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

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576, 19, 4340, 49, 672310, 36, 39, 50-5211, 13, 15, 31, 35...3, 53, 63, 742324, 45, 55, 56532, 53, 74812, 6814, 28, 3823, 3920, 6426, 27, 431, 29, 37, 44, 51...34, 4724, 45, 55, 5617, 36, 514, 5, 7, 914, 38, 48, 4923, 2923, 29173TLR6/2 ligandCD14CD36 activated TLR2/4p-4Y-MALBTK TLR1TLR2 ligandCD14 MyD88 oligomer TLR6TLR2ligandCD14CD36 MyD88 oligomer activated TLR2/4p-4Y-MALBTK p-IRAK2K63-linked pUb oligo-TRAF6 TAB2/3 TLR6TLR2 TLR4MD2LPSCD14 TLR6TLR2 Activated TLR12 or TLR 26 heterodimers or TLR4 homodimer TLR6/2 ligandCD14CD36 TAB2/3 MyD88 oligomer CD14 TLR6TLR2ligandCD14CD36 TLR1TLR2TLR1/2 ligandCD14 oligo-MyD88Malactivated TLR p-IRAK1p-IRAK4oligo-MyD88Malactivated TLR p-IRAK2K63-linked pUb oligo-TRAF6free K63-linked pUbp-TAK1complex TLR6TLR2 recognized ligand TLR1TLR2 ligandCD14 Activated TLR12 or TLR 26 heterodimers or TLR4 homodimer TLR4MD2 MyD88Mal complexed with the activated TLR TLR1TLR2 ligandCD14 p-S,2T-IRAK4oligo-MyD88Malactivated TLR receptor TRAF6p-IRAK2 TRAF6hp-IRAK1 TAK1 complex CD14 TLR6TLR2 TLR1TLR2 ligandCD14 Activated TLR12 or TLR 26 heterodimers or TLR4 homodimer oligo-MyD88Malactivated TLR MyD88 oligomer IKKAIKKBNEMO PorB Homotrimer TLR1TLR2 TLR1TLR2 CD14 TLR6TLR2 PorB Homotrimer CD14 TLR1TLR2 ligandCD14 PorB Homotrimer TLR1TLR2TLR1/2 ligandCD14 TLR6TLR2ligandCD14CD36 TLR6/2 ligandCD14CD36 TLR1TLR2 recognized ligand TLR6TLR2 p-Pellinohp-IRAK1TRAF6 TLR1TLR2 Activated TLR12 or TLR 26 heterodimers or TLR4 homodimer TLR4MD2 TLR1TLR2 ligandCD14 TLR6TLR2 TLR6/2 ligandCD14CD36 TLR1TLR2 ligandCD14 TLR4MD2 TRAF6K63-linked polyUb p-IRAK1IKK complex PorB Homotrimer activated TLR2/4p-4Y-MALBTK TLR1TLR2 recognized ligand p-S,2T-IRAK4oligo-MyD88Malactivated TLR receptor TLR6TLR2 recognized ligand TLR4MD2LPSCD14 TRAF6p-IRAK2 p-IRAK4oligo-MyD88 Malactivated TLR TLR4MD2LPSCD14 TLR4MD2LPSCD14 TRAF6hp-IRAK1Pellino CD14 TLR6TLR2 recognized ligand IRAK1/ IRAK2 oligo-MyD88Malactivated TLR TLR1TLR2 recognized ligand activated TLR2/4p-4Y-MALBTK TLR6TLR2ligandCD14CD36 oligo-MyD88Malactivated TLR TLR6TLR2 recognized ligand cytosolTLR1TLR2 recognized ligand TLR6TLR2 recognized ligand TLR6TLR2 recognized ligand TLR1TLR2 recognized ligand TLR6TLR2 recognized ligand TLR4MD2 TLR6/2 ligandCD14CD36 TLR6TLR2 recognized ligand CD14 Activated TLR12 or TLR 26 heterodimers or TLR4 homodimer TLR4MD2 TLR6TLR2ligandCD14CD36 TLR1TLR2TLR1/2 ligandCD14 CD14 TLR1TLR2 recognized ligand IRAK1p-S,2T-IRAK4 oligo-MyD88Malactivated TLR TLR1TLR2 MALPITLR4MD2 TLR6TLR2 recognized ligand Activated TLR12 or TLR 26 heterodimers or TLR4 homodimer TLR1TLR2TLR1/2 ligandCD14 TLR4MD2 TRAF6hp-IRAK1p-IRAK4oligo-MyD88 Malactivated TLR TLR1TLR2 ligandCD14 TLR1TLR2 recognized ligand TLR1TLR2TLR1/2 ligandCD14 TLR1TLR2TLR1/2 ligandCD14 Activated TLR12 or TLR 26 heterodimers or TLR4 homodimer IRAK4oligo-MyD88Malactivated TLR TLR4MD2 p-IRAK2oligo-TRAF6 TLR1TLR2 MyD88 oligomer TLR1TLR2 ligandCD14 oligo-MyD88Malactivated TLR TLR6TLR2ligandCD14CD36 TLR6TLR2ligandCD14CD36 PorB Homotrimer TLR6/2 ligandCD14CD36 p-IRAK2K63-linked pUb oligo-TRAF6free K63 pUbTAK1 complex TLR1TLR2TLR1/2 ligandCD14 CD14 TLR1TLR2TLR1/2 ligandCD14 activated TLR2/4p-4Y-MALBTK MyD88 oligomer CD14 MyD88 oligomer TLR6TLR2 recognized ligand PorB Homotrimer TLR6TLR2 TAB2/3 TLR1TLR2 ligandCD14 TLR6TLR2 recognized ligand TLR1TLR2 recognized ligand TLR4MD2LPSCD14 oligo-MyD88Malactivated TLR TLR1TLR2 recognized ligand Activated TLR12 or TLR 26 heterodimers or TLR4 homodimer activated TLR2/4p-4Y-MALBTK TLR1TLR2 p-3S,3T-IRAK1p-S,2T-IRAK4oligo-MyD88Malactivated TLR p-IRAK2K63-linked pUb oligo-TRAF6 TLR1TLR2 ligandCD14 activated TLR2/4p-4Y-MALBTK TLR1TLR2 PorB Homotrimer TLR1TLR2 p-S,2T-IRAK4oligo-MyD88Malactivated TLR receptor CD14 TLR6TLR2ligandCD14CD36 IRAK2p-S,2T-IRAK4oligo-MyD88Malactivated TLR TLR1TLR2 TLR6TLR2 recognized ligand p-S,2T-IRAK4oligo-MyD88Malactivated TLR receptor MyD88 oligomer Activated TLR12 or TLR 26 heterodimers or TLR4 homodimer TLR4MD2LPSCD14 TLR6TLR2 TLR1TLR2TLR1/2 ligandCD14 CD14 oligo-MyD88Malactivated TLR PorB Homotrimer TLR6/2 ligandCD14CD36 TLR4MD2LPSCD14 TLR4MD2LPSCD14 oligo-MyD88Malactivated TLR Activated TLR12 or TLR 26 heterodimers or TLR4 homodimer activated TLR2/4p-4Y-MALBTK TLR6TLR2 recognized ligand TLR6TLR2ligandCD14CD36 TLR4MD2 TLR6TLR2ligandCD14CD36 TLR1TLR2 ligandCD14 TLR4MD2 TLR1TLR2TLR1/2 ligandCD14 TLR6TLR2ligandCD14CD36 CD14 TLR1TLR2TLR1/2 ligandCD14 TLR1TLR2 ligandCD14 TLR1TLR2 recognized ligand TLR1TLR2 ligandCD14 TLR6/2 ligandCD14CD36 TLR4MD2LPSCD14 TLR6/2 ligandCD14CD36 TLR4MD2LPSCD14 TLR1TLR2 ligandCD14 TLR6/2 ligandCD14CD36 TLR6TLR2 p-IRAK2K63-linked pUb oligo-TRAF6 TLR4MD2LPSCD14 MEKK1activated TRAF6 MALPITLR1TLR2 recognized ligand PorB Homotrimer TLR6/2 ligandCD14CD36 activated TLR2/4p-4Y-MALBTK TLR6/2 ligandCD14CD36 PorB Homotrimer TLR1TLR2 recognized ligand MALPICD14 PorB Homotrimer TLR6TLR2ligandCD14CD36 p-3S,3T-IRAK1p-S,2T-IRAK4oligo-MyD88Malactivated TLR oligo-MyD88Malactivated TLR TLR6TLR2 TLR4MD2 TLR1TLR2 recognized ligand TLR1TLR2TLR1/2 ligandCD14 pp-IRAK1p-IRAK4oligo-MyD88 Malactivated TLR CD14 p-IRAK2p-IRAK4oligo-MyD88Malactivated TLR oligo-MyD88Malactivated TLR Activated TLR12 or TLR 26 heterodimers or TLR4 homodimer activated TLR2/4p-4Y-MALBTK TRAF6p-IRAK2 TAK1 complex CD14 TLR1TLR2 TLR6TLR2 TLR4MD2 MyD88 oligomer MyD88 oligomer TLR6TLR2 recognized ligand TLR4MD2LPSCD14 MyD88 oligomer p-IRAK2p-IRAK4oligo-MyD88Malactivated TLR TLR1TLR2 ligandCD14 TLR1TLR2 TRAF6hp-IRAK1 TLR4MD2LPSCD14 TLR4MD2LPSCD14 TLR1TLR2TLR1/2 ligandCD14 activated TLR2/4p-4Y-MALBTK p-S,2T-IRAK4oligo-MyD88Malactivated TLR receptor Activated TLR12 or TLR 26 heterodimers or TLR4 homodimer TLR6TLR2 recognized ligand p-S,2T-IRAK4oligo-MyD88Malactivated TLR receptor Activated TLR12 or TLR 26 heterodimers or TLR4 homodimer PorB Homotrimer PorB Homotrimer TLR6/2 ligandCD14CD36 TLR6TLR2 TLR6TLR2ligandCD14CD36 TLR1TLR2TLR1/2 ligandCD14 TLR6TLR2 recognized ligand PorB Homotrimer TLR1TLR2 recognized ligand IRAK1/or IRAK2p-IRAK4MyD88 oligomerMalactivated TLR TLR6TLR2 p-S,2T-IRAK4oligo-MyD88Malactivated TLR receptor Activated TLR12 or TLR 26 heterodimers or TLR4 homodimer Activated TLR12 or TLR 26 heterodimers or TLR4 homodimer TLR4MD2 p-S,2T-IRAK4oligo-MyD88Malactivated TLR receptor TLR6TLR2 recognized ligand Activated TLR12 or TLR 26 heterodimers or TLR4 homodimer IRAK4oligo-MyD88Malactivated TLR TLR1TLR2 recognized ligand TLR6TLR2 TLR4MD2 TLR1TLR2 recognized ligand TLR1TLR2 TLR4MD2 TLR6TLR2 TLR4MD2LPSCD14 MALactivated TLR2/4 TLR1TLR2 IKKAIKKBNEMO TLR1TLR2 ligandCD14 TLR6/2 ligandCD14CD36 TLR1TLR2TLR1/2 ligandCD14 oligo-MyD88Malactivated TLR CD14 TLR1TLR2TLR1/2 ligandCD14 CD14 TLR6TLR2ligandCD14CD36 oligo-MyD88Malactivated TLR TLR4MD2LPSCD14 TLR1TLR2 recognized ligand Ubc13UBE2V1 activated TLR2/4p-4Y-MALBTK TLR6TLR2 TLR6/2 ligandCD14CD36 TLR6/2 ligandCD14CD36 Activated TLR12 or TLR 26 heterodimers or TLR4 homodimer TLR1TLR2TLR1/2 ligandCD14 TLR1TLR2 MYD88 homodimer PorB Homotrimer TLR6TLR2ligandCD14CD36 TLR6/2 ligandCD14CD36 TLR1TLR2 TLR4MD2 TLR6TLR2ligandCD14CD36 TLR1TLR2 TLR4MD2 TLR6TLR2ligandCD14CD36 TLR6TLR2 TLR4MD2LPSCD14 MyD88 oligomer activated TLR2/4p-4Y-MALBTK MALBTKactivated TLR2/4 PorB Homotrimer K63-linked polyUb p-IRAK1TRAF6 TLR1TLR2 p-S,2T-IRAK4oligo-MyD88Malactivated TLR receptor activated TLR2/4p-4Y-MALBTK K63-linked polyUb p-IRAK1TRAF6 PorB Homotrimer TRAF6hp-IRAK1 Lipoteichoic acid CD14MYD88 IRAK2p-S,2T-IRAK4oligo-MyD88Malactivated TLRTLR12xN4GlycoAsn-LY96 Diacyl lipopeptide CHUK TLR2 4xPalmC-CD36 MALactivated TLR2/4Diacyl lipopeptide LPS 2xN4GlycoAsn-TLR4 BTK p-T209-IRAK1 MYD88 TLR1LPS Major outer membrane protein P TLR2 LPS IRAK1, IRAK2Clostridial peptidoglycan IRAK4oligo-MyD88Malactivated TLRTLR1TRAF6 ADPMYD88p-2S,S376,T,T209,T387-IRAK1 IKBKB BTK MYD88 4xPalmC-CD36 CD142xN4GlycoAsn-LY96 2xN4GlycoAsn-TLR4 TLR6 Triacyl lipopeptide GPIN-CD142xN4GlycoAsn-TLR4 Clostridial peptidoglycan Triacyl lipopeptide Diacyl lipopeptide LPS Diacyl lipopeptide Clostridial peptidoglycan TLR6 TLR2 TLR6 GPIN-CD142xN4GlycoAsn-LY96 GPIN-CD14TLR1MAP3K7 TRAF6 IKKAIKKBNEMOTAB3CD14Diacyl lipopeptide MYD88 p-2S,S376,T,T209,T387-IRAK1 Lipoteichoic acid BTK Lipoteichoic acid BTK TLR1p-2S,S376,T,T209,T387-IRAK1 Major outer membrane protein P GPIN-CD14BTK TRAF6hp-IRAK1ADPTRAF6hp-IRAK1p-IRAK4oligo-MyD88 Malactivated TLRp-IRAK2K63-linked pUb oligo-TRAF6free K63-linked pUbp-TAK1complexCD14TRAF6 Triacyl lipopeptide 2xN4GlycoAsn-LY96 Lipoteichoic acid Triacyl lipopeptide TLR1Clostridial peptidoglycan Clostridial peptidoglycan BTK GPIN-CD14Major outer membrane protein P Diacyl lipopeptide p-IRAK1p-IRAK4oligo-MyD88Malactivated TLRp-IRAK2p-IRAK4oligo-MyD88Malactivated TLR2xN4GlycoAsn-LY96 TLR1LPS Lipoteichoic acid Lipoteichoic acid TLR1GPIN-CD14TLR6 K63polyUb-TRAF6 Major outer membrane protein P TLR14xPalmC-CD36 Lipoteichoic acid MEKK1activated TRAF6TLR12xN4GlycoAsn-LY96 p-3S,3T-IRAK1p-S,2T-IRAK4oligo-MyD88Malactivated TLRTRAF6 TLR1TLR1MYD88 TLR6 2xN4GlycoAsn-LY96 LPS IRAK1p-S,2T-IRAK4 oligo-MyD88Malactivated TLRClostridial peptidoglycan 2xN4GlycoAsn-TLR4 p-IRAK2 Clostridial peptidoglycan TLR6 CD14Diacyl lipopeptide p-IRAK2K63-linked pUb oligo-TRAF6free K63 pUbTAK1 complexLPS 2xN4GlycoAsn-LY96 K63polyUb4xPalmC-CD36 4xPalmC-CD36 Triacyl lipopeptide MYD88 2xN4GlycoAsn-LY96 Lipoteichoic acid TLR2 IRAK4 TLR1IRAK1 ATPClostridial peptidoglycan TLR2 p-4Y-TIRAP Clostridial peptidoglycan CD14TAB1 MYD88 4xPalmC-CD36 TLR2 p-4Y-TIRAP ADPIRAK4Triacyl lipopeptide 2xN4GlycoAsn-TLR4 TRAF6 TRAF6 Ubc13UBE2V12xN4GlycoAsn-TLR4 p-4Y-TIRAP BTK TLR1CD14p-4Y-TIRAP p-T342,T345,S346-IRAK4 4xPalmC-CD36 Triacyl lipopeptide TLR2 TLR6 p-T209,T387-IRAK1 TAB2 TLR2 TLR6 TIRAP 4xPalmC-CD36 GPIN-CD14TAB2 LPS Clostridial peptidoglycan 2xN4GlycoAsn-TLR4 MYD88 2xN4GlycoAsn-LY96 p-T342,T345,S346-IRAK4 K63polyUbMYD88 Triacyl lipopeptide 4xPalmC-CD36 TLR2 UBE2N p-Pellinohp-IRAK1TRAF6p-IRAK2 p-IRAK2 IKBKG GPIN-CD14TLR6 TLR2 Lipoteichoic acid Major outer membrane protein P BTK Major outer membrane protein P LPS 4xPalmC-CD36 2xN4GlycoAsn-LY96 TLR6 GPIN-CD14p-T342,T345,S346-IRAK4 2xN4GlycoAsn-LY96 BTK Diacyl lipopeptide Clostridial peptidoglycan LPS ADPMYD88 p-S,2T-IRAK4oligo-MyD88Malactivated TLR receptor2xN4GlycoAsn-LY96 pp-IRAK1p-IRAK4oligo-MyD88 Malactivated TLRp-2S,S376,T,T209,T387-IRAK1 CD14ADPTAB1 Diacyl lipopeptide TLR6 MyD88Mal complexed with the activated TLRTAB3Diacyl lipopeptide Lipoteichoic acid TRAF6 BTK p-IRAK2K63-linked pUb oligo-TRAF6Clostridial peptidoglycan 4xPalmC-CD36 GPIN-CD14TLR2 TRAF6Major outer membrane protein P BTK CD142xN4GlycoAsn-TLR4 MAP3K14xPalmC-CD36 K63polyUb-hp-IRAK1 Lipoteichoic acid TAK1 activates NFkB by phosphorylation and activation of IKKs complexTriacyl lipopeptide p-Pellino-1,2,2xN4GlycoAsn-TLR4 IRAK1 UbLipoteichoic acid Diacyl lipopeptide TRAF6MYD88 MAP kinase activation in TLR cascade2xN4GlycoAsn-TLR4 BTK Lipoteichoic acid Diacyl lipopeptide TRAF6K63-linked polyUb p-IRAK1IKK complexp-IRAK2 Triacyl lipopeptide TRAF6 4xPalmC-CD36 Clostridial peptidoglycan Diacyl lipopeptide p-T342,T345,S346-IRAK4 Major outer membrane protein P LPS MAP3K7 MAP3K1p-4Y-TIRAP IRAK2 Triacyl lipopeptide TLR2 2xN4GlycoAsn-TLR4 Clostridial peptidoglycan PI2xN4GlycoAsn-TLR4 TLR2 p-IRAK2 MALBTKactivated TLR2/4BTK Clostridial peptidoglycan CD14TLR6 K63polyUb-TRAF6 2xN4GlycoAsn-TLR4 p-2S,S376,T,T209,T387-IRAK1 activated TLR2/4p-4Y-MALBTKp-T342,T345,S346-IRAK4 ATP2xN4GlycoAsn-LY96 p-4Y-TIRAP p-4Y-TIRAP CD142xN4GlycoAsn-LY96 Diacyl lipopeptide CD14p-4Y-TIRAP p-4Y-TIRAP GPIN-CD14ADPMajor outer membrane protein P ATPSIGIRRTRAF6p-IRAK2 p-IRAK4oligo-MyD88 Malactivated TLRTAK1 complexK63polyUb-hp-IRAK1 MYD88 2xN4GlycoAsn-TLR4 GPIN-CD14Lipoteichoic acid LPS p-4Y-TIRAP ATPTLR2 TLR1TLR6 Major outer membrane protein P IKBKB CD14TRAF6Triacyl lipopeptide p-T342,T345,S346-IRAK4 2xN4GlycoAsn-TLR4 TLR6 TLR6 BTKADPMajor outer membrane protein P p-4Y-TIRAP p-4Y-TIRAP ECSITGPIN-CD14CD14Triacyl lipopeptide 4xPalmC-CD36 TRAF6 TIRAP p-IRAK2 GPIN-CD14CD14PIMajor outer membrane protein P Clostridial peptidoglycan TRAF6hp-IRAK1PellinoLPS BTK Triacyl lipopeptide Major outer membrane protein P p-4Y-TIRAP oligo-MyD88Malactivated TLRp-IRAK2 LPS Diacyl lipopeptide TLR1Activated TLR12 or TLR 26 heterodimers or TLR4 homodimerTriacyl lipopeptide TAB1 PI4xPalmC-CD36 4xPalmC-CD36 BTK Major outer membrane protein P MYD88 TLR6 p-T342,T345,S346-IRAK4 2xN4GlycoAsn-TLR4 Lipoteichoic acid Lipoteichoic acid ATPTriacyl lipopeptide IRAK4 GPIN-CD14IRAK1/or IRAK2p-IRAK4MyD88 oligomerMalactivated TLRTAB2 p-T184,T187-MAP3K7 TLR2 2xN4GlycoAsn-TLR4 Triacyl lipopeptide 2xN4GlycoAsn-LY96 IRAK3ATPCHUK CD14UBE2V1 TRAF6 LPS CD14IKBKG p-T342,T345,S346-IRAK4 GPIN-CD14p-T342,T345,S346-IRAK4 4xPalmC-CD36 K63-linked polyUb p-IRAK1TRAF6Clostridial peptidoglycan Diacyl lipopeptide Major outer membrane protein P ATPTIRAP TLR2 2xN4GlycoAsn-LY96 GPIN-CD14Major outer membrane protein P TLR2 LPS Lipoteichoic acid TAB3TLR1MALPIDiacyl lipopeptide p-IRAK2oligo-TRAF6p-4Y-TIRAP TRAF6p-IRAK2TLR6 IRAK2 LPS Major outer membrane protein P K63polyUb-TRAF6 36, 51626242, 621662212, 3960, 61166216216242, 6249, 5842, 6242, 62213, 30, 49, 58621681616491642, 626219, 22, 43, 63, 6623, 25, 41161616212, 3916162142, 6221212181642, 62191616362, 3942, 626242, 62166242, 62842, 62162142, 623842, 626251, 7042, 622121161618, 59, 65, 7142, 6216216262621616621616166242, 621651166221163816622119, 22, 63, 66162, 22, 51, 702, 3916492136, 511621161, 332142, 621666, 69


Description

The first known downstream component of TLR4 and TLR2 signaling is the adaptor MyD88. Another adapter MyD88-adaptor-like (Mal; also known as TIR-domain-containing adaptor protein or TIRAP) has also been described for TLR4 and TLR2 signaling. MyD88 comprises an N-terminal Death Domain (DD) and a C-terminal TIR, whereas Mal lacks the DD. The TIR homotypic interactions bring adapters into contact with the activated TLRs, whereas the DD modules recruit serine/threonine kinases such as interleukin-1-receptor-associated kinase (IRAK). Recruitment of these protein kinases is accompanied by phosphorylation, which in turn results in the interaction of IRAKs with TNF-receptor-associated factor 6 (TRAF6). The oligomerization of TRAF6 activates TAK1, a member of the MAP3-kinase family, and this leads to the activation of the IkB kinases. These kinases, in turn, phosphorylate IkB, leading to its proteolytic degradation and the translocation of NF-kB to the nucleus. Concomitantly, members of the activator protein-1 (AP-1) transcription factor family, Jun and Fos, are activated, and both AP-1 transcription factors and NF-kB are required for cytokine production, which in turn produces downstream inflammatory effects. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=166058

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  34. 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
  35. 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
  36. Lee KG, Xu S, Kang ZH, Huo J, Huang M, Liu D, Takeuchi O, Akira S, Lam KP.; ''Bruton's tyrosine kinase phosphorylates Toll-like receptor 3 to initiate antiviral response.''; PubMed Europe PMC Scholia
  37. Kollewe C, Mackensen AC, Neumann D, Knop J, Cao P, Li S, Wesche H, Martin MU.; ''Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adapter in interleukin-1 signaling.''; PubMed Europe PMC Scholia
  38. Gottipati S, Rao NL, Fung-Leung WP.; ''IRAK1: a critical signaling mediator of innate immunity.''; PubMed Europe PMC Scholia
  39. Lamothe B, Besse A, Campos AD, Webster WK, Wu H, Darnay BG.; ''Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation.''; PubMed Europe PMC Scholia
  40. Gray P, Dunne A, Brikos C, Jefferies CA, Doyle SL, O'Neill LA.; ''MyD88 adapter-like (Mal) is phosphorylated by Bruton's tyrosine kinase during TLR2 and TLR4 signal transduction.''; PubMed Europe PMC Scholia
  41. Bardwell AJ, Frankson E, Bardwell L.; ''Selectivity of docking sites in MAPK kinases.''; PubMed Europe PMC Scholia
  42. Cui J, Zhu L, Xia X, Wang HY, Legras X, Hong J, Ji J, Shen P, Zheng S, Chen ZJ, Wang RF.; ''NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways.''; PubMed Europe PMC Scholia
  43. Suzuki N, Suzuki S, Yeh WC.; ''IRAK-4 as the central TIR signaling mediator in innate immunity.''; PubMed Europe PMC Scholia
  44. 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
  45. Smith H, Peggie M, Campbell DG, Vandermoere F, Carrick E, Cohen P.; ''Identification of the phosphorylation sites on the E3 ubiquitin ligase Pellino that are critical for activation by IRAK1 and IRAK4.''; PubMed Europe PMC Scholia
  46. Schauvliege R, Janssens S, Beyaert R.; ''Pellino proteins are more than scaffold proteins in TLR/IL-1R signalling: a role as novel RING E3-ubiquitin-ligases.''; PubMed Europe PMC Scholia
  47. 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
  48. 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
  49. Yamamoto M, Sato S, Hemmi H, Sanjo H, Uematsu S, Kaisho T, Hoshino K, Takeuchi O, Kobayashi M, Fujita T, Takeda K, Akira S.; ''Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4.''; PubMed Europe PMC Scholia
  50. Krappmann D, Hatada EN, Tegethoff S, Li J, Klippel A, Giese K, Baeuerle PA, Scheidereit C.; ''The I kappa B kinase (IKK) complex is tripartite and contains IKK gamma but not IKAP as a regular component.''; PubMed Europe PMC Scholia
  51. 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
  52. 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
  53. Muroi M, Tanamoto K.; ''TRAF6 distinctively mediates MyD88- and IRAK-1-induced activation of NF-kappaB.''; PubMed Europe PMC Scholia
  54. 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
  55. 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
  56. Xiong Y, Qiu F, Piao W, Song C, Wahl LM, Medvedev AE.; ''Endotoxin tolerance impairs IL-1 receptor-associated kinase (IRAK) 4 and TGF-beta-activated kinase 1 activation, K63-linked polyubiquitination and assembly of IRAK1, TNF receptor-associated factor 6, and IkappaB kinase gamma and increases A20 expression.''; PubMed Europe PMC Scholia
  57. Cheung PC, Nebreda AR, Cohen P.; ''TAB3, a new binding partner of the protein kinase TAK1.''; PubMed Europe PMC Scholia
  58. Shim JH, Xiao C, Paschal AE, Bailey ST, Rao P, Hayden MS, Lee KY, Bussey C, Steckel M, Tanaka N, Yamada G, Akira S, Matsumoto K, Ghosh S.; ''TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo.''; PubMed Europe PMC Scholia
  59. Piao W, Song C, Chen H, Wahl LM, Fitzgerald KA, O'Neill LA, Medvedev AE.; ''Tyrosine phosphorylation of MyD88 adapter-like (Mal) is critical for signal transduction and blocked in endotoxin tolerance.''; PubMed Europe PMC Scholia
  60. 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
  61. 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
  62. Takeda K, Akira S.; ''Toll-like receptors in innate immunity.''; PubMed Europe PMC Scholia
  63. Flannery SM, Keating SE, Szymak J, Bowie AG.; ''Human interleukin-1 receptor-associated kinase-2 is essential for Toll-like receptor-mediated transcriptional and post-transcriptional regulation of tumor necrosis factor alpha.''; PubMed Europe PMC Scholia
  64. Fitzgerald KA, Palsson-McDermott EM, Bowie AG, Jefferies CA, Mansell AS, Brady G, Brint E, Dunne A, Gray P, Harte MT, McMurray D, Smith DE, Sims JE, Bird TA, O'Neill LA.; ''Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction.''; PubMed Europe PMC Scholia
  65. Lin SC, Lo YC, Wu H.; ''Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling.''; PubMed Europe PMC Scholia
  66. Kawagoe T, Sato S, Matsushita K, Kato H, Matsui K, Kumagai Y, Saitoh T, Kawai T, Takeuchi O, Akira S.; ''Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2.''; PubMed Europe PMC Scholia
  67. Chang L, Karin M.; ''Mammalian MAP kinase signalling cascades.''; PubMed Europe PMC Scholia
  68. Towb P, Sun H, Wasserman SA.; ''Tube Is an IRAK-4 homolog in a Toll pathway adapted for development and immunity.''; PubMed Europe PMC Scholia
  69. Ohnishi T, Muroi M, Tanamoto K.; ''N-linked glycosylations at Asn(26) and Asn(114) of human MD-2 are required for toll-like receptor 4-mediated activation of NF-kappaB by lipopolysaccharide.''; PubMed Europe PMC Scholia
  70. Dunne A, Ejdeback M, Ludidi PL, O'Neill LA, Gay NJ.; ''Structural complementarity of Toll/interleukin-1 receptor domains in Toll-like receptors and the adaptors Mal and MyD88.''; PubMed Europe PMC Scholia
  71. Kagan JC, Medzhitov R.; ''Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling.''; PubMed Europe PMC Scholia
  72. Cheng H, Addona T, Keshishian H, Dahlstrand E, Lu C, Dorsch M, Li Z, Wang A, Ocain TD, Li P, Parsons TF, Jaffee B, Xu Y.; ''Regulation of IRAK-4 kinase activity via autophosphorylation within its activation loop.''; PubMed Europe PMC Scholia
  73. Kawagoe T, Sato S, Jung A, Yamamoto M, Matsui K, Kato H, Uematsu S, Takeuchi O, Akira S.; ''Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor-mediated immune responses but not in TCR signaling.''; PubMed Europe PMC Scholia
  74. Kopp E, Medzhitov R, Carothers J, Xiao C, Douglas I, Janeway CA, Ghosh S.; ''ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway.''; PubMed Europe PMC Scholia
  75. Brunner C, Müller B, Wirth T.; ''Bruton's Tyrosine Kinase is involved in innate and adaptive immunity.''; PubMed Europe PMC Scholia
  76. Xia ZP, Sun L, Chen X, Pineda G, Jiang X, Adhikari A, Zeng W, Chen ZJ.; ''Direct activation of protein kinases by unanchored polyubiquitin chains.''; PubMed Europe PMC Scholia
  77. Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z.; ''IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family.''; PubMed Europe PMC Scholia
  78. Takaesu G, Kishida S, Hiyama A, Yamaguchi K, Shibuya H, Irie K, Ninomiya-Tsuji J, Matsumoto K.; ''TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway.''; PubMed Europe PMC Scholia
  79. Núñez Miguel R, Wong J, Westoll JF, Brooks HJ, O'Neill LA, Gay NJ, Bryant CE, Monie TP.; ''A dimer of the Toll-like receptor 4 cytoplasmic domain provides a specific scaffold for the recruitment of signalling adaptor proteins.''; PubMed Europe PMC Scholia
  80. Qian Y, Commane M, Ninomiya-Tsuji J, Matsumoto K, Li X.; ''IRAK-mediated translocation of TRAF6 and TAB2 in the interleukin-1-induced activation of NFkappa B.''; PubMed Europe PMC Scholia
  81. Nagpal K, Plantinga TS, Wong J, Monks BG, Gay NJ, Netea MG, Fitzgerald KA, Golenbock DT.; ''A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP results in loss of MyD88 binding and reduced TLR2/TLR4 signaling.''; PubMed Europe PMC Scholia

History

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

External references

DataNodes

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

2 or TLR 2

6 heterodimers or TLR4 homodimer		ComplexREACT_8654 (Reactome)
BTK ProteinQ06187 (Uniprot-TrEMBL)
BTKProteinQ06187 (Uniprot-TrEMBL)
CD14ProteinP08571 (Uniprot-TrEMBL)
CHUK ProteinO15111 (Uniprot-TrEMBL)
Clostridial peptidoglycan MetaboliteCHEBI:8005 (ChEBI)
Diacyl lipopeptide MetaboliteCHEBI:46896 (ChEBI)
ECSITProteinQ9BQ95 (Uniprot-TrEMBL)
GPIN-CD14ProteinP08571 (Uniprot-TrEMBL)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IKKA

IKKB

NEMO		ComplexREACT_7693 (Reactome)
IRAK1

p-S,2T-IRAK4 oligo-MyD88 Mal

activated TLR		ComplexREACT_26684 (Reactome)
IRAK1 ProteinP51617 (Uniprot-TrEMBL)
IRAK1, IRAK2ProteinREACT_26678 (Reactome)
IRAK1/or IRAK2

p-IRAK4 MyD88 oligomer Mal

activated TLR		ComplexREACT_7005 (Reactome)
IRAK2

p-S,2T-IRAK4 oligo-MyD88 Mal

activated TLR		ComplexREACT_26069 (Reactome)
IRAK2 ProteinO43187 (Uniprot-TrEMBL)
IRAK3ProteinQ9Y616 (Uniprot-TrEMBL)
IRAK4

oligo-MyD88 Mal

activated TLR		ComplexREACT_7025 (Reactome)
IRAK4 ProteinQ9NWZ3 (Uniprot-TrEMBL)
IRAK4ProteinQ9NWZ3 (Uniprot-TrEMBL)
K63-linked polyUb p-IRAK1 TRAF6ComplexREACT_25933 (Reactome)
K63polyUb-TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
K63polyUb-hp-IRAK1 ProteinP51617 (Uniprot-TrEMBL)
K63polyUbREACT_21645 (Reactome)
LPS MetaboliteCHEBI:16412 (ChEBI)
Lipoteichoic acid MetaboliteCHEBI:28640 (ChEBI)
MAL

BTK

activated TLR2/4		ComplexREACT_124673 (Reactome)
MAL PIComplexREACT_151450 (Reactome)
MAL activated TLR2/4ComplexREACT_152404 (Reactome)
MAP kinase activation in TLR cascadePathwayWP2792 (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.

MAP3K1ProteinQ13233 (Uniprot-TrEMBL)
MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
MEKK1 activated TRAF6ComplexREACT_7633 (Reactome)
MYD88 ProteinQ99836 (Uniprot-TrEMBL)
MYD88ProteinQ99836 (Uniprot-TrEMBL)
Major outer membrane protein P ProteinP30690 (Uniprot-TrEMBL)
MyD88 Mal complexed with the activated TLRComplexREACT_7694 (Reactome)
PIMetaboliteCHEBI:18348 (ChEBI)
SIGIRRProteinQ6IA17 (Uniprot-TrEMBL)
TAB1 ProteinQ15750 (Uniprot-TrEMBL)
TAB2 ProteinQ9NYJ8 (Uniprot-TrEMBL)
TAB3ProteinQ8N5C8 (Uniprot-TrEMBL)
TAK1 activates NFkB by phosphorylation and activation of IKKs complexPathwayWP2656 (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 complexComplexREACT_22633 (Reactome)
TIRAP ProteinP58753 (Uniprot-TrEMBL)
TLR1ProteinQ5FWG5 (Uniprot-TrEMBL)
TLR2 ProteinO60603 (Uniprot-TrEMBL)
TLR6 ProteinQ9Y2C9 (Uniprot-TrEMBL)
TRAF6

K63-linked polyUb p-IRAK1

IKK complex		ComplexREACT_26014 (Reactome)
TRAF6

hp-IRAK1

Pellino		ComplexREACT_26423 (Reactome)
TRAF6

hp-IRAK1 p-IRAK4 oligo-MyD88 Mal

activated TLR		ComplexREACT_25704 (Reactome)
TRAF6 hp-IRAK1ComplexREACT_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 p-IRAK4 oligo-MyD88 Mal

activated TLR		ComplexREACT_124060 (Reactome)
TRAF6 p-IRAK2ComplexREACT_26255 (Reactome)
TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRAF6ProteinQ9Y4K3 (Uniprot-TrEMBL)
Triacyl lipopeptide MetaboliteCHEBI:60192 (ChEBI)
UBE2N ProteinP61088 (Uniprot-TrEMBL)
UBE2V1 ProteinQ13404 (Uniprot-TrEMBL)
UbProteinREACT_3316 (Reactome)
Ubc13 UBE2V1ComplexREACT_12995 (Reactome)
activated TLR2/4

p-4Y-MAL

BTK		ComplexREACT_125282 (Reactome)
oligo-MyD88

Mal

activated TLR		ComplexREACT_26196 (Reactome)
p-2S,S376,T,T209,T387-IRAK1 ProteinP51617 (Uniprot-TrEMBL) This is the hyperphosphorylated, active form of IRAK1. The unknown coordinate phosphorylation events are to symbolize the multiple phosphorylations that likely take place in the ProST domain (aa10-211).
p-3S,3T-IRAK1

p-S,2T-IRAK4 oligo-MyD88 Mal

activated TLR		ComplexREACT_7712 (Reactome)
p-4Y-TIRAP ProteinP58753 (Uniprot-TrEMBL)
p-IRAK1

p-IRAK4 oligo-MyD88 Mal

activated TLR		ComplexREACT_7256 (Reactome)
p-IRAK2

K63-linked pUb oligo-TRAF6 free K63 pUb

TAK1 complex		ComplexREACT_27027 (Reactome)
p-IRAK2

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

p-TAK1complex		ComplexREACT_26622 (Reactome)
p-IRAK2 K63-linked pUb oligo-TRAF6ComplexREACT_26930 (Reactome)
p-IRAK2 oligo-TRAF6ComplexREACT_25874 (Reactome)
p-IRAK2

p-IRAK4 oligo-MyD88 Mal

activated TLR		ComplexREACT_26900 (Reactome)
p-IRAK2 ProteinO43187 (Uniprot-TrEMBL)
p-Pellino

hp-IRAK1

TRAF6		ComplexREACT_26368 (Reactome)
p-Pellino-1,2,ProteinREACT_22733 (Reactome)
p-S,2T-IRAK4

oligo-MyD88 Mal

activated TLR receptor		ComplexREACT_26813 (Reactome)
p-T184,T187-MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
p-T209,T387-IRAK1 ProteinP51617 (Uniprot-TrEMBL)
p-T209-IRAK1 ProteinP51617 (Uniprot-TrEMBL)
p-T342,T345,S346-IRAK4 ProteinQ9NWZ3 (Uniprot-TrEMBL)
pp-IRAK1

p-IRAK4 oligo-MyD88 Mal

activated TLR		ComplexREACT_7283 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowREACT_25097 (Reactome)
ADPArrowREACT_25200 (Reactome)
ADPArrowREACT_25213 (Reactome)
ADPArrowREACT_25375 (Reactome)
ADPArrowREACT_6794 (Reactome)
ADPArrowREACT_6833 (Reactome)
ADPArrowREACT_6862 (Reactome)
ATPREACT_25097 (Reactome)
ATPREACT_25200 (Reactome)
ATPREACT_25213 (Reactome)
ATPREACT_25375 (Reactome)
ATPREACT_6794 (Reactome)
ATPREACT_6833 (Reactome)
ATPREACT_6862 (Reactome)
Activated TLR1

2 or TLR 2

6 heterodimers or TLR4 homodimer		REACT_121383 (Reactome)
BTKREACT_150418 (Reactome)
ECSITArrowREACT_6962 (Reactome)
IKKA

IKKB

NEMO		REACT_25305 (Reactome)
IRAK1

p-S,2T-IRAK4 oligo-MyD88 Mal

activated TLR		REACT_6833 (Reactome)
IRAK1, IRAK2REACT_6929 (Reactome)
IRAK2

p-S,2T-IRAK4 oligo-MyD88 Mal

activated TLR		REACT_25213 (Reactome)
IRAK3TBarREACT_6736 (Reactome)
IRAK4

oligo-MyD88 Mal

activated TLR		REACT_25097 (Reactome)
IRAK4REACT_6975 (Reactome)
K63-linked polyUb p-IRAK1 TRAF6ArrowREACT_24943 (Reactome)
K63-linked polyUb p-IRAK1 TRAF6REACT_25305 (Reactome)
K63polyUbREACT_24943 (Reactome)
K63polyUbREACT_24985 (Reactome)
MAL

BTK

activated TLR2/4		REACT_120882 (Reactome)
MAL PIREACT_121383 (Reactome)
MAL activated TLR2/4REACT_150418 (Reactome)
MAP3K1REACT_6962 (Reactome)
MYD88REACT_25221 (Reactome)
MYD88REACT_6797 (Reactome)
MyD88 Mal complexed with the activated TLRREACT_25221 (Reactome)
REACT_120733 (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).
REACT_120882 (Reactome) MAL(TIRAP) undergoes tyrosine phosphorylation mediated by Bruton's tyrosine kinase (BTK). BTK-specific inhibitor, LFM-A13, blocked the phosphorylation of MAL in human HEK293 stimulated with LPS or macrophage-activating lipopeptide-2. LFM-A13 also inhibited activation of NF-kB in LPS-treated human monocytic cell line THP-1 [Gray P et al 2006; Jefferies CA et al 2003]. Tyr-86, Tyr-106 and Tyr-187 were identified as possible phosphorylation sites [Gray P et al 2006]. An additional study has shown that Tyr-86, Tyr-106, and Tyr-159 are important residues, as mutagenesis of these residues impaired MAL phosphorylation, affected its interaction with BTK and also impaired downstream signaling [Piao W et al 2008].
REACT_121298 (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_121383 (Reactome) TIRAP/Mal-deficient mice showed normal responses to the TLR3, TLR5, TLR7, and TLR9 ligands, but were defective in TLR4 and TLR2 ligand-induced proinflammatory cytokine production (Horng et al. 2002,Yamamoto et al. 2002). In contrast, TLR4 ligand-induced activation of IRF-3 and expression of IFN-inducible genes were not impaired in TIRAP/Mal knockout macrophages or in mice lacking both MyD88 and TIRAP/Mal (Horng et al. 2002,Yamamoto et al. 2002). Thus, TIRAP/Mal is an essential adapter that is involved in the MyD88-dependent pathway via TLR4 and TLR2, but not in the MyD88-independent pathway. Mal contains a phosphatidylinositol 4,5-bisphosphate-binding domain required for retention in the plasma membrane. The intracellular TIR domains of TLR2 or 4 associate with Mal at the cytoplasmic side of the plasma membrane, which in turn facilitates the binding of MyD88 to the activated TLR, leading to NF-kB and MAPK activation [Nunez Miguel et al 2007].
REACT_150418 (Reactome) Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase, which plays an essential role in B cell receptor (BCR) signaling [Brunner C et al 2005]. BTK has been also implicated in TLR signaling [Lee KG et al 2012, Jefferies CA et al 2003]. Interaction studies revealed that BTK can associate with intracellular TIR-domains of TLRs 4, 6, 8 and 9. Furthermore, BTK was found to interact with other proteins involved in TLR2/4 signaling - MyD88, MAL and IRAK-1 [Jefferies CA et al 2003].
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_25097 (Reactome) IRAK4 is activated by autophosphorylation at 3 positions within the kinase activation loop, Thr-342, Thr-345 and Ser-346.
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_25213 (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_25221 (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_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_6736 (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_6794 (Reactome) Second, Thr387 in the activation loop is phosphorylated, leading to full enzymatic activity.
REACT_6797 (Reactome) MyD88 binds to IRAK (IL-1 receptor-associated kinase) and the receptor heterocomplex (the signaling complex) and thereby mediates the association of IRAK with the receptor. MyD88 therefore couples a serine/threonine protein kinase to the receptor complex.
REACT_6833 (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_6856 (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).
REACT_6862 (Reactome) Phosphorylation of IRAK-1 is due to three sequential phosphorylation steps, which leads to full or hyper-phopshorylation of IRAK1. Under in vitro conditions these are all autophosphorylation events. First, Thr-209 is phosphorylated resulting in a conformational change of the kinase domain. Next, Thr-387 in the activation loop is phosphorylated, leading to full enzymatic activity. Several additional residues are phosphorylated in the proline-, serine-, and threonine-rich (ProST) region between the N-terminal death domain and kinase domain. Hyperphosphorylation of this region leads to dissociation of IRAK1 from the activated receptor complex. The kinase activity of IRAK1 is dispensable for IL1-induced NFkB and MAP kinase activation (Knop & Martin, 1999), unlike that of IRAK4 (Suzuki et al. 2002; Kozicak-Holbro et al. 2007), It has been suggested that IRAK1 primarily acts as an adaptor for TRAF6 (Conze et al. 2008).
REACT_6929 (Reactome)
  • IRAK1 is recruited to the TLR complex through binding with IRAK4[Lin SC et al 2010].

  • 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_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.

REACT_6975 (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].
SIGIRRTBarREACT_6797 (Reactome)
TAK1 complexREACT_24985 (Reactome)
TRAF6

hp-IRAK1

Pellino		REACT_25200 (Reactome)
TRAF6 hp-IRAK1ArrowREACT_6736 (Reactome)
TRAF6 hp-IRAK1REACT_25142 (Reactome)
TRAF6 p-IRAK2ArrowREACT_121298 (Reactome)
TRAF6 p-IRAK2REACT_25119 (Reactome)
TRAF6REACT_120733 (Reactome)
TRAF6REACT_25119 (Reactome)
TRAF6REACT_25362 (Reactome)
TRAF6REACT_6856 (Reactome)
TRAF6REACT_6962 (Reactome)
UbREACT_25022 (Reactome)
Ubc13 UBE2V1ArrowREACT_24943 (Reactome)
Ubc13 UBE2V1REACT_24943 (Reactome)
activated TLR2/4

p-4Y-MAL

BTK		REACT_6797 (Reactome)
oligo-MyD88

Mal

activated TLR		REACT_6975 (Reactome)
p-3S,3T-IRAK1

p-S,2T-IRAK4 oligo-MyD88 Mal

activated TLR		ArrowREACT_6862 (Reactome)
p-3S,3T-IRAK1

p-S,2T-IRAK4 oligo-MyD88 Mal

activated TLR		REACT_6856 (Reactome)
p-IRAK1

p-IRAK4 oligo-MyD88 Mal

activated TLR		ArrowREACT_6833 (Reactome)
p-IRAK1

p-IRAK4 oligo-MyD88 Mal

activated TLR		REACT_6794 (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-linked pUb

p-TAK1complex		ArrowREACT_25375 (Reactome)
p-IRAK2 K63-linked pUb oligo-TRAF6REACT_24985 (Reactome)
p-IRAK2 oligo-TRAF6REACT_25022 (Reactome)
p-IRAK2

p-IRAK4 oligo-MyD88 Mal

activated TLR		ArrowREACT_25213 (Reactome)
p-IRAK2

p-IRAK4 oligo-MyD88 Mal

activated TLR		REACT_120733 (Reactome)
p-Pellino

hp-IRAK1

TRAF6		ArrowREACT_25200 (Reactome)
p-Pellino

hp-IRAK1

TRAF6		REACT_24943 (Reactome)
p-Pellino-1,2,ArrowREACT_24943 (Reactome)
p-Pellino-1,2,REACT_25142 (Reactome)
p-S,2T-IRAK4

oligo-MyD88 Mal

activated TLR receptor		ArrowREACT_121298 (Reactome)
p-S,2T-IRAK4

oligo-MyD88 Mal

activated TLR receptor		ArrowREACT_25097 (Reactome)
p-S,2T-IRAK4

oligo-MyD88 Mal

activated TLR receptor		ArrowREACT_6736 (Reactome)
p-S,2T-IRAK4

oligo-MyD88 Mal

activated TLR receptor		REACT_6929 (Reactome)
pp-IRAK1

p-IRAK4 oligo-MyD88 Mal

activated TLR		ArrowREACT_6794 (Reactome)
pp-IRAK1

p-IRAK4 oligo-MyD88 Mal

activated TLR		REACT_6862 (Reactome)
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