MyD88 dependent cascade initiated on endosome (Homo sapiens)

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5, 6, 2319, 38, 5531, 43, 529, 512, 10, 29, 3718, 344, 464, 462133, 423432, 543422, 347, 13, 4117, 28, 30, 513, 413, 24, 41473, 30, 5111, 20, 3912, 18, 36, 483514, 40203, 22, 26, 447, 50, 53C-ter TLR7 dimer C-ter TLR7 dimer C-ter TLR7 dimer TLR8 dimer TLR8 dimer C-ter TLR7 dimer Ligands recognized by TLR7 and TLR8 C-ter TLR7 dimer TLR8 dimer p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 receptor IRAK1p-S,2T-IRAK4 oligo-MyD88activated TLR 7/8 or 9 C-ter TLR9 dimerunmethylated CpG DNA MyD88 oligomer oligo-MyD88activated TLR7-9 Ligands recognized by TLR7 and TLR8 TLR8 dimer TLR7 or TLR8recognized ligand TRAF6p-IRAK2 C-ter TLR9 dimerunmethylated CpG DNA TLR7 or TLR8recognized ligand endosome lumenC-ter-TLR9 dimer TLR7 or TLR8 Activated TLR7-9 homodimers p-Pellinohp-IRAK1TRAF6 Imidazoquinoline compounds C-ter TLR7 dimer Imidazoquinoline compounds C-ter TLR7 dimer Activated TLR7-9 homodimers Ubc13UBE2V1 Imidazoquinoline compounds p-3S,3T-IRAK1p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 Activated TLR7-9 homodimers Activated TLR7-9 homodimers oligo-MyD88activated TLR7-9 C-ter-TLR9 dimer Ligands recognized by TLR7 and TLR8 TLR7 or TLR8recognized ligand C-ter TLR7 dimer pp-IRAK1p-IRAK4oligo-MyD88activated TLR 7/8 or 9 complex TLR7 or TLR8 TLR8 dimer TRAF6K63-linked polyUb p-IRAK1IKK complex C-ter-TLR9 dimer TLR8 dimer TRAF6hp-IRAK1/or p-IRAK2p-IRAK4oligo-MyD88activated TLR7/8 or 9 C-ter-TLR9 dimer TAK1 complex C-ter-TLR9 dimer TLR7 or TLR8recognized ligand p-IRAK2p-IRAK4oligo-MyD88activated TLR 7/8 or9 Activated TLR7-9 homodimers Activated TLR7-9 homodimers TRAF6hp-IRAK1 p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 receptor p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 receptor oligo-MyD88activated TLR7-9 MyD88 oligomer hp-IRAK1 or p-IRAK2 bound to the pIRAK4MyD88activated TLR7/8 or 9 complex IKKAIKKBNEMO oligo-MyD88activated TLR7-9 IRF7TRAF6p-3S,3T-IRAK1p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 TLR8 dimer TLR8 dimer IRAK2p-S,2T-IRAK4oligo-MyD88activated TLR 7/8 or9 C-ter TLR9 dimerunmethylated CpG DNA C-ter TLR9 dimerunmethylated CpG DNA Activated TLR7-9 homodimers TLR7 or TLR8 C-ter TLR9 dimerunmethylated CpG DNA TLR8 dimer Ligands recognized by TLR7 and TLR8 C-ter TLR9 dimerunmethylated CpG DNA Ligands recognized by TLR7 and TLR8 Imidazoquinoline compounds TLR7 or TLR8recognized ligand TLR7 or TLR8 C-ter TLR7 dimer TLR7 or TLR8 Imidazoquinoline compounds C-ter TLR9 dimerunmethylated CpG DNA TAB2/3 oligo-MyD88activated TLR7-9 Activated TLR7-9 homodimers oligo-MyD88activated TLR7-9 Imidazoquinoline compounds Imidazoquinoline compounds C-ter-TLR9 dimer nucleoplasmhp-IRAK1/p-IRAK2 p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 receptor C-ter-TLR9 dimer oligo-MyD88activated TLR7-9 C-ter TLR7 dimer C-ter TLR7 dimer p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 receptor p-2S-IRF7p-2S-IRF7 TLR7 or TLR8 Ligands recognized by TLR7 and TLR8 Ligands recognized by TLR7 and TLR8 oligo-MyD88activated TLR7-9 TLR7 or TLR8 MyD88 complexed with the activated TLR receptor MyD88 oligomer TLR7 or TLR8recognized ligand C-ter TLR9 dimerunmethylated CpG DNA C-ter TLR9 dimerunmethylated CpG DNA TLR7 or TLR8 Ubc13UBE2V1 Imidazoquinoline compounds TLR7 or TLR8recognized ligand C-ter-TLR9 dimer Imidazoquinoline compounds IKKAIKKBNEMO MyD88 oligomer MyD88 oligomer MyD88 oligomer oligo-MyD88activated TLR7-9 Imidazoquinoline compounds Activated TLR7-9 homodimers oligo-MyD88activated TLR7-9 C-ter TLR7 dimer TAB2/3 Ligands recognized by TLR7 and TLR8 C-ter-TLR9 dimer Activated TLR7-9 homodimers p-IRAK2K63-linked pUb oligo-TRAF6free K63-linked pUbp-TAK1complex p-IRAK2K63-linked pUb oligo-TRAF6 MYD88 homodimer TLR7 or TLR8 Ligands recognized by TLR7 and TLR8 TLR7 or TLR8recognized ligand p-3S,3T-IRAK1p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 C-ter TLR9 dimerunmethylated CpG DNA p-IRAK2K63-linked pUb oligo-TRAF6 TLR7 or TLR8 MyD88 oligomer TLR7 or TLR8 p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 receptor C-ter-TLR9 dimer Activated TLR7-9 homodimers oligo-MyD88activated TLR7-9 C-ter-TLR9 dimer Ligands recognized by TLR7 and TLR8 TRAF6p-IRAK2 TAB2/3 TRAF6hp-IRAK1 Imidazoquinoline compounds Activated TLR7-9 homodimers C-ter-TLR9 dimer TLR7 or TLR8recognized ligand Activated TLR7-9 homodimers TLR8 dimer MyD88 oligomer IRAK1/or IRAK2 p-S,2T-IRAK4oligo-MyD88activated TLR 7/8 or 9 p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 receptor Activated TLR7-9 homodimers Imidazoquinoline compounds TLR8 dimer IRAK1/ IRAK2 p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 receptor p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 receptor MyD88 oligomer TLR8 dimer Ligands recognized by TLR7 and TLR8 C-ter TLR9 dimerunmethylated CpG DNA TRAF6p-3S,3T-IRAK1p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 oligo-MyD88activated TLR7-9 Ligands recognized by TLR7 and TLR8 C-ter TLR9 dimerunmethylated CpG DNA TLR7 or TLR8recognized ligand p-IRAK2K63-linked pUb oligo-TRAF6free K63 pUbTAK1 complex C-ter TLR9 dimerunmethylated CpG DNA TRAF6hp-IRAK1Pellino Ligands recognized by TLR7 and TLR8 TRAF6p-3S,3T-IRAK1p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 TLR7 or TLR8 TLR7 or TLR8 MEKK1activated TRAF6 p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 receptor C-ter TLR7 dimer TLR7 or TLR8 MyD88 oligomer p-IRAK1p-IRAK4oligo-MyD88activated TLR7/8 or 9 complex Ligands recognized by TLR7 and TLR8 hp-IRAK1 or p-IRAK2 bound to the pIRAK4MyD88activated TLR7/8 or 9 complex C-ter TLR9 dimerunmethylated CpG DNA TLR7 or TLR8 hp-IRAK1/p-IRAK2 TLR7 or TLR8recognized ligand Imidazoquinoline compounds C-ter-TLR9 dimer C-ter TLR7 dimer p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 receptor TLR7 or TLR8recognized ligand p-IRAK2oligo-TRAF6 MyD88 oligomer Imidazoquinoline compounds MyD88 oligomer DHX36CpG oligo-MyD88activated TLR7-9 Imidazoquinoline compounds p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 receptor C-ter TLR9 dimerunmethylated CpG DNA C-ter-TLR9 dimer DHX36CpGMyD88 p-3S,3T-IRAK1p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 Ligands recognized by TLR7 and TLR8 MyD88 oligomer oligo-MyD88activated TLR7-9 hp-IRAK1/p-IRAK2 TAK1 complex IRAK4oligo-MyD88activated TLR 7/8 or 9 C-ter TLR7 dimer p-3S,3T-IRAK1p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 MyD88 oligomer TLR7 or TLR8recognized ligand C-ter TLR7 dimer Activated TLR7-9 homodimers p-IRAK2K63-linked pUb oligo-TRAF6 TLR7 or TLR8recognized ligand C-ter TLR9 dimerunmethylated CpG DNA hp-IRAK1/or p-IRAK2 TRAF6 K63-linked poly-Ub-IRF7TRAF6p-3S,3T-IRAK1p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9. Imidazoquinoline compounds TLR8 dimer TRAF6p-3S,3T-IRAK1p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 C-ter-TLR9 dimer TLR8 dimer TLR7 or TLR8 oligo-MyD88activated TLR7-9 p-2S-IRF7p-2S-IRF7 MyD88 oligomer K63-linked poly-Ub-p-3S,3T-IRAK1TRAF6 TLR8 dimer Ligands recognized by TLR7 and TLR8 TLR7 or TLR8recognized ligand C-ter-TLR9 dimer TRAF6hp-IRAK1 cytosolK63-linked poly-Ub-p-3S,3T-IRAK1TRAF6 TLR7 or TLR8recognized ligand p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 receptor TLR8 dimer Activated TLR7-9 homodimers IMIQ p-2S,S376,T,T209,T387-IRAK1 TLR7IRAK2p-S,2T-IRAK4oligo-MyD88activated TLR 7/8 or9TRAF6 IMIQ TRAF6 IMIQ TLR7p-Pellino-1,2,p-T342,T345,S346-IRAK4 p-T209-IRAK1 p-Pellino-1,2,p-2S,S376,T,T209,T387-IRAK1 p-IRAK2 p-IRAK2 TRAF6 MYD88 TAB3TLR9TLR7CHUK IRF7TAB2 TLR9UBE2V1 MYD88 MEKK1activated TRAF6MAP3K7 R-848 IRAK2 ADPTRAF6 R-848 TLR7ADPADPp-IRAK2 p-IRAK2 TAB1 p-2S-IRF7p-2S-IRF7MYD88 IRAK1 TRAF6 oligo-MyD88activated TLR7-9IMIQ p-IRAK2 IKBKG DHX36CpGMyD88R-848 p-2S,S376,T,T209,T387-IRAK1 R-848 TLR7IKBKB IKKAIKKBNEMOK63polyUbp-T342,T345,S346-IRAK4 p-T342,T345,S346-IRAK4 IMIQ R-848 IRAK1p-S,2T-IRAK4 oligo-MyD88activated TLR 7/8 or 9p-Pellinohp-IRAK1TRAF6K63polyUbp-S477,S479-IRF7 TAB2 TLR8 MAP3K1ATPTLR9ADPMYD88 MAP kinase activation in TLR cascadeTRAF6 DHX36 p-IRAK2 IRAK4oligo-MyD88activated TLR 7/8 or 9TLR9UBE2N MYD88 TLR9K63polyUbMYD88 MYD88 p-2S-IRF7p-2S-IRF7p-2S,S376,T,T209,T387-IRAK1 IRAK2 p-T342,T345,S346-IRAK4 R-848 MYD88 UbTAB1 p-T342,T345,S346-IRAK4 TLR9MYD88 R-848 TRAF6 TRAF6K63-linked polyUb p-IRAK1IKK complexTRAF6K63polyUb-TRAF6 TAB2 TLR7p-2S,S376,T,T209,T387-IRAK1 Ubc13UBE2V1TLR9TLR9R-848 Activated TLR7-9 homodimersR-848 IKBKG TAK1 activates NFkB by phosphorylation and activation of IKKs complexUbc13UBE2V1p-2S,S376,T,T209,T387-IRAK1 MYD88 TRAF6 ATPTRAF6hp-IRAK1p-2S,S376,T,T209,T387-IRAK1 MyD88 complexed with the activated TLR receptorTRAF6hp-IRAK1/or p-IRAK2p-IRAK4oligo-MyD88activated TLR7/8 or 9TLR7MYD88 MYD88 p-IRAK2 CHUK IRF7TRAF6p-3S,3T-IRAK1p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9IMIQ ADPIMIQ MAP3K7 TLR8 R-848 ATPMYD88 R-848 IRAK4TLR8 TLR9IRAK1/or IRAK2 p-S,2T-IRAK4oligo-MyD88activated TLR 7/8 or 9TLR8 p-T342,T345,S346-IRAK4 p-2S,S376,T,T209,T387-IRAK1 hp-IRAK1/or p-IRAK2 TRAF6K63polyUb-TRAF6 ADPTLR8 p-S477,S479-IRF7 TLR7IMIQ R-848 p-IRAK2 TLR7ATPIRAK4 p-T342,T345,S346-IRAK4 TLR8 TLR7K63polyUb-hp-IRAK1 TLR7IMIQ UBE2V1 R-848 IRAK1 p-3S,3T-IRAK1p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9TLR9K63polyUb-TRAF6 p-T209,T387-IRAK1 IMIQ p-IRAK2oligo-TRAF6p-IRAK1p-IRAK4oligo-MyD88activated TLR7/8 or 9 complexTLR7TLR8 TLR8 TLR8 IMIQ TLR8 K63polyUb-hp-IRAK1 p-T342,T345,S346-IRAK4 TLR7TAB3hp-IRAK1 or p-IRAK2 bound to the pIRAK4MyD88activated TLR7/8 or 9 complexIRF7 TLR9TRAF6p-3S,3T-IRAK1p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9TLR8 MYD88TLR8 TLR9ATPMYD88 ADPMYD88 TAB1 p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9 receptorIRAK1, IRAK2TRAF6 ATPp-T184,T187-MAP3K7 TLR8 p-IRAK2K63-linked pUb oligo-TRAF6free K63 pUbTAK1 complexIMIQ MYD88 R-848 p-2S,S376,T,T209,T387-IRAK1 TLR8 MYD88 TRAF6hp-IRAK1PellinoK63polyUb-IRF7 p-IRAK2K63-linked pUb oligo-TRAF6IMIQ TRAF6p-IRAK2TLR9p-T342,T345,S346-IRAK4 p-S477,S479-IRF7TRAF6 TAB3TLR7p-T342,T345,S346-IRAK4 TLR8 IMIQ TLR9p-2S,S376,T,T209,T387-IRAK1 p-T342,T345,S346-IRAK4 TAK1 complexTLR9K63-linked poly-Ub-p-3S,3T-IRAK1TRAF6ECSITADPTLR7IKBKB TRAF6 UBE2N pp-IRAK1p-IRAK4oligo-MyD88activated TLR 7/8 or 9 complexIMIQ IMIQ R-848 R-848 p-T342,T345,S346-IRAK4 TRAF6ATPTRAF6 K63-linked poly-Ub-IRF7TRAF6p-3S,3T-IRAK1p-S,2T-IRAK4oligo-MyD88activated TLR7/8 or 9.p-IRAK2p-IRAK4oligo-MyD88activated TLR 7/8 or9p-IRAK2K63-linked pUb oligo-TRAF6free K63-linked pUbp-TAK1complexp-T342,T345,S346-IRAK4 TLR9TLR8 p-IRAK2 TLR7MAP3K1TRAF6 ATP32743474327178, 15, 45, 49513, 4343337434730, 51479416, 253


Description

Upon binding of their ligands, TLR7/8 and TLR9 recruit a cytoplasmic adaptor MyD88 and IRAKs, downstream of which the signaling pathways are divided to induce either inflammatory cytokines or type I IFNs. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=975155

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  53. 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
  54. 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
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  58. Ye H, Arron JR, Lamothe B, Cirilli M, Kobayashi T, Shevde NK, Segal D, Dzivenu OK, Vologodskaia M, Yim M, Du K, Singh S, Pike JW, Darnay BG, Choi Y, Wu H.; ''Distinct molecular mechanism for initiating TRAF6 signalling.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
114887view16:40, 25 January 2021ReactomeTeamReactome version 75
113333view11:40, 2 November 2020ReactomeTeamReactome version 74
112544view15:51, 9 October 2020ReactomeTeamReactome version 73
101458view11:32, 1 November 2018ReactomeTeamreactome version 66
100996view21:11, 31 October 2018ReactomeTeamreactome version 65
100532view19:45, 31 October 2018ReactomeTeamreactome version 64
100079view16:30, 31 October 2018ReactomeTeamreactome version 63
99630view15:01, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99236view12:44, 31 October 2018ReactomeTeamreactome version 62
93914view13:44, 16 August 2017ReactomeTeamreactome version 61
93490view11:25, 9 August 2017ReactomeTeamreactome version 61
88012view13:29, 25 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86586view09:21, 11 July 2016ReactomeTeamreactome version 56
83202view10:22, 18 November 2015ReactomeTeamVersion54
81580view13:07, 21 August 2015ReactomeTeamVersion53
77040view08:34, 17 July 2014ReactomeTeamFixed remaining interactions
76745view12:10, 16 July 2014ReactomeTeamFixed remaining interactions
76070view10:13, 11 June 2014ReactomeTeamRe-fixing comment source
75780view11:30, 10 June 2014ReactomeTeamReactome 48 Update
75130view14:07, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74844view10:07, 30 April 2014ReactomeTeamReactome46
74777view08:51, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated TLR7-9 homodimersComplexREACT_26986 (Reactome)
CHUK ProteinO15111 (Uniprot-TrEMBL)
DHX36

CpG

MyD88		ComplexREACT_161245 (Reactome)
DHX36 ProteinQ9H2U1 (Uniprot-TrEMBL)
ECSITProteinQ9BQ95 (Uniprot-TrEMBL)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IKKA

IKKB

NEMO		ComplexREACT_7693 (Reactome)
IMIQ MetaboliteCHEBI:36704 (ChEBI)
IRAK1

p-S,2T-IRAK4 oligo-MyD88

activated TLR 7/8 or 9		ComplexREACT_26100 (Reactome)
IRAK1 ProteinP51617 (Uniprot-TrEMBL)
IRAK1, IRAK2ProteinREACT_26678 (Reactome)
IRAK1/or IRAK2

p-S,2T-IRAK4 oligo-MyD88

activated TLR 7/8 or 9		ComplexREACT_27033 (Reactome)
IRAK2

p-S,2T-IRAK4 oligo-MyD88

activated TLR 7/8 or9		ComplexREACT_25986 (Reactome)
IRAK2 ProteinO43187 (Uniprot-TrEMBL)
IRAK4

oligo-MyD88

activated TLR 7/8 or 9		ComplexREACT_25785 (Reactome)
IRAK4 ProteinQ9NWZ3 (Uniprot-TrEMBL)
IRAK4ProteinQ9NWZ3 (Uniprot-TrEMBL)
IRF7

TRAF6 p-3S,3T-IRAK1 p-S,2T-IRAK4 oligo-MyD88

activated TLR7/8 or 9		ComplexREACT_25804 (Reactome)
IRF7 ProteinQ92985 (Uniprot-TrEMBL)
IRF7ProteinQ92985 (Uniprot-TrEMBL)
K63-linked poly-Ub-IRF7

TRAF6 p-3S,3T-IRAK1 p-S,2T-IRAK4 oligo-MyD88

activated TLR7/8 or 9.		ComplexREACT_26203 (Reactome)
K63-linked poly-Ub-p-3S,3T-IRAK1 TRAF6ComplexREACT_25541 (Reactome)
K63polyUb-IRF7 ProteinQ92985 (Uniprot-TrEMBL)
K63polyUb-TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
K63polyUb-hp-IRAK1 ProteinP51617 (Uniprot-TrEMBL)
K63polyUbREACT_21645 (Reactome)
MAP kinase activation in TLR cascadePathwayREACT_21308 (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.

MAP3K1ProteinQ13233 (Uniprot-TrEMBL)
MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
MEKK1 activated TRAF6ComplexREACT_7633 (Reactome)
MYD88 ProteinQ99836 (Uniprot-TrEMBL)
MYD88ProteinQ99836 (Uniprot-TrEMBL)
MyD88 complexed with the activated TLR receptorComplexREACT_25822 (Reactome)
R-848 MetaboliteCHEBI:36706 (ChEBI)
TAB1 ProteinQ15750 (Uniprot-TrEMBL)
TAB2 ProteinQ9NYJ8 (Uniprot-TrEMBL)
TAB3ProteinQ8N5C8 (Uniprot-TrEMBL)
TAK1 activates NFkB by phosphorylation and activation of IKKs complexPathwayREACT_21281 (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 complexComplexREACT_22633 (Reactome)
TLR7ProteinQ9NYK1 (Uniprot-TrEMBL)
TLR8 ProteinQ9NR97 (Uniprot-TrEMBL)
TLR9ProteinQ9NR96 (Uniprot-TrEMBL)
TRAF6

K63-linked polyUb p-IRAK1

IKK complex		ComplexREACT_25723 (Reactome)
TRAF6

hp-IRAK1

Pellino		ComplexREACT_26018 (Reactome)
TRAF6

hp-IRAK1/or p-IRAK2 p-IRAK4 oligo-MyD88

activated TLR7/8 or 9		ComplexREACT_26553 (Reactome)
TRAF6 hp-IRAK1ComplexREACT_26576 (Reactome)
TRAF6

p-3S,3T-IRAK1 p-S,2T-IRAK4 oligo-MyD88

activated TLR7/8 or 9		ComplexREACT_26628 (Reactome)
TRAF6 p-IRAK2ComplexREACT_26288 (Reactome)
TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRAF6ProteinQ9Y4K3 (Uniprot-TrEMBL)
UBE2N ProteinP61088 (Uniprot-TrEMBL)
UBE2V1 ProteinQ13404 (Uniprot-TrEMBL)
UbProteinREACT_3316 (Reactome)
Ubc13 UBE2V1ComplexREACT_12995 (Reactome)
hp-IRAK1 or p-IRAK2 bound to the pIRAK4

MyD88

activated TLR7/8 or 9 complex		ComplexREACT_25476 (Reactome)
hp-IRAK1/or p-IRAK2 TRAF6ComplexREACT_26363 (Reactome)
oligo-MyD88 activated TLR7-9ComplexREACT_26395 (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-2S-IRF7 p-2S-IRF7ComplexREACT_21640 (Reactome)
p-2S-IRF7 p-2S-IRF7ComplexREACT_21965 (Reactome)
p-3S,3T-IRAK1

p-S,2T-IRAK4 oligo-MyD88

activated TLR7/8 or 9		ComplexREACT_26344 (Reactome)
p-IRAK1

p-IRAK4 oligo-MyD88

activated TLR7/8 or 9 complex		ComplexREACT_25811 (Reactome)
p-IRAK2

K63-linked pUb oligo-TRAF6 free K63 pUb

TAK1 complex		ComplexREACT_26866 (Reactome)
p-IRAK2

K63-linked pUb oligo-TRAF6 free K63-linked pUb

p-TAK1complex		ComplexREACT_27039 (Reactome)
p-IRAK2 K63-linked pUb oligo-TRAF6ComplexREACT_26097 (Reactome)
p-IRAK2 oligo-TRAF6ComplexREACT_26729 (Reactome)
p-IRAK2

p-IRAK4 oligo-MyD88

activated TLR 7/8 or9		ComplexREACT_26505 (Reactome)
p-IRAK2 ProteinO43187 (Uniprot-TrEMBL)
p-Pellino

hp-IRAK1

TRAF6		ComplexREACT_26952 (Reactome)
p-Pellino-1,2,ProteinREACT_22733 (Reactome)
p-S,2T-IRAK4

oligo-MyD88

activated TLR7/8 or 9 receptor		ComplexREACT_26627 (Reactome)
p-S477,S479-IRF7 ProteinQ92985 (Uniprot-TrEMBL)
p-S477,S479-IRF7ProteinQ92985 (Uniprot-TrEMBL)
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

activated TLR 7/8 or 9 complex		ComplexREACT_25729 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowREACT_24948 (Reactome)
ADPArrowREACT_25001 (Reactome)
ADPArrowREACT_25002 (Reactome)
ADPArrowREACT_25011 (Reactome)
ADPArrowREACT_25086 (Reactome)
ADPArrowREACT_25111 (Reactome)
ADPArrowREACT_25184 (Reactome)
ADPArrowREACT_25241 (Reactome)
ATPREACT_24948 (Reactome)
ATPREACT_25001 (Reactome)
ATPREACT_25002 (Reactome)
ATPREACT_25011 (Reactome)
ATPREACT_25086 (Reactome)
ATPREACT_25111 (Reactome)
ATPREACT_25184 (Reactome)
ATPREACT_25241 (Reactome)
Activated TLR7-9 homodimersREACT_24964 (Reactome)
DHX36

CpG

MyD88		ArrowREACT_24920 (Reactome)
ECSITArrowREACT_6962 (Reactome)
IKKA

IKKB

NEMO		REACT_25072 (Reactome)
IRAK1

p-S,2T-IRAK4 oligo-MyD88

activated TLR 7/8 or 9		REACT_25086 (Reactome)
IRAK1

p-S,2T-IRAK4 oligo-MyD88

activated TLR 7/8 or 9		mim-catalysisREACT_25086 (Reactome)
IRAK1, IRAK2REACT_24966 (Reactome)
IRAK2

p-S,2T-IRAK4 oligo-MyD88

activated TLR 7/8 or9		REACT_25002 (Reactome)
IRAK2

p-S,2T-IRAK4 oligo-MyD88

activated TLR 7/8 or9		mim-catalysisREACT_25002 (Reactome)
IRAK4

oligo-MyD88

activated TLR 7/8 or 9		REACT_25011 (Reactome)
IRAK4

oligo-MyD88

activated TLR 7/8 or 9		mim-catalysisREACT_25011 (Reactome)
IRAK4REACT_24953 (Reactome)
IRF7

TRAF6 p-3S,3T-IRAK1 p-S,2T-IRAK4 oligo-MyD88

activated TLR7/8 or 9		REACT_25001 (Reactome)
IRF7

TRAF6 p-3S,3T-IRAK1 p-S,2T-IRAK4 oligo-MyD88

activated TLR7/8 or 9		REACT_25090 (Reactome)
IRF7

TRAF6 p-3S,3T-IRAK1 p-S,2T-IRAK4 oligo-MyD88

activated TLR7/8 or 9		mim-catalysisREACT_25090 (Reactome)
IRF7REACT_25312 (Reactome)
K63-linked poly-Ub-IRF7

TRAF6 p-3S,3T-IRAK1 p-S,2T-IRAK4 oligo-MyD88

activated TLR7/8 or 9.		ArrowREACT_25090 (Reactome)
K63-linked poly-Ub-p-3S,3T-IRAK1 TRAF6ArrowREACT_24976 (Reactome)
K63-linked poly-Ub-p-3S,3T-IRAK1 TRAF6REACT_25072 (Reactome)
K63polyUbREACT_24976 (Reactome)
K63polyUbREACT_25090 (Reactome)
K63polyUbREACT_25322 (Reactome)
MAP3K1REACT_6962 (Reactome)
MYD88REACT_24964 (Reactome)
MYD88REACT_25392 (Reactome)
MyD88 complexed with the activated TLR receptorREACT_25392 (Reactome)
REACT_21364 (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.
REACT_24920 (Reactome) p-IRF7 dimers are then transported into the nucleus and assemble with the coactivator CBP/p300 to activate transcription of type I interferons and other target genes.
REACT_24948 (Reactome) Second, Thr387 in the activation loop is phosphorylated, leading to full enzymatic activity.
REACT_24953 (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].
REACT_24960 (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.
REACT_24964 (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.
REACT_24966 (Reactome)
  • MYD88 recruits unphosphorylated, inactive IRAK1 to the IL1 receptor complex.
  • IRAK2 has been implicated in IL1R and TLR signaling by the observation that IRAK2 can associate with MyD88 and Mal (Muzio et al. 1997). Like IRAK1, IRAK2 is activated downstream of IRAK4 (Kawagoe et al. 2008). It has been suggested that IRAK1 activates IRAK2 (Wesche et al. 1999) but IRAK2 phosphorylation is observed in IRAK1–/– mouse macrophages while IRAK4 deficiency abrogates IRAK2 phosphorylation (Kawagoe et al. 2008), suggesting that activated IRAK4 phosphorylates IRAK2 as it does IRAK1. IL6 production in response to IL1beta is impaired in embryonic fibroblasts from IRAK1 or IRAK2 knockout mice and abrogated in IRAK1/2 dual knockouts (Kawagoe et al. 2007) suggesting that IRAK1 and IRAK2 are both involved in IL1R signaling downstream of IRAK4.
REACT_24976 (Reactome) IL1 induces the poly-ubiquitination and degradation of IRAK1. This was believed to be K48-linked polyubiquitination, targeting IRAK1 for proteolysis by the proteasome, but recently IL-1R signaling has been shown to lead to K63-linked polyubiquitination of IRAK1 (Windheim et al. 2008; Conze et al. 2008), and demonstrated to have a role in the activation of NF-kappaB. IRAK1 is ubiquitinated on K134 and K180; mutation of these sites impairs IL1R-mediated ubiquitylation of IRAK1 (Conze et al. 2008). Some authors have proposed a role for TRAF6 as the E3 ubiquitin ligase that catalyzes polyubiquitination of IRAK1 (Conze et al. 2008) but this view has been refuted (Windheim et al. 2008; Xiao et al. 2008). There is stronger agreement that Pellino proteins have a role as IRAK1 E3 ubiquitin ligases.
Pellino1-3 possess E3 ligase activity and are believed to directly catalyse polyubiquitylation of IRAK1 (Xiao et al. 2008; Butler et al. 2007; Ordureau et al. 2008). They are capable of catalysing the formation of K63- and K48-linked polyubiquitin chains; the type of linkage is controlled by the collaborating E2 enzyme. All the Pellino proteins can combine with the E2 heterodimer UbcH13–Uev1a to catalyze K63-linked ubiquitylation (Ordureau et al. 2008).
REACT_24996 (Reactome) TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein. In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex.
REACT_25001 (Reactome) IRF7 is phosphorylated on Ser477 and Ser479 residues [Lin R et al 2000] . IRAK1[Uematsu et al 2005] and IKK alpha[Hoshino et al 2006] are thought to mediate the phosphorylation upon TLR7/8/9 activation.
REACT_25002 (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.

REACT_25011 (Reactome) IRAK4 is activated by autophosphorylation at 3 positions within the kinase activation loop, Thr-342, Thr-345 and Ser-346.
REACT_25023 (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.

REACT_25072 (Reactome) NF-kappa-B essential modulator (NEMO, also known as IKKG abbreviated from Inhibitor of nuclear factor kappa-B kinase subunit gamma) is the regulatory subunit of the IKK complex which phosphorylates inhibitors of NF-kappa-B leading to dissociation of the inhibitor/NF-kappa-B complex. NEMO binds to K63-pUb chains (Ea et al. 2006; Wu et al. 2006), linking K63-pUb-hp-IRAK1 with the IKK complex. Models of IL-1R dependent activation of NF-kappaB suggest that the polyubiquitination of both TRAF6 and IRAK1 within a TRAF6:IRAK1 complex and their subsequent interactions with the TAK1 complex and IKK complex respectively brings these complexes into proximity, facilitating the TAK1-catalyzed activation of IKK (Moynagh, 2008).
REACT_25086 (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.
REACT_25090 (Reactome) TRAF6 E3 ubiquitin ligase activity was shown to be essential for IRF7 activation, although the role of TRAF6-dependent ubiquitination remains unclear [Kawai T et al 2004]. It has been demonstrated that IRF7 is ubiquitinated by TRAF6 at multiple sites both in vitro and in vivo[Ning et al 2008].It has been also shown that K63-linked ubiquitination of IRF7 is independent of its C-terminal functional phosphorylation sites.
REACT_25111 (Reactome) The TAK1 complex consists of the transforming growth factor-? (TGF-beta)-activated kinase (TAK1) and the TAK1-binding proteins TAB1, TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Sakurai H et al 2000; Shibuya H et al 2000). TAB1 promotes autophosphorylation of the TAK1 kinase activation lobe, likely through an allosteric mechanism (Sakurai H et al 2000 ; Kishimoyo K et al 2000). The TAK1 complex is regulated by polyubiquitination. The TAK1 complex consists of the transforming growth factor-? (TGF- ?)-activated kinase (TAK1) and the TAK1-binding proteins TAB1, TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya H et al 1996; Sakurai H et al 2000). TAB1 promotes autophosphorylation of the TAK1 kinase activation lobe, likely through an allosteric mechanism (Brown K et al 2005; Ono K et al 2001). The TAK1 complex is regulated by polyubiquitination. Binding of TAB2 and TAB3 to Lys63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Binding of multiple TAK1 complexes onto the same polyubiquitin chain may promote oligomerization of TAK1, facilitating TAK1 autophosphorylation and subsequent activation of its kinase activity (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that leads to the activation of TAK1. Another possibility is that TAB2/3 may recruit the IKK complex by binding to ubiquitinated NEMO; polyubiquitin chains may function as a scaffold for higher order signaling complexes that allow interaction between TAK1 and IKK (Kanayama et al. 2004).
REACT_25150 (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).
  • 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).
REACT_25184 (Reactome) A series of sequential phosphorylation events lead to full or hyper-phopshorylation of IRAK1. Under in vitro conditions these are all autophosphorylation events. First, Thr-209 is phosphorylated resulting in a conformational change of the kinase domain. Next, Thr-387 in the activation loop is phosphorylated, leading to full enzymatic activity. Several additional residues are phosphorylated in the proline-, serine-, and threonine-rich (ProST) region between the N-terminal death domain and kinase domain. Hyperphosphorylation of this region leads to dissociation of IRAK1 from the upstream adapters MyD88 and Tollip. The significance of these phosphorylation events is not clear; the kinase activity of IRAK1 is dispensable for IL1-induced NFkB and MAP kinase activation (Knop & Martin, 1999), unlike that of IRAK4 (Suzuki et al. 2002; Kozicak-Holbro et al. 2007), so IRAK1 is believed to act primarily as an adaptor for TRAF6 (Conze et al. 2008).
REACT_25241 (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.
REACT_25251 (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.

REACT_25292 (Reactome) Phosphorylation stimulates the C-terminal autoinhibitory domain of IRF7 to attain a highly extended conformation triggering dimerization through extensive contacts to a second IRF7 subunit.
REACT_25312 (Reactome) Upon TLR7/8 or 9 stimulation IRF7, but not IRF3, forms a signaling complex with MyD88, TRAF6[Honda K et al 2004, Kawai T et al 2004], IRAK1 [Uematsu S et al 2005], Also IRAK4 was shown to mediate IRF7 activation[Honda K et al 2004].
REACT_25322 (Reactome) TAK1-binding protein 2 (TAB2) and/or TAB3, as part of a complex that also contains TAK1 and TAB1, binds polyubiquitinated TRAF6. The TAB2 and TAB3 regulatory subunits of the TAK1 complex contain C-terminal Npl4 zinc finger (NZF) motifs that recognize with Lys63-pUb chains (Kanayama et al. 2004). The recognition mechanism is specific for Lys63-linked ubiquitin chains [Kulathu Y et al 2009]. TAK1 can be activated by unattached Lys63-polyubiquitinated chains when TRAF6 has no detectable polyubiquitination (Xia et al. 2009) and thus the synthesis of these chains by TRAF6 may be the signal transduction mechanism.
REACT_25392 (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).
REACT_6962 (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.

TAK1 complexREACT_25322 (Reactome)
TRAF6

hp-IRAK1

Pellino		REACT_25241 (Reactome)
TRAF6

hp-IRAK1

Pellino		mim-catalysisREACT_25241 (Reactome)
TRAF6 hp-IRAK1REACT_25023 (Reactome)
TRAF6

p-3S,3T-IRAK1 p-S,2T-IRAK4 oligo-MyD88

activated TLR7/8 or 9		ArrowREACT_25001 (Reactome)
TRAF6

p-3S,3T-IRAK1 p-S,2T-IRAK4 oligo-MyD88

activated TLR7/8 or 9		REACT_25312 (Reactome)
TRAF6 p-IRAK2REACT_24960 (Reactome)
TRAF6REACT_24960 (Reactome)
TRAF6REACT_25150 (Reactome)
TRAF6REACT_6962 (Reactome)
TRAF6mim-catalysisREACT_21364 (Reactome)
UbREACT_24996 (Reactome)
Ubc13 UBE2V1ArrowREACT_24976 (Reactome)
Ubc13 UBE2V1ArrowREACT_25090 (Reactome)
Ubc13 UBE2V1REACT_24976 (Reactome)
Ubc13 UBE2V1REACT_25090 (Reactome)
hp-IRAK1 or p-IRAK2 bound to the pIRAK4

MyD88

activated TLR7/8 or 9 complex		REACT_25150 (Reactome)
hp-IRAK1/or p-IRAK2 TRAF6ArrowREACT_25251 (Reactome)
oligo-MyD88 activated TLR7-9REACT_24953 (Reactome)
p-3S,3T-IRAK1

p-S,2T-IRAK4 oligo-MyD88

activated TLR7/8 or 9		ArrowREACT_25184 (Reactome)
p-IRAK1

p-IRAK4 oligo-MyD88

activated TLR7/8 or 9 complex		ArrowREACT_25086 (Reactome)
p-IRAK1

p-IRAK4 oligo-MyD88

activated TLR7/8 or 9 complex		REACT_24948 (Reactome)
p-IRAK1

p-IRAK4 oligo-MyD88

activated TLR7/8 or 9 complex		mim-catalysisREACT_24948 (Reactome)
p-IRAK2

K63-linked pUb oligo-TRAF6 free K63 pUb

TAK1 complex		REACT_25111 (Reactome)
p-IRAK2

K63-linked pUb oligo-TRAF6 free K63-linked pUb

p-TAK1complex		ArrowREACT_25111 (Reactome)
p-IRAK2 K63-linked pUb oligo-TRAF6REACT_25322 (Reactome)
p-IRAK2 oligo-TRAF6REACT_24996 (Reactome)
p-IRAK2 oligo-TRAF6mim-catalysisREACT_24996 (Reactome)
p-IRAK2

p-IRAK4 oligo-MyD88

activated TLR 7/8 or9		ArrowREACT_25002 (Reactome)
p-Pellino

hp-IRAK1

TRAF6		ArrowREACT_25241 (Reactome)
p-Pellino

hp-IRAK1

TRAF6		REACT_24976 (Reactome)
p-Pellino

hp-IRAK1

TRAF6		mim-catalysisREACT_24976 (Reactome)
p-Pellino-1,2,ArrowREACT_24976 (Reactome)
p-Pellino-1,2,REACT_25023 (Reactome)
p-S,2T-IRAK4

oligo-MyD88

activated TLR7/8 or 9 receptor		ArrowREACT_25011 (Reactome)
p-S,2T-IRAK4

oligo-MyD88

activated TLR7/8 or 9 receptor		ArrowREACT_25251 (Reactome)
p-S,2T-IRAK4

oligo-MyD88

activated TLR7/8 or 9 receptor		REACT_24966 (Reactome)
p-S477,S479-IRF7ArrowREACT_25001 (Reactome)
pp-IRAK1

p-IRAK4 oligo-MyD88

activated TLR 7/8 or 9 complex		ArrowREACT_24948 (Reactome)
pp-IRAK1

p-IRAK4 oligo-MyD88

activated TLR 7/8 or 9 complex		REACT_25184 (Reactome)
pp-IRAK1

p-IRAK4 oligo-MyD88

activated TLR 7/8 or 9 complex		mim-catalysisREACT_25184 (Reactome)
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