Interleukin-1 family signaling (Homo sapiens)

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17, 33, 40, 545212, 32916831, 65191, 881366, 8539, 46, 7123, 9414, 36, 563554, 50, 5114, 39, 5655, 6011, 23, 574, 50, 72, 8384729561341016, 47, 81, 87, 933, 6, 20, 49, 70...3822, 71, 8094939352843, 817572943, 6, 48, 49, 70...77744, 50, 72, 8399426737612, 9225, 64, 78, 9418, 7919, 30, 4128, 3235, 67, 91293, 48, 49, 70, 8990581, 42, 8872415521, 884, 50, 72, 837769458293nucleoplasmcytosolcytosolnucleoplasmp-PELI1 IRAK1 SMAD3 ATPIL36RN, IL1F10MYD88 IL13 NOD2 IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIP:IRAK1ATPTNIP2 TNIP2 p-2S,S376,T,T209,T387-IRAK1 Myr82K-Myr83K-IL1A IL33 ALOX5 gene MAP3K3 hp-IRAK1:K63polyUboligo-TRAF6:Activated TAK1 complexNFKB1(1-433) UbK63polyUb UBA52(1-76) TNIP2 IL36A PTPN2 gene IRAK4IL1F10(?-152)PTPN23 UBC(229-304) K63polyUb PSMC4 IL36RN,IL1F10:IL1RL2NFKBIARELA SKP1 ATPADPp-S32,S36-NFKBIA PSMD4 IL18, ALOX5p-2S,S376,T,T209,T387-IRAK1 NFKB1:RELA:p-S32,S36-NFKBIA:UbUBC(77-152) IL37(?-218) IL37(?-218)MYD88 IL1RAP-1p-PELI3 CUL1 Pellino 1,2,3p-2S,S376,T,T209,T387-IRAK1 ATPTAB3 p-S257,T261-MAP2K4 UbK63polyUb-TRAF6 iE-DAP IL1R1 PTPN14 gene TAB2 BTRC UBC(229-304) BTRC MAP3K8 IL1B,Myr82K-Myr83K-IL1A:IL1R2p-S927,S932-NFKB1(1-968):p-S,T-MAP3K8:TNIP2p-S218,S222-MAP2K1,p-S257,T261-MAP2K4TNIP2IL1R1:IL1:IL1RAP:IRAK4:MYD88 dimer:TOLLIPIL36B CASP1(317-404) Myr82K-Myr83K-IL1A IL37(?-218) K63polyUb-TRAF6 IL18 gene UBC(457-532) BTRC UBC(609-684) IL37(?-218) UBE2N ADPIL37 PTPN12 gene PTPN11 gene Myr82K-Myr83K-IL1A TAB2 IL1F10 p-2S,S376,T,T209,T387-IRAK1:TRAF6K63polyUb UBC(305-380) IL18BP:IL37,IL37(?-218)PTPN4 gene IL1RN MAP2K4 UBE2N UBC(305-380) MAP3K8 IL1RAPL1 SIGIRR NFKB1(1-433) IL37(?-218) PSMB9 IL36RN IL1B K63polyUb-hp-IRAK1MAPK8UBC(153-228) RELA BTRC:CUL1:RBX1:SKP1:NFKB1:RELA:p-S32,S36-NFKBIA:UbTNIP2 PTPN6 UBB(153-228) TOLLIP NFKB1(1-433) RPS27A(1-76) MYD88 UBC(153-228) IL37(?-218) IL1R1 IL1RAP-1 Ub-209-RIPK2 UBE2V1 ATPp-2S,S376,T,T209,T387-IRAK1 IL1RL1-2 MAP3K8IL1RAPL1UBB(77-152) PSMA7 IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIP:p-2S,S376,T,T209,T378-IRAK1TAB2 IL37 UBC(1-76) UBB(77-152) IL37(?-218):SMAD3MAP3K3:SQSTM1RELA p-S400,T290-MAP3K8IKBKG IL33:IL1RL1-2p-S400,T290-MAP3K8 CASP1(120-297) PTPN6 gene Myr82K-Myr83K-IL1A IL37(?-218)UBC(77-152) ATPp-S32,S36-NFKBIA TNIP2 UBC(77-152) SKP1 IRAK1K63polyUb p-S400-MAP3K8 IL18(1-193) IL1RL2 p-S400,T290-MAP3K8 p-PELI2 SHFM1 IL1F10(?-152) PSMD14 PTPN13 IL1F10 PSMB10 PSMB7 TOLLIP IL37(?-218):p-S423,S425-SMAD3TRAF6ATPp-T342,T345,S346-IRAK4Myr82K-Myr83K-IL1A IL1RL1 p-2S,S376,T,T209,T387-IRAK1 IL1B,Myr82K-Myr83K-IL1A:IL1R1TOLLIP hp-IRAK1:3xTRAF6p-S207,T211-MAP2K6p-2S,S376,T,T209,T387-IRAK1 UBC(609-684) MAP2K1 PELI1 IL1RL1p-S400,T290-MAP3K8 p-PELI2 ATPTRAF6 MYD88 TAK1 activates NFkBby phosphorylationand activation ofIKKs complexIL36RNPSMA8 TAK1 complexK63polyUb-TRAF6 IL1R1:IL1:IL1RAPUBB(1-76) IL18R1:IL37,IL37(?-218)UBC(533-608) p-S927,S932-NFKB1(1-968):MAP3K8:TNIP2IL1RAP-1 PSMD6 PSMA6 IL1R1 IKBKG SCF-beta-TrCP1,2:p-S927,S932-NFKB1:p-S,T-MAP3K8:TNIP2ADPIL1RNPSME2 PTPN23 gene PTPN14 NFKB1(1-968)Caspase-1 tetramerIL1RAP-1 PTPN9 gene IL1RAPL1 UBB(1-76) CASP1(317-404) IL4, IL13IL1RAP-1IL36RN IL18BP TAB1 CUL1 RPS27A(1-76) PTPN2 IL1B IL18:IL18R1:IL18RAPp-S400,T290-MAP3K8 IRAK4 UBE2V1 CHUK UBB(1-76) SQSTM1 IL37,IL37(?-218)PSMD13 PSMA2 PSMD2 IL1RAP-1 p-S423,S425-SMAD3 NFKB1:MAP3K8:TNIP2p-PELI1 UBB(153-228) IL37:2x(CASP1(120-197):CASP1(317-404))ADPRPS27A(1-76) p-2S,S376,T,T209,T387-IRAK1 UBE2N TAB3 IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIPUBB(153-228) UBE2N hp-IRAK1:Pellino,IRAK4:PellinoNFKB1(1-968) TOLLIP p-T342,T345,S346-IRAK4 p-2S,S376,T,T209,T387-IRAK1 3xUb-p-S927,S932-NFKB1(1-968)UBC(153-228) p-S32,S36-NFKBIA BTRC:CUL1:RBX1:SKP1PSMC2 p-T342,T345,S346-IRAK4 ATPp-T342,T345,S346-IRAK4 IL1RL1 p-T342,T345,S346-IRAK4 UBC(153-228) IL18 PSMD1 IL1R1 MYD88 IL1R1 UBC(381-456) UBC(1-76) IL1R2K63polyUb IL18 gene, ALOX5geneMAP2K1,MAP2K4SIGIRRPSMC3 IL1B IL36G UBE2N PTPN18 gene IL37(?-218) TOLLIP Myr82K-Myr83K-IL1A ATPUBE2V1 p-S927,S932-NFKB1(1-968) UBC(1-76) IRAK226S proteasomeNFKB1(1-433):RELA:p-S32,S36-NFKBIAp-IRAK2PSMD11 ATPMDP UBB(77-152) IL4 IL37(?-218) MAP3K3 IL1B NFKB1(1-433):RELAALOX5 UBE2N NFKB1(1-968) FBXW11 IL18BP:IL18IL1F10 BTRC p-S32,S36-NFKBIAp-S927,S932-NFKB1(1-968) MYD88 IL1R1PSMA4 PELI2 IL18-2(37-189)UBC(457-532) IRAK4 Poly-K6-Ub-hp-IRAK1:CHUK:IKBKB:IKBKGPSME1 IL37 RBX1 IL1RL1:IL33(BTRC:CUL1:SKP1),(FBXW11:CUL1:SKP1)UBC(1-76) RELA IL18BP UBE2V1 TRAF6 PTPN5 Myr82K-Myr83K-IL1A PSMD8 p-S218,S222-MAP2K1 ADPPSMD3 IL37 p-IRAK2 p-PELI3 IL1RL2 TOLLIP PSMB1 SKP1 UBB(77-152) CASP1(120-297) TRAF6 IL1B IL18R1 p-Pellino-1,2,(3)CASP1(120-297) IL37IL36B IL1B TNIP2 hp-IRAK1:K6-poly-Uboligo-TRAF6:TAK1complexIL1B SKP1 IL18R1 IL1B,Myr82K-Myr83K-IL1AIL18:IL18R1p-S32,S36-NFKBIA IL1F10IL37(1-?):IL37(?-218):CASP1(120-197):CASP1(317-404)UBC(229-304) p-S177,S181-IKBKB UBC(533-608) UBE2V1 TRAF6 BTRC IL1B TAB3 NOD1 IL37(1-?)MYD88 IL1F10(1-?)SMAD3RPS27A(1-76) PTPNgenes2,4,5,6,7,9,11,12,13,14,18,20,23IL37 CASP1(317-404) IL1B PTPN18 IKBKG p-TBK1IL1F10(?-152):IL1RAPL1CUL1 IL1R2 ADPADPIKBKB PELI2 UBC(381-456) ADPTBK1p-2S,S376,T,T209,T387-IRAK1 hp-IRAK1:p-Pellino,IRAK4:p-PellinoIL1RAP-1 UBC(533-608) IL1B p-2S,S376,T,T209,T387-IRAK1 p-T342,T345,S346-IRAK4 IL37(1-?) RELA p-S423,S425-SMAD3 IL36A PSMC1 Myr82K-Myr83K-IL1A UBC(609-684) IKBKG p-PELI2 IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKBhp-IRAK1:3xK63polyUb-TRAF6p-S176,S180-CHUK UBC(381-456) IL1R1:IL1:IL1RAP:MYD88 dimerIRAK4 IL1RAP-1 CHUK:IKBKB:IKBKGUBC(305-380) IL1R2 PSMD9 p-PELI2 IRAK4 IL1R1 hp-IRAK1:p-Pellino-1,2,(3):UBE2N:UBE2V1:K63polyUbp-PELI3 IL1RL2IL36A,IL36B,IL36G3xUb-p-S927,S932-NFKB1(1-968) PTPN20 gene IRAK1:Pellino:E2complexesIL1B IL33 ADPIL18BPp-T184,T187-MAP3K7 SKP1 MAP3K7 IL1R1 PSMC5 PSMA1 IL18 PTPNs2,4,5,6,7,9,11,12,13,14,18,20,23IL1R1 NFKB1:p-T290-MAP3K8:TNIP2NFKB1(1-433) PSMD12 IL1RAP-1 PSMD5 IL18R1 IL37 TAB2 TOLLIPIL1RAP-1 CUL1 p-2S,S376,T,T209,T387-IRAK1 IL1R1:IL1:IL1RAP:IRAK4:MYD88 dimerIL1F10:IL1RAPL1NFKB1(1-433):RELA:p-S32,S36-NFKBIA:BTRC:CUL1:RBX1:SKP1p-S927,S932-NFKB1(1-968) RBX1 SQSTM1 UBE2N:UBE2V1MAP3K3:SQSTM1:TRAF6IL18R1:IL37,IL37(?-218):SIGIRRIL33CHUK TNIP2 TRAF6 K63polyUb-hp-IRAK1 ADPIL36G UBE2N PSMF1 IL18IL1F10:IL1RL2PSMB4 UBE2V1 UBE2N ADPMAP3K7 PSMA3 IL33 UBC(457-532) IL1R1 MAP3K7 IL37(?-218):p-S423,S425-SMAD3NFKB1:p-S400-MAP3K8:TNIP2IKBKB PSMB2 PTPN20 p-2S,S376,T,T209,T387-IRAK1 p-PELI1 PTPN5 gene PTPN4 STAT3p-PELI1 PTPN12 UBB(1-76) 3xUb,2xp-S-NFKB1(1-968):p-S,T-MAP3K8:TNIP2IRAK4 UBE2N:UBE2V1:K63polyUbTAB1 PSMC6 IL1RL2 p-2S,S376,T,T209,T387-IRAK1 NFKB1(1-433) p-2S,S376,T,T209,T387-IRAK1 PSMD7 PELI1 K63polyUb-hp-IRAK1 IL37(?-218) UBA52(1-76) IL1B MYD88 PSMD10 ADPInterleukin-1processingUBC(457-532) PSMA5 PTPN7 gene IL37(?-218) TAB3 MYD88 IL36B PTPN9 MYD88 dimerIL1RL2 UBC(305-380) TAB1 Activated TAKcomplexesIL36:IL1RL2:IL1RAP-1IRAK4 UBC(533-608) p-Y705-STAT3PTPN7 UBA52(1-76) Myr82K-Myr83K-IL1A IL1B(117-269)PSMB8 IL18RAP PSME3 IL37,IL37(?-218)IL1RAP-1 RBX1 IL18R1PELI3 p-2S,S376,T,T209,T387-IRAK1 ATPIL33:IL1RL1:IL1RAP-1hp-IRAK1:3xTRAF6:3xUBE2N:UBE2V1:K63polyUbPSMB5 IL36:IL1RL2IL36A p-2S,S376,T,T209,T387-IRAK1, IRAK4RELA UBE2V1 UBB(153-228) PSMB11 IL36G NFKB1(1-433) p-S177,S181-IKBKBIL1R2 MAP3K7 NFKB1(1-968) IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIP:p-2S,S376,T,T209,T378-IRAK1:TRAF6p-PELI3 IL1RAP-1UBE2V1 PSME4 p-S376,T387-IRAK1 PELI3 NFKB1(1-433):RELAp-S423,S425-SMAD3K63polyUb-TRAF6 PTPN13 gene IL18 IL1F10 IRAK3IL18R1 IL1R1:IL1R2:IL1RNUBA52(1-76) IL1RAP-1 p-PELI3 p-PELI1 UBE2V1 PSMB3 Myr82K-Myr83K-IL1A MAP2K6IL1R1 Myr82K-Myr83K-IL1A p-PELI2 IL1R1 IL1R1 UBC(381-456) IL1RAP-1 PTPN11 TAB1 IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIP:p-S376,T378-IRAK1Myr82K-Myr83K-IL1A IL1R1:IL1R2UBC(229-304) p-T,Y-MAPK8PSMB6 hp-IRAK1:3xK63-polyUb-TRAF6:3xUBE2N:UBE2V1IL18RAPUBC(77-152) UBC(609-684) K63polyUb-hp-IRAK1:p-Pellino-1,2,(3):UBE2N:UBE2V1UBE2N CUL1 K63polyUb-TRAF6 FBXW11 5219, 6253435252524337, 5952444463, 86432, 37, 59434486274319, 21


Description

The Interleukin-1 (IL1) family of cytokines comprises 11 members, namely Interleukin-1 alpha (IL1A), Interleukin-1 beta (IL1B), Interleukin-1 receptor antagonist protein (IL1RN, IL1RA), Interleukin-18 (IL18), Interleukin-33 (IL33), Interleukin-36 receptor antagonist protein (IL36RN, IL36RA), Interleukin-36 alpha (IL36A), Interleukin-36 beta (IL36B), Interleukin-36 gamma (IL36G), Interleukin-37 (IL37) and Interleukin-38 (IL38). The genes encoding all except IL18 and IL33 are on chromosome 2. They share a common C-terminal three-dimensional structure and with apart from IL1RN they are synthesized without a hydrophobic leader sequence and are not secreted via the classical reticulum endoplasmic-Golgi pathway.

IL1B and IL18, are produced as biologically inactive propeptides that are cleaved to produce the mature, active interleukin peptide.

The IL1 receptor (IL1R) family comprises 10 members: Interleukin-1 receptor type 1 (IL1R1, IL1RA), Interleukin-1 receptor type 2 (IL1R2, IL1RB), Interleukin-1 receptor accessory protein (IL1RAP, IL1RAcP, IL1R3), Interleukin-18 receptor 1 (IL18R1, IL18RA) , Interleukin-18 receptor accessory protein (IL18RAP, IL18RB), Interleukin-1 receptor-like 1 (IL1RL1, ST2, IL33R), Interleukin-1 receptor-like 2 (IL1RL2, IL36R), Single Ig IL-1-related receptor (SIGIRR, TIR8), Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1, TIGGIR2) and X-linked interleukin-1 receptor accessory protein-like 2 (IL1RAPL2, TIGGIR1). Most of the genes encoding these receptors are on chromosome 2. IL1 family receptors heterodimerize upon cytokine binding. IL1, IL33 and IL36 bind specific receptors, IL1R1, IL1RL1, and IL1RL2 respectively. All use IL1RAP as a co-receptor. IL18 binds IL18R1 and uses IL18RAP as co-receptor.

The complexes formed by IL1 family cytokines and their heterodimeric receptors recruit intracellular signaling molecules, including Myeloid differentiation primary response protein MyD88 (MYD88), members of he IL1R-associated kinase (IRAK) family, and TNF receptor-associated factor 6 (TRAF6), activating Nuclear factor NF-kappa-B (NFκB), as well as Mitogen-activated protein kinase 14 (MAPK14, p38), c-Jun N-terminal kinases (JNKs), extracellular signal-regulated kinases (ERKs) and other Mitogen-activated protein kinases (MAPKs).

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Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 446652
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Reactome version: 73
Reactome Author 
Reactome Author: Ray, KP

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Bibliography

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  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

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
(BTRC:CUL1:SKP1),(FBXW11:CUL1:SKP1)ComplexR-HSA-1168601 (Reactome)
26S proteasomeComplexR-HSA-68819 (Reactome)
3xUb, 2xp-S-NFKB1(1-968):p-S,T-MAP3K8:TNIP2ComplexR-HSA-5684242 (Reactome)
3xUb-p-S927,S932-NFKB1(1-968) ProteinP19838 (Uniprot-TrEMBL)
3xUb-p-S927,S932-NFKB1(1-968)ProteinP19838 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:456216 (ChEBI)
ALOX5 ProteinP09917 (Uniprot-TrEMBL)
ALOX5 gene ProteinENSG00000012779 (Ensembl)
ATPMetaboliteCHEBI:30616 (ChEBI)
Activated TAK complexesComplexR-HSA-772536 (Reactome)
BTRC ProteinQ9Y297 (Uniprot-TrEMBL)
BTRC:CUL1:RBX1:SKP1:NFKB1:RELA:p-S32,S36-NFKBIA:UbComplexR-HSA-9012428 (Reactome)
BTRC:CUL1:RBX1:SKP1ComplexR-HSA-206748 (Reactome)
CASP1(120-297) ProteinP29466 (Uniprot-TrEMBL)
CASP1(317-404) ProteinP29466 (Uniprot-TrEMBL)
CHUK ProteinO15111 (Uniprot-TrEMBL)
CHUK:IKBKB:IKBKGComplexR-HSA-168113 (Reactome) Co-immunoprecipitation studies and size exclusion chromatography analysis indicate that the high molecular weight (around 700 to 900 kDa) IKK complex is composed of two kinase subunits (IKK1/CHUK/IKBKA and/or IKK2/IKBKB/IKKB) bound to a regulatory gamma subunit (IKBKG/NEMO) (Rothwarf DMet al. 1998; Krappmann D et al. 2000; Miller BS & Zandi E 2001). Variants of the IKK complex containing IKBKA or IKBKB homodimers associated with NEMO may also exist. Crystallographic and quantitative analyses of the binding interactions between N-terminal NEMO and C-terminal IKBKB fragments showed that IKBKB dimers would interact with NEMO dimers resulting in 2:2 stoichiometry (Rushe M et al. 2008). Chemical cross-linking and equilibrium sedimentation analyses of IKBKG (NEMO) suggest a tetrameric oligomerization (dimers of dimers) (Tegethoff S et al. 2003). The tetrameric NEMO could sequester four kinase molecules, yielding an 2xIKBKA:2xIKBKB:4xNEMO stoichiometry (Tegethoff S et al. 2003). The above data suggest that the core IKK complex consists of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies. However, the exact stoichiometry of the IKK complex remains unclear.
CUL1 ProteinQ13616 (Uniprot-TrEMBL)
Caspase-1 tetramerComplexR-HSA-448691 (Reactome)
FBXW11 ProteinQ9UKB1 (Uniprot-TrEMBL)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKBComplexR-HSA-177663 (Reactome) Co-immunoprecipitation studies and size exclusion chromatography analysis indicate that the high molecular weight (around 700 to 900 kDa) IKK complex is composed of two kinase subunits (IKK1/CHUK/IKBKA and/or IKK2/IKBKB/IKKB) bound to a regulatory gamma subunit (IKBKG/NEMO) (Rothwarf DMet al. 1998; Krappmann D et al. 2000; Miller BS & Zandi E 2001). Variants of the IKK complex containing IKBKA or IKBKB homodimers associated with NEMO may also exist. Crystallographic and quantitative analyses of the binding interactions between N-terminal NEMO and C-terminal IKBKB fragments showed that IKBKB dimers would interact with NEMO dimers resulting in 2:2 stoichiometry (Rushe M et al. 2008). Chemical cross-linking and equilibrium sedimentation analyses of IKBKG (NEMO) suggest a tetrameric oligomerization (dimers of dimers) (Tegethoff S et al. 2003). The tetrameric NEMO could sequester four kinase molecules, yielding an 2xIKBKA:2xIKBKB:4xNEMO stoichiometry (Tegethoff S et al. 2003). The above data suggest that the core IKK complex consists of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies. However, the exact stoichiometry of the IKK complex remains unclear.
IL13 ProteinP35225 (Uniprot-TrEMBL)
IL18 ProteinQ14116 (Uniprot-TrEMBL)
IL18 gene ProteinENSG00000150782 (Ensembl)
IL18 gene, ALOX5 geneComplexR-HSA-6797290 (Reactome)
IL18(1-193) ProteinQ14116 (Uniprot-TrEMBL)
IL18, ALOX5ComplexR-HSA-6797291 (Reactome)
IL18-2(37-189)ProteinQ14116-2 (Uniprot-TrEMBL)
IL18:IL18R1:IL18RAPComplexR-HSA-8848398 (Reactome)
IL18:IL18R1ComplexR-HSA-8848366 (Reactome)
IL18BP ProteinO95998 (Uniprot-TrEMBL)
IL18BP:IL18ComplexR-HSA-8848369 (Reactome)
IL18BP:IL37,IL37(?-218)ComplexR-HSA-9008615 (Reactome)
IL18BPProteinO95998 (Uniprot-TrEMBL)
IL18ProteinQ14116 (Uniprot-TrEMBL)
IL18R1 ProteinQ13478 (Uniprot-TrEMBL)
IL18R1:IL37,IL37(?-218):SIGIRRComplexR-HSA-9008597 (Reactome)
IL18R1:IL37,IL37(?-218)ComplexR-HSA-8848514 (Reactome)
IL18R1ProteinQ13478 (Uniprot-TrEMBL)
IL18RAP ProteinO95256 (Uniprot-TrEMBL)
IL18RAPProteinO95256 (Uniprot-TrEMBL)
IL1B ProteinP01584 (Uniprot-TrEMBL)
IL1B(117-269)ProteinP01584 (Uniprot-TrEMBL)
IL1B,Myr82K-Myr83K-IL1A:IL1R1ComplexR-HSA-445755 (Reactome)
IL1B,Myr82K-Myr83K-IL1A:IL1R2ComplexR-HSA-446125 (Reactome)
IL1B,Myr82K-Myr83K-IL1AComplexR-HSA-445744 (Reactome)
IL1F10 ProteinQ8WWZ1 (Uniprot-TrEMBL)
IL1F10(1-?)ProteinQ8WWZ1 (Uniprot-TrEMBL)
IL1F10(?-152) ProteinQ8WWZ1 (Uniprot-TrEMBL)
IL1F10(?-152):IL1RAPL1ComplexR-HSA-9007909 (Reactome)
IL1F10(?-152)ProteinQ8WWZ1 (Uniprot-TrEMBL)
IL1F10:IL1RAPL1ComplexR-HSA-9007912 (Reactome)
IL1F10:IL1RL2ComplexR-HSA-9007902 (Reactome)
IL1F10ProteinQ8WWZ1 (Uniprot-TrEMBL)
IL1R1 ProteinP14778 (Uniprot-TrEMBL)
IL1R1:IL1:IL1RAP:IRAK4:MYD88 dimer:TOLLIPComplexR-HSA-446888 (Reactome)
IL1R1:IL1:IL1RAP:IRAK4:MYD88 dimerComplexR-HSA-446637 (Reactome)
IL1R1:IL1:IL1RAP:MYD88 dimerComplexR-HSA-450120 (Reactome)
IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIP:IRAK1ComplexR-HSA-446693 (Reactome)
IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIP:p-2S,S376,T,T209,T378-IRAK1:TRAF6ComplexR-HSA-446864 (Reactome)
IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIP:p-2S,S376,T,T209,T378-IRAK1ComplexR-HSA-446696 (Reactome)
IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIP:p-S376,T378-IRAK1ComplexR-HSA-446689 (Reactome)
IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIPComplexR-HSA-446643 (Reactome)
IL1R1:IL1:IL1RAPComplexR-HSA-445758 (Reactome)
IL1R1:IL1R2:IL1RNComplexR-HSA-445751 (Reactome)
IL1R1:IL1R2ComplexR-HSA-445750 (Reactome)
IL1R1ProteinP14778 (Uniprot-TrEMBL)
IL1R2 ProteinP27930 (Uniprot-TrEMBL)
IL1R2ProteinP27930 (Uniprot-TrEMBL)
IL1RAP-1 ProteinQ9NPH3-1 (Uniprot-TrEMBL)
IL1RAP-1ProteinQ9NPH3-1 (Uniprot-TrEMBL)
IL1RAPL1 ProteinQ9NZN1 (Uniprot-TrEMBL)
IL1RAPL1ProteinQ9NZN1 (Uniprot-TrEMBL)
IL1RL1 ProteinQ01638 (Uniprot-TrEMBL)
IL1RL1-2 ProteinQ01638-2 (Uniprot-TrEMBL)
IL1RL1:IL33ComplexR-HSA-448601 (Reactome)
IL1RL1ProteinQ01638 (Uniprot-TrEMBL)
IL1RL2 ProteinQ9HB29 (Uniprot-TrEMBL)
IL1RL2ProteinQ9HB29 (Uniprot-TrEMBL)
IL1RN ProteinP18510 (Uniprot-TrEMBL)
IL1RNProteinP18510 (Uniprot-TrEMBL)
IL33 ProteinO95760 (Uniprot-TrEMBL)
IL33:IL1RL1-2ComplexR-HSA-8981967 (Reactome)
IL33:IL1RL1:IL1RAP-1ComplexR-HSA-448571 (Reactome)
IL33ProteinO95760 (Uniprot-TrEMBL)
IL36:IL1RL2:IL1RAP-1ComplexR-HSA-8848318 (Reactome)
IL36:IL1RL2ComplexR-HSA-8848321 (Reactome)
IL36A ProteinQ9UHA7 (Uniprot-TrEMBL)
IL36A,IL36B,IL36GComplexR-HSA-8848325 (Reactome)
IL36B ProteinQ9NZH7 (Uniprot-TrEMBL)
IL36G ProteinQ9NZH8 (Uniprot-TrEMBL)
IL36RN ProteinQ9UBH0 (Uniprot-TrEMBL)
IL36RN, IL1F10ComplexR-HSA-8981684 (Reactome)
IL36RN,IL1F10:IL1RL2ComplexR-HSA-8940997 (Reactome)
IL36RNProteinQ9UBH0 (Uniprot-TrEMBL)
IL37 ProteinQ9NZH6 (Uniprot-TrEMBL)
IL37(1-?) ProteinQ9NZH6 (Uniprot-TrEMBL)
IL37(1-?):IL37(?-218):CASP1(120-197):CASP1(317-404)ComplexR-HSA-9012554 (Reactome)
IL37(1-?)ProteinQ9NZH6 (Uniprot-TrEMBL)
IL37(?-218) ProteinQ9NZH6 (Uniprot-TrEMBL)
IL37(?-218):SMAD3ComplexR-HSA-9008698 (Reactome)
IL37(?-218):p-S423,S425-SMAD3ComplexR-HSA-9009901 (Reactome)
IL37(?-218):p-S423,S425-SMAD3ComplexR-HSA-9009912 (Reactome)
IL37(?-218)ProteinQ9NZH6 (Uniprot-TrEMBL)
IL37,IL37(?-218)ComplexR-HSA-9008576 (Reactome)
IL37,IL37(?-218)ComplexR-HSA-9011364 (Reactome)
IL37:2x(CASP1(120-197):CASP1(317-404))ComplexR-HSA-9012553 (Reactome)
IL37ProteinQ9NZH6 (Uniprot-TrEMBL)
IL4 ProteinP05112 (Uniprot-TrEMBL)
IL4, IL13ComplexR-HSA-6797283 (Reactome)
IRAK1 ProteinP51617 (Uniprot-TrEMBL)
IRAK1:Pellino:E2 complexesComplexR-HSA-8948067 (Reactome)
IRAK1ProteinP51617 (Uniprot-TrEMBL)
IRAK2ProteinO43187 (Uniprot-TrEMBL)
IRAK3ProteinQ9Y616 (Uniprot-TrEMBL)
IRAK4 ProteinQ9NWZ3 (Uniprot-TrEMBL)
IRAK4ProteinQ9NWZ3 (Uniprot-TrEMBL)
Interleukin-1 processingPathwayR-HSA-448706 (Reactome) The IL-1 family of cytokines that interact with the Type 1 IL-1R include IL-1α (IL1A), IL-1β (IL1B) and the IL-1 receptor antagonist protein (IL1RAP). IL1RAP is synthesized with a signal peptide and secreted as a mature protein via the classical secretory pathway. IL1A and IL1B are synthesised as cytoplasmic precursors (pro-IL1A and pro-IL1B) in activated cells. They have no signal sequence, precluding secretion via the classical ER-Golgi route (Rubartelli et al. 1990). Processing of pro-IL1B to the active form requires caspase-1 (Thornberry et al. 1992), which is itself activated by a molecular scaffold termed the inflammasome (Martinon et al. 2002). Processing and release of IL1B are thought to be closely linked, because mature IL1B is only seen inside inflammatory cells just prior to release (Brough et al. 2003). It has been reported that in monocytes a fraction of cellular IL1B is released by the regulated secretion of late endosomes and early lysosomes, and that this may represent a cellular compartment where caspase-1 processing of pro-IL1B takes place (Andrei et al. 1999). Shedding of microvesicles from the plasma membrane has also been proposed as a mechanism of secretion (MacKenzie et al. 2001). These proposals superceded previous models in which non-specific release due to cell lysis and passage through a plasma membrane pore were considered. However, there is evidence in the literature that supports all of these mechanisms and there is still controversy over how IL1B exits from cells (Brough & Rothwell 2007). A calpain-like potease has been reported to be important for the processing of pro-IL1A, but much less is known about how IL1A is released from cells and what specific roles it plays in biology.
K63polyUb R-HSA-450152 (Reactome)
K63polyUb-TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
K63polyUb-hp-IRAK1 ProteinP51617 (Uniprot-TrEMBL)
K63polyUb-hp-IRAK1:p-Pellino-1,2,(3):UBE2N:UBE2V1ComplexR-HSA-8948058 (Reactome)
K63polyUb-hp-IRAK1ProteinP51617 (Uniprot-TrEMBL)
MAP2K1 ProteinQ02750 (Uniprot-TrEMBL)
MAP2K1,MAP2K4ComplexR-HSA-451647 (Reactome)
MAP2K4 ProteinP45985 (Uniprot-TrEMBL)
MAP2K6ProteinP52564 (Uniprot-TrEMBL)
MAP3K3 ProteinQ99759 (Uniprot-TrEMBL)
MAP3K3:SQSTM1:TRAF6ComplexR-HSA-507716 (Reactome)
MAP3K3:SQSTM1ComplexR-HSA-507714 (Reactome)
MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
MAP3K8 ProteinP41279 (Uniprot-TrEMBL)
MAP3K8ProteinP41279 (Uniprot-TrEMBL)
MAPK8ProteinP45983 (Uniprot-TrEMBL)
MDP MetaboliteCHEBI:59414 (ChEBI)
MYD88 ProteinQ99836 (Uniprot-TrEMBL)
MYD88 dimerComplexR-HSA-193932 (Reactome)
Myr82K-Myr83K-IL1A ProteinP01583 (Uniprot-TrEMBL)
NFKB1(1-433) ProteinP19838 (Uniprot-TrEMBL)
NFKB1(1-433):RELA:p-S32,S36-NFKBIA:BTRC:CUL1:RBX1:SKP1ComplexR-HSA-206891 (Reactome)
NFKB1(1-433):RELA:p-S32,S36-NFKBIAComplexR-HSA-206842 (Reactome)
NFKB1(1-433):RELAComplexR-HSA-194043 (Reactome)
NFKB1(1-433):RELAComplexR-HSA-194047 (Reactome)
NFKB1(1-968) ProteinP19838 (Uniprot-TrEMBL)
NFKB1(1-968)ProteinP19838 (Uniprot-TrEMBL)
NFKB1:MAP3K8:TNIP2ComplexR-HSA-451638 (Reactome)
NFKB1:RELA:p-S32,S36-NFKBIA:UbComplexR-HSA-206877 (Reactome)
NFKB1:p-S400-MAP3K8:TNIP2ComplexR-HSA-5687880 (Reactome)
NFKB1:p-T290-MAP3K8:TNIP2ComplexR-HSA-5684265 (Reactome)
NFKBIAProteinP25963 (Uniprot-TrEMBL)
NOD1 ProteinQ9Y239 (Uniprot-TrEMBL)
NOD2 ProteinQ9HC29 (Uniprot-TrEMBL)
PELI1 ProteinQ96FA3 (Uniprot-TrEMBL)
PELI2 ProteinQ9HAT8 (Uniprot-TrEMBL)
PELI3 ProteinQ8N2H9 (Uniprot-TrEMBL)
PSMA1 ProteinP25786 (Uniprot-TrEMBL)
PSMA2 ProteinP25787 (Uniprot-TrEMBL)
PSMA3 ProteinP25788 (Uniprot-TrEMBL)
PSMA4 ProteinP25789 (Uniprot-TrEMBL)
PSMA5 ProteinP28066 (Uniprot-TrEMBL)
PSMA6 ProteinP60900 (Uniprot-TrEMBL)
PSMA7 ProteinO14818 (Uniprot-TrEMBL)
PSMA8 ProteinQ8TAA3 (Uniprot-TrEMBL)
PSMB1 ProteinP20618 (Uniprot-TrEMBL)
PSMB10 ProteinP40306 (Uniprot-TrEMBL)
PSMB11 ProteinA5LHX3 (Uniprot-TrEMBL)
PSMB2 ProteinP49721 (Uniprot-TrEMBL)
PSMB3 ProteinP49720 (Uniprot-TrEMBL)
PSMB4 ProteinP28070 (Uniprot-TrEMBL)
PSMB5 ProteinP28074 (Uniprot-TrEMBL)
PSMB6 ProteinP28072 (Uniprot-TrEMBL)
PSMB7 ProteinQ99436 (Uniprot-TrEMBL)
PSMB8 ProteinP28062 (Uniprot-TrEMBL)
PSMB9 ProteinP28065 (Uniprot-TrEMBL)
PSMC1 ProteinP62191 (Uniprot-TrEMBL)
PSMC2 ProteinP35998 (Uniprot-TrEMBL)
PSMC3 ProteinP17980 (Uniprot-TrEMBL)
PSMC4 ProteinP43686 (Uniprot-TrEMBL)
PSMC5 ProteinP62195 (Uniprot-TrEMBL)
PSMC6 ProteinP62333 (Uniprot-TrEMBL)
PSMD1 ProteinQ99460 (Uniprot-TrEMBL)
PSMD10 ProteinO75832 (Uniprot-TrEMBL)
PSMD11 ProteinO00231 (Uniprot-TrEMBL)
PSMD12 ProteinO00232 (Uniprot-TrEMBL)
PSMD13 ProteinQ9UNM6 (Uniprot-TrEMBL)
PSMD14 ProteinO00487 (Uniprot-TrEMBL)
PSMD2 ProteinQ13200 (Uniprot-TrEMBL)
PSMD3 ProteinO43242 (Uniprot-TrEMBL)
PSMD4 ProteinP55036 (Uniprot-TrEMBL)
PSMD5 ProteinQ16401 (Uniprot-TrEMBL)
PSMD6 ProteinQ15008 (Uniprot-TrEMBL)
PSMD7 ProteinP51665 (Uniprot-TrEMBL)
PSMD8 ProteinP48556 (Uniprot-TrEMBL)
PSMD9 ProteinO00233 (Uniprot-TrEMBL)
PSME1 ProteinQ06323 (Uniprot-TrEMBL)
PSME2 ProteinQ9UL46 (Uniprot-TrEMBL)
PSME3 ProteinP61289 (Uniprot-TrEMBL)
PSME4 ProteinQ14997 (Uniprot-TrEMBL)
PSMF1 ProteinQ92530 (Uniprot-TrEMBL)
PTPN genes2,4,5,6,7,9,11,12,13,14,18,20,23ComplexR-HSA-9008904 (Reactome)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN11 gene ProteinENSG00000179295 (Ensembl)
PTPN12 ProteinQ05209 (Uniprot-TrEMBL)
PTPN12 gene ProteinENSG00000127947 (Ensembl)
PTPN13 ProteinQ12923 (Uniprot-TrEMBL)
PTPN13 gene ProteinENSG00000163629 (Ensembl)
PTPN14 ProteinQ15678 (Uniprot-TrEMBL)
PTPN14 gene ProteinENSG00000152104 (Ensembl)
PTPN18 ProteinQ99952 (Uniprot-TrEMBL)
PTPN18 gene ProteinENSG00000072135 (Ensembl)
PTPN2 ProteinP17706 (Uniprot-TrEMBL)
PTPN2 gene ProteinENSG00000175354 (Ensembl)
PTPN20 ProteinQ4JDL3 (Uniprot-TrEMBL)
PTPN20 gene ProteinENSG00000204179 (Ensembl)
PTPN23 ProteinQ9H3S7 (Uniprot-TrEMBL)
PTPN23 gene ProteinENSG00000076201 (Ensembl)
PTPN4 ProteinP29074 (Uniprot-TrEMBL)
PTPN4 gene ProteinENSG00000088179 (Ensembl)
PTPN5 ProteinP54829 (Uniprot-TrEMBL)
PTPN5 gene ProteinENSG00000110786 (Ensembl)
PTPN6 ProteinP29350 (Uniprot-TrEMBL)
PTPN6 gene ProteinENSG00000111679 (Ensembl)
PTPN7 ProteinP35236 (Uniprot-TrEMBL)
PTPN7 gene ProteinENSG00000143851 (Ensembl)
PTPN9 ProteinP43378 (Uniprot-TrEMBL)
PTPN9 gene ProteinENSG00000169410 (Ensembl)
PTPNs2,4,5,6,7,9,11,12,13,14,18,20,23ComplexR-HSA-9008912 (Reactome)
Pellino 1,2,3ComplexR-HSA-450814 (Reactome)
Poly-K6-Ub-hp-IRAK1:CHUK:IKBKB:IKBKGComplexR-HSA-451560 (Reactome)
RBX1 ProteinP62877 (Uniprot-TrEMBL)
RELA ProteinQ04206 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
SCF-beta-TrCP1,2:p-S927,S932-NFKB1:p-S,T-MAP3K8:TNIP2ComplexR-HSA-5684270 (Reactome)
SHFM1 ProteinP60896 (Uniprot-TrEMBL)
SIGIRR ProteinQ6IA17 (Uniprot-TrEMBL)
SIGIRRProteinQ6IA17 (Uniprot-TrEMBL)
SKP1 ProteinP63208 (Uniprot-TrEMBL)
SMAD3 ProteinP84022 (Uniprot-TrEMBL)
SMAD3ProteinP84022 (Uniprot-TrEMBL)
SQSTM1 ProteinQ13501 (Uniprot-TrEMBL)
STAT3ProteinP40763 (Uniprot-TrEMBL)
TAB1 ProteinQ15750 (Uniprot-TrEMBL)
TAB2 ProteinQ9NYJ8 (Uniprot-TrEMBL)
TAB3 ProteinQ8N5C8 (Uniprot-TrEMBL)
TAK1 activates NFkB

by phosphorylation and activation of

IKKs complex
PathwayR-HSA-445989 (Reactome) NF-kappaB is sequestered in the cytoplasm in a complex with inhibitor of NF-kappaB (IkB). Almost all NF-kappaB activation pathways are mediated by IkB kinase (IKK), which phosphorylates IkB resulting in dissociation of NF-kappaB from the complex. This allows translocation of NF-kappaB to the nucleus where it regulates gene expression.
TAK1 complexComplexR-HSA-446878 (Reactome)
TBK1ProteinQ9UHD2 (Uniprot-TrEMBL)
TNIP2 ProteinQ8NFZ5 (Uniprot-TrEMBL)
TNIP2ProteinQ8NFZ5 (Uniprot-TrEMBL)
TOLLIP ProteinQ9H0E2 (Uniprot-TrEMBL)
TOLLIPProteinQ9H0E2 (Uniprot-TrEMBL)
TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRAF6ProteinQ9Y4K3 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UBE2N ProteinP61088 (Uniprot-TrEMBL)
UBE2N:UBE2V1:K63polyUbComplexR-HSA-8948017 (Reactome)
UBE2N:UBE2V1ComplexR-HSA-202463 (Reactome)
UBE2V1 ProteinQ13404 (Uniprot-TrEMBL)
Ub-209-RIPK2 ProteinO43353 (Uniprot-TrEMBL)
UbComplexR-HSA-113595 (Reactome)
hp-IRAK1: p-Pellino-1,2,(3):UBE2N:UBE2V1:K63polyUbComplexR-HSA-8948064 (Reactome)
hp-IRAK1:3xK63-polyUb-TRAF6:3xUBE2N:UBE2V1ComplexR-HSA-450144 (Reactome)
hp-IRAK1:3xK63polyUb-TRAF6ComplexR-HSA-8948065 (Reactome)
hp-IRAK1:3xTRAF6:3xUBE2N:UBE2V1:K63polyUbComplexR-HSA-8948014 (Reactome)
hp-IRAK1:3xTRAF6ComplexR-HSA-450159 (Reactome)
hp-IRAK1:K6-poly-Ub

oligo-TRAF6:TAK1

complex
ComplexR-HSA-450185 (Reactome)
hp-IRAK1:K63polyUboligo-TRAF6:Activated TAK1 complexComplexR-HSA-450186 (Reactome)
hp-IRAK1:Pellino, IRAK4:PellinoComplexR-HSA-451413 (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-2S,S376,T,T209,T387-IRAK1, IRAK4ComplexR-HSA-450810 (Reactome)
p-2S,S376,T,T209,T387-IRAK1:TRAF6ComplexR-HSA-450121 (Reactome)
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-CHUK ProteinO15111 (Uniprot-TrEMBL)
p-S177,S181-IKBKB ProteinO14920 (Uniprot-TrEMBL)
p-S177,S181-IKBKBProteinO14920 (Uniprot-TrEMBL)
p-S207,T211-MAP2K6ProteinP52564 (Uniprot-TrEMBL)
p-S218,S222-MAP2K1 ProteinQ02750 (Uniprot-TrEMBL)
p-S218,S222-MAP2K1,p-S257,T261-MAP2K4ComplexR-HSA-451654 (Reactome)
p-S257,T261-MAP2K4 ProteinP45985 (Uniprot-TrEMBL)
p-S32,S36-NFKBIA ProteinP25963 (Uniprot-TrEMBL)
p-S32,S36-NFKBIAProteinP25963 (Uniprot-TrEMBL)
p-S376,T387-IRAK1 ProteinP51617 (Uniprot-TrEMBL)
p-S400,T290-MAP3K8 ProteinP41279 (Uniprot-TrEMBL)
p-S400,T290-MAP3K8ProteinP41279 (Uniprot-TrEMBL)
p-S400-MAP3K8 ProteinP41279 (Uniprot-TrEMBL)
p-S423,S425-SMAD3 ProteinP84022 (Uniprot-TrEMBL)
p-S423,S425-SMAD3ProteinP84022 (Uniprot-TrEMBL)
p-S927,S932-NFKB1(1-968) ProteinP19838 (Uniprot-TrEMBL)
p-S927,S932-NFKB1(1-968):MAP3K8:TNIP2ComplexR-HSA-5687885 (Reactome)
p-S927,S932-NFKB1(1-968):p-S,T-MAP3K8:TNIP2ComplexR-HSA-5684268 (Reactome)
p-T,Y-MAPK8ProteinP45983 (Uniprot-TrEMBL)
p-T184,T187-MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
p-T342,T345,S346-IRAK4 ProteinQ9NWZ3 (Uniprot-TrEMBL)
p-T342,T345,S346-IRAK4ProteinQ9NWZ3 (Uniprot-TrEMBL)
p-TBK1ProteinQ9UHD2 (Uniprot-TrEMBL)
p-Y705-STAT3ProteinP40763 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
(BTRC:CUL1:SKP1),(FBXW11:CUL1:SKP1)ArrowR-HSA-5684250 (Reactome)
(BTRC:CUL1:SKP1),(FBXW11:CUL1:SKP1)R-HSA-5684248 (Reactome)
26S proteasomemim-catalysisR-HSA-209061 (Reactome)
3xUb, 2xp-S-NFKB1(1-968):p-S,T-MAP3K8:TNIP2ArrowR-HSA-5684250 (Reactome)
3xUb, 2xp-S-NFKB1(1-968):p-S,T-MAP3K8:TNIP2R-HSA-5684273 (Reactome)
3xUb, 2xp-S-NFKB1(1-968):p-S,T-MAP3K8:TNIP2TBarR-HSA-451634 (Reactome)
3xUb-p-S927,S932-NFKB1(1-968)TBarR-HSA-451634 (Reactome)
ADPArrowR-HSA-168184 (Reactome)
ADPArrowR-HSA-209087 (Reactome)
ADPArrowR-HSA-446634 (Reactome)
ADPArrowR-HSA-446694 (Reactome)
ADPArrowR-HSA-446701 (Reactome)
ADPArrowR-HSA-450827 (Reactome)
ADPArrowR-HSA-451649 (Reactome)
ADPArrowR-HSA-5684261 (Reactome)
ADPArrowR-HSA-5684267 (Reactome)
ADPArrowR-HSA-5684275 (Reactome)
ADPArrowR-HSA-727819 (Reactome)
ADPArrowR-HSA-9008043 (Reactome)
ADPArrowR-HSA-9008684 (Reactome)
ADPArrowR-HSA-9009072 (Reactome)
ATPR-HSA-168184 (Reactome)
ATPR-HSA-209087 (Reactome)
ATPR-HSA-446634 (Reactome)
ATPR-HSA-446694 (Reactome)
ATPR-HSA-446701 (Reactome)
ATPR-HSA-450827 (Reactome)
ATPR-HSA-451649 (Reactome)
ATPR-HSA-5684261 (Reactome)
ATPR-HSA-5684267 (Reactome)
ATPR-HSA-5684275 (Reactome)
ATPR-HSA-727819 (Reactome)
ATPR-HSA-9008043 (Reactome)
ATPR-HSA-9008684 (Reactome)
ATPR-HSA-9009072 (Reactome)
Activated TAK complexesmim-catalysisR-HSA-168184 (Reactome)
BTRC:CUL1:RBX1:SKP1:NFKB1:RELA:p-S32,S36-NFKBIA:UbArrowR-HSA-209063 (Reactome)
BTRC:CUL1:RBX1:SKP1R-HSA-209125 (Reactome)
BTRC:CUL1:RBX1:SKP1mim-catalysisR-HSA-209063 (Reactome)
CHUK:IKBKB:IKBKGR-HSA-168184 (Reactome)
CHUK:IKBKB:IKBKGR-HSA-451561 (Reactome)
Caspase-1 tetramerArrowR-HSA-9012689 (Reactome)
Caspase-1 tetramerR-HSA-9012542 (Reactome)
IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKBArrowR-HSA-168184 (Reactome)
IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKBmim-catalysisR-HSA-5684267 (Reactome)
IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKBmim-catalysisR-HSA-5684275 (Reactome)
IL18 gene, ALOX5 geneR-HSA-6797293 (Reactome)
IL18, ALOX5ArrowR-HSA-6797293 (Reactome)
IL18-2(37-189)ArrowR-HSA-8848370 (Reactome)
IL18:IL18R1:IL18RAPArrowR-HSA-8848395 (Reactome)
IL18:IL18R1ArrowR-HSA-8848370 (Reactome)
IL18:IL18R1R-HSA-8848395 (Reactome)
IL18BP:IL18ArrowR-HSA-8848392 (Reactome)
IL18BP:IL18TBarR-HSA-8848370 (Reactome)
IL18BP:IL37,IL37(?-218)ArrowR-HSA-9008587 (Reactome)
IL18BP:IL37,IL37(?-218)TBarR-HSA-8848395 (Reactome)
IL18BPR-HSA-8848392 (Reactome)
IL18BPR-HSA-9008587 (Reactome)
IL18R-HSA-8848370 (Reactome)
IL18R-HSA-8848392 (Reactome)
IL18R1:IL37,IL37(?-218):SIGIRRArrowR-HSA-9008577 (Reactome)
IL18R1:IL37,IL37(?-218):SIGIRRArrowR-HSA-9009072 (Reactome)
IL18R1:IL37,IL37(?-218):SIGIRRTBarR-HSA-9008684 (Reactome)
IL18R1:IL37,IL37(?-218)ArrowR-HSA-8848335 (Reactome)
IL18R1:IL37,IL37(?-218)R-HSA-9008577 (Reactome)
IL18R1R-HSA-8848335 (Reactome)
IL18R1R-HSA-8848370 (Reactome)
IL18RAPR-HSA-8848395 (Reactome)
IL1B(117-269)TBarR-HSA-507719 (Reactome)
IL1B,Myr82K-Myr83K-IL1A:IL1R1ArrowR-HSA-445753 (Reactome)
IL1B,Myr82K-Myr83K-IL1A:IL1R1R-HSA-445752 (Reactome)
IL1B,Myr82K-Myr83K-IL1A:IL1R2ArrowR-HSA-446130 (Reactome)
IL1B,Myr82K-Myr83K-IL1AR-HSA-445753 (Reactome)
IL1B,Myr82K-Myr83K-IL1AR-HSA-446130 (Reactome)
IL1F10(1-?)ArrowR-HSA-9007882 (Reactome)
IL1F10(?-152):IL1RAPL1ArrowR-HSA-9008052 (Reactome)
IL1F10(?-152):IL1RAPL1TBarR-HSA-9008043 (Reactome)
IL1F10(?-152)ArrowR-HSA-9007882 (Reactome)
IL1F10(?-152)R-HSA-9008052 (Reactome)
IL1F10:IL1RAPL1ArrowR-HSA-9008054 (Reactome)
IL1F10:IL1RL2ArrowR-HSA-9007901 (Reactome)
IL1F10R-HSA-9007882 (Reactome)
IL1F10R-HSA-9007901 (Reactome)
IL1F10R-HSA-9008054 (Reactome)
IL1R1:IL1:IL1RAP:IRAK4:MYD88 dimer:TOLLIPArrowR-HSA-446868 (Reactome)
IL1R1:IL1:IL1RAP:IRAK4:MYD88 dimer:TOLLIPR-HSA-446634 (Reactome)
IL1R1:IL1:IL1RAP:IRAK4:MYD88 dimerArrowR-HSA-446648 (Reactome)
IL1R1:IL1:IL1RAP:IRAK4:MYD88 dimerR-HSA-446868 (Reactome)
IL1R1:IL1:IL1RAP:MYD88 dimerArrowR-HSA-446894 (Reactome)
IL1R1:IL1:IL1RAP:MYD88 dimerArrowR-HSA-450133 (Reactome)
IL1R1:IL1:IL1RAP:MYD88 dimerR-HSA-446648 (Reactome)
IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIP:IRAK1ArrowR-HSA-446692 (Reactome)
IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIP:IRAK1R-HSA-446694 (Reactome)
IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIP:IRAK1mim-catalysisR-HSA-446694 (Reactome)
IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIP:p-2S,S376,T,T209,T378-IRAK1:TRAF6ArrowR-HSA-446862 (Reactome)
IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIP:p-2S,S376,T,T209,T378-IRAK1:TRAF6R-HSA-446894 (Reactome)
IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIP:p-2S,S376,T,T209,T378-IRAK1ArrowR-HSA-446701 (Reactome)
IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIP:p-2S,S376,T,T209,T378-IRAK1R-HSA-446862 (Reactome)
IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIP:p-S376,T378-IRAK1ArrowR-HSA-446694 (Reactome)
IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIP:p-S376,T378-IRAK1R-HSA-446701 (Reactome)
IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIP:p-S376,T378-IRAK1mim-catalysisR-HSA-446701 (Reactome)
IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIPArrowR-HSA-446634 (Reactome)
IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIPR-HSA-446684 (Reactome)
IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIPR-HSA-446692 (Reactome)
IL1R1:IL1:IL1RAPArrowR-HSA-445752 (Reactome)
IL1R1:IL1:IL1RAPR-HSA-450133 (Reactome)
IL1R1:IL1R2:IL1RNArrowR-HSA-445757 (Reactome)
IL1R1:IL1R2R-HSA-445757 (Reactome)
IL1R1R-HSA-445753 (Reactome)
IL1R2R-HSA-446130 (Reactome)
IL1RAP-1R-HSA-445752 (Reactome)
IL1RAP-1R-HSA-448603 (Reactome)
IL1RAP-1R-HSA-8848314 (Reactome)
IL1RAPL1ArrowR-HSA-9008043 (Reactome)
IL1RAPL1R-HSA-9008052 (Reactome)
IL1RAPL1R-HSA-9008054 (Reactome)
IL1RL1:IL33ArrowR-HSA-448629 (Reactome)
IL1RL1:IL33R-HSA-448603 (Reactome)
IL1RL1R-HSA-448629 (Reactome)
IL1RL2R-HSA-8848316 (Reactome)
IL1RL2R-HSA-8940998 (Reactome)
IL1RL2R-HSA-9007901 (Reactome)
IL1RNR-HSA-445757 (Reactome)
IL33:IL1RL1-2TBarR-HSA-448629 (Reactome)
IL33:IL1RL1:IL1RAP-1ArrowR-HSA-448603 (Reactome)
IL33R-HSA-448629 (Reactome)
IL36:IL1RL2:IL1RAP-1ArrowR-HSA-8848314 (Reactome)
IL36:IL1RL2ArrowR-HSA-8848316 (Reactome)
IL36:IL1RL2R-HSA-8848314 (Reactome)
IL36A,IL36B,IL36GR-HSA-8848316 (Reactome)
IL36RN, IL1F10R-HSA-8940998 (Reactome)
IL36RN,IL1F10:IL1RL2ArrowR-HSA-8940998 (Reactome)
IL36RN,IL1F10:IL1RL2TBarR-HSA-8848314 (Reactome)
IL36RNTBarR-HSA-8848316 (Reactome)
IL37(1-?):IL37(?-218):CASP1(120-197):CASP1(317-404)ArrowR-HSA-9012556 (Reactome)
IL37(1-?):IL37(?-218):CASP1(120-197):CASP1(317-404)R-HSA-9012689 (Reactome)
IL37(1-?)ArrowR-HSA-9012689 (Reactome)
IL37(?-218):SMAD3ArrowR-HSA-9008692 (Reactome)
IL37(?-218):p-S423,S425-SMAD3ArrowR-HSA-9008894 (Reactome)
IL37(?-218):p-S423,S425-SMAD3ArrowR-HSA-9008928 (Reactome)
IL37(?-218):p-S423,S425-SMAD3ArrowR-HSA-9009910 (Reactome)
IL37(?-218):p-S423,S425-SMAD3R-HSA-9008928 (Reactome)
IL37(?-218)ArrowR-HSA-9008696 (Reactome)
IL37(?-218)ArrowR-HSA-9012689 (Reactome)
IL37(?-218)R-HSA-9008692 (Reactome)
IL37(?-218)R-HSA-9008696 (Reactome)
IL37(?-218)R-HSA-9009910 (Reactome)
IL37,IL37(?-218)ArrowR-HSA-9008694 (Reactome)
IL37,IL37(?-218)R-HSA-8848335 (Reactome)
IL37,IL37(?-218)R-HSA-9008587 (Reactome)
IL37,IL37(?-218)R-HSA-9008694 (Reactome)
IL37:2x(CASP1(120-197):CASP1(317-404))ArrowR-HSA-9012542 (Reactome)
IL37:2x(CASP1(120-197):CASP1(317-404))R-HSA-9012556 (Reactome)
IL37:2x(CASP1(120-197):CASP1(317-404))mim-catalysisR-HSA-9012556 (Reactome)
IL37R-HSA-9012542 (Reactome)
IL4, IL13TBarR-HSA-6797293 (Reactome)
IRAK1:Pellino:E2 complexesArrowR-HSA-8948063 (Reactome)
IRAK1R-HSA-446692 (Reactome)
IRAK2R-HSA-446684 (Reactome)
IRAK3TBarR-HSA-446894 (Reactome)
IRAK4R-HSA-446648 (Reactome)
K63polyUb-hp-IRAK1:p-Pellino-1,2,(3):UBE2N:UBE2V1ArrowR-HSA-451418 (Reactome)
K63polyUb-hp-IRAK1:p-Pellino-1,2,(3):UBE2N:UBE2V1R-HSA-8948066 (Reactome)
K63polyUb-hp-IRAK1ArrowR-HSA-8948066 (Reactome)
K63polyUb-hp-IRAK1R-HSA-451561 (Reactome)
MAP2K1,MAP2K4R-HSA-451649 (Reactome)
MAP2K6R-HSA-727819 (Reactome)
MAP3K3:SQSTM1:TRAF6ArrowR-HSA-507719 (Reactome)
MAP3K3:SQSTM1R-HSA-507719 (Reactome)
MAP3K8R-HSA-451634 (Reactome)
MAPK8R-HSA-9008043 (Reactome)
MYD88 dimerR-HSA-450133 (Reactome)
NFKB1(1-433):RELA:p-S32,S36-NFKBIA:BTRC:CUL1:RBX1:SKP1ArrowR-HSA-209125 (Reactome)
NFKB1(1-433):RELA:p-S32,S36-NFKBIA:BTRC:CUL1:RBX1:SKP1R-HSA-209063 (Reactome)
NFKB1(1-433):RELA:p-S32,S36-NFKBIAR-HSA-209125 (Reactome)
NFKB1(1-433):RELAArrowR-HSA-209061 (Reactome)
NFKB1(1-433):RELAArrowR-HSA-2730894 (Reactome)
NFKB1(1-433):RELAR-HSA-2730894 (Reactome)
NFKB1(1-968)R-HSA-451634 (Reactome)
NFKB1:MAP3K8:TNIP2ArrowR-HSA-451634 (Reactome)
NFKB1:MAP3K8:TNIP2R-HSA-5684261 (Reactome)
NFKB1:MAP3K8:TNIP2R-HSA-5684267 (Reactome)
NFKB1:MAP3K8:TNIP2R-HSA-5684275 (Reactome)
NFKB1:RELA:p-S32,S36-NFKBIA:UbR-HSA-209061 (Reactome)
NFKB1:p-S400-MAP3K8:TNIP2ArrowR-HSA-5684275 (Reactome)
NFKB1:p-T290-MAP3K8:TNIP2ArrowR-HSA-5684261 (Reactome)
NFKBIAR-HSA-209087 (Reactome)
PTPN genes2,4,5,6,7,9,11,12,13,14,18,20,23R-HSA-9008894 (Reactome)
PTPNs2,4,5,6,7,9,11,12,13,14,18,20,23ArrowR-HSA-9008894 (Reactome)
Pellino 1,2,3R-HSA-450690 (Reactome)
Poly-K6-Ub-hp-IRAK1:CHUK:IKBKB:IKBKGArrowR-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-209061 (Reactome) Ubiquitinated IKBA is degraded by the proteasome complex.
R-HSA-209063 (Reactome) SCF (Beta-TrCP) ubiquitinates phosphorylated I kappa B alpha.
R-HSA-209087 (Reactome) Human IKBA, orthologue of Drosophila Cactus (CACT), is phosphorylated by activated IKKB kinase at residues Ser32 and Ser36.
R-HSA-209125 (Reactome) Human beta-TrCP forms part of the SCF E3 ubiquitin ligase complex which binds to phosphorylated residues Ser32 and Ser 36 at the IKK target motif in IKBA complex with P65:P50 heterodimer.
R-HSA-2730894 (Reactome) The released NF-kB transcription factor (p50/p65) with unmasked nuclear localization signal (NLS) moves in to the nucleus. Once in the nucleus, NF-kB binds DNA and regulate the expression of genes encoding cytokines, cytokine receptors, and apoptotic regulators.
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-448603 (Reactome) The Interleukin-33 (IL33):Interleukin-1 receptor-like 1 (IL1RL1, ST2) complex binds the membrane-associated form of Interleukin-1 receptor accessory protein (IL1RAP-1).

After IL33:IL1RL1 ligand binding, IL1RL1 undergoes a conformational change, which allows the recruitment of IL1RAP-1 (Lingel et al. 2009, Liu et al. 2013).
R-HSA-448629 (Reactome) Interleukin-1 receptor-like 1 (IL1RL1, ST2), known for many years to be an orphan receptor within the IL1 receptor family, can bind Interleukin-33 (IL33) (Schmitz et al. 2005). The functional IL33 receptor is a heteromeric receptor complex consisting of IL1RL1 and Interleukin-1 receptor accessory protein (IL1RAP1) (Chackerian et al. 2007, Lingel et al. 2009). IL33 is found constitutively in the nucleus of endothelial cells where it can bind histone H2A-H2B (Roussel et al. 2008) leading to poorly understood intracrine gene regulatory functions (Carriere et al. 2007, Martin et al. 2013). It can be passively released from damaged cells, hence it has been termed an alarmin or damage-associated molecular pattern (DAMP), though IL33 is also released by undamaged cells (Lefrancais & Cayrol 2012).
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 Transforming growth factor-beta (TGFB)-activated kinase (TAK1) and TAK1-binding protein 1 (TAB1), TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya et al. 1996, Sakurai et al. 2000). TAB1 promotes TAK1 autophosphorylation at the kinase activation lobe, probably through an allosteric mechanism (Brown et al. 2005, Ono 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 to 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 lead to TAK1 activation. 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 UBE2N:UBE2V1 (Ubc13: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-451634 (Reactome) The C-terminal half of NFKB1 p105 forms a high-affinity stoichiometric association with MAP3K8 (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 ot TNIP2) 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.

R-HSA-451649 (Reactome) Tpl2 (also known as Cot, officially known as MAP3K8) 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 (MAP2K4). 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).
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-5684248 (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.
R-HSA-5684250 (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.
R-HSA-5684261 (Reactome) The activity of tumor progression locus-2 (TPL2, also known as COT and MAP3K8) is regulated by means of phosphorylation (Gantke T 2011).

The catalytic subunit of MAP3K8 (TPL2) was reported to undergo phosphorylation at Thr290 in human embryonic kidney 293 (HEK293) cells transfected with MAP3K8 (Luciano BS et al. 2004; Cho J et al. 2005; Stafford MJ et al. 2006). Mutation of this residue to alanine prevented the LPS-stimulated activation of MAP3K8 in mouse macrophages (Cho J et al. 2005). Experiments with a small-molecule inhibitor of MAP3K8 have suggested that Thr290 is autophosphosphorylated after IL-1 beta stimulation of IL-1R-expressing HEK293T cells (Handoyo H et al. 2009). However, a catalytically inactive mutant of MAP3K8 (Tpl2-K167M) was reported to become phosphorylated at Thr290 in transfected HEK-293 cells, suggesting that Thr290 phosphorylation did not occur as a result of autophosphorylation (Cho J et al. 2005) In addition, the phosphorylation at Thr290 was also reported to be catalysed by IKBKB, based on small interfering RNA(siRNA)-knockdown studies and the use of high concentrations of the IKBKB inhibitor PS1145 (Cho J et al. 2005). However, the other work showed that lower concentrations of PS1145, but nevertheless sufficient to completely inhibit IKBKB, did not affect the IL-1-stimulated phosphorylation of transfected MAP3K8 at Thr290, suggesting that the IL-1 beta stimulated phosphorylation of Thr290 is catalysed by a protein kinase distinct from IKBKB. (Stafford MJ et al. 2006). Thus, phosphorylation at Thr290 is required for the physiological activation of MAP3K8 by external signals, although the mode of the modification remains to be clarified.

Activation of MAP3K8 may also occur trough phosphorylation on Ser62 and Ser400 (Stafford MJ et al. 2006; Roget K et al. 2012).

R-HSA-5684267 (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.
R-HSA-5684273 (Reactome) IKBKB-induced proteolysis of NFkB p105 to p50 releases MAP3K8 (TPL2) from the complex with NFkB p105 and ABIN2. On TLR or IL1beta stimulation, dissociated MAP3K8 with an adequate phosphorylation state activates MAP2K (MKK1/2) and consequently MAPK1/3 (ERK1/2).
R-HSA-5684275 (Reactome) The activity of tumor progression locus-2 (TPL2, also known as COT and MAP3K8) is regulated by means of phosphorylation. MAP3K8 undergoes phosphorylated on S400 in its C-terminal tail to activate MAP2Ks (MEK1/2) following LPS stimulation of macrophages. Different experimental systems have suggested that S400 is either autophosphosphorylated by MAPK3P8 (IL-1?-stimulated IL-1R-293T cells) or transphosphorylated by an unknown kinase (LPS-stimulated RAW264.7 macrophages).
R-HSA-6797293 (Reactome) In human peripheral blood, monocytes Interleukin-4 (IL4) and Interleukin-13 significantly downregulate the expression of classical proinflammatory signal transducers, such as Interleukin-1 (IL1), Interleukin-6, Interleukin-8, Interleukin-18, C-C motif chemokine 2 (CCL2) and Tumor necrosis factor (TNF). Expression of Prostaglandin G/H synthase 2 (PTGS2, COX2) and Arachidonate 5-lipoxygenase (ALOX5), enzymes involved in the biosynthesis of the proinflammatory eicosanoids, is also attenuated (Chatidis et al. 2005).
This is a black box event because the mechanism of gene regulation is not fully defined.
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).
R-HSA-8848314 (Reactome) After binding of IL36 to IL1RL2, the complex associates with the coreceptor IL1RAP to form the interleukin-36 receptor complex. The IL-36 signaling system is thought to be present in epithelial barriers and to take part in local inflammatory response; it is similar to the IL-1 system (Gresnigt & van de Veerdonk 2013).
R-HSA-8848316 (Reactome) Interleukin-1 receptor-like 2 (IL1RL2) is a receptor for interleukin-36 (IL36A, IL36B and IL36G). After binding to interleukin-36 IL1RL2 associates with the coreceptor IL1RAP to form the interleukin-36 receptor complex which mediates interleukin-36-dependent activation of NF-kappa-B, MAPK and other pathways. IL1RL2 also binds Interleukin-1 family member 10 (IL38, IL1F10) (van de Veerdonk et al. 2012). The biological function of IL1F10 is thought to be inhibition of IL36 binding to IL36R (Yuan et al. 2015, Yi et al. 2016).
R-HSA-8848335 (Reactome) Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL-37, IL-1F7) is a member of the IL-1 family. There are five isoforms of IL37 (a e) of which transcript IL-37 is known to be functional (Sharma et al. 2008). This isoform is represented in UniProt as the canonical form of IL-37 and in Reactome as the full length, unprocessed form of IL-37. Like several other IL-1 family members, IL-37 is synthesized as a precursor that requires processing (primarily by caspase 1) to attain full receptor agonist or antagonist function. (Kumar et al. 2002). Both full length and processed IL-37 can bind the Interleukin 18 receptor 1 (IL-18R1) but binding of processed IL-37 is more effective (Shi et al. 2003, Kumar et al. 2002). Subsequently, Single Ig IL-1 related receptor (SIGIRR, TIR 8,IL-1R8) is recruited and facilitates the suppression of cytokine production in several types of immune cells resulting in reduced inflammation.
R-HSA-8848370 (Reactome) Interleukin-18 (IL18) binds IL18 receptor alpha chain (IL18R1), with low affinity (Torigoe et al. 1997, Kato et al. 2007).
R-HSA-8848392 (Reactome) Interleukin-18 binding protein (IL18BP) is a constitutively secreted protein, with an exceptionally high affinity for IL18 (400 pM) (Kim et al. 2000). It is present in the serum of healthy humans at a 20-fold molar excess compared to IL18 (Novick et al. 2001) and may blunt the Th1 response to foreign organisms, thereby reducing any autoimmune responses to a routine infection (Dinarello et al. 2013). Some studies indicate this IL18BP:IL18 complex negatively regulates IL18:IL18 receptor interaction (Kim et al. 2002, Im et al. 2002).

R-HSA-8848395 (Reactome) Interleukin-18/Interleukin-18 receptor 1 (IL18:IL18R1) complex binds Interleukin-18 receptor accessory protein (IL18RAP, IL18 receptor beta chain), forming a high-affinity signaling complex (Born et al. 1998, Debets et al. 2001). This IL18RAP subunit seems to be necessary for the signal transduction (Kim et al. 2001).
R-HSA-8940998 (Reactome) Interleukin-36 receptor antagonist protein (IL36RN, IL-36Ra) binds the interleukin-36 receptor subunit IL1RL2 (Interleukin-1 receptor-like 2, IL-1Rrp2). This inhibits the activity of interleukin-36 (IL36) by preventing IL1RL2 and IL1RAP from associating to form the interleukin-36 receptor complex (Towne et al. 2015). Similarly, Interleukin-1 family member 10 (IL1F10), also referred to as Interleukin-38, binds the interleukin-36 receptor subunit IL1RL2 inhibiting IL36 signaling (van de Veerdonk et al. 2012). Homozygous and compound heterozygous mutations in IL36RN have been identified to cause generalized pustular psoriasis (GPP) (Onoufriadis et al. 2011, Marrakchi et al. 2011).
R-HSA-8948015 (Reactome) Activated ubiquitin is transferred to a heterodimeric E2 conjugating enzyme UBE2N (Ubc13) and UBEE2V1 (Uev1A) forming an E2-Ub thioester.
R-HSA-8948018 (Reactome) Following the TRAF6-mediated transfer of ubiquitin from the E2 conjugating enzyme UBE2N:UBE2V1 it dissociates.
R-HSA-8948063 (Reactome) IL1 induces the poly-ubiquitination and degradation of IRAK1.

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 UBE2N:UBE2V1 (Ubc13:Uev1a) to catalyze K63-linked ubiquitylation (Ordureau et al. 2008).

IRAK1 polyubiquitination was originally thought to tag IRAK1 for proteolysis by the proteasome, but more recently has been shown to involve K63-linked, not K48-linked polyubiquitination (Windheim et al. 2008; Conze et al. 2008), which is believed to have a scaffoling function. IRAK1 is ubiquitinated on K134 and K180; mutation of these sites impairs IL1R-mediated ubiquitination 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). The current consensus is that Pellino proteins are the physiologically-relevant IRAK1 E3 ubiquitin ligases.
R-HSA-8948066 (Reactome) Pellino1, 2 and possibly 3 are believed to directly catalyse polyubiquitylation of IRAK1 (Xiao et al. 2008; Butler et al. 2007; Ordureau et al. 2008). Following ubiquitination IRAK1 dissociates.
R-HSA-9007882 (Reactome) Interleukins are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 1 family member 10 (IL1F10, IL 38) is a member of the IL1 family (Lin et al. 2001, Bensen et al. 2001). IL1F10 is produced in Human apoptotic cells (Mora et al. 2016) and human epidermal keratinocytes (based on mRNA studies) (Boutet M A et al. 2016). Like several other IL1 family members, IL1F10 is synthesized as precursors that require N terminal processing to attain full receptor agonist or antagonist function. The N terminal truncation of IL1F10 precursor occurs during apoptosis and the predicted cleavage site is at amino acid 19 (Mora et al. 2016). The proteases from apoptosis are believed to be the responsible for the cleavage process. This truncated form of IL1F10 may undergo additional processing before becoming an active interleukin. This event is a black box because the precise cleavage site of IL1F10 and requirement of additional processing steps are uncertain.
R-HSA-9007901 (Reactome) Interleukins are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 1 family member 10 (IL1F10, IL 38) is a member of the IL1 family (Lin et al. 2001, Bensen et al. 2001). IL1F10 is produced in Human apoptotic cells (Mora et al. 2016) and human epidermal keratinocytes (based on mRNA studies) (Boutet M A et al. 2016). IL1F10 can bind to interleukin 1 receptor like 2 (IL1RL2, IL 36R, IL1Rrp2, IL1R6). This binding has biological consequences similar to another IL1RL2 ligand IL 36 receptor antagonist (IL 36Ra), such as suppression of IL17 and IL22 and induction of IL6 production (van de Veerdonk et al. 2012, Mora et al. 2016). Ultimately, these events lead to suppression of cytokine production in several types of immune cells resulting in reduced inflammation.
R-HSA-9008043 (Reactome) Interleukin 1 family member 10 (IL1F10, IL 38) is a member of the IL1 family (Lin et al. 2001, Bensen et al. 2001). IL1F10 can bind with X linked interleukin 1 receptor accessory protein like 1 (IL 1RAPL 1) (Mora et al. 2016). Stimulated IL1RAPL1 can activate Mitogen Activated Protein Kinase 8 (MAPK8, JNK1) signaling, which is required for transcription factor AP 1 activation (Born T L et al. 2000, Khan J A et al. 2004). Full length (1 – 152 amino acids) and N terminal truncated (20 – 152 amino acids) IL1F10 can bind with IL1RAPL1. The binding affinity of truncated IL1F10 is much higher than that of the full length. Binding of truncated IL1F10 to IL1RAPL1 results in inhibition of JNK signaling, which consequently leads to IL6 suppression (Mora et al. 2016). This is represented as a black box event because the mechanism of MAPK8 activation by IL1RAPL1 is uncertain.
R-HSA-9008052 (Reactome) Interleukins are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 1 family member 10 (IL1F10, IL 38) is a member of the IL1 family (Lin et al. 2001, Bensen et al. 2001). IL1F10 is selectively produced by human apoptotic cells (Mora et al. 2016) and human epidermal keratinocytes (based on mRNA studies) (Boutet M A et al. 2016). IL1F10 can bind to interleukin 1 receptor like 2 (IL1RL2) and may result in the suppression of IL 17 and IL 22 and induction of IL 6 production (van de Veerdonk et al. 2012, Mora et al. 2016). IL1F10 is synthesized as precursors that require N terminal processing to attain full receptor agonist or antagonist function (Mora et al. 2016). Both full length (1 – 152 amino acids) and N terminal truncated (20 – 152 amino acids) IL1F10 can bind Interleukin 1 receptor accessory protein like 1 (IL1RAPL1) (Mora et al. 2016). The binding affinity of truncated IL1F10 is much higher than that of the full length. However, binding of the full length or truncated forms has distinct outcomes; the former induces IL6 and the latter suppresses IL6 via JNK and AP1 signaling (Mora et al. 2016).
R-HSA-9008054 (Reactome) Interleukins are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 1 family member 10 (IL1F10, IL 38) is a member of the IL1 family (Lin et al. 2001, Bensen et al. 2001 IL1F10 is produced in Human apoptotic cells (Mora et al. 2016) and human epidermal keratinocytes (based on mRNA studies) (Boutet M A et al. 2016). Full length (1 – 152 amino acids) IL1F10 can bind Interleukin 1 receptor accessory protein like 1 (IL1RAPL1) (Mora et al. 2016). N-terminally truncated IL1F10 (20 – 152 amino acids) is also known to bind IL1RAPL1 but with much higher affinity. The physiological significance of full length IL1F10 binding to IL1RAPL1 is not known.
R-HSA-9008577 (Reactome) Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL-37, IL-1 F7) is a member of the IL-1 family. There are five isoforms of IL-37 (a-e) of which transcript IL-37b is known to be functional (Sharma et al. 2008). This isoform is represented in UniProt as the canonical form of IL-37 and in Reactome as the full length, unprocessed form of IL-37. IL-37 can bind the Interleukin-18 receptor 1 (IL-18R1) (Shi et al. 2003, Kumar et al. 2002). Upon binding to IL-18R1, IL-37 facilitates the recruitment of Single Ig IL 1 related receptor (SIGIRR, TIR-8, IL-1R8) forming a complex (Nold Petry et al. 2015). These events ultimately lead to suppression of cytokine production in several types of immune cells resulting in reduced inflammation.
R-HSA-9008587 (Reactome) Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL-37, IL-1 F7) is a member of the IL-1 family. There are five isoforms of IL-37 (a-e) of which transcript IL-37b is known to be functional (Sharma et al. 2008). This isoform is represented in UniProt as the canonical form of IL-37 and in Reactome as the full length, unprocessed form of IL-37. Like several other IL-1 family members, IL-37 is synthesized as a precursor that requires processing (primarily by caspase 1) to attain full receptor agonist or antagonist function. (Kumar et al. 2002). IL-18 binding protein (IL-18BP) binds IL-18 with high affinity inhibiting its activity (Kim et al. 2000). Both full length and processed IL-37 bind the third extracellular domain (D3) of IL-18BP. The binding of IL-18BP to IL-37 makes it unavailable for neutralization of IL-18 activity (Bufler et al. 2002). These events ultimately lead to suppression of cytokine production in several types of immune cells resulting in reduced inflammation.
R-HSA-9008684 (Reactome) Serine/threonine protein kinase TBK1 plays a key role in regulating inflammatory responses. TBK1 activity is regulated by phosphorylation of Ser 172 within the kinase activation loop (Kishore et al. 2002). TBK1 phosphorylation is thought to be an autoactivation event. The IL 37b:IL-18R1:SIGIRR complex can suppress TBK1 activity (Nold Petry et al. 2015, Clark K et al. 2009). This event is set as a black box event instance because the precise mechanism of TBK1 suppression by IL 37b:IL-18R1:SIGIRR complex is uncertain.
R-HSA-9008692 (Reactome) Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL-37, IL-1 F7) is a member of the IL-1 family. There are five isoforms of IL-37 (a-e) of which transcript IL-37b is known to be functional (Sharma et al. 2008). This isoform is represented in UniProt as the canonical form of IL-37 and in Reactome as the full length, unprocessed form of IL-37. Like several other IL-1 family members, IL-37 is synthesized as a precursor that requires processing (primarily by caspase 1) to attain full receptor agonist or antagonist function. The putative caspase 1 cleavage site is at aspartic acid 20 (Kumar et al. 2002). Mothers against decapentaplegic homolog 3 (SMAD3) binds SMAD4 and this complex modulates the transcription of several genes downstream. IL-37(? 218) can bind SMAD3 (Nold M F et al. 2010, Grimsby S et al. 2004) and may affect its function.
R-HSA-9008694 (Reactome) Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL-37, IL-1 F7) is a member of the IL-1 family. There are five isoforms of IL-37 (a-e) of which transcript IL-37b is known to be functional (Sharma et al. 2008). This isoform is represented in UniProt as the canonical form of IL-37 and in Reactome as the full length, unprocessed form of IL-37. Like several other IL-1 family members, IL-37 is synthesized as a precursor that requires processing (primarily by caspase 1) to attain full receptor agonist or antagonist function. The putative caspase 1 cleavage site is at aspartic acid 20 (Kumar et al. 2002). Both full length and cleaved IL-37 can be secreted from the cytosol to the extracellular space via a mechanism dependent on caspase 1 cleavage of IL-37 (Bulau A M et al. 2014).
R-HSA-9008696 (Reactome) Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL-37, IL-1 F7) is a member of the IL-1 family. There are five isoforms of IL-37 (a-e) of which transcript IL-37b is known to be functional (Sharma et al. 2008). This isoform is represented in UniProt as the canonical form of IL-37 and in Reactome as the full length, unprocessed form of IL-37. Like several other IL-1 family members, IL-37 is synthesized as a precursor that requires processing (primarily by caspase 1) to attain full receptor agonist or antagonist function. The putative caspase 1 cleavage site is at aspartic acid 20 (Kumar et al. 2002). Truncated IL-37 can be translocated from the cytosol to the nucleus via a mechanism dependent on caspase 1 cleavage of IL-37 (Bulau A M et al. 2014). These events ultimately lead to suppression of cytokine production in several types of immune cells resulting in reduced inflammation.
R-HSA-9008894 (Reactome) Tyrosine protein phosphatase non receptors (PTPNs) are a family of enzymes that act in coordination with protein tyrosine kinases to control various signalling pathways downstream. This event represents the transcription and translation of the PTPN set comprising the members: 2, 4, 5, 6, 7, 9, 11, 12, 13, 14, 18, 20 and 23. This event is positively regulated by IL-37b(? 218):SMAD3 and promotes dephosphorylation and suppression of the activation of tyrosine phosphorylation-dependent signaling pathways such as ERK, p38 MAPK, JNK, PI3K, NF-κB, and STAT3 pathways. (Luo et al., 2017).
R-HSA-9008928 (Reactome) Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL 37), also known as IL 1F7, is a member of the IL 1 family. There are five isoforms of IL 37 (a e) of which transcript IL 37b is known to be functional (Sharma S et al., 2008). Like several other IL 1 family members, IL 37b is synthesized as precursors that require processing (primarily by caspase 1) to attain full receptor agonist or antagonist function (Kumar S et al., 2002). Mothers against decapentaplegic homolog 3 (SMAD3) binds SMAD4 and this complex modulates the transcription of several genes downstream. Processed IL 37b can bind with phosphorylated SMAD3 in the cytosol of A549 cells (Nold M F et al., 2010, Grimsby S et al., 2004). This complex may then translocate from the cytosol to the nucleus (Nold M F et al., 2010, Dinarello et al. 2016) and may affect the function of SMAD3. These events ultimately lead to suppression of cytokine production in several types of immune cells resulting in reduced inflammation. This is a black box event because SMAD3 assisted IL-37 translocation to the nucleus is not fully understood.
R-HSA-9009072 (Reactome) Signal transducer and activator of transcription 3 (STAT3) acts downstream of various cellular receptors and is primarily involved in gene transcription. STAT3 is activated by serine/threonine kinases (Rebe et al. 2013). The IL-37:IL-18R1:SIGIRR complex can facilitate the phosphorylation and activation of STAT3 (Nold Petry et al. 2015). However, the precise mechanism is unclear. Hence, this event is represented as a black box.
R-HSA-9009910 (Reactome) Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL-37, IL-1 F7) is a member of the IL-1 family. There are five isoforms of IL-37 (a-e) of which transcript IL-37b is known to be functional (Sharma et al. 2008). This isoform is represented in UniProt as the canonical form of IL-37 and in Reactome as the full length, unprocessed form of IL-37. Like several other IL-1 family members, IL-37 is synthesized as a precursor that requires processing (primarily by caspase 1) to attain full receptor agonist or antagonist function. The putative caspase 1 cleavage site is at aspartic acid 20 (Kumar et al. 2002). Mothers against decapentaplegic homolog 3 (SMAD3) binds SMAD4 and this complex modulates the transcription of several genes downstream. IL-37(? 218) can bind phosphorylated SMAD3 in A549 cells (Nold M F et al. 2010, Grimsby S et al. 2004) and may affect its function.
R-HSA-9012542 (Reactome) Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL-37, IL-1 F7) is a member of the IL-1 family. There are five isoforms of IL-37 (a-e) of which transcript IL-37b is known to be functional (Sharma et al. 2008). This isoform is represented in UniProt as the canonical form of IL-37 and in Reactome as the full length, unprocessed form of IL-37. Like several other IL-1 family members, IL-37 is synthesized as a precursor that requires processing (primarily by caspase 1) to attain full receptor agonist or antagonist function. The processing of IL-37 begins by the binding of Caspase to the protein. This is a black box event because the precise Caspase binding site in IL-37 is unclear.
R-HSA-9012556 (Reactome) Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL-37, IL-1 F7) is a member of the IL-1 family. There are five isoforms of IL-37 (a-e) of which transcript IL-37b is known to be functional (Sharma et al. 2008). This isoform is represented in UniProt as the canonical form of IL-37 and in Reactome as the full length, unprocessed form of IL-37. Like several other IL-1 family members, IL-37 is synthesized as a precursor that requires processing (primarily by caspase 1) to attain full receptor agonist or antagonist function. The putative caspase 1 cleavage site is at aspartic acid 20 (Kumar et al. 2002). However, other truncation sites in IL-37 have been suggested (Pan et al. 2001). Caspase 1 may not be the only enzyme responsible for IL-37 processing (Sharma et al. 2008). This is a black box event because the cleavage sites and the enzymes responsible for the processing of IL-37 are uncertain.
R-HSA-9012689 (Reactome) Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL-37, IL-1 F7) is a member of the IL-1 family. There are five isoforms of IL-37 (a-e) of which transcript IL-37b is known to be functional (Sharma et al. 2008). This isoform is represented in UniProt as the canonical form of IL-37 and in Reactome as the full length, unprocessed form of IL-37. Like several other IL-1 family members, IL-37 is synthesized as a precursor that requires processing (primarily by caspase 1) to attain full receptor agonist or antagonist function. The putative caspase 1 cleavage site is at aspartic acid 20 (Kumar et al. 2002). However, other truncation sites in IL-37 have been suggested (Pan et al. 2001). Once processed, Caspase 1 dissociates from the protein. Caspase 1 may not be the only enzyme responsible for IL-37 processing (Sharma et al. 2008). These events ultimately lead to suppression of cytokine production in several types of immune cells resulting in reduced inflammation. This is a black box event because the cleavage sites and the enzymes responsible for the processing of IL-37 are uncertain.
SCF-beta-TrCP1,2:p-S927,S932-NFKB1:p-S,T-MAP3K8:TNIP2ArrowR-HSA-5684248 (Reactome)
SCF-beta-TrCP1,2:p-S927,S932-NFKB1:p-S,T-MAP3K8:TNIP2R-HSA-5684250 (Reactome)
SCF-beta-TrCP1,2:p-S927,S932-NFKB1:p-S,T-MAP3K8:TNIP2mim-catalysisR-HSA-5684250 (Reactome)
SIGIRRR-HSA-9008577 (Reactome)
SMAD3R-HSA-9008692 (Reactome)
STAT3R-HSA-9009072 (Reactome)
TAK1 complexR-HSA-446870 (Reactome)
TAK1 complexmim-catalysisR-HSA-727819 (Reactome)
TBK1R-HSA-9008684 (Reactome)
TNIP2ArrowR-HSA-5684273 (Reactome)
TNIP2R-HSA-451634 (Reactome)
TOLLIPArrowR-HSA-446894 (Reactome)
TOLLIPR-HSA-446868 (Reactome)
TRAF6R-HSA-446862 (Reactome)
TRAF6R-HSA-450173 (Reactome)
TRAF6R-HSA-507719 (Reactome)
UBE2N:UBE2V1:K63polyUbR-HSA-8948015 (Reactome)
UBE2N:UBE2V1:K63polyUbR-HSA-8948063 (Reactome)
UBE2N:UBE2V1ArrowR-HSA-8948018 (Reactome)
UBE2N:UBE2V1ArrowR-HSA-8948066 (Reactome)
UbArrowR-HSA-209061 (Reactome)
UbArrowR-HSA-5684273 (Reactome)
UbR-HSA-209063 (Reactome)
UbR-HSA-5684250 (Reactome)
hp-IRAK1: p-Pellino-1,2,(3):UBE2N:UBE2V1:K63polyUbR-HSA-451418 (Reactome)
hp-IRAK1: p-Pellino-1,2,(3):UBE2N:UBE2V1:K63polyUbmim-catalysisR-HSA-451418 (Reactome)
hp-IRAK1:3xK63-polyUb-TRAF6:3xUBE2N:UBE2V1ArrowR-HSA-446877 (Reactome)
hp-IRAK1:3xK63-polyUb-TRAF6:3xUBE2N:UBE2V1R-HSA-8948018 (Reactome)
hp-IRAK1:3xK63polyUb-TRAF6ArrowR-HSA-8948018 (Reactome)
hp-IRAK1:3xK63polyUb-TRAF6R-HSA-446870 (Reactome)
hp-IRAK1:3xTRAF6:3xUBE2N:UBE2V1:K63polyUbArrowR-HSA-8948015 (Reactome)
hp-IRAK1:3xTRAF6:3xUBE2N:UBE2V1:K63polyUbR-HSA-446877 (Reactome)
hp-IRAK1:3xTRAF6:3xUBE2N:UBE2V1:K63polyUbmim-catalysisR-HSA-446877 (Reactome)
hp-IRAK1:3xTRAF6ArrowR-HSA-450173 (Reactome)
hp-IRAK1:3xTRAF6R-HSA-8948015 (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:K63polyUboligo-TRAF6:Activated TAK1 complexArrowR-HSA-450187 (Reactome)
hp-IRAK1:Pellino, IRAK4:PellinoArrowR-HSA-450690 (Reactome)
hp-IRAK1:Pellino, IRAK4:PellinoR-HSA-450827 (Reactome)
hp-IRAK1:Pellino, IRAK4:Pellinomim-catalysisR-HSA-450827 (Reactome)
hp-IRAK1:p-Pellino, IRAK4:p-PellinoArrowR-HSA-450827 (Reactome)
hp-IRAK1:p-Pellino, IRAK4:p-PellinoR-HSA-8948063 (Reactome)
p-2S,S376,T,T209,T387-IRAK1, IRAK4R-HSA-450690 (Reactome)
p-2S,S376,T,T209,T387-IRAK1:TRAF6ArrowR-HSA-446894 (Reactome)
p-2S,S376,T,T209,T387-IRAK1:TRAF6R-HSA-450173 (Reactome)
p-IRAK2ArrowR-HSA-446684 (Reactome)
p-Pellino-1,2,(3)ArrowR-HSA-8948066 (Reactome)
p-S177,S181-IKBKBmim-catalysisR-HSA-209087 (Reactome)
p-S207,T211-MAP2K6ArrowR-HSA-727819 (Reactome)
p-S218,S222-MAP2K1,p-S257,T261-MAP2K4ArrowR-HSA-451649 (Reactome)
p-S32,S36-NFKBIAArrowR-HSA-209087 (Reactome)
p-S400,T290-MAP3K8ArrowR-HSA-5684273 (Reactome)
p-S400,T290-MAP3K8mim-catalysisR-HSA-451649 (Reactome)
p-S423,S425-SMAD3R-HSA-9009910 (Reactome)
p-S927,S932-NFKB1(1-968):MAP3K8:TNIP2ArrowR-HSA-5684267 (Reactome)
p-S927,S932-NFKB1(1-968):p-S,T-MAP3K8:TNIP2R-HSA-5684248 (Reactome)
p-T,Y-MAPK8ArrowR-HSA-9008043 (Reactome)
p-T342,T345,S346-IRAK4ArrowR-HSA-446894 (Reactome)
p-TBK1ArrowR-HSA-9008684 (Reactome)
p-Y705-STAT3ArrowR-HSA-9009072 (Reactome)
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