MyD88:MAL(TIRAP) cascade initiated on plasma membrane (Homo sapiens)

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5112, 24, 43, 5036, 3818, 7018, 702, 17, 18, 41, 45...22, 29, 40, 637, 9, 31, 33, 47...42, 54, 57, 61, 69...7013, 26, 30, 4639, 59, 6213, 26, 30, 4619, 35, 625, 373, 28, 65, 7170, 7316, 3227, 65, 7125229, 63, 6828, 56, 6734, 57, 69434470cytosolp-PELI3 PI(4,5)P2 UBB(77-152) MYD88 p-2S,S376,T,T209,T387-IRAK1 Clostridial peptidoglycan Diacyl lipopeptide 2xN4GlycoAsn-TLR4 p-Pellino-1,2,(3)TRAF6 IKBKG Clostridial peptidoglycan TLR6 PI(4,5)P2 p-T342,T345,S346-IRAK4 BTK p-IRAK2 CD14(20-345) BTK PI(4,5)P2 Triacyl lipopeptide PI(4,5)P2 TLR6 UBC(609-684) 2xN4GlycoAsn-TLR4 CD14(20-345) p-T342,T345,S346-IRAK4 CD14(20-345) TLR6 TLR6 Diacyl lipopeptide Lipoteichoic acid TRAF6 GPIN-CD14(20-345) Diacyl lipopeptide Major outer membrane protein P 2xN4GlycoAsn-TLR4 TRAF6 Triacyl lipopeptide 2xN4GlycoAsn-TLR4 TRAF6 4xPalmC-CD36 TLR2 p-PELI1 TLR1 p-IRAK2 SIGIRRTLR1 p-T342,T345,S346-IRAK4 4xPalmC-CD36 TRAF6 p-T209,T387-IRAK1 Major outer membrane protein P 4xPalmC-CD36 Lipoteichoic acid TRAF6 4xPalmC-CD36 p-4Y-TIRAP BTK p-2S,S376,T,T209,T387-IRAK1 PI(4,5)P2 oligo-MyD88:Mal:BTK:activated TLRTLR6 MAP3K1 Diacyl lipopeptide 2xN4GlycoAsn-TLR4 BTK ATPIRAK4:oligo-MyD88:Mal:activated TLRIKBKB UBE2V1 2xN4GlycoAsn-TLR4 Diacyl lipopeptide PI(4,5)P2 p-T342,T345,S346-IRAK4 IRAK2:p-S,2T-IRAK4:oligo-MyD88:Mal:activated TLRLPS 2xN4GlycoAsn-LY96 Diacyl lipopeptide TLR2 IRAK2 TRAF6:hp-IRAK1:PellinoLipoteichoic acid MYD88 LPS Lipoteichoic acid TAB3 p-4Y-TIRAP TLR2 PI(4,5)P2 TLR6 ADP4xPalmC-CD36 LPS ADPUBC(457-532) TLR1 PI(4,5)P2 PI(4,5)P2 TLR2 BTK TRAF6TAB2 Major outer membrane protein P p-T342,T345,S346-IRAK4 TRAF6 2xN4GlycoAsn-LY96 p-IRAK2:K63-linkedpUboligo-TRAF6:freeK63 pUb:TAK1complex2xN4GlycoAsn-LY96 MYD88 p-4Y-TIRAP TLR2 2xN4GlycoAsn-TLR4 IKKA:IKBKB:IKBKGATPBTKTIRAP p-IRAK2 GPIN-CD14(20-345) Lipoteichoic acid p-T184,T187-MAP3K7 p-4Y-TIRAP 2xN4GlycoAsn-TLR4 TLR1 LPS TIRAP MYD88 MAP3K1p-PELI2 2xN4GlycoAsn-LY96 UBB(153-228) ADPMAP kinaseactivation in TLRcascadeSOCS1Major outer membrane protein P MYD88 pp-IRAK1:p-IRAK4:oligo-MyD88 :Mal:activated TLRTLR6 BTK Diacyl lipopeptide p-T342,T345,S346-IRAK4 LPS MYD88 TLR1 p-IRAK2:K63-linkedpUb oligo-TRAF64xPalmC-CD36 Major outer membrane protein P 4xPalmC-CD36 4xPalmC-CD36 Clostridial peptidoglycan IRAK4 PI(4,5)P2 4xPalmC-CD36 ATPLPS p-4Y-TIRAP UBB(1-76) TLR6 TRAF6IRAK42xN4GlycoAsn-LY96 LPS ADPK63polyUb-hp-IRAK1 Diacyl lipopeptide MAL:PI(4,5)P2:BTK:activated TLR2/4ATPIKKA MYD88 IRAK2 K63polyUb 2xN4GlycoAsn-LY96 TLR1 Lipoteichoic acid Major outer membrane protein P CD14(20-345) TAB1 TAB1 4xPalmC-CD36 UBC(77-152) K63polyUb-hp-IRAK1 CD14(20-345) TLR2 Diacyl lipopeptide LPS Clostridial peptidoglycan ADPTriacyl lipopeptide TLR2 Triacyl lipopeptide K63polyUbp-IRAK2 4xPalmC-CD36 p-4Y-TIRAP p-T342,T345,S346-IRAK4 TRAF6:hp-IRAK1Major outer membrane protein P TRAF6:hp-IRAK1:p-IRAK4:oligo-MyD88 :Mal:activated TLRp-T342,T345,S346-IRAK4 Triacyl lipopeptide TAB2 p-4Y-TIRAP LPS IRAK1/orIRAK2:p-IRAK4:MyD88oligomer:Mal:activated TLRK63polyUbTLR1 TLR6 Triacyl lipopeptide p-4Y-TIRAP MyD88:MAL:BTK:activated TLR2/4Lipoteichoic acid Major outer membrane protein P IRAK1 p-IRAK1:p-IRAK4:oligo-MyD88:Mal:activated TLRLipoteichoic acid 2xN4GlycoAsn-LY96 UBA52(1-76) 2xN4GlycoAsn-TLR4 UbTLR1 CD14(20-345) p-IRAK2:oligo-TRAF6CD14(20-345) TRAF62xN4GlycoAsn-TLR4 BTK Activated TLR1:2 orTLR 2:6heterodimers orTLR4 homodimerp-4Y-TIRAP CD14(20-345) ATPTLR6 Triacyl lipopeptide Lipoteichoic acid Triacyl lipopeptide LPS BTK Major outer membrane protein P TRAF6:K63-linkedpolyUb p-IRAK1:IKKcomplexDiacyl lipopeptide TLR2 TLR6 TLR2 Clostridial peptidoglycan p-IRAK2:p-IRAK4:oligo-MyD88:Mal:activated TLR2xN4GlycoAsn-TLR4 2xN4GlycoAsn-TLR4 Triacyl lipopeptide 4xPalmC-CD36 IRAK1:p-S,2T-IRAK4:oligo-MyD88:Mal:activated TLRMajor outer membrane protein P Clostridial peptidoglycan IKBKG BTK TLR1 TLR1 2xN4GlycoAsn-TLR4 GPIN-CD14(20-345) TLR2 2xN4GlycoAsn-TLR4 PI(4,5)P2 Clostridial peptidoglycan LPS TLR1 IKKA RPS27A(1-76) GPIN-CD14(20-345) p-Pellino:hp-IRAK1:TRAF6UBC(229-304) MYD88 2xN4GlycoAsn-LY96 MAL:PI(4,5)P2:activated TLR2/4TLR1 GPIN-CD14(20-345) 2xN4GlycoAsn-LY96 Lipoteichoic acid Triacyl lipopeptide K63polyUb-TRAF6 Major outer membrane protein P Major outer membrane protein P GPIN-CD14(20-345) TLR6 CD14(20-345) TLR2 Clostridial peptidoglycan p-2S,S376,T,T209,T387-IRAK1 PI(4,5)P2 Lipoteichoic acid 2xN4GlycoAsn-TLR4 Lipoteichoic acid Triacyl lipopeptide p-4Y-TIRAP p-T209-IRAK1 4xPalmC-CD36 Clostridial peptidoglycan IRAK1, IRAK2Clostridial peptidoglycan Triacyl lipopeptide p-PELI2 Clostridial peptidoglycan MYD88ADPK63polyUb K63polyUb-TRAF6 CD14(20-345) Clostridial peptidoglycan Triacyl lipopeptide GPIN-CD14(20-345) TLR1 TLR2 Clostridial peptidoglycan 2xN4GlycoAsn-LY96 p-4Y-TIRAP UBC(305-380) TAB3 Diacyl lipopeptide IRAK3BTK TAK1 complexDiacyl lipopeptide ATPDiacyl lipopeptide 2xN4GlycoAsn-LY96 PI(4,5)P2 IRAK1 BTK 2xN4GlycoAsn-LY96 TRAF6 TLR6 MYD88 LPS TRAF6:p-IRAK2:p-IRAK4:oligo-MyD88 :Mal:activated TLRADPp-IRAK2 TLR6 TLR6 IKBKB BTK 2xN4GlycoAsn-LY96 CD14(20-345) Major outer membrane protein P MAP3K7 TLR1 TLR1 Diacyl lipopeptide Triacyl lipopeptide GPIN-CD14(20-345) LPS p-4Y-TIRAP CD14(20-345) CD14(20-345) MAL:PI(4,5)P2Clostridial peptidoglycan K63-linked polyUbp-IRAK1:TRAF6TRAF6:p-IRAK2BTK K63polyUb-TRAF6 activatedTLR2/4:p-4Y-MAL:PI(4,5)P2:BTK2xN4GlycoAsn-LY96 p-PELI2 TLR2 TLR2 TAB3 CD14(20-345) IRAK2 p-IRAK2 ECSITMAP3K7 GPIN-CD14(20-345) TLR2 LPS TRAF6 Ubc13:UBE2V1Triacyl lipopeptide CD14(20-345) p-PELI3 MYD88 GPIN-CD14(20-345) TLR1 PI(4,5)P2 UBC(153-228) Lipoteichoic acid PI(4,5)P2 BTK 4xPalmC-CD36 Clostridial peptidoglycan TLR2 GPIN-CD14(20-345) GPIN-CD14(20-345) UBC(1-76) Lipoteichoic acid Diacyl lipopeptide 4xPalmC-CD36 LPS Clostridial peptidoglycan Triacyl lipopeptide Major outer membrane protein P TIRAP PI(4,5)P2 TLR6 4xPalmC-CD36 2xN4GlycoAsn-LY96 TLR6 2xN4GlycoAsn-TLR4 IRAK4 TAB2 p-4Y-TIRAP p-4Y-TIRAP LPS MYD88 GPIN-CD14(20-345) UBE2N 4xPalmC-CD36 p-S,2T-IRAK4:oligo-MyD88:Mal:activated TLR receptorPI(4,5)P2 Clostridial peptidoglycan TRAF6 IRAK1 LPS MEKK1:activatedTRAF6Diacyl lipopeptide p-IRAK2 2xN4GlycoAsn-TLR4 Lipoteichoic acid p-T342,T345,S346-IRAK4 GPIN-CD14(20-345) p-2S,S376,T,T209,T387-IRAK1 CD14(20-345) TAK1 activates NFkBby phosphorylationand activation ofIKKs complexGPIN-CD14(20-345) BTK p-PELI3 p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:Mal:activated TLRMajor outer membrane protein P TLR2 UBC(381-456) GPIN-CD14(20-345) p-PELI1 CD14(20-345) Lipoteichoic acid MYD88 p-PELI1 Major outer membrane protein P UBC(533-608) GPIN-CD14(20-345) 2xN4GlycoAsn-LY96 TLR1 TAB1 Major outer membrane protein P 2xN4GlycoAsn-LY96 Diacyl lipopeptide p-2S,S376,T,T209,T387-IRAK1 MYD88 ATPLipoteichoic acid p-IRAK2:K63-linkedpUboligo-TRAF6:freeK63-linkedpUb:p-TAK1complexTriacyl lipopeptide 141, 11, 22, 281415, 7323853, 55142, 58141423, 49655723, 4914823, 492323141423, 4944148142323, 4923, 49141410, 21141427814815, 73142323823, 49232714231414236923, 4986, 6923, 4920, 64, 66, 742357, 69238828148234, 6, 15, 6923, 49142315, 7323141423, 498141457, 6911, 281423, 49354423, 49814654, 35, 40, 55, 6248, 70, 72815, 73142323, 491423, 4982723, 494, 35, 40, 55141444823238823, 4914281414


Description

The first known downstream component of TLR4 and TLR2 signaling is the adaptor MyD88. Another adapter MyD88-adaptor-like (Mal; also known as TIR-domain-containing adaptor protein or TIRAP) has also been described for TLR4 and TLR2 signaling. MyD88 comprises an N-terminal Death Domain (DD) and a C-terminal TIR, whereas Mal lacks the DD. The TIR homotypic interactions bring adapters into contact with the activated TLRs, whereas the DD modules recruit serine/threonine kinases such as interleukin-1-receptor-associated kinase (IRAK). Recruitment of these protein kinases is accompanied by phosphorylation, which in turn results in the interaction of IRAKs with TNF-receptor-associated factor 6 (TRAF6). The oligomerization of TRAF6 activates TAK1, a member of the MAP3-kinase family, and this leads to the activation of the IkB kinases. These kinases, in turn, phosphorylate IkB, leading to its proteolytic degradation and the translocation of NF-kB to the nucleus. Concomitantly, members of the activator protein-1 (AP-1) transcription factor family, Jun and Fos, are activated, and both AP-1 transcription factors and NF-kB are required for cytokine production, which in turn produces downstream inflammatory effects. View original pathway at:Reactome.

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  70. Dunne A, Ejdeback M, Ludidi PL, O'Neill LA, Gay NJ.; ''Structural complementarity of Toll/interleukin-1 receptor domains in Toll-like receptors and the adaptors Mal and MyD88.''; PubMed Europe PMC Scholia
  71. Kagan JC, Medzhitov R.; ''Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling.''; PubMed Europe PMC Scholia
  72. Cheng H, Addona T, Keshishian H, Dahlstrand E, Lu C, Dorsch M, Li Z, Wang A, Ocain TD, Li P, Parsons TF, Jaffee B, Xu Y.; ''Regulation of IRAK-4 kinase activity via autophosphorylation within its activation loop.''; PubMed Europe PMC Scholia
  73. Kawagoe T, Sato S, Jung A, Yamamoto M, Matsui K, Kato H, Uematsu S, Takeuchi O, Akira S.; ''Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor-mediated immune responses but not in TCR signaling.''; PubMed Europe PMC Scholia
  74. Kopp E, Medzhitov R, Carothers J, Xiao C, Douglas I, Janeway CA, Ghosh S.; ''ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway.''; PubMed Europe PMC Scholia
  75. Brunner C, Müller B, Wirth T.; ''Bruton's Tyrosine Kinase is involved in innate and adaptive immunity.''; PubMed Europe PMC Scholia
  76. Xia ZP, Sun L, Chen X, Pineda G, Jiang X, Adhikari A, Zeng W, Chen ZJ.; ''Direct activation of protein kinases by unanchored polyubiquitin chains.''; PubMed Europe PMC Scholia
  77. Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z.; ''IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family.''; PubMed Europe PMC Scholia
  78. Takaesu G, Kishida S, Hiyama A, Yamaguchi K, Shibuya H, Irie K, Ninomiya-Tsuji J, Matsumoto K.; ''TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway.''; PubMed Europe PMC Scholia
  79. Núñez Miguel R, Wong J, Westoll JF, Brooks HJ, O'Neill LA, Gay NJ, Bryant CE, Monie TP.; ''A dimer of the Toll-like receptor 4 cytoplasmic domain provides a specific scaffold for the recruitment of signalling adaptor proteins.''; PubMed Europe PMC Scholia
  80. Qian Y, Commane M, Ninomiya-Tsuji J, Matsumoto K, Li X.; ''IRAK-mediated translocation of TRAF6 and TAB2 in the interleukin-1-induced activation of NFkappa B.''; PubMed Europe PMC Scholia
  81. Nagpal K, Plantinga TS, Wong J, Monks BG, Gay NJ, Netea MG, Fitzgerald KA, Golenbock DT.; ''A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP results in loss of MyD88 binding and reduced TLR2/TLR4 signaling.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
114639view16:10, 25 January 2021ReactomeTeamReactome version 75
113087view11:14, 2 November 2020ReactomeTeamReactome version 74
112321view15:24, 9 October 2020ReactomeTeamReactome version 73
101220view11:11, 1 November 2018ReactomeTeamreactome version 66
100758view20:36, 31 October 2018ReactomeTeamreactome version 65
100302view19:13, 31 October 2018ReactomeTeamreactome version 64
99849view15:58, 31 October 2018ReactomeTeamreactome version 63
99406view14:34, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99095view12:39, 31 October 2018ReactomeTeamreactome version 62
93832view13:39, 16 August 2017ReactomeTeamreactome version 61
93386view11:22, 9 August 2017ReactomeTeamreactome version 61
88021view13:31, 25 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86472view09:19, 11 July 2016ReactomeTeamreactome version 56
83182view10:18, 18 November 2015ReactomeTeamVersion54
81550view13:05, 21 August 2015ReactomeTeamVersion53
77020view08:31, 17 July 2014ReactomeTeamFixed remaining interactions
76725view12:09, 16 July 2014ReactomeTeamFixed remaining interactions
76051view10:11, 11 June 2014ReactomeTeamRe-fixing comment source
75760view11:26, 10 June 2014ReactomeTeamReactome 48 Update
75110view14:06, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74757view08:50, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2xN4GlycoAsn-LY96 ProteinQ9Y6Y9 (Uniprot-TrEMBL)
2xN4GlycoAsn-TLR4 ProteinO00206 (Uniprot-TrEMBL)
4xPalmC-CD36 ProteinP16671 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated TLR1:2 or

TLR 2:6 heterodimers or

TLR4 homodimer		ComplexR-HSA-181230 (Reactome)
BTK ProteinQ06187 (Uniprot-TrEMBL)
BTKProteinQ06187 (Uniprot-TrEMBL)
CD14(20-345) ProteinP08571 (Uniprot-TrEMBL)
Clostridial peptidoglycan MetaboliteCHEBI:8005 (ChEBI)
Diacyl lipopeptide MetaboliteCHEBI:46896 (ChEBI)
ECSITProteinQ9BQ95 (Uniprot-TrEMBL)
GPIN-CD14(20-345) ProteinP08571 (Uniprot-TrEMBL)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IKKA ProteinO15111 (Uniprot-TrEMBL)
IKKA:IKBKB:IKBKGComplexR-HSA-168113 (Reactome)
IRAK1 ProteinP51617 (Uniprot-TrEMBL)
IRAK1, IRAK2ComplexR-HSA-937023 (Reactome)
IRAK1/or

IRAK2:p-IRAK4:MyD88

oligomer:Mal:activated TLR		ComplexR-HSA-166100 (Reactome)
IRAK1:p-S,2T-IRAK4
oligo-MyD88:Mal:activated TLR
ComplexR-HSA-937018 (Reactome)
IRAK2 ProteinO43187 (Uniprot-TrEMBL)
IRAK2:p-S,2T-IRAK4:oligo-MyD88:Mal:activated TLRComplexR-HSA-937028 (Reactome)
IRAK3ProteinQ9Y616 (Uniprot-TrEMBL)
IRAK4 ProteinQ9NWZ3 (Uniprot-TrEMBL)
IRAK4:oligo-MyD88:Mal:activated TLRComplexR-HSA-166080 (Reactome)
IRAK4ProteinQ9NWZ3 (Uniprot-TrEMBL)
K63-linked polyUb p-IRAK1:TRAF6ComplexR-HSA-937043 (Reactome)
K63polyUb R-HSA-450152 (Reactome)
K63polyUb-TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
K63polyUb-hp-IRAK1 ProteinP51617 (Uniprot-TrEMBL)
K63polyUbR-HSA-450152 (Reactome)
LPS MetaboliteCHEBI:16412 (ChEBI)
Lipoteichoic acid MetaboliteCHEBI:28640 (ChEBI)
MAL:PI(4,5)P2:BTK:activated TLR2/4ComplexR-HSA-2201331 (Reactome)
MAL:PI(4,5)P2:activated TLR2/4ComplexR-HSA-2559411 (Reactome)
MAL:PI(4,5)P2ComplexR-HSA-2559415 (Reactome)
MAP kinase

activation in TLR

cascade		PathwayR-HSA-450294 (Reactome) The mitogen activated protein kinase (MAPK) cascade, one of the most ancient and evolutionarily conserved signaling pathways, is involved in many processes of immune responses. The MAP kinases cascade transduces signals from the cell membrane to the nucleus in response to a wide range of stimuli (Chang and Karin, 2001; Johnson et al, 2002).

There are three major groups of MAP kinases

  • the extracellular signal-regulated protein kinases ERK1/2,
  • the p38 MAP kinase
  • and the c-Jun NH-terminal kinases JNK.

ERK1 and ERK2 are activated in response to growth stimuli. Both JNKs and p38-MAPK are activated in response to a variety of cellular and environmental stresses. The MAP kinases are activated by dual phosphorylation of Thr and Tyr within the tripeptide motif Thr-Xaa-Tyr. The sequence of this tripeptide motif is different in each group of MAP kinases: ERK (Thr-Glu-Tyr); p38 (Thr-Gly-Tyr); and JNK (Thr-Pro-Tyr).

MAPK activation is mediated by signal transduction in the conserved three-tiered kinase cascade: MAPKKKK (MAP4K or MKKKK or MAPKKK Kinase) activates the MAPKKK. The MAPKKKs then phosphorylates a dual-specificity protein kinase MAPKK, which in turn phosphorylates the MAPK.

The dual specificity MAP kinase kinases (MAPKK or MKK) differ for each group of MAPK. The ERK MAP kinases are activated by the MKK1 and MKK2; the p38 MAP kinases are activated by MKK3, MKK4, and MKK6; and the JNK pathway is activated by MKK4 and MKK7. The ability of MAP kinase kinases (MKKs, or MEKs) to recognize their cognate MAPKs is facilitated by a short docking motif (the D-site) in the MKK N-terminus, which binds to a complementary region on the MAPK. MAPKs then recognize many of their targets using the same strategy, because many MAPK substrates also contain D-sites.

The upstream signaling events in the TLR cascade that initiate and mediate the ERK signaling pathway remain unclear.

MAP3K1 ProteinQ13233 (Uniprot-TrEMBL)
MAP3K1ProteinQ13233 (Uniprot-TrEMBL)
MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
MEKK1:activated TRAF6ComplexR-HSA-166867 (Reactome)
MYD88 ProteinQ99836 (Uniprot-TrEMBL)
MYD88ProteinQ99836 (Uniprot-TrEMBL)
Major outer membrane protein P ProteinP30690 (Uniprot-TrEMBL)
MyD88:MAL:BTK:activated TLR2/4ComplexR-HSA-166062 (Reactome)
PI(4,5)P2 MetaboliteCHEBI:18348 (ChEBI)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
SIGIRRProteinQ6IA17 (Uniprot-TrEMBL)
SOCS1ProteinO15524 (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)
TIRAP ProteinP58753 (Uniprot-TrEMBL)
TLR1 ProteinQ15399 (Uniprot-TrEMBL)
TLR2 ProteinO60603 (Uniprot-TrEMBL)
TLR6 ProteinQ9Y2C9 (Uniprot-TrEMBL)
TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRAF6:K63-linked

polyUb p-IRAK1:IKK

complex		ComplexR-HSA-937038 (Reactome)
TRAF6:hp-IRAK1:PellinoComplexR-HSA-937020 (Reactome)
TRAF6:hp-IRAK1:p-IRAK4:oligo-MyD88 :Mal:activated TLRComplexR-HSA-937053 (Reactome)
TRAF6:hp-IRAK1ComplexR-HSA-937036 (Reactome) The listed studies describe an activation of IRAK-TRAF6-TAK1 axes downstream of IL1 receptor signaling cascade, which is mediated by its cytosolic domain called Toll/IL1R (TIR) domain. TLRs and IL1R are thought to share a similar downstream signaling pathway due to a high homology of their C-terminal TIR domains.
TRAF6:p-IRAK2
p-IRAK4:oligo-MyD88 :Mal:activated TLR
ComplexR-HSA-2262774 (Reactome)
TRAF6:p-IRAK2ComplexR-HSA-936961 (Reactome)
TRAF6ProteinQ9Y4K3 (Uniprot-TrEMBL)
Triacyl lipopeptide MetaboliteCHEBI:60192 (ChEBI)
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)
UBE2V1 ProteinQ13404 (Uniprot-TrEMBL)
UbComplexR-HSA-113595 (Reactome)
Ubc13:UBE2V1ComplexR-HSA-202463 (Reactome)
activated TLR2/4:p-4Y-MAL:PI(4,5)P2:BTKComplexR-HSA-2201325 (Reactome)
oligo-MyD88:Mal:BTK:activated TLRComplexR-HSA-937033 (Reactome)
p-2S,S376,T,T209,T387-IRAK1 ProteinP51617 (Uniprot-TrEMBL) This is the hyperphosphorylated, active form of IRAK1. The unknown coordinate phosphorylation events are to symbolize the multiple phosphorylations that likely take place in the ProST domain (aa10-211).
p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:Mal:activated TLRComplexR-HSA-166360 (Reactome)
p-4Y-TIRAP ProteinP58753 (Uniprot-TrEMBL)
p-IRAK1:p-IRAK4:oligo-MyD88:Mal:activated TLRComplexR-HSA-166118 (Reactome)
p-IRAK2 ProteinO43187 (Uniprot-TrEMBL)
p-IRAK2:K63-linked

pUb oligo-TRAF6:free K63 pUb:TAK1

complex		ComplexR-HSA-936953 (Reactome)
p-IRAK2:K63-linked

pUb oligo-TRAF6:free K63-linked

pUb:p-TAK1complex		ComplexR-HSA-937008 (Reactome)
p-IRAK2:K63-linked pUb oligo-TRAF6ComplexR-HSA-936988 (Reactome)
p-IRAK2:oligo-TRAF6ComplexR-HSA-936990 (Reactome)
p-IRAK2:p-IRAK4:oligo-MyD88:Mal:activated TLRComplexR-HSA-937055 (Reactome)
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-Pellino:hp-IRAK1:TRAF6ComplexR-HSA-937040 (Reactome)
p-S,2T-IRAK4:oligo-MyD88:Mal:activated TLR receptorComplexR-HSA-937048 (Reactome)
p-T184,T187-MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
p-T209,T387-IRAK1 ProteinP51617 (Uniprot-TrEMBL)
p-T209-IRAK1 ProteinP51617 (Uniprot-TrEMBL)
p-T342,T345,S346-IRAK4 ProteinQ9NWZ3 (Uniprot-TrEMBL)
pp-IRAK1:p-IRAK4:oligo-MyD88 :Mal:activated TLRComplexR-HSA-166281 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-166119 (Reactome)
ADPArrowR-HSA-166284 (Reactome)
ADPArrowR-HSA-166286 (Reactome)
ADPArrowR-HSA-936991 (Reactome)
ADPArrowR-HSA-937022 (Reactome)
ADPArrowR-HSA-937034 (Reactome)
ADPArrowR-HSA-937059 (Reactome)
ATPR-HSA-166119 (Reactome)
ATPR-HSA-166284 (Reactome)
ATPR-HSA-166286 (Reactome)
ATPR-HSA-936991 (Reactome)
ATPR-HSA-937022 (Reactome)
ATPR-HSA-937034 (Reactome)
ATPR-HSA-937059 (Reactome)
Activated TLR1:2 or

TLR 2:6 heterodimers or

TLR4 homodimer		R-HSA-2201316 (Reactome)
BTKR-HSA-2559414 (Reactome)
ECSITArrowR-HSA-166869 (Reactome)
IKKA:IKBKB:IKBKGR-HSA-937032 (Reactome)
IRAK1, IRAK2R-HSA-166091 (Reactome)
IRAK1/or

IRAK2:p-IRAK4:MyD88

oligomer:Mal:activated TLR		ArrowR-HSA-166091 (Reactome)
IRAK1:p-S,2T-IRAK4
oligo-MyD88:Mal:activated TLR
R-HSA-166119 (Reactome)
IRAK1:p-S,2T-IRAK4
oligo-MyD88:Mal:activated TLR
mim-catalysisR-HSA-166119 (Reactome)
IRAK2:p-S,2T-IRAK4:oligo-MyD88:Mal:activated TLRR-HSA-937059 (Reactome)
IRAK2:p-S,2T-IRAK4:oligo-MyD88:Mal:activated TLRmim-catalysisR-HSA-937059 (Reactome)
IRAK3TBarR-HSA-166362 (Reactome)
IRAK4:oligo-MyD88:Mal:activated TLRArrowR-HSA-166082 (Reactome)
IRAK4:oligo-MyD88:Mal:activated TLRR-HSA-937022 (Reactome)
IRAK4:oligo-MyD88:Mal:activated TLRmim-catalysisR-HSA-937022 (Reactome)
IRAK4R-HSA-166082 (Reactome)
K63-linked polyUb p-IRAK1:TRAF6ArrowR-HSA-937050 (Reactome)
K63-linked polyUb p-IRAK1:TRAF6R-HSA-937032 (Reactome)
K63polyUbArrowR-HSA-936986 (Reactome)
K63polyUbR-HSA-936960 (Reactome)
K63polyUbR-HSA-937050 (Reactome)
MAL:PI(4,5)P2:BTK:activated TLR2/4ArrowR-HSA-2559414 (Reactome)
MAL:PI(4,5)P2:BTK:activated TLR2/4R-HSA-2201322 (Reactome)
MAL:PI(4,5)P2:BTK:activated TLR2/4mim-catalysisR-HSA-2201322 (Reactome)
MAL:PI(4,5)P2:activated TLR2/4ArrowR-HSA-2201316 (Reactome)
MAL:PI(4,5)P2:activated TLR2/4R-HSA-2559414 (Reactome)
MAL:PI(4,5)P2R-HSA-2201316 (Reactome)
MAP3K1R-HSA-166869 (Reactome)
MEKK1:activated TRAF6ArrowR-HSA-166869 (Reactome)
MYD88R-HSA-166072 (Reactome)
MYD88R-HSA-937079 (Reactome)
MyD88:MAL:BTK:activated TLR2/4ArrowR-HSA-166072 (Reactome)
MyD88:MAL:BTK:activated TLR2/4R-HSA-937079 (Reactome)
R-HSA-166072 (Reactome) MyD88 binds to IRAK (IL-1 receptor-associated kinase) and the receptor heterocomplex (the signaling complex) and thereby mediates the association of IRAK with the receptor. MyD88 therefore couples a serine/threonine protein kinase to the receptor complex.
R-HSA-166082 (Reactome) IRAK4 is the mammalian homolog of Drosophila melanogaster Tube [Towb P et al 2009; Moncrieffe MC et al 2008]. Like Tube, IRAK4 possesses a conserved N-terminal death domain (DD), which mediates interactions with MyD88 at one binding site and a downstream IRAK kinase at the other, thereby bridging MyD88 and IRAK1/2 association [Towb P et al 2009; Lin SC e al 2010]. IRAK-4 plays a critical role in Toll receptor signaling - any interference with IRAK-4's kinase activity virtually abolishes downstream events. This is not the case with other members of the IRAK family [Suzuki N et al 2002; Li S et al 2002].
R-HSA-166091 (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-166119 (Reactome) First, IRAK1 is phosphorylated at Thr209 by IRAK4. This results in a conformational change of the kinase domain, permitting further phosphorylations to take place. Substitution of Thr209 by alanine results in a kinase-inactive IRAK1.
R-HSA-166284 (Reactome) Second, Thr387 in the activation loop is phosphorylated, leading to full enzymatic activity.
R-HSA-166286 (Reactome) Phosphorylation of IRAK-1 is due to three sequential phosphorylation steps, which leads 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 activated receptor complex. 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), It has been suggested that IRAK1 primarily acts as an adaptor for TRAF6 (Conze et al. 2008).
R-HSA-166362 (Reactome) Hyperphosphorylated IRAK1 and TRAF6 are thought to dissociate from the activated receptor. (Gottipati et al. 2007) but the IRAK1:TRAF6 complex may remain associated with the membrane (Dong et al. 2006).

Phosphorylated IRAK2, like its paralog IRAK1, possibly dissociates from the activated receptor as shown here, although mechanism of IRAK2 activation by IRAK4 followed by TRAF6 binding remains to be deciphered.

R-HSA-166363 (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-166869 (Reactome) TRAF6 binding to MAPK kinase kinase 1 (MEKK1) is mediated by the adapter protein evolutionarily conserved signaling intermediate in Toll pathway or in short ECSIT (Kopp E et al 1999). Induced MEKK1 can activate both IKK alpha and IKK beta thus leading to induction of NF-kappa-B activation. MEKK1 was also shown to induce ERK1/2 and JNK activation [Yujiri T et al 1998].

Although TRAF6 interacts with several upstream mediators (IRAK1, IRAK2, TRIF), there is no data showing MEKK1 participating in the interaction with the TRAF6 activators. Therefore this reaction is simplified to include only TRAF6 and MEKK1.

R-HSA-2201316 (Reactome) TIRAP/Mal-deficient mice showed normal responses to the TLR3, TLR5, TLR7, and TLR9 ligands, but were defective in TLR4 and TLR2 ligand-induced proinflammatory cytokine production (Horng et al. 2002,Yamamoto et al. 2002). In contrast, TLR4 ligand-induced activation of IRF-3 and expression of IFN-inducible genes were not impaired in TIRAP/Mal knockout macrophages or in mice lacking both MyD88 and TIRAP/Mal (Horng et al. 2002,Yamamoto et al. 2002). Thus, TIRAP/Mal is an essential adapter that is involved in the MyD88-dependent pathway via TLR4 and TLR2, but not in the MyD88-independent pathway. Mal contains a phosphatidylinositol 4,5-bisphosphate-binding domain required for retention in the plasma membrane. The intracellular TIR domains of TLR2 or 4 associate with Mal at the cytoplasmic side of the plasma membrane, which in turn facilitates the binding of MyD88 to the activated TLR, leading to NF-kB and MAPK activation [Nunez Miguel et al 2007].
R-HSA-2201322 (Reactome) Upon activation of TLR2/or 4 signaling pathway TIRAP(MAL), a TIR domain–containing adapter protein, undergoes tyrosine phosphorylation (Piao W et al. 2008; Gray P et al. 2006). Bruton's tyrosine kinase (BTK) was shown to mediate the TIRAP phosphorylation (Jefferies CA et al. 2003; Gray P et al. 2006). BTK-specific inhibitor, LFM-A13, blocked the phosphorylation of TIRAP in human monocytic cell line THP-1 stimulated with LPS or macrophage-activating lipopeptide-2 (MALP-2) (Gray P et al. 2006). LFM-A13 also inhibited activation of NFkappaB in LPS-treated THP-1 (Jefferies CA et al. 2003). Besides BTK kinase TIRAP was shown to associate with other kinases such as protein kinase C delta (PKC delta) suggesting their regulatory role in TIRAP activation (Kubo-Murai M et al. 2007).

Tyr-86, Tyr-106 and Tyr-187 were identified as possible phosphorylation sites (Gray P et al. 2006). An additional study has shown that Tyr-86, Tyr-106, and Tyr-159 are important residues, as mutagenesis of these residues impaired TIRAP (MAL) phosphorylation, affected its interaction with BTK and also impaired downstream signaling (Piao W et al. 2008). BTK-mediated phosphorylation of TIRAP leads to recruitment of suppressor of cytokine signaling 1 (SOCS1), which assembles K48-linked polyubiquitin chains resulting in TIRAP's proteosomal degradation, disrupting the TLR complex, and terminating signaling (Mansell A et al. 2006). TIRAP function is also regulated by the cysteine protease caspase-1, which cleaves the protein in a region of the molecule that interacts with MyD88 and TLR4 (Ulrichts P et al. 2010).

R-HSA-2262775 (Reactome) Hyperphosphorylated IRAK1 and TRAF6 are thought to dissociate from the activated receptor. (Gottipati et al. 2007) but the IRAK1:TRAF6 complex may remain associated with the membrane (Dong et al. 2006).

Phosphorylated IRAK2, like its paralog IRAK1, possibly dissociates from the activated receptor as shown here, although mechanism of IRAK2 activation by IRAK4 followed by TRAF6 binding remains to be deciphered.

R-HSA-2262777 (Reactome) IRAK-2 has two TRAF6 binding motifs that are responsible for initiating TRAF6 signaling transduction (Ye H et al 2002). IRAK2 point mutants with mutated TRAF6-binding motifs abrogate NFkB activation and are incapable to stimulate TRAF6 ubiquitination (Keating SE et al 2007).
R-HSA-2559414 (Reactome) Bruton's tyrosine kinase (BTK) is a cytoplasmic protein tyrosine kinase, which plays an essential role in B cell receptor (BCR) signaling (Brunner C et al. 2005). BTK has been also implicated in TLR signaling (Lee KG et al. 2012, Jefferies CA et al. 2003; Doyle SL et al. 2007). Interaction studies revealed that BTK can associate with intracellular TIR-domains of TLRs 4, 6, 8 and 9. Furthermore, BTK was found to interact with other proteins involved in TLR2/4 signaling - MyD88, MAL and IRAK-1 (Jefferies CA et al. 2003)

Loss of BTK function causes X-linked agammaglobulinemia (XLA), a rare primary immunode?ciency disease with severe defects in early B-cell development resulting in an almost complete absence of peripheral B cells and severely reduced serum levels of immunoglobulins of all classes (Väliaho J et al. 2006). Affected individuals suffer from recurrent bacterial and enteroviral infections. It remains unclear whether XLA patients have normal or impared TLR signaling functions. LPS-stimulated monocytes from XLA patients were found to produce reduced amounts of TNFalpha (Horwood NJ et al. 2003), These data contradict a study that showed enhanced amounts of TNFalpha and IL6 comparing to control cells, starting at 6 hours and extending for 48 hours (Marron TU et al. 2012). The other group reported similar expression TNFalpha upon TLR4 triggering, compared with healthy control cells (Perez de Diego R et al. 2006). Thus, the effect of BTK deficiency on TLR-mediated inflammation needs to be further clarified.

R-HSA-936942 (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-936960 (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-936963 (Reactome) The mechanism by which IRAK-2 induces TRAF6 E3 ligase activity remains to be deciphered, but one possibility is that IRAK-2 may direct TRAF6 oligomerization.
R-HSA-936986 (Reactome) Polyubiquitinated TRAF6 (as E3 ubiquitin ligase) generates free K63 -linked polyubiquitin chains that non-covalently associate with ubiquitin receptors of TAB2/TAB3 regulatory proteins of the TAK1 complex, leading to the activation of the TAK1 kinase.
R-HSA-936991 (Reactome) The TAK1 complex consists of the transforming growth factor-? (TGF-beta)-activated kinase (TAK1) and the TAK1-binding proteins TAB1, TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Sakurai H et al 2000; Shibuya H et al 2000). TAB1 promotes autophosphorylation of the TAK1 kinase activation lobe, likely through an allosteric mechanism (Sakurai H et al 2000 ; Kishimoyo K et al 2000). The TAK1 complex is regulated by polyubiquitination. The TAK1 complex consists of the transforming growth factor-? (TGF- ?)-activated kinase (TAK1) and the TAK1-binding proteins TAB1, TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya H et al 1996; Sakurai H et al 2000). TAB1 promotes autophosphorylation of the TAK1 kinase activation lobe, likely through an allosteric mechanism (Brown K et al 2005; Ono K et al 2001). The TAK1 complex is regulated by polyubiquitination. Binding of TAB2 and TAB3 to Lys63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Binding of multiple TAK1 complexes onto the same polyubiquitin chain may promote oligomerization of TAK1, facilitating TAK1 autophosphorylation and subsequent activation of its kinase activity (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that leads to the activation of TAK1. Another possibility is that TAB2/3 may recruit the IKK complex by binding to ubiquitinated NEMO; polyubiquitin chains may function as a scaffold for higher order signaling complexes that allow interaction between TAK1 and IKK (Kanayama et al. 2004).
R-HSA-937022 (Reactome) IRAK4 is activated by autophosphorylation at 3 positions within the kinase activation loop, Thr-342, Thr-345 and Ser-346.
R-HSA-937032 (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-937034 (Reactome) Both IRAK1 and IRAK4 were shown to phosphorylate Pellino isoforms in vitro. The phosphorylation of Pellino proteins is a necessary step in enhancing of their E3 ubiquitin ligase activity. It remains unclear whether IRAK1(as shown here), IRAK4, or both protein kinases mediate the activation of Pellino isoforms in vivo.
R-HSA-937044 (Reactome) Pellino isoforms -1, 2 and 3 have been shown to interact with IRAK1 and IRAK4 (Jiang et al. 2003, Strellow et al. 2003, Butler et al. 2005, 2007). It has been also reported that Pellino-1 forms a complex with TRAF6, but not TAK1 or IL1R (Jiang et al. 2003), suggesting that Pellino-1 function as intermediate complex with IRAK1 in the propagation of signal from the activated receptor to activation of TAK1.

All Pellino isoforms function as E3 ubiquitin ligases in conjunction with several different E2-conjugating enzymes - Ubc13-Uev1a, UbcH4, or UbcH5a/5b.(Schauvliege R et al. 2006, Butler MP et al. 2007, Ordureau A et al. 2008). Their C-terminus contains a RING-like domain which is responsible for IL1-induced Lys63-linked polyubiquitination of IRAK1 in vitro.

R-HSA-937050 (Reactome) IL1R/TLR induces the Lys48- polyubiquitination and proteosomal degradation of IRAK1. IRAK1 has been shown to undergo Lys63-linked polyubiquitination which induced activation of NFkB (Windheim et al 2008; Conze et al 2008). These two forms of ubiquitination are not mutually exclusive for a protein (Newton K et al 2008). Upon stimulation Lys63-linked ubiquitination may occur first to activate NFkB, but at later time Lys48-linked ubiquitination occurs to target the proteins for proteosomal degradation.

IRAK1 is ubiquitinated on Lys134 and Lys180; 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 a 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 Lys48-linked polyubiquitin chains; the type of linkage is controlled by the collaborating E2 enzyme. All the Pellino proteins can combine with the E2 heterodimer UbcH13/Uev1a to catalyze Lys63-linked ubiquitylation (Ordureau et al 2008).

R-HSA-937059 (Reactome) IRAK4 deficient macrophages fail to induce IRAK2 phosphorylation (Kawagoe et al. 2008), suggesting that activated IRAK4 phosphorylates IRAK2 as it does IRAK1.

Phosphorylation sites of IRAK2 remain to be characterized.

R-HSA-937079 (Reactome) Structural analysis of MyD88:IRAK4 and MyD88:IRAK4:IRAK2 suggested that upon MyD88 recruitment to an activated dimerized TLR the MyD88 death domains clustering induces the formation of Mydosome, a large oligomeric signaling platform (Motshwene PG et al 2009, Lin SC et al 2010). Assembly of these Myddosome complexes brings the kinase domains of IRAKs into proximity for phosphorylation and activation. The oligomer complex stoichiometry was reported as 7:4 and 8:4 for MyD88:IRAK4 (Motshwene PG et al 2009), and 6:4:4 in the complex of MyD88:IRAK4:IRAK2(Lin SC et al 2010).
SIGIRRTBarR-HSA-166072 (Reactome)
SOCS1TBarR-HSA-166072 (Reactome)
TAK1 complexR-HSA-936960 (Reactome)
TRAF6:K63-linked

polyUb p-IRAK1:IKK

complex		ArrowR-HSA-937032 (Reactome)
TRAF6:hp-IRAK1:PellinoArrowR-HSA-937044 (Reactome)
TRAF6:hp-IRAK1:PellinoR-HSA-937034 (Reactome)
TRAF6:hp-IRAK1:Pellinomim-catalysisR-HSA-937034 (Reactome)
TRAF6:hp-IRAK1:p-IRAK4:oligo-MyD88 :Mal:activated TLRArrowR-HSA-166363 (Reactome)
TRAF6:hp-IRAK1:p-IRAK4:oligo-MyD88 :Mal:activated TLRR-HSA-166362 (Reactome)
TRAF6:hp-IRAK1ArrowR-HSA-166362 (Reactome)
TRAF6:hp-IRAK1R-HSA-937044 (Reactome)
TRAF6:p-IRAK2
p-IRAK4:oligo-MyD88 :Mal:activated TLR
ArrowR-HSA-2262777 (Reactome)
TRAF6:p-IRAK2
p-IRAK4:oligo-MyD88 :Mal:activated TLR
R-HSA-2262775 (Reactome)
TRAF6:p-IRAK2ArrowR-HSA-2262775 (Reactome)
TRAF6:p-IRAK2R-HSA-936963 (Reactome)
TRAF6R-HSA-166363 (Reactome)
TRAF6R-HSA-166869 (Reactome)
TRAF6R-HSA-2262777 (Reactome)
TRAF6R-HSA-936963 (Reactome)
TRAF6mim-catalysisR-HSA-936986 (Reactome)
UbR-HSA-936942 (Reactome)
UbR-HSA-936986 (Reactome)
Ubc13:UBE2V1ArrowR-HSA-937050 (Reactome)
Ubc13:UBE2V1R-HSA-937050 (Reactome)
activated TLR2/4:p-4Y-MAL:PI(4,5)P2:BTKArrowR-HSA-2201322 (Reactome)
activated TLR2/4:p-4Y-MAL:PI(4,5)P2:BTKR-HSA-166072 (Reactome)
oligo-MyD88:Mal:BTK:activated TLRArrowR-HSA-937079 (Reactome)
oligo-MyD88:Mal:BTK:activated TLRR-HSA-166082 (Reactome)
p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:Mal:activated TLRArrowR-HSA-166286 (Reactome)
p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:Mal:activated TLRR-HSA-166363 (Reactome)
p-IRAK1:p-IRAK4:oligo-MyD88:Mal:activated TLRArrowR-HSA-166119 (Reactome)
p-IRAK1:p-IRAK4:oligo-MyD88:Mal:activated TLRR-HSA-166284 (Reactome)
p-IRAK1:p-IRAK4:oligo-MyD88:Mal:activated TLRmim-catalysisR-HSA-166284 (Reactome)
p-IRAK2:K63-linked

pUb oligo-TRAF6:free K63 pUb:TAK1

complex		ArrowR-HSA-936960 (Reactome)
p-IRAK2:K63-linked

pUb oligo-TRAF6:free K63 pUb:TAK1

complex		R-HSA-936991 (Reactome)
p-IRAK2:K63-linked

pUb oligo-TRAF6:free K63 pUb:TAK1

complex		mim-catalysisR-HSA-936991 (Reactome)
p-IRAK2:K63-linked

pUb oligo-TRAF6:free K63-linked

pUb:p-TAK1complex		ArrowR-HSA-936991 (Reactome)
p-IRAK2:K63-linked pUb oligo-TRAF6ArrowR-HSA-936942 (Reactome)
p-IRAK2:K63-linked pUb oligo-TRAF6R-HSA-936960 (Reactome)
p-IRAK2:oligo-TRAF6ArrowR-HSA-936963 (Reactome)
p-IRAK2:oligo-TRAF6R-HSA-936942 (Reactome)
p-IRAK2:oligo-TRAF6mim-catalysisR-HSA-936942 (Reactome)
p-IRAK2:p-IRAK4:oligo-MyD88:Mal:activated TLRArrowR-HSA-937059 (Reactome)
p-IRAK2:p-IRAK4:oligo-MyD88:Mal:activated TLRR-HSA-2262777 (Reactome)
p-Pellino-1,2,(3)ArrowR-HSA-937050 (Reactome)
p-Pellino-1,2,(3)R-HSA-937044 (Reactome)
p-Pellino:hp-IRAK1:TRAF6ArrowR-HSA-937034 (Reactome)
p-Pellino:hp-IRAK1:TRAF6R-HSA-937050 (Reactome)
p-Pellino:hp-IRAK1:TRAF6mim-catalysisR-HSA-937050 (Reactome)
p-S,2T-IRAK4:oligo-MyD88:Mal:activated TLR receptorArrowR-HSA-166362 (Reactome)
p-S,2T-IRAK4:oligo-MyD88:Mal:activated TLR receptorArrowR-HSA-2262775 (Reactome)
p-S,2T-IRAK4:oligo-MyD88:Mal:activated TLR receptorArrowR-HSA-937022 (Reactome)
p-S,2T-IRAK4:oligo-MyD88:Mal:activated TLR receptorR-HSA-166091 (Reactome)
pp-IRAK1:p-IRAK4:oligo-MyD88 :Mal:activated TLRArrowR-HSA-166284 (Reactome)
pp-IRAK1:p-IRAK4:oligo-MyD88 :Mal:activated TLRR-HSA-166286 (Reactome)
pp-IRAK1:p-IRAK4:oligo-MyD88 :Mal:activated TLRmim-catalysisR-HSA-166286 (Reactome)
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