MyD88 dependent cascade initiated on endosome (Homo sapiens)

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2, 15, 271, 1731, 3525, 35, 44, 5810, 24, 3620, 29, 34, 477, 46, 536, 21, 5728, 37, 557, 13, 42, 465717, 533216, 38, 48, 5312, 39, 5439, 52, 542231, 483118, 265, 12, 3046, 564, 49401, 17319, 50endosome lumennucleoplasmcytosolTRAF6:K63-linkedpolyUb p-IRAK1:IKKcomplexTICAM1 HCV dsRNA intermediate form TLR8 ADPMYD88 p-IRAK2 K63polyUb-TRAF6 TLR8 Imidazoquinoline compounds Imidazoquinoline compounds ADPp-Pellino-1,2,(3)TLR8 TLR8 MYD88 ssRNA UBC(533-608) IKBKB p-T342,T345,S346-IRAK4 IRAK4TRAF6 ATPssRNA Unmethylated CpG DNA TRAF6 TAB1 MYD88 Unmethylated CpG DNA CHUK IRF7 ATPp-PELI2 TRAF6 IRAK4:oligo-MyD88:activated TLR 7/8 or 9TLR9(?-1032) p-2S,S376,T,T209,T387-IRAK1 K63polyUb-hp-IRAK1 MYD88IKBKG ssRNA K63-linkedpoly-Ub-IRF7:TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9.TAB2 TAB3 TRAF6 p-Pellino:hp-IRAK1:TRAF6Imidazoquinoline compounds TRAF6 Imidazoquinoline compounds TRAF6 TLR7(?-1049) p-T209,T387-IRAK1 MYD88 Imidazoquinoline compounds Imidazoquinoline compounds TLR8 UBE2N:UBE2V1TLR7(?-1049) TLR9(?-1032) p-T342,T345,S346-IRAK4 K63polyUb-TRAF6 IRAK1 p-T342,T345,S346-IRAK4 Imidazoquinoline compounds MYD88 hp-IRAK1orp-IRAK2boundtothepIRAK4:MyD88:activated TLR7/8 or 9 complexp-PELI1 p-2S,S376,T,T209,T387-IRAK1 TLR8 UBB(153-228) UBB(77-152) TLR7(?-1049) IRF7:TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9TLR9(?-1032) UBE2N:UBE2V1ssRNA IRAK1, IRAK2TRAF6 IRAK2 ssRNA TLR9(?-1032) ADPMYD88 Unmethylated CpG DNA GPIN-CD14(20-345) p-2S,S376,T,T209,T387-IRAK1 ATPTICAM1 p-PELI1 TLR8 UbTLR9(?-1032) p-PELI3 Imidazoquinoline compounds p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9Imidazoquinoline compounds TAB1 TLR8 CHUK:IKBKB:IKBKGp-Pellino-1,2,(3)TRAF6ATPInfluenza A dsRNA intermediate form p-PELI2 TLR7(?-1049) MYD88 p-S477,S479-IRF7 p-IRAK2 TLR7(?-1049) Rotavirus dsRNA ADPMAP3K7 p-PELI1 TRAF6:hp-IRAK1/orp-IRAK2:p-IRAK4:oligo-MyD88:activated TLR7/8 or 9ATPUnmethylated CpG DNA IRAK2:p-S,2T-IRAK4:oligo-MyD88:activated TLR 7/8 or9TLR7(?-1049) K63polyUb-TRAF6 TLR8 TLR9(?-1032) ssRNA p-IRAK1:p-IRAK4:oligo-MyD88:activated TLR7/8 or 9 complexUnmethylated CpG DNA p-IRAK2 MYD88 K63polyUb-IRF7 TLR9(?-1032) IRAK2 CHUK TRAF6TLR9(?-1032) TAK1 activates NFkBby phosphorylationand activation ofIKKs complexp-T184,T187-MAP3K7 p-PELI2 ATPTLR8 p-T342,T345,S346-IRAK4 HBV dsRNA intermediate form Imidazoquinoline compounds TRAF6 TRAF6 TLR7(?-1049) p-IRAK2 MYD88 UBC(305-380) p-PELI1 p-2S,S376,T,T209,T387-IRAK1 ADPMyD88 complexed withthe activated TLRreceptoroligo-MyD88:activated TLR7-9p-IRAK2:K63-linkedpUb oligo-TRAF6K63polyUbTLR7(?-1049) p-PELI3 TLR9(?-1032) ADPp-T342,T345,S346-IRAK4 MyrG-p-S16-TICAM2 p-IRAK2 p-2S,S376,T,T209,T387-IRAK1 ssRNA UBC(457-532) TAB2 TRAF6:hp-IRAK1:PellinoTLR8 ssRNA IRAK1/orIRAK2:p-S,2T-IRAK4:oligo-MyD88:activated TLR 7/8 or 9ssRNA IRF7p-2S,S376,T,T209,T387-IRAK1 TLR7(?-1049) p-IRAK2:K63-linkedpUboligo-TRAF6:freeK63 pUb:TAK1complexImidazoquinoline compounds UBE2V1 p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9 receptorTLR8 ssRNA ATPImidazoquinoline compounds TRAF6 HSV1 dsRNA intermediate form K63polyUbp-IRAK2 Unmethylated CpG DNA MAP3K7 TLR7(?-1049) p-IRAK2:K63-linkedpUboligo-TRAF6:freeK63-linkedpUb:p-TAK1complexp-2S,S376,T,T209,T387-IRAK1 TAB3 UBC(1-76) p-IRAK2:p-IRAK4:oligo-MyD88:activated TLR 7/8 or9TLR7(?-1049) p-T342,T345,S346-IRAK4 UBC(153-228) K63polyUbssRNA TLR3 TLR7(?-1049) ATPMYD88 LPS TRAF6:p-IRAK2MYD88 IRAK4 Unmethylated CpG DNA Unmethylated CpG DNA p-T342,T345,S346-IRAK4 TRAF6:hp-IRAK1TRAF6 TLR9(?-1032) UBE2N MYD88 UBC(77-152) UBA52(1-76) Imidazoquinoline compounds TLR7(?-1049) Unmethylated CpG DNA TLR7(?-1049) Unmethylated CpG DNA p-T209-IRAK1 ssRNA TLR8 TAB2 TAK1 complexUnmethylated CpG DNA p-IRAK2 TLR9(?-1032) IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR 7/8 or 9K63-linked polyUbTRAF6 complexesssRNA p-2S,S376,T,T209,T387-IRAK1 Unmethylated CpG DNA p-IRAK2 IKBKG ADPUBC(609-684) p-PELI3 UBE2V1 K63polyUb TLR8 p-T342,T345,S346-IRAK4 p-2S,S376,T,T209,T387-IRAK1 TLR8 pp-IRAK1:p-IRAK4:oligo-MyD88:activated TLR 7/8 or 9 complexTRAF6 IKBKB TLR9(?-1032) MAP3K1 K63polyUb-TRAF6 p-PELI3 2xp-S477,S479-IRF7Activated TLR7-9homodimersTLR7(?-1049) IRAK1 TAB1 p-T342,T345,S346-IRAK4 ADPp-S477,S479-IRF7 IRAK2 p-2S-IRF7:p-2S-IRF7ssRNA p-T342,T345,S346-IRAK4 TLR9(?-1032) TLR4 p-T342,T345,S346-IRAK4 K63-linkedpoly-Ub-p-3S,3T-IRAK1:TRAF6hp-IRAK1/or p-IRAK2:TRAF6MYD88 MYD88 Unmethylated CpG DNA TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9Unmethylated CpG DNA UBC(381-456) p-IRAK2:oligo-TRAF6Imidazoquinoline compounds TLR9(?-1032) ssRNA Imidazoquinoline compounds MEKK1:activatedTRAF6ssRNA UBC(229-304) p-T342,T345,S346-IRAK4 p-S477,S479-IRF7TLR7(?-1049) p-T342,T345,S346-IRAK4 IRAK1 UBB(1-76) MAP kinaseactivationp-IRAK2 RPS27A(1-76) ECSITMAP3K1ssRNA TAB3 MYD88 MYD88 Unmethylated CpG DNA K63polyUb-TRAF6 p-PELI2 p-IRAK2 K63polyUb-hp-IRAK1 Unmethylated CpG DNA TLR8 LY96 p-2S,S376,T,T209,T387-IRAK1 TLR7(?-1049) Imidazoquinoline compounds K63polyUb TLR8 TRAF6 TLR9(?-1032) TLR9(?-1032) Unmethylated CpG DNA UBE2N TLR9(?-1032) Imidazoquinoline compounds 33172833123, 8, 23, 595252532222562841, 43125352532853227, 4628, 532845522219, 43224611, 14, 51


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. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 975155
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: de Bono, Bernard

Quality Tags

Ontology Terms

 

Bibliography

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History

View all...
CompareRevisionActionTimeUserComment
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
2xp-S477,S479-IRF7ComplexR-HSA-450306 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated TLR7-9 homodimersComplexR-HSA-975158 (Reactome)
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.
ECSITProteinQ9BQ95 (Uniprot-TrEMBL)
GPIN-CD14(20-345) ProteinP08571 (Uniprot-TrEMBL)
HBV dsRNA intermediate form R-HBV-8982481 (Reactome)
HCV dsRNA intermediate form R-HCV-8982462 (Reactome)
HSV1 dsRNA intermediate form R-HER-6791257 (Reactome)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IRAK1 ProteinP51617 (Uniprot-TrEMBL)
IRAK1, IRAK2ComplexR-HSA-937023 (Reactome)
IRAK1/or

IRAK2

p-S,2T-IRAK4:oligo-MyD88:activated TLR 7/8 or 9
ComplexR-HSA-975113 (Reactome)
IRAK1:p-S,2T-IRAK4
oligo-MyD88:activated TLR 7/8 or 9
ComplexR-HSA-975132 (Reactome)
IRAK2 ProteinO43187 (Uniprot-TrEMBL)
IRAK2:p-S,2T-IRAK4:oligo-MyD88:activated TLR 7/8 or9ComplexR-HSA-975146 (Reactome)
IRAK4 ProteinQ9NWZ3 (Uniprot-TrEMBL)
IRAK4:oligo-MyD88:activated TLR 7/8 or 9ComplexR-HSA-975183 (Reactome)
IRAK4ProteinQ9NWZ3 (Uniprot-TrEMBL)
IRF7 ProteinQ92985 (Uniprot-TrEMBL)
IRF7:TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9ComplexR-HSA-975131 (Reactome)
IRF7ProteinQ92985 (Uniprot-TrEMBL)
Imidazoquinoline compounds R-ALL-188128 (Reactome)
Influenza A dsRNA intermediate form R-FLU-9028895 (Reactome)
K63-linked poly-Ub-IRF7:TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9.ComplexR-HSA-975174 (Reactome)
K63-linked poly-Ub-p-3S,3T-IRAK1:TRAF6ComplexR-HSA-975172 (Reactome)
K63-linked polyUb TRAF6 complexesComplexR-HSA-975153 (Reactome)
K63polyUb R-HSA-450152 (Reactome)
K63polyUb-IRF7 ProteinQ92985 (Uniprot-TrEMBL)
K63polyUb-TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
K63polyUb-hp-IRAK1 ProteinP51617 (Uniprot-TrEMBL)
K63polyUbR-HSA-450152 (Reactome)
LPS MetaboliteCHEBI:16412 (ChEBI)
LY96 ProteinQ9Y6Y9 (Uniprot-TrEMBL)
MAP kinase activationPathwayR-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)
MyD88 complexed with

the activated TLR

receptor
ComplexR-HSA-975124 (Reactome)
MyrG-p-S16-TICAM2 ProteinQ86XR7 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
Rotavirus dsRNA R-ROT-8982440 (Reactome)
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)
TICAM1 ProteinQ8IUC6 (Uniprot-TrEMBL)
TLR3 ProteinO15455 (Uniprot-TrEMBL)
TLR4 ProteinO00206 (Uniprot-TrEMBL)
TLR7(?-1049) ProteinQ9NYK1 (Uniprot-TrEMBL)
TLR8 ProteinQ9NR97 (Uniprot-TrEMBL)
TLR9(?-1032) ProteinQ9NR96 (Uniprot-TrEMBL)
TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRAF6:K63-linked

polyUb p-IRAK1:IKK

complex
ComplexR-HSA-975121 (Reactome)
TRAF6:hp-IRAK1/or p-IRAK2:p-IRAK4:oligo-MyD88:activated TLR7/8 or 9ComplexR-HSA-975182 (Reactome)
TRAF6:hp-IRAK1:PellinoComplexR-HSA-975143 (Reactome)
TRAF6:hp-IRAK1ComplexR-HSA-975150 (Reactome)
TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9ComplexR-HSA-975148 (Reactome)
TRAF6:p-IRAK2ComplexR-HSA-975108 (Reactome)
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:UBE2V1ComplexR-HSA-202463 (Reactome)
UBE2V1 ProteinQ13404 (Uniprot-TrEMBL)
UbComplexR-HSA-113595 (Reactome)
Unmethylated CpG DNA R-ALL-167913 (Reactome)
hp-IRAK1

or p-IRAK2 bound to the

pIRAK4:MyD88:activated TLR7/8 or 9 complex
ComplexR-HSA-975178 (Reactome)
hp-IRAK1/or p-IRAK2
TRAF6
ComplexR-HSA-975126 (Reactome)
oligo-MyD88:activated TLR7-9ComplexR-HSA-975114 (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-IRF7ComplexR-HSA-450344 (Reactome)
p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9ComplexR-HSA-975107 (Reactome)
p-IRAK1:p-IRAK4:oligo-MyD88:activated TLR7/8 or 9 complexComplexR-HSA-975130 (Reactome)
p-IRAK2 ProteinO43187 (Uniprot-TrEMBL)
p-IRAK2:K63-linked

pUb oligo-TRAF6:free K63 pUb:TAK1

complex
ComplexR-HSA-975099 (Reactome)
p-IRAK2:K63-linked

pUb oligo-TRAF6:free K63-linked

pUb:p-TAK1complex
ComplexR-HSA-975171 (Reactome)
p-IRAK2:K63-linked pUb oligo-TRAF6ComplexR-HSA-975164 (Reactome)
p-IRAK2:oligo-TRAF6ComplexR-HSA-975137 (Reactome)
p-IRAK2:p-IRAK4:oligo-MyD88:activated TLR 7/8 or9ComplexR-HSA-975133 (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-975166 (Reactome)
p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9 receptorComplexR-HSA-975159 (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 complexComplexR-HSA-975161 (Reactome)
ssRNA R-ALL-167963 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2xp-S477,S479-IRF7ArrowR-HSA-933531 (Reactome)
ADPArrowR-HSA-975103 (Reactome)
ADPArrowR-HSA-975106 (Reactome)
ADPArrowR-HSA-975125 (Reactome)
ADPArrowR-HSA-975134 (Reactome)
ADPArrowR-HSA-975139 (Reactome)
ADPArrowR-HSA-975160 (Reactome)
ADPArrowR-HSA-975170 (Reactome)
ADPArrowR-HSA-975180 (Reactome)
ATPR-HSA-975103 (Reactome)
ATPR-HSA-975106 (Reactome)
ATPR-HSA-975125 (Reactome)
ATPR-HSA-975134 (Reactome)
ATPR-HSA-975139 (Reactome)
ATPR-HSA-975160 (Reactome)
ATPR-HSA-975170 (Reactome)
ATPR-HSA-975180 (Reactome)
Activated TLR7-9 homodimersR-HSA-975175 (Reactome)
CHUK:IKBKB:IKBKGR-HSA-975119 (Reactome)
ECSITArrowR-HSA-166869 (Reactome)
IRAK1, IRAK2R-HSA-975115 (Reactome)
IRAK1/or

IRAK2

p-S,2T-IRAK4:oligo-MyD88:activated TLR 7/8 or 9
ArrowR-HSA-975115 (Reactome)
IRAK1:p-S,2T-IRAK4
oligo-MyD88:activated TLR 7/8 or 9
R-HSA-975180 (Reactome)
IRAK1:p-S,2T-IRAK4
oligo-MyD88:activated TLR 7/8 or 9
mim-catalysisR-HSA-975180 (Reactome)
IRAK2:p-S,2T-IRAK4:oligo-MyD88:activated TLR 7/8 or9R-HSA-975160 (Reactome)
IRAK2:p-S,2T-IRAK4:oligo-MyD88:activated TLR 7/8 or9mim-catalysisR-HSA-975160 (Reactome)
IRAK4:oligo-MyD88:activated TLR 7/8 or 9ArrowR-HSA-975156 (Reactome)
IRAK4:oligo-MyD88:activated TLR 7/8 or 9R-HSA-975170 (Reactome)
IRAK4:oligo-MyD88:activated TLR 7/8 or 9mim-catalysisR-HSA-975170 (Reactome)
IRAK4R-HSA-975156 (Reactome)
IRF7:TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9ArrowR-HSA-975188 (Reactome)
IRF7:TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9R-HSA-975106 (Reactome)
IRF7:TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9R-HSA-975118 (Reactome)
IRF7:TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9mim-catalysisR-HSA-975118 (Reactome)
IRF7R-HSA-975188 (Reactome)
K63-linked poly-Ub-IRF7:TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9.ArrowR-HSA-975118 (Reactome)
K63-linked poly-Ub-p-3S,3T-IRAK1:TRAF6ArrowR-HSA-975122 (Reactome)
K63-linked poly-Ub-p-3S,3T-IRAK1:TRAF6R-HSA-975119 (Reactome)
K63-linked polyUb TRAF6 complexesmim-catalysisR-HSA-450358 (Reactome)
K63polyUbArrowR-HSA-450358 (Reactome)
K63polyUbR-HSA-975097 (Reactome)
K63polyUbR-HSA-975118 (Reactome)
K63polyUbR-HSA-975122 (Reactome)
MAP3K1R-HSA-166869 (Reactome)
MEKK1:activated TRAF6ArrowR-HSA-166869 (Reactome)
MYD88R-HSA-975098 (Reactome)
MYD88R-HSA-975175 (Reactome)
MyD88 complexed with

the activated TLR

receptor
ArrowR-HSA-975175 (Reactome)
MyD88 complexed with

the activated TLR

receptor
R-HSA-975098 (Reactome)
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-450358 (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-933531 (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.
R-HSA-933533 (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.
R-HSA-975097 (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-975098 (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).
R-HSA-975100 (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-975103 (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-975106 (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.
R-HSA-975111 (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-975115 (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-975118 (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.
R-HSA-975119 (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-975122 (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-975125 (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-975134 (Reactome) Second, Thr387 in the activation loop is phosphorylated, leading to full enzymatic activity.
R-HSA-975139 (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-975142 (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-975147 (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-975156 (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-975160 (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-975170 (Reactome) IRAK4 is activated by autophosphorylation at 3 positions within the kinase activation loop, Thr-342, Thr-345 and Ser-346.
R-HSA-975175 (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-975180 (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-975185 (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-975188 (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].
TAK1 complexR-HSA-975097 (Reactome)
TRAF6:K63-linked

polyUb p-IRAK1:IKK

complex
ArrowR-HSA-975119 (Reactome)
TRAF6:hp-IRAK1/or p-IRAK2:p-IRAK4:oligo-MyD88:activated TLR7/8 or 9ArrowR-HSA-975111 (Reactome)
TRAF6:hp-IRAK1/or p-IRAK2:p-IRAK4:oligo-MyD88:activated TLR7/8 or 9R-HSA-975100 (Reactome)
TRAF6:hp-IRAK1:PellinoArrowR-HSA-975142 (Reactome)
TRAF6:hp-IRAK1:PellinoR-HSA-975139 (Reactome)
TRAF6:hp-IRAK1:Pellinomim-catalysisR-HSA-975139 (Reactome)
TRAF6:hp-IRAK1R-HSA-975142 (Reactome)
TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9ArrowR-HSA-975106 (Reactome)
TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9R-HSA-975188 (Reactome)
TRAF6:p-IRAK2R-HSA-975185 (Reactome)
TRAF6R-HSA-166869 (Reactome)
TRAF6R-HSA-975111 (Reactome)
TRAF6R-HSA-975185 (Reactome)
UBE2N:UBE2V1ArrowR-HSA-975118 (Reactome)
UBE2N:UBE2V1ArrowR-HSA-975122 (Reactome)
UBE2N:UBE2V1R-HSA-975118 (Reactome)
UBE2N:UBE2V1R-HSA-975122 (Reactome)
UbR-HSA-450358 (Reactome)
UbR-HSA-975147 (Reactome)
hp-IRAK1

or p-IRAK2 bound to the

pIRAK4:MyD88:activated TLR7/8 or 9 complex
R-HSA-975111 (Reactome)
hp-IRAK1/or p-IRAK2
TRAF6
ArrowR-HSA-975100 (Reactome)
oligo-MyD88:activated TLR7-9ArrowR-HSA-975098 (Reactome)
oligo-MyD88:activated TLR7-9R-HSA-975156 (Reactome)
p-2S-IRF7:p-2S-IRF7ArrowR-HSA-933533 (Reactome)
p-2S-IRF7:p-2S-IRF7R-HSA-933531 (Reactome)
p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9ArrowR-HSA-975125 (Reactome)
p-IRAK1:p-IRAK4:oligo-MyD88:activated TLR7/8 or 9 complexArrowR-HSA-975180 (Reactome)
p-IRAK1:p-IRAK4:oligo-MyD88:activated TLR7/8 or 9 complexR-HSA-975134 (Reactome)
p-IRAK1:p-IRAK4:oligo-MyD88:activated TLR7/8 or 9 complexmim-catalysisR-HSA-975134 (Reactome)
p-IRAK2:K63-linked

pUb oligo-TRAF6:free K63 pUb:TAK1

complex
ArrowR-HSA-975097 (Reactome)
p-IRAK2:K63-linked

pUb oligo-TRAF6:free K63 pUb:TAK1

complex
R-HSA-975103 (Reactome)
p-IRAK2:K63-linked

pUb oligo-TRAF6:free K63-linked

pUb:p-TAK1complex
ArrowR-HSA-975103 (Reactome)
p-IRAK2:K63-linked pUb oligo-TRAF6ArrowR-HSA-975147 (Reactome)
p-IRAK2:K63-linked pUb oligo-TRAF6R-HSA-975097 (Reactome)
p-IRAK2:oligo-TRAF6ArrowR-HSA-975185 (Reactome)
p-IRAK2:oligo-TRAF6R-HSA-975147 (Reactome)
p-IRAK2:oligo-TRAF6mim-catalysisR-HSA-975147 (Reactome)
p-IRAK2:p-IRAK4:oligo-MyD88:activated TLR 7/8 or9ArrowR-HSA-975160 (Reactome)
p-Pellino-1,2,(3)ArrowR-HSA-975122 (Reactome)
p-Pellino-1,2,(3)R-HSA-975142 (Reactome)
p-Pellino:hp-IRAK1:TRAF6ArrowR-HSA-975139 (Reactome)
p-Pellino:hp-IRAK1:TRAF6R-HSA-975122 (Reactome)
p-Pellino:hp-IRAK1:TRAF6mim-catalysisR-HSA-975122 (Reactome)
p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9 receptorArrowR-HSA-975100 (Reactome)
p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9 receptorArrowR-HSA-975170 (Reactome)
p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9 receptorR-HSA-975115 (Reactome)
p-S477,S479-IRF7ArrowR-HSA-975106 (Reactome)
p-S477,S479-IRF7R-HSA-933533 (Reactome)
pp-IRAK1:p-IRAK4:oligo-MyD88:activated TLR 7/8 or 9 complexArrowR-HSA-975134 (Reactome)
pp-IRAK1:p-IRAK4:oligo-MyD88:activated TLR 7/8 or 9 complexR-HSA-975125 (Reactome)
pp-IRAK1:p-IRAK4:oligo-MyD88:activated TLR 7/8 or 9 complexmim-catalysisR-HSA-975125 (Reactome)
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