MyD88 cascade initiated on plasma membrane (Homo sapiens)

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33, 5145, 5421, 27, 28, 40, 41, 48...22, 37, 421, 55114, 13, 19, 499, 18, 3644, 5538, 501218, 20, 36, 3723, 251, 611, 5271426, 30, 32, 348, 296, 45, 56cytosolTRAF6 p-IRAK2:K63-linkedpUb oligo-TRAF6p-T342,T345,S346-IRAK4 p-PELI1 RPS27A(1-76) p-PELI2 p-T342,T345,S346-IRAK4 IRAK1 TLR5 TLR5 TRAF6 Activated TLR5 orTLR10 homodimerLigand recognized by TLR10 TRAF6:hp-IRAK1/orp-IRAK2:p-IRAK4:oligo-MyD88 :activated TLR5 or 10ADPATPCHUK p-2S,S376,T,T209,T387-IRAK1 MYD88 CHUK TLR10 p-2S,S376,T,T209,T387-IRAK1 Ligand recognized by TLR10 Ligand recognized by TLR10 UBB(153-228) p-T342,T345,S346-IRAK4 MAP3K7 Ligand recognized by TLR10 UbUBB(1-76) Ligand recognized by TLR10 IRAK2 TAB2 p-IRAK2:K63-linkedpUboligo-TRAF6:freeK63-linkedpUb:p-TAK1complexTLR5 p-IRAK2 MYD88 ADPIRAK2 Flagellin Ligand recognized by TLR10 CHUK:IKBKB:IKBKGp-T342,T345,S346-IRAK4 TLR5 MYD88 Flagellin Ligand recognized by TLR10 Flagellin TRAF6TRAF6 MyD88 complexed withthe activated TLR5or 10 receptorUBE2N TAB1 p-T209,T387-IRAK1 p-Pellino-1,2,(3)Ligand recognized by TLR10 K63polyUb-hp-IRAK1 hp-IRAK1orp-IRAK2:pIRAK4:MyD88:activated TLR5/10IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR5/10TLR10 MYD88 MYD88 p-T342,T345,S346-IRAK4 TLR10 Ligand recognized by TLR10 TAK1 complexTRAF6 Flagellin p-PELI3 p-IRAK1:p-IRAK4:oligo-MyD88l:activated TLR5 or 10IRAK1 ADPTAB3 IRAK1 ADPIKBKG TRAF6 p-PELI2 hp-IRAK1:activatedIRAK4:MyD88oligomer:activated TLR5 or 10MYD88 p-T342,T345,S346-IRAK4 p-PELI1 Ligand recognized by TLR10 pp-IRAK1:p-IRAK4:oligo-MyD88 :activated TLR5 or 10 complexp-S,2T-IRAK4:oligo-MyD88:activated TLR5 or 10UBC(381-456) MEKK1:activatedTRAF6TLR10 Flagellin p-T342,T345,S346-IRAK4 TLR5 p-PELI3 p-PELI2 MAP kinaseactivationMAP3K7 TAB1 p-IRAK2 Ligand recognized by TLR10 Flagellin p-T342,T345,S346-IRAK4 IRAK4 IRAK1, IRAK2TLR5 Flagellin TAB3 TLR5 K63polyUb-TRAF6 K63polyUbIRAK4TLR5 UBE2N:UBE2V1p-IRAK2 p-Pellino-1,2,(3)p-2S,S376,T,T209,T387-IRAK1 TLR5 TLR10 ATPp-2S,S376,T,T209,T387-IRAK1 K63polyUb p-PELI1 TRAF6:hp-IRAK1TLR10 MYD88 TRAF6p-PELI1 TLR10 p-PELI3 ADPADPLigand recognized by TLR10 TLR5 TLR10 Flagellin UBE2V1 MAP3K1 K63polyUb-TRAF6 K63-linked polyUbp-IRAK1:TRAF6p-IRAK2 TRAF6:p-IRAK2p-IRAK2 MYD88 UBC(229-304) MYD88IRAK2:p-S,2T-IRAK4:oligo-MyD88:activated TLR5/10TRAF6 K63polyUb-hp-IRAK1 MYD88 p-IRAK2 TLR10 p-2S,S376,T,T209,T387-IRAK1 p-T209-IRAK1 p-IRAK2:oligo-TRAF6TAB3 p-2S,S376,T,T209,T387-IRAK1 UBC(1-76) TLR5 p-PELI2 ATPTLR10 p-IRAK2 IKBKB ATPUBC(153-228) p-IRAK2 TAB2 TLR10 TAK1 activates NFkBby phosphorylationand activation ofIKKs complexTRAF6:K63-linkedpolyUb p-IRAK1:IKKcomplexFlagellin p-T342,T345,S346-IRAK4 K63polyUb-TRAF6 Flagellin UBC(533-608) ATPTRAF6 TLR5 IRAK4:oligo-MyD88:activated TLR5 or 10UBC(609-684) TRAF6MYD88 Ligand recognized by TLR10 TLR10 TRAF6:hp-IRAK1:PellinoECSITp-IRAK2:K63-linkedpUboligo-TRAF6:freeK63 pUb:TAK1complexp-T342,T345,S346-IRAK4 p-2S,S376,T,T209,T387-IRAK1 UBB(77-152) ADPTRAF6 TLR10 IRAK2 IKBKB TLR10 p-PELI3 IKBKG p-IRAK2 p-Pellino:hp-IRAK1:TRAF6TRAF6 TLR5 IRAK1 or IRAK2:p-IRAK4:MyD88oligomer:activatedTLR5 or 10ATPFlagellin p-IRAK2:p-IRAK4:oligo-MyD88:activated TLR5 or 10MAP3K1Flagellin Ligand recognized by TLR10 UBA52(1-76) hp-IRAK1/orp-IRAK2:TRAF6Flagellin MYD88 UBC(77-152) TAB1 TLR5 p-T184,T187-MAP3K7 MYD88 K63polyUboligo-MyD88:activated TLR5 or 10UBC(457-532) K63polyUb UBC(305-380) MYD88 ATPTRAF6 TAB2 Flagellin 37149189931, 473, 16, 35, 43141415, 3791810, 471, 24, 392, 17, 4637


Mammalian myeloid differentiation factor 88 (MyD88) is Toll/interleukin (IL)-1 (TIR)-domain containing adapter protein which plays crucial role in TLR signaling. All TLRs, with only one exception of TLR3, can initiate downstream signaling trough MyD88. In the MyD88 - dependent pathway, once the adaptor is bound to TLR it leads to recruitment of IL1 receptor associated kinase family IRAK which is followed by activation of tumour necrosis factor receptor-associated factor 6 (TRAF6) . TRAF6 is an ubiquitin E3 ligase which in turn induces TGF-beta activating kinase 1 (TAK1) auto phosphorylation. Once activated TAK1 can ultimately mediate the induction of the transcription factor NF-kB or the mitogen-activated protein kinases (MAPK), such as JNK, p38 and ERK. This results in the translocation of the activated NF-kB and MAPKs to the nucleus and the initiation of appropriate gene transcription leading to the production of many proinflammatory cytokines and antimicrobial peptides. View original pathway at Reactome.


Pathway is converted from Reactome ID: 975871
Reactome version: 75
Reactome Author 
Reactome Author: Shamovsky, Veronica

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114700view16:17, 25 January 2021ReactomeTeamReactome version 75
113145view11:21, 2 November 2020ReactomeTeamReactome version 74
112375view15:30, 9 October 2020ReactomeTeamReactome version 73
101278view11:16, 1 November 2018ReactomeTeamreactome version 66
100815view20:46, 31 October 2018ReactomeTeamreactome version 65
100356view19:22, 31 October 2018ReactomeTeamreactome version 64
99902view16:05, 31 October 2018ReactomeTeamreactome version 63
99458view14:38, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93886view13:42, 16 August 2017ReactomeTeamreactome version 61
93454view11:24, 9 August 2017ReactomeTeamreactome version 61
88004view13:27, 25 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86548view09:20, 11 July 2016ReactomeTeamreactome version 56
83425view11:11, 18 November 2015ReactomeTeamVersion54
81629view13:10, 21 August 2015ReactomeTeamVersion53
77090view08:38, 17 July 2014ReactomeTeamFixed remaining interactions
76796view12:17, 16 July 2014ReactomeTeamFixed remaining interactions
76119view10:18, 11 June 2014ReactomeTeamRe-fixing comment source
75831view11:40, 10 June 2014ReactomeTeamReactome 48 Update
75200view09:59, 9 May 2014AnweshaNew pathway

External references


View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:456216 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
Activated TLR5 or TLR10 homodimerComplexR-HSA-975862 (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)
Flagellin ProteinP04949 (Uniprot-TrEMBL)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IRAK1 ProteinP51617 (Uniprot-TrEMBL)


TLR5 or 10
ComplexR-HSA-975875 (Reactome)
IRAK1, IRAK2ComplexR-HSA-937023 (Reactome)
IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR5/10ComplexR-HSA-975868 (Reactome)
IRAK2 ProteinO43187 (Uniprot-TrEMBL)
IRAK2:p-S,2T-IRAK4:oligo-MyD88:activated TLR5/10ComplexR-HSA-975859 (Reactome)
IRAK4 ProteinQ9NWZ3 (Uniprot-TrEMBL)
IRAK4:oligo-MyD88:activated TLR5 or 10ComplexR-HSA-975876 (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)
Ligand recognized by TLR10 R-ALL-168948 (Reactome)
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 TLR5

or 10 receptor
ComplexR-HSA-975860 (Reactome)
RPS27A(1-76) ProteinP62979 (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)
TLR10 ProteinQ9BXR5 (Uniprot-TrEMBL)
TLR5 ProteinO60602 (Uniprot-TrEMBL)
TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)

polyUb p-IRAK1:IKK

ComplexR-HSA-937038 (Reactome)
TRAF6:hp-IRAK1/or p-IRAK2:p-IRAK4:oligo-MyD88 :activated TLR5 or 10ComplexR-HSA-975869 (Reactome)
TRAF6:hp-IRAK1:PellinoComplexR-HSA-937020 (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-IRAK2ComplexR-HSA-936961 (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)

or p-IRAK2

pIRAK4:MyD88:activated TLR5/10
ComplexR-HSA-975881 (Reactome)
hp-IRAK1/or p-IRAK2:TRAF6ComplexR-HSA-937058 (Reactome)
hp-IRAK1:activated IRAK4:MyD88oligomer:activated TLR5 or 10ComplexR-HSA-975877 (Reactome)
oligo-MyD88:activated TLR5 or 10ComplexR-HSA-975864 (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-IRAK1:p-IRAK4:oligo-MyD88l:activated TLR5 or 10ComplexR-HSA-975872 (Reactome)
p-IRAK2 ProteinO43187 (Uniprot-TrEMBL)

pUb oligo-TRAF6:free K63 pUb:TAK1

ComplexR-HSA-936953 (Reactome)

pUb oligo-TRAF6:free K63-linked

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:activated TLR5 or 10ComplexR-HSA-975867 (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:activated TLR5 or 10ComplexR-HSA-975870 (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 :activated TLR5 or 10 complexComplexR-HSA-975883 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-936991 (Reactome)
ADPArrowR-HSA-937034 (Reactome)
ADPArrowR-HSA-975853 (Reactome)
ADPArrowR-HSA-975861 (Reactome)
ADPArrowR-HSA-975865 (Reactome)
ADPArrowR-HSA-975874 (Reactome)
ADPArrowR-HSA-975878 (Reactome)
ATPR-HSA-936991 (Reactome)
ATPR-HSA-937034 (Reactome)
ATPR-HSA-975853 (Reactome)
ATPR-HSA-975861 (Reactome)
ATPR-HSA-975865 (Reactome)
ATPR-HSA-975874 (Reactome)
ATPR-HSA-975878 (Reactome)
Activated TLR5 or TLR10 homodimerR-HSA-975866 (Reactome)
CHUK:IKBKB:IKBKGR-HSA-937032 (Reactome)
ECSITArrowR-HSA-166869 (Reactome)


TLR5 or 10
ArrowR-HSA-975852 (Reactome)
IRAK1, IRAK2R-HSA-975852 (Reactome)
IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR5/10R-HSA-975878 (Reactome)
IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR5/10mim-catalysisR-HSA-975878 (Reactome)
IRAK2:p-S,2T-IRAK4:oligo-MyD88:activated TLR5/10R-HSA-975861 (Reactome)
IRAK2:p-S,2T-IRAK4:oligo-MyD88:activated TLR5/10mim-catalysisR-HSA-975861 (Reactome)
IRAK4:oligo-MyD88:activated TLR5 or 10ArrowR-HSA-975873 (Reactome)
IRAK4:oligo-MyD88:activated TLR5 or 10R-HSA-975865 (Reactome)
IRAK4:oligo-MyD88:activated TLR5 or 10mim-catalysisR-HSA-975865 (Reactome)
IRAK4R-HSA-975873 (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)
MAP3K1R-HSA-166869 (Reactome)
MEKK1:activated TRAF6ArrowR-HSA-166869 (Reactome)
MYD88R-HSA-975866 (Reactome)
MYD88R-HSA-975880 (Reactome)
MyD88 complexed with

the activated TLR5

or 10 receptor
ArrowR-HSA-975866 (Reactome)
MyD88 complexed with

the activated TLR5

or 10 receptor
R-HSA-975880 (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-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 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-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-975852 (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-975853 (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-975857 (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-975861 (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-975865 (Reactome) IRAK4 is activated by autophosphorylation at 3 positions within the kinase activation loop, Thr-342, Thr-345 and Ser-346.
R-HSA-975866 (Reactome) MyD88 is the downstream adaptor which is utilized by all TLRs, except TLR3. MyD88 comprises an N-terminal Death Domain (DD) and a C-terminal TIR. Upon ligand binding to the IL-1R or a TLR, MyD88 is rapidly recruited to the activated receptor via homotypic interactions of TIR domain, whereas the DD module recruits serine/threonine kinases such as interleukin-1-receptor-associated kinases (IRAKs).
R-HSA-975873 (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-975874 (Reactome) Second, Thr387 in the activation loop is phosphorylated, leading to full enzymatic activity.
R-HSA-975878 (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-975879 (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-975880 (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).
TAK1 complexR-HSA-936960 (Reactome)

polyUb p-IRAK1:IKK

ArrowR-HSA-937032 (Reactome)
TRAF6:hp-IRAK1/or p-IRAK2:p-IRAK4:oligo-MyD88 :activated TLR5 or 10ArrowR-HSA-975857 (Reactome)
TRAF6:hp-IRAK1/or p-IRAK2:p-IRAK4:oligo-MyD88 :activated TLR5 or 10R-HSA-975879 (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-IRAK1R-HSA-937044 (Reactome)
TRAF6:p-IRAK2R-HSA-936963 (Reactome)
TRAF6R-HSA-166869 (Reactome)
TRAF6R-HSA-936963 (Reactome)
TRAF6R-HSA-975857 (Reactome)
UBE2N:UBE2V1ArrowR-HSA-937050 (Reactome)
UBE2N:UBE2V1R-HSA-937050 (Reactome)
UbR-HSA-936942 (Reactome)
UbR-HSA-936986 (Reactome)

or p-IRAK2

pIRAK4:MyD88:activated TLR5/10
R-HSA-975857 (Reactome)
hp-IRAK1/or p-IRAK2:TRAF6ArrowR-HSA-975879 (Reactome)
hp-IRAK1:activated IRAK4:MyD88oligomer:activated TLR5 or 10ArrowR-HSA-975853 (Reactome)
oligo-MyD88:activated TLR5 or 10ArrowR-HSA-975880 (Reactome)
oligo-MyD88:activated TLR5 or 10R-HSA-975873 (Reactome)
p-IRAK1:p-IRAK4:oligo-MyD88l:activated TLR5 or 10ArrowR-HSA-975878 (Reactome)
p-IRAK1:p-IRAK4:oligo-MyD88l:activated TLR5 or 10R-HSA-975874 (Reactome)
p-IRAK1:p-IRAK4:oligo-MyD88l:activated TLR5 or 10mim-catalysisR-HSA-975874 (Reactome)

pUb oligo-TRAF6:free K63 pUb:TAK1

ArrowR-HSA-936960 (Reactome)

pUb oligo-TRAF6:free K63 pUb:TAK1

R-HSA-936991 (Reactome)

pUb oligo-TRAF6:free K63 pUb:TAK1

mim-catalysisR-HSA-936991 (Reactome)

pUb oligo-TRAF6:free K63-linked

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:K63-linked pUb oligo-TRAF6mim-catalysisR-HSA-936986 (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:activated TLR5 or 10ArrowR-HSA-975861 (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:activated TLR5 or 10ArrowR-HSA-975865 (Reactome)
p-S,2T-IRAK4:oligo-MyD88:activated TLR5 or 10ArrowR-HSA-975879 (Reactome)
p-S,2T-IRAK4:oligo-MyD88:activated TLR5 or 10R-HSA-975852 (Reactome)
pp-IRAK1:p-IRAK4:oligo-MyD88 :activated TLR5 or 10 complexArrowR-HSA-975874 (Reactome)
pp-IRAK1:p-IRAK4:oligo-MyD88 :activated TLR5 or 10 complexR-HSA-975853 (Reactome)
pp-IRAK1:p-IRAK4:oligo-MyD88 :activated TLR5 or 10 complexmim-catalysisR-HSA-975853 (Reactome)
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