MyD88 cascade initiated on plasma membrane (Homo sapiens)

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Bibliography

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10. Cheung PC, Nebreda AR, Cohen P.; ''TAB3, a new binding partner of the protein kinase TAK1.''; PubMed Europe PMC Scholia
11. Horng T, Barton GM, Flavell RA, Medzhitov R.; ''The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors.''; PubMed Europe PMC Scholia
12. Keating SE, Maloney GM, Moran EM, Bowie AG.; ''IRAK-2 participates in multiple toll-like receptor signaling pathways to NFkappaB via activation of TRAF6 ubiquitination.''; PubMed Europe PMC Scholia
13. Kanayama A, Seth RB, Sun L, Ea CK, Hong M, Shaito A, Chiu YH, Deng L, Chen ZJ.; ''TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains.''; PubMed Europe PMC Scholia
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18. Butler MP, Hanly JA, Moynagh PN.; ''Kinase-active interleukin-1 receptor-associated kinases promote polyubiquitination and degradation of the Pellino family: direct evidence for PELLINO proteins being ubiquitin-protein isopeptide ligases.''; PubMed Europe PMC Scholia
19. Kulathu Y, Akutsu M, Bremm A, Hofmann K, Komander D.; ''Two-sided ubiquitin binding explains specificity of the TAB2 NZF domain.''; PubMed Europe PMC Scholia
20. Newton K, Matsumoto ML, Wertz IE, Kirkpatrick DS, Lill JR, Tan J, Dugger D, Gordon N, Sidhu SS, Fellouse FA, Komuves L, French DM, Ferrando RE, Lam C, Compaan D, Yu C, Bosanac I, Hymowitz SG, Kelley RF, Dixit VM.; ''Ubiquitin chain editing revealed by polyubiquitin linkage-specific antibodies.''; PubMed Europe PMC Scholia
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22. Windheim M, Stafford M, Peggie M, Cohen P.; ''Interleukin-1 (IL-1) induces the Lys63-linked polyubiquitination of IL-1 receptor-associated kinase 1 to facilitate NEMO binding and the activation of IkappaBalpha kinase.''; PubMed Europe PMC Scholia
23. Kawagoe T, Sato S, Jung A, Yamamoto M, Matsui K, Kato H, Uematsu S, Takeuchi O, Akira S.; ''Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor-mediated immune responses but not in TCR signaling.''; PubMed Europe PMC Scholia
24. Qian Y, Commane M, Ninomiya-Tsuji J, Matsumoto K, Li X.; ''IRAK-mediated translocation of TRAF6 and TAB2 in the interleukin-1-induced activation of NFkappa B.''; PubMed Europe PMC Scholia
25. Cheng H, Addona T, Keshishian H, Dahlstrand E, Lu C, Dorsch M, Li Z, Wang A, Ocain TD, Li P, Parsons TF, Jaffee B, Xu Y.; ''Regulation of IRAK-4 kinase activity via autophosphorylation within its activation loop.''; PubMed Europe PMC Scholia
26. 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
27. Shibuya H, Yamaguchi K, Shirakabe K, Tonegawa A, Gotoh Y, Ueno N, Irie K, Nishida E, Matsumoto K.; ''TAB1: an activator of the TAK1 MAPKKK in TGF-beta signal transduction.''; PubMed Europe PMC Scholia
28. Sakurai H, Miyoshi H, Mizukami J, Sugita T.; ''Phosphorylation-dependent activation of TAK1 mitogen-activated protein kinase kinase kinase by TAB1.''; PubMed Europe PMC Scholia
29. Moynagh PN.; ''The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling.''; PubMed Europe PMC Scholia
30. Muroi M, Tanamoto K.; ''TRAF6 distinctively mediates MyD88- and IRAK-1-induced activation of NF-kappaB.''; PubMed Europe PMC Scholia
31. Thiefes A, Wolter S, Mushinski JF, Hoffmann E, Dittrich-Breiholz O, Graue N, Dörrie A, Schneider H, Wirth D, Luckow B, Resch K, Kracht M.; ''Simultaneous blockade of NFkappaB, JNK, and p38 MAPK by a kinase-inactive mutant of the protein kinase TAK1 sensitizes cells to apoptosis and affects a distinct spectrum of tumor necrosis factor [corrected] target genes.''; PubMed Europe PMC Scholia
32. Ross K, Yang L, Dower S, Volpe F, Guesdon F.; ''Identification of threonine 66 as a functionally critical residue of the interleukin-1 receptor-associated kinase.''; PubMed Europe PMC Scholia
33. Zhang Z, Louboutin JP, Weiner DJ, Goldberg JB, Wilson JM.; ''Human airway epithelial cells sense Pseudomonas aeruginosa infection via recognition of flagellin by Toll-like receptor 5.''; PubMed Europe PMC Scholia
34. Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV.; ''TRAF6 is a signal transducer for interleukin-1.''; PubMed Europe PMC Scholia
35. Bardwell AJ, Frankson E, Bardwell L.; ''Selectivity of docking sites in MAPK kinases.''; PubMed Europe PMC Scholia
36. Ordureau A, Smith H, Windheim M, Peggie M, Carrick E, Morrice N, Cohen P.; ''The IRAK-catalysed activation of the E3 ligase function of Pellino isoforms induces the Lys63-linked polyubiquitination of IRAK1.''; PubMed Europe PMC Scholia
37. Conze DB, Wu CJ, Thomas JA, Landstrom A, Ashwell JD.; ''Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activation.''; PubMed Europe PMC Scholia
38. Lee FS, Hagler J, Chen ZJ, Maniatis T.; ''Activation of the IkappaB alpha kinase complex by MEKK1, a kinase of the JNK pathway.''; PubMed Europe PMC Scholia
39. Jiang Z, Ninomiya-Tsuji J, Qian Y, Matsumoto K, Li X.; ''Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and activate TAK1 in the cytosol.''; PubMed Europe PMC Scholia
40. Sato S, Sanjo H, Takeda K, Ninomiya-Tsuji J, Yamamoto M, Kawai T, Matsumoto K, Takeuchi O, Akira S.; ''Essential function for the kinase TAK1 in innate and adaptive immune responses.''; PubMed Europe PMC Scholia
41. Brown K, Vial SC, Dedi N, Long JM, Dunster NJ, Cheetham GM.; ''Structural basis for the interaction of TAK1 kinase with its activating protein TAB1.''; PubMed Europe PMC Scholia
42. Wu CJ, Conze DB, Li T, Srinivasula SM, Ashwell JD.; ''Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected].''; PubMed Europe PMC Scholia
43. Dong C, Davis RJ, Flavell RA.; ''MAP kinases in the immune response.''; PubMed Europe PMC Scholia
44. Suzuki N, Suzuki S, Yeh WC.; ''IRAK-4 as the central TIR signaling mediator in innate immunity.''; PubMed Europe PMC Scholia
45. Rao N, Nguyen S, Ngo K, Fung-Leung WP.; ''A novel splice variant of interleukin-1 receptor (IL-1R)-associated kinase 1 plays a negative regulatory role in Toll/IL-1R-induced inflammatory signaling.''; PubMed Europe PMC Scholia
46. Rothwarf DM, Zandi E, Natoli G, Karin M.; ''IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex.''; PubMed Europe PMC Scholia
47. Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ.; ''TAK1 is a ubiquitin-dependent kinase of MKK and IKK.''; PubMed Europe PMC Scholia
48. 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
49. Takaesu G, Kishida S, Hiyama A, Yamaguchi K, Shibuya H, Irie K, Ninomiya-Tsuji J, Matsumoto K.; ''TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway.''; PubMed Europe PMC Scholia
50. 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
51. Hasan U, Chaffois C, Gaillard C, Saulnier V, Merck E, Tancredi S, Guiet C, Brière F, Vlach J, Lebecque S, Trinchieri G, Bates EE.; ''Human TLR10 is a functional receptor, expressed by B cells and plasmacytoid dendritic cells, which activates gene transcription through MyD88.''; PubMed Europe PMC Scholia
52. Wesche H, Henzel WJ, Shillinglaw W, Li S, Cao Z.; ''MyD88: an adapter that recruits IRAK to the IL-1 receptor complex.''; PubMed Europe PMC Scholia
53. Ono K, Ohtomo T, Sato S, Sugamata Y, Suzuki M, Hisamoto N, Ninomiya-Tsuji J, Tsuchiya M, Matsumoto K.; ''An evolutionarily conserved motif in the TAB1 C-terminal region is necessary for interaction with and activation of TAK1 MAPKKK.''; PubMed Europe PMC Scholia
54. Motshwene PG, Moncrieffe MC, Grossmann JG, Kao C, Ayaluru M, Sandercock AM, Robinson CV, Latz E, Gay NJ.; ''An oligomeric signaling platform formed by the Toll-like receptor signal transducers MyD88 and IRAK-4.''; PubMed Europe PMC Scholia
55. Li S, Strelow A, Fontana EJ, Wesche H.; ''IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase.''; PubMed Europe PMC Scholia
56. Wan Y, Xiao H, Affolter J, Kim TW, Bulek K, Chaudhuri S, Carlson D, Hamilton T, Mazumder B, Stark GR, Thomas J, Li X.; ''Interleukin-1 receptor-associated kinase 2 is critical for lipopolysaccharide-mediated post-transcriptional control.''; PubMed Europe PMC Scholia

History

External references

DataNodes

Name	Type	Database reference	Comment
ADP	Metabolite	CHEBI:16761 (ChEBI)
ATP	Metabolite	CHEBI:15422 (ChEBI)
Activated TLR5 or TLR10 homodimer	Complex	REACT_27376 (Reactome)
CHUK [cytosol]	Protein	O15111 (Uniprot-TrEMBL)
ECSIT	Protein	Q9BQ95 (Uniprot-TrEMBL)
Flagellin [plasma membrane]	Protein	P04949 (Uniprot-TrEMBL)
IKBKB [cytosol]	Protein	O14920 (Uniprot-TrEMBL)
IKBKG [cytosol]	Protein	Q9Y6K9 (Uniprot-TrEMBL)
IKKA:IKKB:NEMO	Complex	REACT_7693 (Reactome)
IRAK1 [plasma membrane]	Protein	P51617 (Uniprot-TrEMBL)
IRAK1 or IRAK2 p-IRAK4:MyD88 oligomer:activated TLR5 or 10	Complex	REACT_27359 (Reactome)
IRAK1, IRAK2	Protein	REACT_26678 (Reactome)
IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR5/10	Complex	REACT_27973 (Reactome)
IRAK2 [plasma membrane]	Protein	O43187 (Uniprot-TrEMBL)
IRAK2:p-S,2T-IRAK4:oligo-MyD88:activated TLR5/10	Complex	REACT_27414 (Reactome)
IRAK4 [plasma membrane]	Protein	Q9NWZ3 (Uniprot-TrEMBL)
IRAK4:oligo-MyD88:activated TLR5 or 10	Complex	REACT_27378 (Reactome)
IRAK4	Protein	Q9NWZ3 (Uniprot-TrEMBL)
K63-linked polyUb p-IRAK1:TRAF6	Complex	REACT_25933 (Reactome)
K63polyUb-TRAF6 [plasma membrane]	Protein	Q9Y4K3 (Uniprot-TrEMBL)
K63polyUb-hp-IRAK1 [cytosol]	Protein	P51617 (Uniprot-TrEMBL)
K63polyUb		REACT_21645 (Reactome)
MAP kinase activation in TLR cascade	Pathway	WP2792 (WikiPathways)	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(2-1512) [cytosol]	Protein	Q13233 (Uniprot-TrEMBL)
MAP3K1(2-1512)	Protein	Q13233 (Uniprot-TrEMBL)
MAP3K7 [cytosol]	Protein	O43318 (Uniprot-TrEMBL)
MEKK1:activated TRAF6	Complex	REACT_7633 (Reactome)
MYD88 [plasma membrane]	Protein	Q99836 (Uniprot-TrEMBL)
MYD88	Protein	Q99836 (Uniprot-TrEMBL)
MyD88 complexed with the activated TLR5 or 10 receptor	Complex	REACT_27814 (Reactome)
TAB1 [cytosol]	Protein	Q15750 (Uniprot-TrEMBL)
TAB2 [plasma membrane]	Protein	Q9NYJ8 (Uniprot-TrEMBL)
TAB3(1-712) [plasma membrane]	Protein	Q8N5C8 (Uniprot-TrEMBL)
TAK1 activates NFkB by phosphorylation and activation of IKKs complex	Pathway	WP2656 (WikiPathways)	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 complex	Complex	REACT_22633 (Reactome)
TLR10 [plasma membrane]	Protein	Q9BXR5 (Uniprot-TrEMBL)
TLR5 [plasma membrane]	Protein	O60602 (Uniprot-TrEMBL)
TRAF6 [cytosol]	Protein	Q9Y4K3 (Uniprot-TrEMBL)
TRAF6 [plasma membrane]	Protein	Q9Y4K3 (Uniprot-TrEMBL)
TRAF6:K63-linked polyUb p-IRAK1:IKK complex	Complex	REACT_26014 (Reactome)
TRAF6:hp-IRAK1/or p-IRAK2:p-IRAK4:oligo-MyD88 activated TLR5 or 10	Complex	REACT_27677 (Reactome)
TRAF6:hp-IRAK1:Pellino	Complex	REACT_26423 (Reactome)
TRAF6:hp-IRAK1	Complex	REACT_25583 (Reactome)	The listed studies describe an activation of IRAK-TRAF6-TAK1 axes downstream of IL1 receptor signaling cascade, which is mediated by its cytosolic domain called Toll/IL1R (TIR) domain. TLRs and IL1R are thought to share a similar downstream signaling pathway due to a high homology of their C-terminal TIR domains.
TRAF6:p-IRAK2	Complex	REACT_26255 (Reactome)
TRAF6	Protein	Q9Y4K3 (Uniprot-TrEMBL)
UBE2N [cytosol]	Protein	P61088 (Uniprot-TrEMBL)
UBE2V1 [cytosol]	Protein	Q13404 (Uniprot-TrEMBL)
Ub	Protein	REACT_3316 (Reactome)
Ubc13:UBE2V1	Complex	REACT_12995 (Reactome)
hp-IRAK1 or p-IRAK2 pIRAK4:MyD88:activated TLR5/10	Complex	REACT_27498 (Reactome)
hp-IRAK1/or p-IRAK2:TRAF6	Complex	REACT_26897 (Reactome)
hp-IRAK1:activated IRAK4:MyD88oligomer:activated TLR5 or 10	Complex	REACT_27391 (Reactome)
oligo-MyD88:activated TLR5 or 10	Complex	REACT_27690 (Reactome)
p-2S,S376,T,T209,T387-IRAK1 [plasma membrane]	Protein	P51617 (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 10	Complex	REACT_27502 (Reactome)
p-IRAK2 [plasma membrane]	Protein	O43187 (Uniprot-TrEMBL)
p-IRAK2:K63-linked pUb oligo-TRAF6:free K63 pUb:TAK1 complex	Complex	REACT_27027 (Reactome)
p-IRAK2:K63-linked pUb oligo-TRAF6:free K63-linked pUb:p-TAK1complex	Complex	REACT_26622 (Reactome)
p-IRAK2:K63-linked pUb oligo-TRAF6	Complex	REACT_26930 (Reactome)
p-IRAK2:oligo-TRAF6	Complex	REACT_25874 (Reactome)
p-IRAK2:p-IRAK4:oligo-MyD88:activated TLR5 or 10	Complex	REACT_27632 (Reactome)
p-Pellino-1,2,(3)	Protein	REACT_22733 (Reactome)
p-Pellino:hp-IRAK1:TRAF6	Complex	REACT_26368 (Reactome)
p-S,2T-IRAK4:oligo-MyD88:activated TLR5 or 10	Complex	REACT_27900 (Reactome)
p-T184,T187-MAP3K7 [cytosol]	Protein	O43318 (Uniprot-TrEMBL)
p-T209,T387-IRAK1 [plasma membrane]	Protein	P51617 (Uniprot-TrEMBL)
p-T209-IRAK1 [plasma membrane]	Protein	P51617 (Uniprot-TrEMBL)
p-T342,T345,S346-IRAK4 [plasma membrane]	Protein	Q9NWZ3 (Uniprot-TrEMBL)
pp-IRAK1:p-IRAK4:oligo-MyD88 activated TLR5 or 10 complex	Complex	REACT_27453 (Reactome)

Annotated Interactions

Source	Target	Type	Database reference	Comment
	ADP	Arrow	REACT_25200 (Reactome)
	ADP	Arrow	REACT_25375 (Reactome)
	ADP	Arrow	REACT_27151 (Reactome)
	ADP	Arrow	REACT_27163 (Reactome)
	ADP	Arrow	REACT_27165 (Reactome)
	ADP	Arrow	REACT_27180 (Reactome)
	ADP	Arrow	REACT_27228 (Reactome)
ATP			REACT_25200 (Reactome)
ATP			REACT_25375 (Reactome)
ATP			REACT_27151 (Reactome)
ATP			REACT_27163 (Reactome)
ATP			REACT_27165 (Reactome)
ATP			REACT_27180 (Reactome)
ATP			REACT_27228 (Reactome)
Activated TLR5 or TLR10 homodimer			REACT_27256 (Reactome)
ECSIT		Arrow	REACT_6962 (Reactome)
IKKA:IKKB:NEMO			REACT_25305 (Reactome)
	IRAK1 or IRAK2 p-IRAK4:MyD88 oligomer:activated TLR5 or 10	Arrow	REACT_27140 (Reactome)
IRAK1, IRAK2			REACT_27140 (Reactome)
IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR5/10			REACT_27228 (Reactome)
IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR5/10		mim-catalysis	REACT_27228 (Reactome)
IRAK2:p-S,2T-IRAK4:oligo-MyD88:activated TLR5/10			REACT_27165 (Reactome)
IRAK2:p-S,2T-IRAK4:oligo-MyD88:activated TLR5/10		mim-catalysis	REACT_27165 (Reactome)
	IRAK4:oligo-MyD88:activated TLR5 or 10	Arrow	REACT_27293 (Reactome)
IRAK4:oligo-MyD88:activated TLR5 or 10			REACT_27180 (Reactome)
IRAK4:oligo-MyD88:activated TLR5 or 10		mim-catalysis	REACT_27180 (Reactome)
IRAK4			REACT_27293 (Reactome)
	K63-linked polyUb p-IRAK1:TRAF6	Arrow	REACT_24943 (Reactome)
K63-linked polyUb p-IRAK1:TRAF6			REACT_25305 (Reactome)
	K63polyUb	Arrow	REACT_25362 (Reactome)
K63polyUb			REACT_24943 (Reactome)
K63polyUb			REACT_24985 (Reactome)
MAP3K1(2-1512)			REACT_6962 (Reactome)
	MEKK1:activated TRAF6	Arrow	REACT_6962 (Reactome)
MYD88			REACT_27210 (Reactome)
MYD88			REACT_27256 (Reactome)
	MyD88 complexed with the activated TLR5 or 10 receptor	Arrow	REACT_27256 (Reactome)
MyD88 complexed with the activated TLR5 or 10 receptor			REACT_27210 (Reactome)
			REACT_24943 (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).
			REACT_24985 (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_25022 (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_25119 (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_25142 (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_25200 (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_25305 (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_25362 (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_25375 (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_27140 (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_27141 (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_27151 (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_27163 (Reactome)	Second, Thr387 in the activation loop is phosphorylated, leading to full enzymatic activity.
			REACT_27165 (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_27177 (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_27180 (Reactome)	IRAK4 is activated by autophosphorylation at 3 positions within the kinase activation loop, Thr-342, Thr-345 and Ser-346.
			REACT_27210 (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_27228 (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_27256 (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).
			REACT_27293 (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_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 complex			REACT_24985 (Reactome)
	TRAF6:K63-linked polyUb p-IRAK1:IKK complex	Arrow	REACT_25305 (Reactome)
	TRAF6:hp-IRAK1/or p-IRAK2:p-IRAK4:oligo-MyD88 activated TLR5 or 10	Arrow	REACT_27141 (Reactome)
TRAF6:hp-IRAK1/or p-IRAK2:p-IRAK4:oligo-MyD88 activated TLR5 or 10			REACT_27177 (Reactome)
	TRAF6:hp-IRAK1:Pellino	Arrow	REACT_25142 (Reactome)
TRAF6:hp-IRAK1:Pellino			REACT_25200 (Reactome)
TRAF6:hp-IRAK1:Pellino		mim-catalysis	REACT_25200 (Reactome)
TRAF6:hp-IRAK1			REACT_25142 (Reactome)
TRAF6:p-IRAK2			REACT_25119 (Reactome)
TRAF6			REACT_25119 (Reactome)
TRAF6			REACT_27141 (Reactome)
TRAF6			REACT_6962 (Reactome)
TRAF6		mim-catalysis	REACT_25362 (Reactome)
Ub			REACT_25022 (Reactome)
Ub			REACT_25362 (Reactome)
	Ubc13:UBE2V1	Arrow	REACT_24943 (Reactome)
Ubc13:UBE2V1			REACT_24943 (Reactome)
hp-IRAK1 or p-IRAK2 pIRAK4:MyD88:activated TLR5/10			REACT_27141 (Reactome)
	hp-IRAK1/or p-IRAK2:TRAF6	Arrow	REACT_27177 (Reactome)
	hp-IRAK1:activated IRAK4:MyD88oligomer:activated TLR5 or 10	Arrow	REACT_27151 (Reactome)
	oligo-MyD88:activated TLR5 or 10	Arrow	REACT_27210 (Reactome)
oligo-MyD88:activated TLR5 or 10			REACT_27293 (Reactome)
	p-IRAK1:p-IRAK4:oligo-MyD88l:activated TLR5 or 10	Arrow	REACT_27228 (Reactome)
p-IRAK1:p-IRAK4:oligo-MyD88l:activated TLR5 or 10			REACT_27163 (Reactome)
p-IRAK1:p-IRAK4:oligo-MyD88l:activated TLR5 or 10		mim-catalysis	REACT_27163 (Reactome)
	p-IRAK2:K63-linked pUb oligo-TRAF6:free K63 pUb:TAK1 complex	Arrow	REACT_24985 (Reactome)
p-IRAK2:K63-linked pUb oligo-TRAF6:free K63 pUb:TAK1 complex			REACT_25375 (Reactome)
p-IRAK2:K63-linked pUb oligo-TRAF6:free K63 pUb:TAK1 complex		mim-catalysis	REACT_25375 (Reactome)
	p-IRAK2:K63-linked pUb oligo-TRAF6:free K63-linked pUb:p-TAK1complex	Arrow	REACT_25375 (Reactome)
	p-IRAK2:K63-linked pUb oligo-TRAF6	Arrow	REACT_25022 (Reactome)
p-IRAK2:K63-linked pUb oligo-TRAF6			REACT_24985 (Reactome)
	p-IRAK2:oligo-TRAF6	Arrow	REACT_25119 (Reactome)
p-IRAK2:oligo-TRAF6			REACT_25022 (Reactome)
p-IRAK2:oligo-TRAF6		mim-catalysis	REACT_25022 (Reactome)
	p-IRAK2:p-IRAK4:oligo-MyD88:activated TLR5 or 10	Arrow	REACT_27165 (Reactome)
	p-Pellino-1,2,(3)	Arrow	REACT_24943 (Reactome)
p-Pellino-1,2,(3)			REACT_25142 (Reactome)
	p-Pellino:hp-IRAK1:TRAF6	Arrow	REACT_25200 (Reactome)
p-Pellino:hp-IRAK1:TRAF6			REACT_24943 (Reactome)
p-Pellino:hp-IRAK1:TRAF6		mim-catalysis	REACT_24943 (Reactome)
	p-S,2T-IRAK4:oligo-MyD88:activated TLR5 or 10	Arrow	REACT_27177 (Reactome)
	p-S,2T-IRAK4:oligo-MyD88:activated TLR5 or 10	Arrow	REACT_27180 (Reactome)
p-S,2T-IRAK4:oligo-MyD88:activated TLR5 or 10			REACT_27140 (Reactome)
	pp-IRAK1:p-IRAK4:oligo-MyD88 activated TLR5 or 10 complex	Arrow	REACT_27163 (Reactome)
pp-IRAK1:p-IRAK4:oligo-MyD88 activated TLR5 or 10 complex			REACT_27151 (Reactome)
pp-IRAK1:p-IRAK4:oligo-MyD88 activated TLR5 or 10 complex		mim-catalysis	REACT_27151 (Reactome)