexR-HSA-451411 (Reactome)
hp-IRAK1:K6 poly-Ub oligo-TRAF6ComplexR-HSA-450144 (Reactome)
hp-IRAK1:K6-poly-Ub oligo-TRAF6:Activated TAK1 complexComplexR-HSA-450186 (Reactome)
hp-IRAK1:K6-poly-Ub

oligo-TRAF6:TAK1

complex		ComplexR-HSA-450185 (Reactome)
hp-IRAK1:Pellino, IRAK4:PellinoComplexR-HSA-451413 (Reactome)
hp-IRAK1:TRAF6ComplexR-HSA-450121 (Reactome)
hp-IRAK1:oligo-TRAF6ComplexR-HSA-450159 (Reactome)
hp-IRAK1:p-Pellino, IRAK4:p-PellinoComplexR-HSA-451425 (Reactome)
iE-DAP MetaboliteCHEBI:59271 (ChEBI)
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-IRAK2 ProteinO43187 (Uniprot-TrEMBL)
p-IRAK2ProteinO43187 (Uniprot-TrEMBL)
p-PELI1 ProteinQ96FA3 (Uniprot-TrEMBL)
p-PELI2 ProteinQ9HAT8 (Uniprot-TrEMBL)
p-PELI3 ProteinQ8N2H9 (Uniprot-TrEMBL)
p-Pellino-1,2,(3)ComplexR-HSA-450819 (Reactome)
p-S176,S180-IKKA ProteinO15111 (Uniprot-TrEMBL)
p-S177,S181-IKBKB ProteinO14920 (Uniprot-TrEMBL)
p-S207,T211-MAP2K6ProteinP52564 (Uniprot-TrEMBL)
p-S376,T387-IRAK1 ProteinP51617 (Uniprot-TrEMBL)
p-T184,T187-MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
p-T342,T345,S346-IRAK4 ProteinQ9NWZ3 (Uniprot-TrEMBL)
p-T342,T345,S346-IRAK4ProteinQ9NWZ3 (Uniprot-TrEMBL)
p62:MEKK3:TRAF6ComplexR-HSA-507716 (Reactome)
p62:MEKK3ComplexR-HSA-507714 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-168184 (Reactome)
ADPArrowR-HSA-446634 (Reactome)
ADPArrowR-HSA-446694 (Reactome)
ADPArrowR-HSA-446701 (Reactome)
ADPArrowR-HSA-450827 (Reactome)
ADPArrowR-HSA-727819 (Reactome)
ATPR-HSA-168184 (Reactome)
ATPR-HSA-446634 (Reactome)
ATPR-HSA-446694 (Reactome)
ATPR-HSA-446701 (Reactome)
ATPR-HSA-450827 (Reactome)
ATPR-HSA-727819 (Reactome)
Activated IKK ComplexArrowR-HSA-168184 (Reactome)
Activated TAK complexesmim-catalysisR-HSA-168184 (Reactome)
IKKA:IKBKB:IKBKGR-HSA-168184 (Reactome)
IKKA:IKBKB:IKBKGR-HSA-451561 (Reactome)
IL1

receptor complex- activated

IRAK4:TOLLIP:hp-IRAK1		ArrowR-HSA-446701 (Reactome)
IL1

receptor complex- activated

IRAK4:TOLLIP:hp-IRAK1		R-HSA-446862 (Reactome)
IL1

receptor complex- activated

IRAK4:TOLLIP:p-IRAK1		ArrowR-HSA-446694 (Reactome)
IL1

receptor complex- activated

IRAK4:TOLLIP:p-IRAK1		R-HSA-446701 (Reactome)
IL1

receptor complex- activated

IRAK4:TOLLIP:p-IRAK1		mim-catalysisR-HSA-446701 (Reactome)
IL1

receptor complex-activated

IRAK4:TOLLIP:hp-IRAK:TRAF6		ArrowR-HSA-446862 (Reactome)
IL1

receptor complex-activated

IRAK4:TOLLIP:hp-IRAK:TRAF6		R-HSA-446894 (Reactome)
IL1 receptor

complex-activated

IRAK4:TOLLIP:IRAK1		ArrowR-HSA-446692 (Reactome)
IL1 receptor

complex-activated

IRAK4:TOLLIP:IRAK1		R-HSA-446694 (Reactome)
IL1 receptor

complex-activated

IRAK4:TOLLIP:IRAK1		mim-catalysisR-HSA-446694 (Reactome)
IL1 receptor complex:TOLLIPArrowR-HSA-446868 (Reactome)
IL1 receptor complex:TOLLIPR-HSA-446634 (Reactome)
IL1 receptor complex

- activated

IRAK4:TOLLIP		ArrowR-HSA-446634 (Reactome)
IL1 receptor complex

- activated

IRAK4:TOLLIP		R-HSA-446684 (Reactome)
IL1 receptor complex

- activated

IRAK4:TOLLIP		R-HSA-446692 (Reactome)
IL1 receptor complexArrowR-HSA-446648 (Reactome)
IL1 receptor complexR-HSA-446868 (Reactome)
IL1:IL1R1:IL1RAP:MYD88 homodimerArrowR-HSA-446894 (Reactome)
IL1:IL1R1:IL1RAP:MYD88 homodimerArrowR-HSA-450133 (Reactome)
IL1:IL1R1:IL1RAP:MYD88 homodimerR-HSA-446648 (Reactome)
IL1B(117-269)TBarR-HSA-507719 (Reactome)
IL1R1:IL1:IL1RAPArrowR-HSA-445752 (Reactome)
IL1R1:IL1:IL1RAPR-HSA-450133 (Reactome)
IL1R1R-HSA-445753 (Reactome)
IL1R2R-HSA-446130 (Reactome)
IL1RAP-1R-HSA-445752 (Reactome)
IL1RNR-HSA-445757 (Reactome)
IRAK1R-HSA-446692 (Reactome)
IRAK2R-HSA-446684 (Reactome)
IRAK3TBarR-HSA-446894 (Reactome)
IRAK4R-HSA-446648 (Reactome)
Interleukin 1

receptor type

2:interleukin 1		ArrowR-HSA-446130 (Reactome)
Interleukin 1 receptors:IL1RNArrowR-HSA-445757 (Reactome)
Interleukin 1 receptorsR-HSA-445757 (Reactome)
Interleukin-1

receptor type

1:Interleukin-1		ArrowR-HSA-445753 (Reactome)
Interleukin-1

receptor type

1:Interleukin-1		R-HSA-445752 (Reactome)
Interleukin-1R-HSA-445753 (Reactome)
Interleukin-1R-HSA-446130 (Reactome)
K63polyUb-hp-IRAK1ArrowR-HSA-451418 (Reactome)
K63polyUb-hp-IRAK1R-HSA-451561 (Reactome)
K63polyUbR-HSA-446877 (Reactome)
K63polyUbR-HSA-451418 (Reactome)
MAP2K6R-HSA-727819 (Reactome)
MYD88 homodimerR-HSA-450133 (Reactome)
Pellino 1,2,3R-HSA-450690 (Reactome)
Poly-K6-Ub-hp-IRAK1:IKK complexArrowR-HSA-451561 (Reactome)
R-HSA-168184 (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.

R-HSA-445752 (Reactome) Interleukin receptor 1 type 1 when bound to interleukin 1 binds interleukin 1 receptor accessory protein, essential for eliciting a signaling cascade.
R-HSA-445753 (Reactome) Interleukin-1 receptor type 1 (IL1R1) is the receptor responsible for transmitting the inflammatory effects of Interleukin-1 (IL1).
R-HSA-445757 (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).
R-HSA-446130 (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.
R-HSA-446634 (Reactome) IRAK4 is activated by autophosphorylation at 3 positions within the kinase activation loop, Thr-342, Thr-345 and Ser-346.
R-HSA-446648 (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).
R-HSA-446684 (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.
R-HSA-446692 (Reactome) MYD88 recruits unphosphorylated, inactive IRAK1 to the IL1 receptor complex.
R-HSA-446694 (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).
R-HSA-446701 (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).
R-HSA-446862 (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).
R-HSA-446868 (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.
R-HSA-446870 (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.
R-HSA-446877 (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.
R-HSA-446894 (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).
R-HSA-450133 (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).
R-HSA-450173 (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).
R-HSA-450187 (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).
R-HSA-450690 (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.
R-HSA-450827 (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.
R-HSA-451418 (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).
R-HSA-451561 (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).
R-HSA-507719 (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).
R-HSA-727819 (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).
TAK1 complexR-HSA-446870 (Reactome)
TAK1 complexmim-catalysisR-HSA-727819 (Reactome)
TOLLIPArrowR-HSA-446894 (Reactome)
TOLLIPR-HSA-446868 (Reactome)
TRAF6R-HSA-446862 (Reactome)
TRAF6R-HSA-450173 (Reactome)
TRAF6R-HSA-507719 (Reactome)
Ubc13:UBE2V1ArrowR-HSA-446877 (Reactome)
Ubc13:UBE2V1ArrowR-HSA-451418 (Reactome)
Ubc13:UBE2V1R-HSA-446877 (Reactome)
Ubc13:UBE2V1R-HSA-451418 (Reactome)
hp-IRAK1, IRAK4R-HSA-450690 (Reactome)
hp-IRAK1, IRAK4mim-catalysisR-HSA-450827 (Reactome)
hp-IRAK1: p-Pellino-1,2,(3)R-HSA-451418 (Reactome)
hp-IRAK1: p-Pellino-1,2,(3)mim-catalysisR-HSA-451418 (Reactome)
hp-IRAK1:K6 poly-Ub oligo-TRAF6ArrowR-HSA-446877 (Reactome)
hp-IRAK1:K6 poly-Ub oligo-TRAF6R-HSA-446870 (Reactome)
hp-IRAK1:K6-poly-Ub oligo-TRAF6:Activated TAK1 complexArrowR-HSA-450187 (Reactome)
hp-IRAK1:K6-poly-Ub

oligo-TRAF6:TAK1

complex		ArrowR-HSA-446870 (Reactome)
hp-IRAK1:K6-poly-Ub

oligo-TRAF6:TAK1

complex		R-HSA-450187 (Reactome)
hp-IRAK1:Pellino, IRAK4:PellinoArrowR-HSA-450690 (Reactome)
hp-IRAK1:Pellino, IRAK4:PellinoR-HSA-450827 (Reactome)
hp-IRAK1:TRAF6ArrowR-HSA-446894 (Reactome)
hp-IRAK1:TRAF6R-HSA-450173 (Reactome)
hp-IRAK1:oligo-TRAF6ArrowR-HSA-450173 (Reactome)
hp-IRAK1:oligo-TRAF6R-HSA-446877 (Reactome)
hp-IRAK1:oligo-TRAF6mim-catalysisR-HSA-446877 (Reactome)
hp-IRAK1:p-Pellino, IRAK4:p-PellinoArrowR-HSA-450827 (Reactome)
p-IRAK2ArrowR-HSA-446684 (Reactome)
p-Pellino-1,2,(3)ArrowR-HSA-451418 (Reactome)
p-S207,T211-MAP2K6ArrowR-HSA-727819 (Reactome)
p-T342,T345,S346-IRAK4ArrowR-HSA-446894 (Reactome)
p62:MEKK3:TRAF6ArrowR-HSA-507719 (Reactome)
p62:MEKK3R-HSA-507719 (Reactome)
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