C-type lectin receptors (Homo sapiens)

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27, 719830, 466754, 59, 8596646028, 64742, 12, 42, 43, 5040, 72, 7852415, 9573, 8444, 802093, 10216, 8257, 601129, 31, 61, 91, 9421, 56, 58, 89, 98...24, 54, 70, 8818, 1015, 10, 45265249, 664363, 976019879, 33, 65, 6881383, 3423256, 604248, 8718, 1015, 375, 33, 53, 90, 10014, 32, 35, 51, 9243, 83, 846741, 44, 6936, 43, 8375176, 8617, 30, 3916, 8259, 858, 7942nucleoplasmendoplasmic reticulum lumencytosolcytosolITPR3 p-S176,S180-IKKA SRC-1ATPRELA K48-polyUb-p-7S-p100:RELBPI(3,4,5)P3 RELA p-6Y-SYK FYN, LYNK63polyUb-NEMO Ub-124-UBB(77-152) PSMD6 PSMD12 p-S32,S36-NFKBIA p-S177,S181-IKBKB Ub-504-UBC(457-532) TAB1 K48-polyUb-p-7S-p100 PSMB10 PSMD3 pathogens:CLEC6A,CLEC4E:FCER1G dimerUBC(609-684) Ubc13:UBE2V1p-12S-NFATC1 Ub-428-UBC(381-456) CLEC6A MALT1oligomers:activecaspase-8:ASCK48PolyUb-K21,22-p-S32,36-IkBA:NF-kB complexp-S177,S181-IKKB:IKKA:pUb-NEMOPSMD5 CLEC4E 1,3-beta-D-glucan:p-Y15-CLEC7APSMB6 PSMF1 TDM IL1B(1-269)p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TAB1:TAB2/TAB3:K63polyUb-34,158-TAK1RPS6KA5 CALM1 PPP3CA Ub-48-UBA52(1-76) Ub-580-UBC(533-608) PSMB9 PSMC5 alpha-mannan DAGsp-T507,S645,S664-PRKCD PSMD11 TRAF6 NRAS PSMB5 UBE2V1 Protein Kinase A, catalytic subunits p21RAS:GTP:p-S338,Y340,Y341-RAF1Ub-48-UBC(1-76) RELA AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerPSMB3 Ub-656-UBC(609-684) PSMB10 CASP8(385-479) PSME1 RAF1 p-Y65,Y76-FCER1G TDM MALT1 oligomer ATPTDM CCL17,CCL22 mRNAp-7S-p100 PPP3CB NFKB1:p-S276-RELABCL10 oligomer p-Y15-CLEC7A BCL10 oligomer CDC34 CD209:ICAM2HCV Genome polyprotein PPP3R1 CLEC6A I(1,4,5)P3 ATPPSMD4 UBE2N Fe3+ K63polyUb-TRAF6 oligomer K63polyUb-34,158-TAK1 PPiUBC(153-228) AMP1,3-beta-D-glucanIKKA:IKBKB:IKBKGCREBBP p-T231-CARD9:BCL10:MALT1:TRAF6 oligomersp-S276-RELA Active NIK PSMC4 UBB(77-152) K48PolyUb-K21,22-p-S32,S36-IkBA K63polyUb-TRAF6 oligomer IL1B(117-269)PSME3 UBB(153-228) IKBKG NFKB1(1-433) Zn2+ Ub-124-UBC(77-152) BCL10 oligomer PLCG2SKP1 PSMD9 Ub-352-UBC(305-380) EP300 PSME3 TAB1 p-T231-CARD9 oligomer p-S243-NFATC2 Ac-CoAPSMB11 ADPUbc13:UBE2V1TRAF6CLEC4E ADPUb-276-UBC(229-304) PSMC2 p-Y753,Y759-PLCG2UBE2V1 p100:RELBPSMA8 CCL22 gene CASP8(217-374) PSMD10 p-T231-CARD9:BCL10:MALT1 oligomers:TRAF6GTP Ca2+ ITPR1 ICAM3 CLEC4C:FCER1Gdimer:HIV gp120,HCVgp E21,3-beta-D-glucan p-S338-RAF1 RELB p-T231-CARD9:BCL10:MALT1 oligomersTAB1:TAB2,TAB3:TAK1RELA PSMD7 I(1,4,5)P3 CLEC4D alpha-mannan ATPGDPp-Y65,Y76-FCER1G CCL17 mRNA SYKPSMB7 CLEC4AK63polyUbRELB p-T231-CARD9 oligomer PSMA4 UBE2D1 ITPR3 p-S176,S180-IKKA ITPR2 CLEC4D:FCER1Gdimer:TDMUb-200-UBC(153-228) FYN, LYNFCER1G p-S276-RELATRAF6 oligomer CLEC6A:FCER1G dimerp-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TAB1:TAB2/TAB3:K63polyUb-34,158-p3Y,1S-TAK1FYN ATPalpha-mannan PSME4 ITPR:I(1,4,5)P3tetramerPSMA7 p21 RAS:GTPCLEC4C:FCER1G dimerPSMA5 IL1B(1-116)ICAM2 Calcineurin (CaN)Active NIK NFKB1(1-433) FYN p-S276-RELA Zn2+ p-T507,S645,S664-PRKCDPSMC5 CALM1 UBE2D2,UBE2D1,(CDC34)MAP3K14BCL10 oligomer NF-kB complexSKP1 BTRC NFKB1:p-S276,5AcK-RELA:p300/CBPPPP3CB PPP3R1 p21 RAS:GDPCLEC6A CLEC6A RPS6KA5(MSK1/SAPK1):PKA catalytic subunitsTAB2 TAB3 p-14S-NFATC2 ATPTAB2 p21RAS:GTP:p-S338-RAF1GTP BCL10 oligomer Fe3+ K63polyUb-TRAF6 oligomer PSMB8 TAB3 KRAS NFKB1(1-433) alpha-mannan PSMB1 AMPADPTAB2 IKKA Ub-580-UBC(533-608) PSMD13 DAGs:p-T507,S645,S664-PRKCDIP3 receptorhomotetramerPPP3R1 Ubc13:UBE2V1TDM PSMF1 Active NIKCD209RELB K63polyUb-TRAF6 oligomer CALM1 p-T231-CARD9 oligomer MALT1 oligomer Ub-48-UBB(1-76) CASP8(217-374) PSME1 PSMD6 TAB3 CCL17,CCL22 genesATP1,3-beta-D-glucan PSMD7 PSMA4 BCL10 oligomer 26S proteasomep-T231-CARD9p-7S-p100 Ub-48-UBA52(1-76) Ub-48-UBB(1-76) Ub-200-UBB(153-228) RPS27A(1-76) CCL22 mRNA ATPp-S276-RELA:RELBBTRC PSMD4 ATPTAB1 alpha-mannan PLCG2 Ub-124-UBB(77-152) CLEC4E Ub-TRAF6 trimerbound to CBMcomplexK63polyUb-34,158-p-T178,184,187,S192-TAK1 IKKA CD209:ManLAMTDM ActiveNIK:p-S176,180-IKKAdimer:p100:RELBENV polyprotein CD209 PSMA1 FCER1G Ub-504-UBC(457-532) ENV polyprotein PSMA3 active caspase-8p-T231-CARD9 oligomer Fe3+ FCER1G FBXW11 RELB ADPADPUBC(457-532) p-Y15-CLEC7A PSMD8 Ub-48-UBC(1-76) HRAS CUL1 PAK2 p-T231-CARD9 oligomer ADPATPADPp-Y65,Y76-FCER1G p-T231-CARD9 oligomer p-13S-NFATC3 ICAM3BCL10PPP3CB p-S177,S181-IKBKB FCER1G NFKB1(1-433) Zn2+ CLEC4E PSMB2 PSMB9 RAF1CLEC6A PSMA7 Ub-200-UBC(153-228) BCL10 oligomer TDM UBB(1-76) Ub-200-UBB(153-228) alpha-mannan p-S552-CARD11 I(1,4,5)P3PAK1,2,3TDM MALT1:activecaspase-8SYK p-S176,S180-IKKA TDM Zn2+ UBE2V1 PSMD5 IKKA dimerCLEC4C TDMCLEC4E ICAM2NFKB2(1-900) alpha-mannan BCL10 oligomer PSMC4 p-S276,5xAcK-RELA PPP3CB CLEC6A:FCER1Gdimer:alpha-mannanp-Y753,Y759-PLCG2 UBC(305-380) CLEC4E:FCER1G dimerATP1,3-beta-D-glucan:p-Y15-CLEC7A:SYKPSMD10 ADPMALT1 UBE2D2 HRAS PSMB6 CLEC4E Pi4xCa2+:CaMIKKA UBC(77-152) MALT1 oligomer MALT1 oligomer ManLAM NRAS CREBBP HIV gp120,HCV gp E2IL1B mRNAPSMD14 p-S177,S181-IKKB:IKKA:NEMOManLAMMALT1 oligomer SYK CLEC7A p-S276-RELA p-6Y-SYK DAGs MAP3K7 ADPNFAT:CaN:CaMITPR2 p52:RELBCASP8(217-374) CLEC4E:FCER1Gdimer:TDM,alpha-mannanCLEC4D:FCER1G dimerp-S257-NFATC1 pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer:p-6Y-SYK:PLCG2ITPR1 alpha-mannan FCER1G p52 p-T231-CARD9 oligomer FBXW11 NFKB2(1-900) CLEC7ARELB ATPNFAT:CaN:CaMUBC(1-76) Ca2+ActiveNIK:p-S176,180-IKKAdimer:p-7S-p100:RELBMALT1K48-Ubpathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer:p-6Y-SYK:p-Y753,Y759-PLCG2GTP PSMC6 p52:RELBUBA3IkB(alpha):NF-kBcomplexATPPSMB7 p-T231-CARD9oligomer:BCL10PSMD2 MALT1 CUL1 GTP NFKB1(1-433) NRAS BCL10 oligomer Active NIK UBC(229-304) UBC(533-608) 26S proteasomep-BCL10 RELBUbPSMC3 PSMA5 GTPNFKB1(1-433) PPP3CA FCER1G PhosphorylatedNFATC1,2,3Calcineurin:Calmodulin (CaN:CaM)CBP/p300PSMB11 FCER1G HCV Genome polyprotein Ca2+CLEC4E PSMC1 CREBBP pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer:p-6Y-SYKPSME2 CARD9CALM1NFKB1:p-S276-RELA:p300/CBPp-T231-CARD9oligomerPSMA2 PSMD12 CLEC4C TDM CLEC4D p-Y65,Y76-FCER1G PSMD13 p-T231-CARD9 oligomer IKKA CLEC6A K63polyUbp-T231-CARD9 oligomer HCV Genome polyprotein PSMD1 ITPR2 p-S265-NFATC3 pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer:SYKCASP8(385-479) p21 RAS:GTP:RAF1ADPp-Y753,Y759-PLCG2PAK1 FCER1G PSMD14 CLEC4A:HIV gp120,HCVgpE2PSMA6 DAGs ATPPSMA2 pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimerCD209:ICAM3:Ca+2NFKBIA Ub-656-UBC(609-684) RELB ATPPSME4 SYKRELB MALT1 oligomer ENV polyprotein NRAS PPP3R1 MAP3K7 1,3-beta-D-glucan Ca2+H2OUBA52(1-76) CLEC6A IKBKG BCL10 KRAS ADPp-S265-NFATC3 NEDD8-C111-UBE2MFe3+ NRAS CALM1 UBC(381-456) PSMA1 Ub-48-RPS27A(1-76) Ub-276-UBC(229-304) PSMB1 PSMB4 CLEC4E PDPK1 PI(4,5)P2PSMD3 Ub-352-UBC(305-380) ITPR3 FCER1G PPP3CA CLEC7A:1,3-beta-D-glucanKRAS PPP3CA PPip-S243-NFATC2 EP300 MALT1 PSMB3 LYN p-T231-CARD9:BCL10oligomers:MALT1LYN PSMA8 active p-T507,S645,S664-PRKCD PYCARD PSMD8 p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TRIKA2KRAS CD209 K63polyUbp-S338,Y340,Y341-RAF1 NAD+ HRAS PSMB4 NF-kB complexADPKRAS CASP8(385-479) p-T231-CARD9 oligomer PSMD2 PI(3,4)P2 Ub-428-UBC(381-456) MALT1 CLEC6A HRAS p-S257-NFATC1 DAGs:activep-T507,S645,S664-PRKCDp52 K63polyUb TRAF6 TDM,alpha-mannanp-S32,36-IkB-alpha:NF-kB complexPSMC6 RELA PSMC1 CLEC4A RELB Ca2+ Ca2+ p-Y65,Y76-FCER1G PSMD9 PAK3 PSMA3 TAB3 K48-UbEP300 Ub-124-UBC(77-152) PLCG2CARD9TAB1 ADPActiveNIK:p-176,S180-IKKAdimer:p-7S-p100:SCF-beta-TRCPPSMC2 Ca2+ ADPUb-48-RPS27A(1-76) p-6Y-SYK UBE2N IL1B geneActiveNIK:p-S176,180-IKKAdimerNFKB1(1-433) PSMA6 IKBKB Active NIK PYCARDSCF-beta-TRCPPSMD11 CoA-SHTAB2 alpha-mannanMALT1 oligomer PSMB8 p-T231-CARD9:BCL10oligomersI(1,4,5)P3PSME2 p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomersalpha-mannan Ca2+ GDP AHCYL1 ITPR1 PSMB5 p-S176,S180-IKKA CCL17 gene UBE2N PSMB2 H2OPSMD1 NFKB1(1-433) PSMC3 HRAS ATPCD209 773775572213, 4722762629762


Description

Pathogen recognition is central to the induction of T cell differentiation. Groups of pathogens share similar structures known as pathogen-associated molecular patterns (PAMPs), which are recognised by pattern recognition receptors (PRRs) expressed on dendritic cells (DCs) to induce cytokine expression. PRRs include archetypical Toll-like receptors (TLRs) and non-TLRs such as retinoic acid-inducible gene I (RIG-I)-like receptors, C-type lectin receptors (CLRs) and intracellular nucleotide-binding domain and leucine-rich-repeat-containing family (NLRs). PRR recognition of PAMPs can lead to the activation of intracellular signalling pathways that elicit innate responses against pathogens and direct the development of adaptive immunity.
CLRs comprises a large family of receptors which bind carbohydrates, through one or more carbohydrate recognition domains (CRDs), or which possess structurally similar C-type lectin-like domains (CTLDs) which do not necessarily recognise carbohydrate ligands. Some CLRs can induce signalling pathways that directly activate nuclear factor-kB (NF-kB), whereas other CLRs affect signalling by Toll-like receptors. These signalling pathways trigger cellular responses, including phagocytosis, DC maturation, chemotaxis, the respiratory burst, inflammasome activation, and cytokine production. View original pathway at:Reactome.

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  58. Yamasaki S, Ishikawa E, Sakuma M, Hara H, Ogata K, Saito T.; ''Mincle is an ITAM-coupled activating receptor that senses damaged cells.''; PubMed Europe PMC Scholia
  59. Gorjestani S, Yu M, Tang B, Zhang D, Wang D, Lin X.; ''Phospholipase Cγ2 (PLCγ2) is key component in Dectin-2 signaling pathway, mediating anti-fungal innate immune responses.''; PubMed Europe PMC Scholia
  60. Strasser D, Neumann K, Bergmann H, Marakalala MJ, Guler R, Rojowska A, Hopfner KP, Brombacher F, Urlaub H, Baier G, Brown GD, Leitges M, Ruland J.; ''Syk kinase-coupled C-type lectin receptors engage protein kinase C-δ to elicit Card9 adaptor-mediated innate immunity.''; PubMed Europe PMC Scholia
  61. Kim YJ, Sekiya F, Poulin B, Bae YS, Rhee SG.; ''Mechanism of B-cell receptor-induced phosphorylation and activation of phospholipase C-gamma2.''; PubMed Europe PMC Scholia
  62. Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen ZJ.; ''Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain.''; PubMed Europe PMC Scholia
  63. Loh C, Shaw KT, Carew J, Viola JP, Luo C, Perrino BA, Rao A.; ''Calcineurin binds the transcription factor NFAT1 and reversibly regulates its activity.''; PubMed Europe PMC Scholia
  64. Zhong H, Voll RE, Ghosh S.; ''Phosphorylation of NF-kappa B p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300.''; PubMed Europe PMC Scholia
  65. Geijtenbeek TB, Gringhuis SI.; ''Signalling through C-type lectin receptors: shaping immune responses.''; PubMed Europe PMC Scholia
  66. Riboldi E, Daniele R, Parola C, Inforzato A, Arnold PL, Bosisio D, Fremont DH, Bastone A, Colonna M, Sozzani S.; ''Human C-type lectin domain family 4, member C (CLEC4C/BDCA-2/CD303) is a receptor for asialo-galactosyl-oligosaccharides.''; PubMed Europe PMC Scholia
  67. Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMed Europe PMC Scholia
  68. Kawakami N, Shimohama S, Hayakawa T, Sumida Y, Fujimoto S.; ''Tyrosine phosphorylation and translocation of phospholipase C-gamma 2 in polymorphonuclear leukocytes treated with pervanadate.''; PubMed Europe PMC Scholia
  69. Uren AG, O'Rourke K, Aravind LA, Pisabarro MT, Seshagiri S, Koonin EV, Dixit VM.; ''Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma.''; PubMed Europe PMC Scholia
  70. Park S, Uesugi M, Verdine GL.; ''A second calcineurin binding site on the NFAT regulatory domain.''; PubMed Europe PMC Scholia
  71. 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
  72. Kroll M, Conconi M, Desterro MJ, Marin A, Thomas D, Friguet B, Hay RT, Virelizier JL, Arenzana-Seisdedos F, Rodriguez MS.; ''The carboxy-terminus of I kappaB alpha determines susceptibility to degradation by the catalytic core of the proteasome.''; PubMed Europe PMC Scholia
  73. Blanchard H, Kodandapani L, Mittl PR, Marco SD, Krebs JF, Wu JC, Tomaselli KJ, Grütter MG.; ''The three-dimensional structure of caspase-8: an initiator enzyme in apoptosis.''; PubMed Europe PMC Scholia
  74. Xiao G, Fong A, Sun SC.; ''Induction of p100 processing by NF-kappaB-inducing kinase involves docking IkappaB kinase alpha (IKKalpha) to p100 and IKKalpha-mediated phosphorylation.''; PubMed Europe PMC Scholia
  75. Cleghon V, Morrison DK.; ''Raf-1 interacts with Fyn and Src in a non-phosphotyrosine-dependent manner.''; PubMed Europe PMC Scholia
  76. Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ, Miller DK, Molineaux SM, Weidner JR, Aunins J.; ''A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes.''; PubMed Europe PMC Scholia
  77. Liu J, Sudom A, Min X, Cao Z, Gao X, Ayres M, Lee F, Cao P, Johnstone S, Plotnikova O, Walker N, Chen G, Wang Z.; ''Structure of the nuclear factor κB-inducing kinase (NIK) kinase domain reveals a constitutively active conformation.''; PubMed Europe PMC Scholia
  78. Tsang E, Giannetti AM, Shaw D, Dinh M, Tse JK, Gandhi S, Ho H, Wang S, Papp E, Bradshaw JM.; ''Molecular mechanism of the Syk activation switch.''; PubMed Europe PMC Scholia
  79. Sebban-Benin H, Pescatore A, Fusco F, Pascuale V, Gautheron J, Yamaoka S, Moncla A, Ursini MV, Courtois G.; ''Identification of TRAF6-dependent NEMO polyubiquitination sites through analysis of a new NEMO mutation causing incontinentia pigmenti.''; PubMed Europe PMC Scholia
  80. Hoving JC, Wilson GJ, Brown GD.; ''Signalling C-type lectin receptors, microbial recognition and immunity.''; PubMed Europe PMC Scholia
  81. Chen ZJ, Parent L, Maniatis T.; ''Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity.''; PubMed Europe PMC Scholia
  82. Chen LF, Mu Y, Greene WC.; ''Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF-kappaB.''; PubMed Europe PMC Scholia
  83. 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
  84. Mortezai N, Behnken HN, Kurze AK, Ludewig P, Buck F, Meyer B, Wagener C.; ''Tumor-associated Neu5Ac-Tn and Neu5Gc-Tn antigens bind to C-type lectin CLEC10A (CD301, MGL).''; PubMed Europe PMC Scholia
  85. Rogers NC, Slack EC, Edwards AD, Nolte MA, Schulz O, Schweighoffer E, Williams DL, Gordon S, Tybulewicz VL, Brown GD, Reis e Sousa C.; ''Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins.''; PubMed Europe PMC Scholia
  86. Besse A, Lamothe B, Campos AD, Webster WK, Maddineni U, Lin SC, Wu H, Darnay BG.; ''TAK1-dependent signaling requires functional interaction with TAB2/TAB3.''; PubMed Europe PMC Scholia
  87. Stahelin RV, Digman MA, Medkova M, Ananthanarayanan B, Rafter JD, Melowic HR, Cho W.; ''Mechanism of diacylglycerol-induced membrane targeting and activation of protein kinase Cdelta.''; PubMed Europe PMC Scholia
  88. Voges D, Zwickl P, Baumeister W.; ''The 26S proteasome: a molecular machine designed for controlled proteolysis.''; PubMed Europe PMC Scholia
  89. Suzuki-Inoue K, Wilde JI, Andrews RK, Auger JM, Siraganian RP, Sekiya F, Rhee SG, Watson SP.; ''Glycoproteins VI and Ib-IX-V stimulate tyrosine phosphorylation of tyrosine kinase Syk and phospholipase Cgamma2 at distinct sites.''; PubMed Europe PMC Scholia
  90. 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
  91. Kikkawa U, Matsuzaki H, Yamamoto T.; ''Protein kinase C delta (PKC delta): activation mechanisms and functions.''; PubMed Europe PMC Scholia
  92. Brown GD.; ''Dectin-1: a signalling non-TLR pattern-recognition receptor.''; PubMed Europe PMC Scholia
  93. Shen X, Li H, Ou Y, Tao W, Dong A, Kong J, Ji C, Yu S.; ''The secondary structure of calcineurin regulatory region and conformational change induced by calcium/calmodulin binding.''; PubMed Europe PMC Scholia
  94. Hara H, Saito T.; ''CARD9 versus CARMA1 in innate and adaptive immunity.''; PubMed Europe PMC Scholia
  95. Qiu L, Dhe-Paganon S.; ''Oligomeric structure of the MALT1 tandem Ig-like domains.''; PubMed Europe PMC Scholia
  96. Chen TY, Illing M, Molday LL, Hsu YT, Yau KW, Molday RS.; ''Subunit 2 (or beta) of retinal rod cGMP-gated cation channel is a component of the 240-kDa channel-associated protein and mediates Ca(2+)-calmodulin modulation.''; PubMed Europe PMC Scholia
  97. Caparrós E, Munoz P, Sierra-Filardi E, Serrano-Gómez D, Puig-Kröger A, Rodríguez-Fernández JL, Mellado M, Sancho J, Zubiaur M, Corbí AL.; ''DC-SIGN ligation on dendritic cells results in ERK and PI3K activation and modulates cytokine production.''; PubMed Europe PMC Scholia
  98. Vermeulen L, De Wilde G, Van Damme P, Vanden Berghe W, Haegeman G.; ''Transcriptional activation of the NF-kappaB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1).''; PubMed Europe PMC Scholia
  99. Kerrigan AM, Brown GD.; ''Syk-coupled C-type lectin receptors that mediate cellular activation via single tyrosine based activation motifs.''; PubMed Europe PMC Scholia
  100. Gringhuis SI, Kaptein TM, Wevers BA, Theelen B, van der Vlist M, Boekhout T, Geijtenbeek TB.; ''Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1β via a noncanonical caspase-8 inflammasome.''; PubMed Europe PMC Scholia
  101. Geijtenbeek TB, Van Vliet SJ, Koppel EA, Sanchez-Hernandez M, Vandenbroucke-Grauls CM, Appelmelk B, Van Kooyk Y.; ''Mycobacteria target DC-SIGN to suppress dendritic cell function.''; PubMed Europe PMC Scholia
  102. Sato K, Yang XL, Yudate T, Chung JS, Wu J, Luby-Phelps K, Kimberly RP, Underhill D, Cruz PD, Ariizumi K.; ''Dectin-2 is a pattern recognition receptor for fungi that couples with the Fc receptor gamma chain to induce innate immune responses.''; PubMed Europe PMC Scholia
  103. Cardozo T, Pagano M.; ''The SCF ubiquitin ligase: insights into a molecular machine.''; PubMed Europe PMC Scholia
  104. Rothwarf DM, Zandi E, Natoli G, Karin M.; ''IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex.''; PubMed Europe PMC Scholia
  105. 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
  106. Bertin J, Guo Y, Wang L, Srinivasula SM, Jacobson MD, Poyet JL, Merriam S, Du MQ, Dyer MJ, Robison KE, DiStefano PS, Alnemri ES.; ''CARD9 is a novel caspase recruitment domain-containing protein that interacts with BCL10/CLAP and activates NF-kappa B.''; PubMed Europe PMC Scholia
  107. Miyake Y, Toyonaga K, Mori D, Kakuta S, Hoshino Y, Oyamada A, Yamada H, Ono K, Suyama M, Iwakura Y, Yoshikai Y, Yamasaki S.; ''C-type lectin MCL is an FcRγ-coupled receptor that mediates the adjuvanticity of mycobacterial cord factor.''; PubMed Europe PMC Scholia
  108. Newton AC.; ''Protein kinase C: poised to signal.''; PubMed Europe PMC Scholia
  109. Yoon C, Korade Z, Carter BD.; ''Protein kinase A-induced phosphorylation of the p65 subunit of nuclear factor-kappaB promotes Schwann cell differentiation into a myelinating phenotype.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
123634view09:43, 7 August 2022EgonwModified title
115005view16:53, 25 January 2021ReactomeTeamReactome version 75
113449view11:52, 2 November 2020ReactomeTeamReactome version 74
112649view16:03, 9 October 2020ReactomeTeamReactome version 73
101564view11:43, 1 November 2018ReactomeTeamreactome version 66
101100view21:26, 31 October 2018ReactomeTeamreactome version 65
100629view20:01, 31 October 2018ReactomeTeamreactome version 64
100179view16:45, 31 October 2018ReactomeTeamreactome version 63
99729view15:12, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
94015view13:51, 16 August 2017ReactomeTeamreactome version 61
93634view11:29, 9 August 2017ReactomeTeamreactome version 61
87097view14:30, 18 July 2016MkutmonOntology Term : 'inflammatory response pathway' added !
86747view09:25, 11 July 2016ReactomeTeamreactome version 56
83342view10:51, 18 November 2015ReactomeTeamVersion54
81497view13:02, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
1,3-beta-D-glucan MetaboliteCHEBI:37671 (ChEBI)
1,3-beta-D-glucan:p-Y15-CLEC7A:SYKComplexR-HSA-5607685 (Reactome)
1,3-beta-D-glucan:p-Y15-CLEC7AComplexR-HSA-5607677 (Reactome)
1,3-beta-D-glucanMetaboliteCHEBI:37671 (ChEBI)
26S proteasomeComplexR-HSA-68819 (Reactome)
4xCa2+:CaMComplexR-HSA-74294 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
AHCYL1 ProteinO43865 (Uniprot-TrEMBL)
AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerComplexR-HSA-5226920 (Reactome)
AMPMetaboliteCHEBI:16027 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
Active

NIK:p-176,S180-IKKA

dimer:p-7S-p100:SCF-beta-TRCP		ComplexR-HSA-5607693 (Reactome)
Active

NIK:p-S176,180-IKKA

dimer:p-7S-p100:RELB		ComplexR-HSA-5607698 (Reactome)
Active

NIK:p-S176,180-IKKA

dimer:p100:RELB		ComplexR-HSA-5607690 (Reactome)
Active

NIK:p-S176,180-IKKA

dimer		ComplexR-HSA-5607681 (Reactome)
Active NIK ProteinQ99558 (Uniprot-TrEMBL)
Active NIKProteinQ99558 (Uniprot-TrEMBL)
BCL10 ProteinO95999 (Uniprot-TrEMBL)
BCL10 oligomer R-HSA-2685702 (Reactome)
BCL10ProteinO95999 (Uniprot-TrEMBL)
BTRC ProteinQ9Y297 (Uniprot-TrEMBL)
CALM1 ProteinP62158 (Uniprot-TrEMBL)
CALM1ProteinP62158 (Uniprot-TrEMBL)
CARD9ProteinQ9H257 (Uniprot-TrEMBL)
CASP8(217-374) ProteinQ14790 (Uniprot-TrEMBL)
CASP8(385-479) ProteinQ14790 (Uniprot-TrEMBL)
CBP/p300ComplexR-HSA-1027362 (Reactome)
CCL17 gene ProteinENSG00000102970 (Ensembl)
CCL17 mRNA ProteinENST00000219244 (Ensembl)
CCL17,CCL22 genesComplexR-HSA-5660969 (Reactome)
CCL17,CCL22 mRNAComplexR-HSA-5660972 (Reactome)
CCL22 gene ProteinENSG00000102962 (Ensembl)
CCL22 mRNA ProteinENST00000219235 (Ensembl)
CD209 ProteinQ9NNX6 (Uniprot-TrEMBL)
CD209:ICAM2ComplexR-HSA-5621570 (Reactome)
CD209:ICAM3:Ca+2ComplexR-HSA-5621572 (Reactome)
CD209:ManLAMComplexR-HSA-5621611 (Reactome)
CD209ProteinQ9NNX6 (Uniprot-TrEMBL)
CDC34 ProteinP49427 (Uniprot-TrEMBL)
CLEC4A ProteinQ9UMR7 (Uniprot-TrEMBL)
CLEC4A:HIV gp120,HCV gpE2ComplexR-HSA-5621150 (Reactome)
CLEC4AProteinQ9UMR7 (Uniprot-TrEMBL)
CLEC4C ProteinQ8WTT0 (Uniprot-TrEMBL)
CLEC4C:FCER1G

dimer:HIV gp120,HCV

gp E2		ComplexR-HSA-5621155 (Reactome)
CLEC4C:FCER1G dimerComplexR-HSA-5621153 (Reactome)
CLEC4D ProteinQ8WXI8 (Uniprot-TrEMBL)
CLEC4D:FCER1G dimer:TDMComplexR-HSA-5621151 (Reactome)
CLEC4D:FCER1G dimerComplexR-HSA-5621148 (Reactome)
CLEC4E ProteinQ9ULY5 (Uniprot-TrEMBL)
CLEC4E:FCER1G dimer:TDM,alpha-mannanComplexR-HSA-5621144 (Reactome)
CLEC4E:FCER1G dimerComplexR-HSA-5621137 (Reactome)
CLEC6A ProteinQ6EIG7 (Uniprot-TrEMBL)
CLEC6A:FCER1G dimer:alpha-mannanComplexR-HSA-5621146 (Reactome)
CLEC6A:FCER1G dimerComplexR-HSA-5621143 (Reactome)
CLEC7A ProteinQ9BXN2 (Uniprot-TrEMBL)
CLEC7A:1,3-beta-D-glucanComplexR-HSA-5607680 (Reactome)
CLEC7AProteinQ9BXN2 (Uniprot-TrEMBL)
CREBBP ProteinQ92793 (Uniprot-TrEMBL)
CUL1 ProteinQ13616 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
Calcineurin (CaN)ComplexR-HSA-2025977 (Reactome)
Calcineurin:Calmodulin (CaN:CaM)ComplexR-HSA-2025947 (Reactome)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
DAGs MetaboliteCHEBI:18035 (ChEBI)
DAGs:active p-T507,S645,S664-PRKCDComplexR-HSA-5607689 (Reactome)
DAGs:p-T507,S645,S664-PRKCDComplexR-HSA-5607700 (Reactome)
DAGsMetaboliteCHEBI:18035 (ChEBI)
ENV polyprotein R-HIV-173465 (Reactome)
EP300 ProteinQ09472 (Uniprot-TrEMBL)
FBXW11 ProteinQ9UKB1 (Uniprot-TrEMBL)
FCER1G ProteinP30273 (Uniprot-TrEMBL)
FYN ProteinP06241 (Uniprot-TrEMBL)
FYN, LYNComplexR-HSA-5621132 (Reactome)
Fe3+ MetaboliteCHEBI:29034 (ChEBI)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HCV Genome polyprotein ProteinQ99IB8 (Uniprot-TrEMBL)
HIV gp120,HCV gp E2ComplexR-HSA-R-HEP-5621134 (Reactome)
HRAS ProteinP01112 (Uniprot-TrEMBL)
I(1,4,5)P3 MetaboliteCHEBI:16595 (ChEBI)
I(1,4,5)P3MetaboliteCHEBI:16595 (ChEBI)
ICAM2 ProteinP13598 (Uniprot-TrEMBL)
ICAM2ProteinP13598 (Uniprot-TrEMBL)
ICAM3 ProteinP32942 (Uniprot-TrEMBL)
ICAM3ProteinP32942 (Uniprot-TrEMBL)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IKKA ProteinO15111 (Uniprot-TrEMBL)
IKKA dimerComplexR-HSA-5607705 (Reactome)
IKKA:IKBKB:IKBKGComplexR-HSA-168113 (Reactome)
IL1B geneGeneProductENSG00000125538 (Ensembl)
IL1B mRNARnaENST00000263341 (Ensembl)
IL1B(1-116)ProteinP01584 (Uniprot-TrEMBL)
IL1B(1-269)ProteinP01584 (Uniprot-TrEMBL)
IL1B(117-269)ProteinP01584 (Uniprot-TrEMBL)
IP3 receptor homotetramerComplexR-HSA-169686 (Reactome)
ITPR1 ProteinQ14643 (Uniprot-TrEMBL)
ITPR2 ProteinQ14571 (Uniprot-TrEMBL)
ITPR3 ProteinQ14573 (Uniprot-TrEMBL)
ITPR:I(1,4,5)P3 tetramerComplexR-HSA-169696 (Reactome)
IkB(alpha):NF-kB complexComplexR-HSA-193938 (Reactome)
K48-UbComplexR-HSA-912722 (Reactome) The most studied polyubiquitin chains - lysine48-linked - target proteins for destruction
K48-polyUb-p-7S-p100 ProteinQ00653 (Uniprot-TrEMBL)
K48-polyUb-p-7S-p100:RELBComplexR-HSA-5607694 (Reactome)
K48PolyUb-K21,22-p-S32,36-IkBA:NF-kB complexComplexR-HSA-5607697 (Reactome)
K48PolyUb-K21,22-p-S32,S36-IkBA ProteinP25963 (Uniprot-TrEMBL)
K63polyUb TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
K63polyUb-34,158-TAK1 ProteinO43318 (Uniprot-TrEMBL)
K63polyUb-34,158-p-T178,184,187,S192-TAK1 ProteinO43318 (Uniprot-TrEMBL)
K63polyUb-NEMO ProteinQ9Y6K9 (Uniprot-TrEMBL)
K63polyUb-TRAF6 oligomer R-HSA-5607625 (Reactome)
K63polyUbR-HSA-450152 (Reactome)
KRAS ProteinP01116 (Uniprot-TrEMBL)
LYN ProteinP07948 (Uniprot-TrEMBL)
MALT1

oligomers:active

caspase-8:ASC		ComplexR-HSA-5660653 (Reactome)
MALT1 ProteinQ9UDY8 (Uniprot-TrEMBL)
MALT1 oligomer R-HSA-2685673 (Reactome)
MALT1:active caspase-8ComplexR-HSA-5660654 (Reactome)
MALT1ProteinQ9UDY8 (Uniprot-TrEMBL)
MAP3K14ProteinQ99558 (Uniprot-TrEMBL)
MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
ManLAM MetaboliteCHEBI:59524 (ChEBI)
ManLAMMetaboliteCHEBI:59524 (ChEBI)
NAD+ MetaboliteCHEBI:15846 (ChEBI)
NEDD8-C111-UBE2MProteinP61081 (Uniprot-TrEMBL)
NF-kB complexComplexR-HSA-194043 (Reactome)
NF-kB complexComplexR-HSA-194047 (Reactome)
NFAT:CaN:CaMComplexR-HSA-2685690 (Reactome)
NFAT:CaN:CaMComplexR-HSA-2685705 (Reactome)
NFKB1(1-433) ProteinP19838 (Uniprot-TrEMBL)
NFKB1:p-S276,5AcK-RELA:p300/CBPComplexR-HSA-5660657 (Reactome)
NFKB1:p-S276-RELA:p300/CBPComplexR-HSA-5660656 (Reactome)
NFKB1:p-S276-RELAComplexR-HSA-5624488 (Reactome)
NFKB2(1-900) ProteinQ00653 (Uniprot-TrEMBL)
NFKBIA ProteinP25963 (Uniprot-TrEMBL)
NRAS ProteinP01111 (Uniprot-TrEMBL)
PAK1 ProteinQ13153 (Uniprot-TrEMBL)
PAK1,2,3ComplexR-HSA-390765 (Reactome)
PAK2 ProteinQ13177 (Uniprot-TrEMBL)
PAK3 ProteinO75914 (Uniprot-TrEMBL)
PDPK1 ProteinO15530 (Uniprot-TrEMBL)
PI(3,4)P2 MetaboliteCHEBI:16152 (ChEBI)
PI(3,4,5)P3 MetaboliteCHEBI:16618 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PLCG2 ProteinP16885 (Uniprot-TrEMBL)
PLCG2ProteinP16885 (Uniprot-TrEMBL)
PPP3CA ProteinQ08209 (Uniprot-TrEMBL)
PPP3CB ProteinP16298 (Uniprot-TrEMBL)
PPP3R1 ProteinP63098 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
PSMA1 ProteinP25786 (Uniprot-TrEMBL)
PSMA2 ProteinP25787 (Uniprot-TrEMBL)
PSMA3 ProteinP25788 (Uniprot-TrEMBL)
PSMA4 ProteinP25789 (Uniprot-TrEMBL)
PSMA5 ProteinP28066 (Uniprot-TrEMBL)
PSMA6 ProteinP60900 (Uniprot-TrEMBL)
PSMA7 ProteinO14818 (Uniprot-TrEMBL)
PSMA8 ProteinQ8TAA3 (Uniprot-TrEMBL)
PSMB1 ProteinP20618 (Uniprot-TrEMBL)
PSMB10 ProteinP40306 (Uniprot-TrEMBL)
PSMB11 ProteinA5LHX3 (Uniprot-TrEMBL)
PSMB2 ProteinP49721 (Uniprot-TrEMBL)
PSMB3 ProteinP49720 (Uniprot-TrEMBL)
PSMB4 ProteinP28070 (Uniprot-TrEMBL)
PSMB5 ProteinP28074 (Uniprot-TrEMBL)
PSMB6 ProteinP28072 (Uniprot-TrEMBL)
PSMB7 ProteinQ99436 (Uniprot-TrEMBL)
PSMB8 ProteinP28062 (Uniprot-TrEMBL)
PSMB9 ProteinP28065 (Uniprot-TrEMBL)
PSMC1 ProteinP62191 (Uniprot-TrEMBL)
PSMC2 ProteinP35998 (Uniprot-TrEMBL)
PSMC3 ProteinP17980 (Uniprot-TrEMBL)
PSMC4 ProteinP43686 (Uniprot-TrEMBL)
PSMC5 ProteinP62195 (Uniprot-TrEMBL)
PSMC6 ProteinP62333 (Uniprot-TrEMBL)
PSMD1 ProteinQ99460 (Uniprot-TrEMBL)
PSMD10 ProteinO75832 (Uniprot-TrEMBL)
PSMD11 ProteinO00231 (Uniprot-TrEMBL)
PSMD12 ProteinO00232 (Uniprot-TrEMBL)
PSMD13 ProteinQ9UNM6 (Uniprot-TrEMBL)
PSMD14 ProteinO00487 (Uniprot-TrEMBL)
PSMD2 ProteinQ13200 (Uniprot-TrEMBL)
PSMD3 ProteinO43242 (Uniprot-TrEMBL)
PSMD4 ProteinP55036 (Uniprot-TrEMBL)
PSMD5 ProteinQ16401 (Uniprot-TrEMBL)
PSMD6 ProteinQ15008 (Uniprot-TrEMBL)
PSMD7 ProteinP51665 (Uniprot-TrEMBL)
PSMD8 ProteinP48556 (Uniprot-TrEMBL)
PSMD9 ProteinO00233 (Uniprot-TrEMBL)
PSME1 ProteinQ06323 (Uniprot-TrEMBL)
PSME2 ProteinQ9UL46 (Uniprot-TrEMBL)
PSME3 ProteinP61289 (Uniprot-TrEMBL)
PSME4 ProteinQ14997 (Uniprot-TrEMBL)
PSMF1 ProteinQ92530 (Uniprot-TrEMBL)
PYCARD ProteinQ9ULZ3 (Uniprot-TrEMBL)
PYCARDProteinQ9ULZ3 (Uniprot-TrEMBL)
Phosphorylated NFATC1,2,3ComplexR-HSA-2025924 (Reactome)
PiMetaboliteCHEBI:18367 (ChEBI)
Protein Kinase A, catalytic subunits R-HSA-111917 (Reactome)
RAF1 ProteinP04049 (Uniprot-TrEMBL)
RAF1ProteinP04049 (Uniprot-TrEMBL)
RELA ProteinQ04206 (Uniprot-TrEMBL)
RELB ProteinQ01201 (Uniprot-TrEMBL)
RELBProteinQ01201 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
RPS6KA5 ProteinO75582 (Uniprot-TrEMBL)
RPS6KA5(MSK1/SAPK1):PKA catalytic subunitsComplexR-HSA-5660649 (Reactome)
SCF-beta-TRCPComplexR-HSA-5607687 (Reactome)
SKP1 ProteinP63208 (Uniprot-TrEMBL)
SRC-1ProteinP12931-1 (Uniprot-TrEMBL)
SYK ProteinP43405 (Uniprot-TrEMBL)
SYKProteinP43405 (Uniprot-TrEMBL)
TAB1 ProteinQ15750 (Uniprot-TrEMBL)
TAB1:TAB2,TAB3:TAK1ComplexR-HSA-450277 (Reactome)
TAB2 ProteinQ9NYJ8 (Uniprot-TrEMBL)
TAB3 ProteinQ8N5C8 (Uniprot-TrEMBL)
TDM MetaboliteCHEBI:82624 (ChEBI)
TDM,alpha-mannanComplexR-HSA-R-CAL-5621131 (Reactome)
TDMMetaboliteCHEBI:82624 (ChEBI)
TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRAF6 oligomer R-HSA-2685708 (Reactome)
TRAF6ProteinQ9Y4K3 (Uniprot-TrEMBL)
UBA3ProteinQ8TBC4 (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)
UBE2D1 ProteinP51668 (Uniprot-TrEMBL)
UBE2D2 ProteinP62837 (Uniprot-TrEMBL)
UBE2D2,UBE2D1,(CDC34)ComplexR-HSA-5607669 (Reactome)
UBE2N ProteinP61088 (Uniprot-TrEMBL)
UBE2V1 ProteinQ13404 (Uniprot-TrEMBL)
Ub-124-UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
Ub-124-UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-200-UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
Ub-200-UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-276-UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-352-UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-428-UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-48-RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
Ub-48-UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
Ub-48-UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
Ub-48-UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-504-UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-580-UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-656-UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-TRAF6 trimer

bound to CBM

complex		ComplexR-HSA-202456 (Reactome)
UbComplexR-HSA-113595 (Reactome)
Ubc13:UBE2V1ComplexR-HSA-202463 (Reactome)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
active caspase-8ComplexR-HSA-5660651 (Reactome)
active p-T507,S645,S664-PRKCD ProteinQ05655 (Uniprot-TrEMBL)
alpha-mannan MetaboliteCHEBI:28808 (ChEBI)
alpha-mannanMetaboliteCHEBI:28808 (ChEBI)
p-12S-NFATC1 ProteinO95644 (Uniprot-TrEMBL)
p-13S-NFATC3 ProteinQ12968 (Uniprot-TrEMBL)
p-14S-NFATC2 ProteinQ13469 (Uniprot-TrEMBL)
p-6Y-SYK ProteinP43405 (Uniprot-TrEMBL)
p-7S-p100 ProteinQ00653 (Uniprot-TrEMBL)
p-BCL10 ProteinO95999 (Uniprot-TrEMBL)
p-S176,S180-IKKA ProteinO15111 (Uniprot-TrEMBL)
p-S177,S181-IKBKB ProteinO14920 (Uniprot-TrEMBL)
p-S177,S181-IKKB:IKKA:NEMOComplexR-HSA-202513 (Reactome)
p-S177,S181-IKKB:IKKA:pUb-NEMOComplexR-HSA-202562 (Reactome)
p-S243-NFATC2 ProteinQ13469 (Uniprot-TrEMBL)
p-S257-NFATC1 ProteinO95644 (Uniprot-TrEMBL)
p-S265-NFATC3 ProteinQ12968 (Uniprot-TrEMBL)
p-S276,5xAcK-RELA ProteinQ04206 (Uniprot-TrEMBL)
p-S276-RELA ProteinQ04206 (Uniprot-TrEMBL)
p-S276-RELA:RELBComplexR-HSA-5660974 (Reactome)
p-S276-RELAProteinQ04206 (Uniprot-TrEMBL)
p-S32,36-IkB-alpha:NF-kB complexComplexR-HSA-5607671 (Reactome)
p-S32,S36-NFKBIA ProteinP25963 (Uniprot-TrEMBL)
p-S338,Y340,Y341-RAF1 ProteinP04049 (Uniprot-TrEMBL)
p-S338-RAF1 ProteinP04049 (Uniprot-TrEMBL)
p-S552-CARD11 ProteinQ9BXL7 (Uniprot-TrEMBL)
p-T231-CARD9 oligomer:BCL10ComplexR-HSA-5607678 (Reactome)
p-T231-CARD9 oligomerR-HSA-5607622 (Reactome)
p-T231-CARD9 oligomer R-HSA-5607622 (Reactome)
p-T231-CARD9:BCL10 oligomers:MALT1ComplexR-HSA-5607682 (Reactome)
p-T231-CARD9:BCL10 oligomersComplexR-HSA-5607676 (Reactome)
p-T231-CARD9:BCL10:MALT1 oligomers:TRAF6ComplexR-HSA-5607701 (Reactome)
p-T231-CARD9:BCL10:MALT1 oligomersComplexR-HSA-5607696 (Reactome)
p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TAB1:TAB2/TAB3:K63polyUb-34,158-TAK1ComplexR-HSA-5607695 (Reactome)
p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TAB1:TAB2/TAB3:K63polyUb-34,158-p3Y,1S-TAK1ComplexR-HSA-5607673 (Reactome)
p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TRIKA2ComplexR-HSA-5607672 (Reactome)
p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomersComplexR-HSA-5607675 (Reactome)
p-T231-CARD9:BCL10:MALT1:TRAF6 oligomersComplexR-HSA-5607674 (Reactome)
p-T231-CARD9ProteinQ9H257 (Uniprot-TrEMBL)
p-T507,S645,S664-PRKCD ProteinQ05655 (Uniprot-TrEMBL)
p-T507,S645,S664-PRKCDProteinQ05655 (Uniprot-TrEMBL)
p-Y15-CLEC7A ProteinQ9BXN2 (Uniprot-TrEMBL)
p-Y65,Y76-FCER1G ProteinP30273 (Uniprot-TrEMBL)
p-Y753,Y759-PLCG2 ProteinP16885 (Uniprot-TrEMBL)
p-Y753,Y759-PLCG2ProteinP16885 (Uniprot-TrEMBL)
p100:RELBComplexR-HSA-5607703 (Reactome)
p21 RAS:GTP:p-S338,Y340,Y341-RAF1ComplexR-HSA-5624477 (Reactome)
p21 RAS:GTP:p-S338-RAF1ComplexR-HSA-5624470 (Reactome)
p21 RAS:GDPComplexR-HSA-109796 (Reactome)
p21 RAS:GTP:RAF1ComplexR-HSA-5624478 (Reactome)
p21 RAS:GTPComplexR-HSA-109783 (Reactome)
p52 ProteinQ00653 (Uniprot-TrEMBL)
p52:RELBComplexR-HSA-5607679 (Reactome)
p52:RELBComplexR-HSA-5607699 (Reactome)
pathogens:CLEC6A,CLEC4E:FCER1G dimerComplexR-HSA-5621130 (Reactome)
pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer:SYKComplexR-HSA-5621149 (Reactome)
pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer:p-6Y-SYK:PLCG2ComplexR-HSA-5621157 (Reactome)
pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer:p-6Y-SYK:p-Y753,Y759-PLCG2ComplexR-HSA-5621158 (Reactome)
pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer:p-6Y-SYKComplexR-HSA-5621160 (Reactome)
pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimerComplexR-HSA-5621145 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
1,3-beta-D-glucan:p-Y15-CLEC7A:SYKArrowR-HSA-5607738 (Reactome)
1,3-beta-D-glucan:p-Y15-CLEC7A:SYKmim-catalysisR-HSA-5607745 (Reactome)
1,3-beta-D-glucan:p-Y15-CLEC7AArrowR-HSA-5607750 (Reactome)
1,3-beta-D-glucan:p-Y15-CLEC7AR-HSA-5607738 (Reactome)
1,3-beta-D-glucanR-HSA-5607758 (Reactome)
26S proteasomemim-catalysisR-HSA-5607724 (Reactome)
26S proteasomemim-catalysisR-HSA-5607731 (Reactome)
4xCa2+:CaMArrowR-HSA-74448 (Reactome)
4xCa2+:CaMR-HSA-2730872 (Reactome)
ADPArrowR-HSA-202541 (Reactome)
ADPArrowR-HSA-5607722 (Reactome)
ADPArrowR-HSA-5607726 (Reactome)
ADPArrowR-HSA-5607732 (Reactome)
ADPArrowR-HSA-5607740 (Reactome)
ADPArrowR-HSA-5607742 (Reactome)
ADPArrowR-HSA-5607745 (Reactome)
ADPArrowR-HSA-5607750 (Reactome)
ADPArrowR-HSA-5621355 (Reactome)
ADPArrowR-HSA-5621363 (Reactome)
ADPArrowR-HSA-5621370 (Reactome)
ADPArrowR-HSA-5624473 (Reactome)
ADPArrowR-HSA-5624486 (Reactome)
ADPArrowR-HSA-5624492 (Reactome)
AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerTBarR-HSA-169683 (Reactome)
AMPArrowR-HSA-5607756 (Reactome)
AMPArrowR-HSA-5607757 (Reactome)
ATPR-HSA-202541 (Reactome)
ATPR-HSA-5607722 (Reactome)
ATPR-HSA-5607726 (Reactome)
ATPR-HSA-5607732 (Reactome)
ATPR-HSA-5607740 (Reactome)
ATPR-HSA-5607742 (Reactome)
ATPR-HSA-5607745 (Reactome)
ATPR-HSA-5607750 (Reactome)
ATPR-HSA-5607756 (Reactome)
ATPR-HSA-5607757 (Reactome)
ATPR-HSA-5621355 (Reactome)
ATPR-HSA-5621363 (Reactome)
ATPR-HSA-5621370 (Reactome)
ATPR-HSA-5624473 (Reactome)
ATPR-HSA-5624486 (Reactome)
ATPR-HSA-5624492 (Reactome)
Ac-CoAR-HSA-5660660 (Reactome)
Active

NIK:p-176,S180-IKKA

dimer:p-7S-p100:SCF-beta-TRCP		ArrowR-HSA-5607723 (Reactome)
Active

NIK:p-176,S180-IKKA

dimer:p-7S-p100:SCF-beta-TRCP		R-HSA-5607725 (Reactome)
Active

NIK:p-176,S180-IKKA

dimer:p-7S-p100:SCF-beta-TRCP		mim-catalysisR-HSA-5607725 (Reactome)
Active

NIK:p-S176,180-IKKA

dimer:p-7S-p100:RELB		ArrowR-HSA-5607726 (Reactome)
Active

NIK:p-S176,180-IKKA

dimer:p-7S-p100:RELB		R-HSA-5607723 (Reactome)
Active

NIK:p-S176,180-IKKA

dimer:p100:RELB		ArrowR-HSA-5607720 (Reactome)
Active

NIK:p-S176,180-IKKA

dimer:p100:RELB		R-HSA-5607726 (Reactome)
Active

NIK:p-S176,180-IKKA

dimer:p100:RELB		mim-catalysisR-HSA-5607726 (Reactome)
Active

NIK:p-S176,180-IKKA

dimer		ArrowR-HSA-5607722 (Reactome)
Active

NIK:p-S176,180-IKKA

dimer		ArrowR-HSA-5607725 (Reactome)
Active

NIK:p-S176,180-IKKA

dimer		R-HSA-5607720 (Reactome)
Active NIKArrowR-HSA-5607721 (Reactome)
Active NIKR-HSA-5607722 (Reactome)
Active NIKmim-catalysisR-HSA-5607722 (Reactome)
BCL10R-HSA-5607733 (Reactome)
BCL10R-HSA-5607737 (Reactome)
CALM1R-HSA-74448 (Reactome)
CARD9R-HSA-5607740 (Reactome)
CARD9R-HSA-5607753 (Reactome)
CBP/p300R-HSA-5660666 (Reactome)
CCL17,CCL22 genesR-HSA-5660965 (Reactome)
CCL17,CCL22 mRNAArrowR-HSA-5660965 (Reactome)
CD209:ICAM2ArrowR-HSA-5621571 (Reactome)
CD209:ICAM3:Ca+2ArrowR-HSA-5621615 (Reactome)
CD209:ManLAMArrowR-HSA-5621573 (Reactome)
CD209:ManLAMArrowR-HSA-5621606 (Reactome)
CD209R-HSA-5621571 (Reactome)
CD209R-HSA-5621606 (Reactome)
CD209R-HSA-5621615 (Reactome)
CLEC4A:HIV gp120,HCV gpE2ArrowR-HSA-5621367 (Reactome)
CLEC4AR-HSA-5621367 (Reactome)
CLEC4C:FCER1G

dimer:HIV gp120,HCV

gp E2		ArrowR-HSA-5621371 (Reactome)
CLEC4C:FCER1G dimerR-HSA-5621371 (Reactome)
CLEC4D:FCER1G dimer:TDMArrowR-HSA-5621353 (Reactome)
CLEC4D:FCER1G dimerR-HSA-5621353 (Reactome)
CLEC4E:FCER1G dimer:TDM,alpha-mannanArrowR-HSA-5621354 (Reactome)
CLEC4E:FCER1G dimerR-HSA-5621354 (Reactome)
CLEC6A:FCER1G dimer:alpha-mannanArrowR-HSA-5621352 (Reactome)
CLEC6A:FCER1G dimerR-HSA-5621352 (Reactome)
CLEC7A:1,3-beta-D-glucanArrowR-HSA-5607758 (Reactome)
CLEC7A:1,3-beta-D-glucanR-HSA-5607750 (Reactome)
CLEC7AR-HSA-5607758 (Reactome)
Ca2+ArrowR-HSA-169683 (Reactome)
Ca2+R-HSA-169683 (Reactome)
Ca2+R-HSA-2730872 (Reactome)
Ca2+R-HSA-5621615 (Reactome)
Ca2+R-HSA-74448 (Reactome)
Calcineurin (CaN)R-HSA-2730872 (Reactome)
Calcineurin:Calmodulin (CaN:CaM)ArrowR-HSA-2730872 (Reactome)
Calcineurin:Calmodulin (CaN:CaM)R-HSA-2730849 (Reactome)
Calcineurin:Calmodulin (CaN:CaM)mim-catalysisR-HSA-2730849 (Reactome)
CoA-SHArrowR-HSA-5660660 (Reactome)
DAGs:active p-T507,S645,S664-PRKCDArrowR-HSA-5607746 (Reactome)
DAGs:active p-T507,S645,S664-PRKCDmim-catalysisR-HSA-5607740 (Reactome)
DAGs:p-T507,S645,S664-PRKCDArrowR-HSA-5607734 (Reactome)
DAGs:p-T507,S645,S664-PRKCDR-HSA-5607746 (Reactome)
DAGsArrowR-HSA-5607735 (Reactome)
DAGsR-HSA-5607734 (Reactome)
FYN, LYNmim-catalysisR-HSA-5621355 (Reactome)
FYN, LYNmim-catalysisR-HSA-5624486 (Reactome)
GDPArrowR-HSA-5621573 (Reactome)
GTPR-HSA-5621573 (Reactome)
H2OR-HSA-2730849 (Reactome)
H2OR-HSA-5607735 (Reactome)
HIV gp120,HCV gp E2R-HSA-5621367 (Reactome)
HIV gp120,HCV gp E2R-HSA-5621371 (Reactome)
I(1,4,5)P3ArrowR-HSA-169683 (Reactome)
I(1,4,5)P3ArrowR-HSA-5607735 (Reactome)
I(1,4,5)P3R-HSA-169680 (Reactome)
ICAM2R-HSA-5621571 (Reactome)
ICAM3R-HSA-5621615 (Reactome)
IKKA dimerR-HSA-5607722 (Reactome)
IKKA:IKBKB:IKBKGR-HSA-5607742 (Reactome)
IL1B geneR-HSA-5660622 (Reactome)
IL1B mRNAArrowR-HSA-5660622 (Reactome)
IL1B(1-116)ArrowR-HSA-5660663 (Reactome)
IL1B(1-269)R-HSA-5660663 (Reactome)
IL1B(117-269)ArrowR-HSA-5660663 (Reactome)
IP3 receptor homotetramerR-HSA-169680 (Reactome)
ITPR:I(1,4,5)P3 tetramerArrowR-HSA-169680 (Reactome)
ITPR:I(1,4,5)P3 tetramermim-catalysisR-HSA-169683 (Reactome)
IkB(alpha):NF-kB complexR-HSA-202541 (Reactome)
K48-UbR-HSA-5607725 (Reactome)
K48-UbR-HSA-5607728 (Reactome)
K48-polyUb-p-7S-p100:RELBArrowR-HSA-5607725 (Reactome)
K48-polyUb-p-7S-p100:RELBR-HSA-5607731 (Reactome)
K48PolyUb-K21,22-p-S32,36-IkBA:NF-kB complexArrowR-HSA-5607728 (Reactome)
K48PolyUb-K21,22-p-S32,36-IkBA:NF-kB complexR-HSA-5607724 (Reactome)
K63polyUbR-HSA-202534 (Reactome)
K63polyUbR-HSA-5607756 (Reactome)
K63polyUbR-HSA-5607757 (Reactome)
MALT1

oligomers:active

caspase-8:ASC		ArrowR-HSA-5660662 (Reactome)
MALT1

oligomers:active

caspase-8:ASC		mim-catalysisR-HSA-5660663 (Reactome)
MALT1:active caspase-8ArrowR-HSA-5660665 (Reactome)
MALT1:active caspase-8R-HSA-5660662 (Reactome)
MALT1R-HSA-5607736 (Reactome)
MALT1R-HSA-5607744 (Reactome)
MALT1R-HSA-5660665 (Reactome)
MAP3K14R-HSA-5607721 (Reactome)
ManLAMR-HSA-5621606 (Reactome)
NEDD8-C111-UBE2MArrowR-HSA-5607725 (Reactome)
NEDD8-C111-UBE2MR-HSA-5607725 (Reactome)
NF-kB complexArrowR-HSA-2730894 (Reactome)
NF-kB complexArrowR-HSA-5607724 (Reactome)
NF-kB complexArrowR-HSA-5660622 (Reactome)
NF-kB complexR-HSA-2730894 (Reactome)
NF-kB complexR-HSA-5624473 (Reactome)
NFAT:CaN:CaMArrowR-HSA-2730849 (Reactome)
NFAT:CaN:CaMArrowR-HSA-2730867 (Reactome)
NFAT:CaN:CaMR-HSA-2730867 (Reactome)
NFKB1:p-S276,5AcK-RELA:p300/CBPArrowR-HSA-5660660 (Reactome)
NFKB1:p-S276-RELA:p300/CBPArrowR-HSA-5660666 (Reactome)
NFKB1:p-S276-RELA:p300/CBPR-HSA-5660660 (Reactome)
NFKB1:p-S276-RELA:p300/CBPmim-catalysisR-HSA-5660660 (Reactome)
NFKB1:p-S276-RELAArrowR-HSA-5624473 (Reactome)
NFKB1:p-S276-RELAR-HSA-5660666 (Reactome)
PAK1,2,3mim-catalysisR-HSA-5624492 (Reactome)
PI(4,5)P2R-HSA-5607735 (Reactome)
PLCG2R-HSA-5607745 (Reactome)
PLCG2R-HSA-5621356 (Reactome)
PPiArrowR-HSA-5607756 (Reactome)
PPiArrowR-HSA-5607757 (Reactome)
PYCARDR-HSA-5660662 (Reactome)
Phosphorylated NFATC1,2,3R-HSA-2730849 (Reactome)
PiArrowR-HSA-2730849 (Reactome)
R-HSA-169680 (Reactome) The IP3 receptor (IP3R) is an IP3-gated calcium channel. It is a large, homotetrameric protein, similar to other calcium channel proteins such as ryanodine. The four subunits form a 'four-leafed clover' structure arranged around the central calcium channel. Binding of ligands such as IP3 results in conformational changes in the receptor's structure that leads to channel opening.
R-HSA-169683 (Reactome) IP3 promotes the release of intracellular calcium.
R-HSA-202534 (Reactome) During the phosphorylation of the IKK beta, the regulatory subunit NEMO undergoes K-63-linked polyubiquitination. Ubiquitinated TRAF6 trimer, acts as a E3 ligase and induces this ubiquitination. The ubiquitin target sites in NEMO are not yet clearly identified. Studies of different NF-kB signaling pathways revealed several potential ubiquitination sites on NEMO (e.g., K285, K277, K309 and K399) (Fuminori et al. 2009).
R-HSA-202541 (Reactome) NF-kB is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins, called IkBs, which mask the nuclear localization signal (NLS) of NF-kB and prevent its nuclear translocation. A key event in NF-kB activation involves phosphorylation of IkB (at sites equivalent to Ser32 and Ser36 of IkB-alpha or Ser19 and Ser22 of IkB-beta) by IKK. The phosphorylated IkB-alpha is recognized by the E3 ligase complex and targeted for ubiquitin-mediated proteasomal degradation, releasing the NF-kB dimer p50/p65 into the nucleus to turn on target genes. (Karin & Ben-Neriah 2000)
R-HSA-2730849 (Reactome) Nuclear factor of activated T-cells (NFAT) is a transcription factor which induces genes responsible for cytokine production, for cell-cell interactions etc. NFAT transcription activity is modulated by calcium and Calcineurin concentration. In resting cells NFAT is phosphorylated and resides in the cytoplasm. Phosphorylation sites are located in NFAT's regulatory domain in three different serine rich motifs, termed SRR1, SP2 and SP. Upon stimulation, these serine residues are dephosphorylated by calcineurin, that thought to cause exposure of nuclear localization signal sequences triggering translocation of the dephosphorylated NFAT-CaN complex to the nucleus. Among all the phosphorylation sites one of the site in SRR-2 motif is not susceptable to dephosphorylation by CaN (Takeuchi et al. 2007, Hogan et al. 2003).
R-HSA-2730867 (Reactome) Dephosphorylated NFAT-calcineurin (CaN) complex translocates to nucleus, where it activates transcription of several cytokine genes (e.g..IL2).
R-HSA-2730872 (Reactome) Calcineurin (CaN), also called protein phosphatase 2B (PP2B), is a calcium/Calmodulin (CaM)-dependent serine/threonine protein phosphatase. It exists as a heterodimer consisting of CaM-binding catalytic subunit CaN A chain and a Ca+2 binding regulatory CaN B chain. At low calcium concentrations, CaN exists in an inactive state, where the autoinhibitory domain (AID) binds to the active-site cleft. Upon an increase in calcium concentration CaM binds to Ca+2 ions and gets activated. Active CaM binds to CaN regulatory domain (RD) and this causes release of the AID and activation of the phosphatase (Rumi-Masante et al. 2012). Binding of calcium to CaN B regulatory chain also causes a conformational change of the RD of CaN A chain (Yang & Klee 2000).
R-HSA-2730894 (Reactome) The released NF-kB transcription factor (p50/p65) with unmasked nuclear localization signal (NLS) then moves in to the nucleus. Once in the nucleus, NF-kB binds DNA and regulate the expression of genes encoding cytokines, cytokine receptors, and apoptotic regulators.
R-HSA-5607720 (Reactome) NFKB2 (also known as p100) is a member of the NF-kB family of transcription factors. It is synthesised as large precursor with an N-terminal RHD (Rel homology domain) and a C-terminal series of ankyrin repeats that masks the nuclear localization signal of NFKB2/p100 localising it to the cytosol. In resting cells, p100 is associated with RELB (Transcription factor RelB) in the cytosol. Upon cell stimulation, the IkB-like C terminus of p100 is proteolyzed, resulting in RELB-p52 dimers that translocate to the nucleus (Senftleben et al. 2001, Hayden & Ghosh 2004). IKKA (I kappa-B kinase alpha) does not associate directly with p100 but in the presence of NIK (NF-kB-inducing kinase), IKKA stably binds to p100. Serine residues 866 and 870 of p100 are essential for the recruitment of IKKA to p100 by NIK. This interaction is required for p100 phosphorylation and subsequent processing by IKKA (Xiao et al. 2001, 2004).
R-HSA-5607721 (Reactome) The catalytic activity of NF-kB-inducing kinase (NIK) is regulated by structural conformation rather than by phosphorylation events. Under normal conditions NIK may be present in an autoinhibited state in which its constitutively active kinase domain is shielded by the N-terminal inhibitory element and upon receptor induction NIK kinase domain adopts an active conformation, in agreement with its catalytic activity. This catalytically competent conformation is maintained by an N-terminal extension prior to the kinase domain rather than through a phosphorylation event (Liu et al. 2012). NIK, also known as MAP3K14 (MAPK kinase kinase 14), is a serine/threonine kinase in the MAP3K family (Malinin et al. 1997). In unstimulated cells NIK associates with a complex composed of TNF receptor-associated factor 2 (TRAF2), TRAF3 and cellular inhibitor of apoptosis 1 (cIAP1) and cIAP2. This molecular interaction with TRAF-cIAP complex appears to target NIK for ubiquitination and proteasomal degradation. In response to receptor stimulation, TRAF2 or TRAF3, or both are targeted for proteasomal degradation by cIAP-mediated ubiquitination, which triggers the release and stabilization of NIK (Razani et al. 2010).
R-HSA-5607722 (Reactome) Accumulated NF-kB-inducing kinase (NIK) activates I kappa-B kinase alpha (IKKA) by directly phosphorylating the Ser176 and Ser180 with in the activation loop of IKKA. This phoshorylation is required for IKKA activity (Ling et al. 1998). Besides activating IKKA, NIK also serves as a docking molecule recruiting IKKA to p100 (Xiao et al. 2004).
R-HSA-5607723 (Reactome) Phosphorylated C-terminal serines 866, 870 and 872 in NFKB2 creates binding site for beta-TRCP (beta-transducin repeat-containing protein), the receptor subunit of a SCF-type of E3 ubiquitin ligase, SCF beta-TRCP (Liang et al. 2006). The SKP1-CUL1-F-box (SCF) ubiquitin E3 ligase superfamily is the largest family of cullin-RING ligases, with interchangeable F-box proteins orchestrating the trafficking proteins for ubiquitination and degradation (Weathington & Mallampalli 2013). Beta-TRCP is an F-box protein that contains two domains, an F-box motif that binds SKP1 and allows assembly into SKP1-CUL1 complexes and a second protein-protein interaction domain that interacts with phosphorylated serines in NFKB2 (Bai et al. 1996, Skowyra et al. 1997, Patton et al. 1998).
R-HSA-5607724 (Reactome) Following ubiquitination Ikappa B-alpha (IKBA) is rapidly degraded by 26S-proteasome, allowing NF-kB to translocate into the nucleus where it activates gene transcription (Spencer et al. 1999).
R-HSA-5607725 (Reactome) Ubiquitination of p100 is very specific. Lysine residue K855 has been identified as the anchoring site for ubiquitin and required for signaling mediated processing of p100 to p52. In the presence of SCF-beta-TRCP E3 ligase the ubiquitin (Ub) conjugated to E2 (E2-Ub thioester) is attached to p100 at K855 (Amir et al. 2004). Several rounds of ubiquitin conjugation can produce long chains of ubiquitin moieties (polyubiquitylation), the first of which is covalently bound to p100. At this point the polyubiquitylated p100 is committed to association with, and unfolding and processing by, the 26S proteasome (Pickart & Cohen 2004).
Efficient ubiquitination of phosphorylated p100 by SCF-beta-TRCP E3 ligase also requires the presence of the components of the NEDD8 pathway: UBA3 (NEDD8-activating enzyme E1 catalytic subunit), UBC12 (NEDD8-conjugating enzyme Ubc12 (E2)), NEDD8 (Neural precursor cell expressed developmentally down-regulated protein 8). NEDD8 binds and promotes a conformational change in CUL1 that may result in efficient formation of an E2-E3 complex, thus stimulating SCF complexes activity (Kawakami et al. 2001, Morimoto et al. 2000, Read et al. 2000).
R-HSA-5607726 (Reactome) After being recruited into the NIK (NFkB-inducing kinase) complex, activated IKKA (I kappaB kinase alpha) phosphorylates serine residues 99, 108, 115, 123, 866, 870 and 872 located in both N- and C-terminal regions of NFKB2/p100. The phosphorylation of these specific serines is the prerequisite for ubiquitination and subsequent processing of p100. The C-terminal serine residues create a binding site for beta-TRCP (beta-transducinrepeat-containing protein), a ubiquitin E3 ligase (Xiao et al. 2001 & 2004, Liang et al. 2006).
R-HSA-5607728 (Reactome) Two major signaling steps are required for the removal of IkappaB (IkB) alpha an inhibitor of NF-kB: activation of the IkB kinase (IKK) and degradation of the phosphorylated IkB alpha. IKK activation and IkB degradation involve different ubiquitination modes; the former is mediated by K63-ubiquitination and the later by K48-ubiquitination. Mutational analysis of IkB alpha has indicated that K21 and K22 are the primary sites for addition of multiubiquitination chains while K38 and K47 are the secondary sites. In a transesterification reaction the ubiquitin is transferred from the ubiquitin-activating enzyme (E1) to an E2 ubiquitin-conjugating enzyme, which may, in turn, transfer the ubiquitin to an E3 ubiquitin protein ligase. UBE2D2 (UBC4) or UBE2D1 (UBCH5) or CDC34 (UBC3) acts as the E2 and SCF (SKP1-CUL1-F-box)-beta-TRCP complex acts as the E3 ubiquitin ligase (Strack et al. 2000, Wu et al. 2010). beta-TRCP (beta-transducin repeats-containing protein) is the substrate recognition subunit for the SCF-beta-TRCP E3 ubiquitin ligase. beta-TRCP binds specifically to phosphorylated IkB alpha and recruits it to the SCF complex, allowing the associated E2, such as UBC4 and or UBCH5 to ubiquitinate Ikappa B alpha (Baldi et al. 1996, Rodriguez et al. 1996, Scherer et al. 1995, Alkalay et al. 1995).
R-HSA-5607731 (Reactome) Once polyubiquitinated, the precursor p100 undergoes 26S proteasome mediated processing to form the mature p52 NF-kB subuunit. Different from complete degradation of other IkB proteins, the proteasome-mediated degradation of p100 only leads to loss of their C-terminal ankyrin repeat regions, leaving intact N-termini, p52 respectively (Amir et al. 2004).
R-HSA-5607732 (Reactome) TAK1-binding protein 1 (TAB1) is a TAK1-interacting protein and induces TAK1 (Transforming growth factor beta-associated kinase 1) kinase activity through promoting autophosphorylation of key serine/threonine sites of the kinase activation loop. There are four phosphorylation sites in the activation loop and analysis of these site mutants indicate that autophosphorylation of S192, is followed by sequential phosphorylation of T178, T187, and finally T184 (Scholz et al. 2010).
R-HSA-5607733 (Reactome) B-cell lymphoma/leukemia 10 (BCL10) is the downstream signaling partner of CARD9 and it interacts selectively with the CARD activation domain of CARD9. BCL10 functions as an adaptor between the effector IKK complex and the proximal signaling complexes that interact with CARD9 (Bertin et al. 2000).
R-HSA-5607734 (Reactome) Protein kinase C-delta (PRKCD), activated upon CLEC7A (Dectin-1)-SYK signaling, phosphorylates CARD9 leading to NF-kB activation (Strasser et al. 2012) and complex formation between CARD9 and BCL10. CLEC6A (Dectin-2) and CLEC4E (Mincle) also induces intracellular signaling through PRKCD and CARD9-BCL10-MALT1 pathway. Similar to the CLEC7A responses, both CLEC6A and CLEC4E-induced interleukin 10 (IL10) and tumour necrotic factor (TNF) production were severely impaired in the absence of PRKCD (Strasser et al. 2012). PRKCD is a member of the Ca2+ independent and diacylglycerol (DAG) dependent novel PKC subfamily. PKC family members exist in an immature inactive conformation that requires post-translational modifications to achieve catalytic maturity. The catalytic maturation of PRKCD involves the auto-phosphorylation of Ser645 and the phosphorylation of Thr507 and Ser664 (Li et al. 1997, Keranen et al. 1995). These phosphorylations of activation loop residues act as a priming step that allows the catalytic maturation of PRKCD (Dutil et al. 1998). Fully phosphorylated and primed PRKCD localises to the cytosol with its pseudosubstrate occupying the substrate-binding cavity. Signals that cause the lipid hydrolysis recruit PKC to membranes. The C1 domain in PRKCD is a cysteine-rich compact structure, identified as the interaction site for DAG and phorbol ester. PRKCD preferentially translocates to the plasma membrane (Stahelin et al. 2004, Newton 2010).
R-HSA-5607735 (Reactome) Following tyrosine phosphorylation, phospholipase C-gamma 2 (PLCG2) catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2 or PIP2] to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).
R-HSA-5607736 (Reactome) After binding BCL10, MALT1 also undergoes oligomerization. Like traditional caspases, MALT1 also becomes activated through the formation of oligomers. Once the CARD9-BCL10-MALT1 (CBM) signalosome is assembled, MALT1 functions as the effector protein and mediates activation of the IKK complex (McAllister-Lucas & Lucas 2008).
R-HSA-5607737 (Reactome) CARD interactions between CARD9 and BCL10 induce BCL10 oligomerization (through its CARD domain), required for oligomerization and activation of MALT1.
R-HSA-5607738 (Reactome) Spleen tyrosine kinase (SYK) is the key mediator of CLEC7A's (Dectin-1) downstream cellular responses, such as cytokine production and induction of the respiratory burst (Brown 2006). A phosphorylated tyrosine in CLEC7A provides the docking site for SYK. In contrast to usual ITAM receptors where dually phosphorylated tyrosines are necessary for SYK recruitment, phosphorylation of only the membrane proximal tyrosine is sufficient for SYK association with CLEC7A. Binding of SYK to the phosphorylated ITAM motif is sufficient to fully activate SYK (Tsang et al. 2008). SYK deficiency or SYK inhibitors inhibit CLEC7A-dependent cytokine production, MAPK activation and NF-kB activation, suggesting that SYK is essential for CLEC7A signalling (Rogers et al. 2005, Underhill et al. 2005, Fuller et al. 2007). Activation of NF-kB by SYK can be categorised into both canonical (c-Rel and p65) and NIK (NF-kB inhibitory kinase)-dependent non-canonical (RelB) routes (Gringhuis et al. 2009).
R-HSA-5607740 (Reactome) Activation of NF-kB signaling is a critical event downstream of CLEC7A (Dectin-1), CLEC6A (Dectin-2) (Bi et al. 2010) and CLEC4E (Mincle) (Yamasaki et al. 2008), requiring the adapter protein Caspase recruitment domain (CARD)-containing protein 9 (CARD9) in dendritic cells and in macrophages (Gross et al. 2006, Hara et al. 2007). CARD9 is analogous to CARD-containing MAGUK protein 1 (CARMA1), which mediates T-cell receptor (TCR) activation of NF-kB in lymphocytes. CARD9 is downstream of SYK and becomes phosphorylated by PRKCD (Protein kinase C-delta) phosphorylates CARD9 on Thr-231 (T231), which is required for the signal-induced association of CARD9 with B-cell lymphoma 10 (BCL10) and Mucosa-associated lymphoid tissue 1 (MALT1) and the subsequent recruitment of MAP3K transforming growth factor beta activated kinase 1 (TAK1), leading to activation of the NF-kB pathway (Strasser et al. 2012). A homozygous loss-of-function mutation in human CARD9 results in a premature termination codon (Gln295*). Patients with this mutation are highly susceptible to fungal infections (Glocker et al. 2009).
R-HSA-5607741 (Reactome) Following 26S-proteasomal processing, NFKB2 p52:RELB dimer is translocated from cytosol into the nucleus where it stimulates expression of target genes (Lin & Karin 2003). Dectin-1 induced RELB-p52 triggers the transcription of chemokines C-C motif chemokine 17 (CCL17) and CCL22 and repression of interleukin 12B (IL12B) transcription (Gringhuis et al. 2009).
R-HSA-5607742 (Reactome) In humans, the IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. It contains two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex is dependent on the phosphorylation of IKK alpha/beta at its activation loop and the K63-linked ubiquitination of NEMO. This basic trimolecular complex is referred to as the IKK complex.
IKK subunits have a N-term kinase domain a leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-ter NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs. IKK beta is the major IKK catalytic subunit for NF-kB activation. Activated TAK1 phosphorylate IKK beta on S177 and S181 (S176 and S180 in IKK alpha) in the activation loop and thus activate the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.
R-HSA-5607744 (Reactome) Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is the main downstream target of BCL10. MALT1 interacts directly with BCL10 and this interaction involves a short stretch of amino acids that follow the BCL10 CARD motif (amino acids 107–119 of human BCL10) and the two immunoglobulin-like domains of MALT1 (Uren et al. 2000, Lucas et al. 2001).
R-HSA-5607745 (Reactome) Activation of SYK triggers multiple cascades, which induces NF-kB activation through a CARD9-dependent pathway. Phospholipase C-gamma 2 (PLCG2) is one of the key signaling components of the CLEC7A (Dectin-1) pathway that connects SYK activation to CARD9 recruitment. PLCG2 is activated upon CLEC7A engagement and triggers an intracellular Ca2+ flux. SYK and Src family kinases are upstream of PLCG2 (Xu et al. 2009, Tassi et al. 2009, Gorjestani et al. 2011). SYK phosphorylates PLCG2 on Y753 and Y759, enhancing the activity of PLCG2 (Suzuki-Inoue et al. 2004).
R-HSA-5607746 (Reactome) Membrane-bound PKC adopts an open conformation, in which the pseudosubstrate is released from the kinase domain, allowing downstream signaling (Newton 2010).
R-HSA-5607747 (Reactome) TRAF6 (tumor necrosis factor receptor-associated factor 6) is a RING (really interesting new gene) domain ubiquitin (Ub) ligase that mediates NF-kB activation by regulating the ubiquitination of transforming growth factor beta-activated kinase (TAK1) and IkB kinase (IKK). TRAF6 has been implicated as downstream effector of MALT1. MALT1 binds to TRAF6 through two putative C-terminal TRAF6-binding motifs (Sun et al. 2004). Gorjestani et al. demonstrate that TRAF6 and TAK1 are required for C-type lectin receptor-induced NF-kB activation and play critical roles in anti-fungal innate immune responses (Gorjestani et al. 2012).
R-HSA-5607750 (Reactome) The signalling abilities of CLEC7A (Dectin-1) depend on its cytoplasmic (immunoreceptor tyrosine based activation motif) ITAM-like motif. In contrast to traditional ITAM sequences which consists of dual YXXL sequences, CLEC7A's ITAM (hemi-ITAM) has only a single YXXL motif (Ariizumi et al. 2000). Despite its unusual ITAM, CLEC7A upon ligation with beta-glucan containing particles undergoes tyrosine phoshorylation by SRC kinases (Kerrigan & Brown 2010).
R-HSA-5607751 (Reactome) The MALT1 oligomers bound to TRAF6 induce TRAF6 oligomerization and activate TRAF6 E3 ubiquitin ligase activity (Sun et al. 2004).
R-HSA-5607753 (Reactome) Activated CARD9 localised in lipid rafts may self-associate with other CARD9 molecules (oligomerization). Residues 140-420 of CARD9 contain heptad repeats characteristic of coiled-coil structures that function in protein oligomerization (Bertin et al. 2000).
R-HSA-5607755 (Reactome) Tyrosine-phosphorylated Phospholipase C-gamma 2 (PLCG2) translocates from the cytosol to the plasma membrane. At the membrane PLCG2 is in close proximity to phosphatidylinositol 4,5-bisphosphate (PIP2) and its other substrates generating the second messengers IP3 and DAG (Rhee 2001). This leads to the activation of CARD9-BCL10-MALT1/NF-kB signaling and stimulates calcineurin/NFAT signaling.
R-HSA-5607756 (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 also known as TRIKA1 (TRAF6-regulated IKK activator 1)) 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 (Deng et al. 2000, Lamothe et al. 2007). 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-5607757 (Reactome) TAK1-binding protein 2 (TAB2), or its homologue TAB3, binds preferentially to K63-linked polyubiquitin chains in TRAF6 and links TRAF6 (TNF receptor-associated factor 6) to TAK1 (Transforming growth factor beta-associated kinase 1). TRAF6 ubiquitinates TAK1 on K34 and K158 and this triggers conformational changes in TAK1 that lead to autophosphorylation and activation (Fan et al. 2010, Hamidi et al. 2011).
R-HSA-5607758 (Reactome) CLEC7A (Dectin-1) was identified as a primary receptor for beta-glucans from fungi, bacteria, and plants and specifically recognises beta 1-3 linked glucans. Human CLEC7A has eight alternatively splice products of which only two are functional for beta-glucan binding (isoforms A and B) (Willment et al. 2001). CLEC7A possesses an extracellular C-type lectin-like domain (CTLD) that is connected by a stalk region to a transmembrane domain and cytoplasmic tail, which contains an immunoreceptor tyrosine-based activation (ITAM)-like motif. Two highly conserved amino acids (222W 224H in Human; 221W, 223H in Mouse) within the CTLD which have been identified as essential for beta-glucan binding (Brown et al. 2007, Adachi et al. 2004). Through the recognition of beta-glucans, CLEC7A binds several fungal species such as Aspergillus, Candida, Coccidioides, Pencillium, Pneumocystis and Saccharimyces.
Ferwerda et al. (2009) suggest that chronic mucocutaneous candidiasis may be caused by a genetic defect of CLEC7A. The mutation of nucleotide A-->C causes a change of amino acid 238 from tyrosine to a stop codon (Tyr238*), leading to the loss of the last nine amino acids of the carbohydrate-recognition domain (CRD). This mutated form of CLEC7A is poorly expressed and does not mediate beta-glucan binding, leading to defective production of cytokines after stimulation with beta-glucans or Candida albicans (Ferwerda et al. 2009).
R-HSA-5607759 (Reactome) K-63 linked polyubiquitin (pUb) chain on TRAF6 provides a scaffold to recruit downstream effector molecules to activate NF-kB. Transforming growth factor beta-associated kinase 1 (TAK1) is a member of the mitogen-activated protein kinase (MAPK) kinase kinase family that is shown to be an essential intermediate that transmits the upstream signals from the receptor complex to the downstream MAPKs and to the NF-kB pathway (Broglie et al. 2009). As a member of the MAP3K family, TAK1 is unique in that its activity requires its binding proteins TAK1-binding protein 1 (TAB1), TAB2 and TAB3. TAB1 acts as the kinase subunit of the TAK1 complex, aiding in the autophosphorylation of TAK1, whereas TAB2 and its homologue TAB3, acts as an adaptor of TAK1 that facilitate the assembly of TAK1 complex to TRAF6 (Takaesu et al. 2000, Ishitani et al. 2003). This protein kinase complex containing the kinase subunit TAK1 and the regulatory subunits TAB1 and TAB2/TAB3 is also known as TRIKA2 (TRAF6-regulated IKK activator 2) (Adhikari et al. 2007).
R-HSA-5621347 (Reactome) Tyrosine-phosphorylated Phospholipase C-gamma 2 (PLCG2) translocates from the cytosol to the plasma membrane. At the membrane PLCG2 is in close proximity to phosphatidylinositol 4,5-bisphosphate (PIP2) and its other substrates generating the second messengers IP3 and DAG (Rhee 2001). This leads to the activation of CARD9-BCL10-MALT1/NF-kB signaling.
R-HSA-5621352 (Reactome) CLEC6A (C-type lectin domain family 6 member A/Dectin-2 (Dendritic cell-associated C-type lectin 2)) a C-type lectin expressed by dendritic cells (DCs) and activated macrophages has been shown to bind structures with high mannose content (McGreal et al. 2006). It is reported to recognise a variety of pathogens including Candida albicans, Saccharomyces cerevisiae, Mycobacterium tuberculosis, Paracoccidioides brasiliensis, Histoplasma capsulatum, Aspergillus fumigatus, non-encapsulated Cryptococcus neoformans, Microsporum audouinii, Trichophyton rubrum, Schistosoma mansoni and house dust mite allergens (Sato et al. 2006, Gorjestani et al. 2011, Ritter et al. 2010, McGreal et al. 2006, Kerscher et al. 2013).
Like other members of the Dectin-2 family, cytoplasmic region of CLEC6A has no obvious signalling motif and it associates with transmembrane adapter FCERG (High affinity immunoglobulin epsilon receptor subunit gamma) to transduce a CLEC6A/Dectin-2 signalling.
R-HSA-5621353 (Reactome) CLEC4D (Macrophage C-type lectin (MCL)) is a member of the C-type lectin that recognises mycobacterial trehalose-6,6'-dimycolate (TDM) or cord factor likely to arise from gene duplication of CLEC4E (also called Minicle). CLEC4D is constitutively expressed on myeloid cells. It couples with FCERG (High affinity immunoglobulin epsilon receptor subunit gamma) and acts as an activating receptor (Miyake et al. 2013).
R-HSA-5621354 (Reactome) CLEC4E (also called Mincle or CLECSF9) is a C-type lectin receptor (CLR) expressed in activated macrophages and dendritic cells (DCs) in response to several inflammatory stimuli, including LPS, TNF, IL6, IFN-gamma and cellular stresses (Matsumoto et al. 1999). Like the other activating receptors in the Dectin-2 family, CLEC4E is coupled with the FCERG (High affinity immunoglobulin epsilon receptor subunit gamma) to transduce intracellular signalling (Yamasaki et al. 2008). CLEC4E possesses a typical carbohydrate recognition domain (CRD) containing an EPN (Glu-Pro-Asn) motif which is capable of recognising several types of carbohydrates, particularly those containing alpha-mannose. CLEC4E can recognise fungal (Candida albicans and Malassezia), mycobacterial (trehalose-6,6?-dimycolate (TDM)) and necrotic cell ligands implicating this receptor in anti-microbial immunity and homeostasis (Schoenen et al. 2010, Yamasaki et al. 2009, Graham & Brown. 2009).
R-HSA-5621355 (Reactome) Ligation of CLEC6A (C-type lectin domain family 6 member A/Dectin-2) and CLEC4E (Mincle) with their appropriate ligands trigger the tyrosine phosphorylation of the immune receptor tyrosine-based activation motif (ITAM) in the cytoplasmic tail of FCER1G chain. Tyrosine Y65 and Y76 in the ITAM are phosphorylated and this phosphorylation is mediated by Src kinases Lyn and Fyn (Sato et al. 2006, Yamasaki et al. 2008, Quek et al. 1998).
R-HSA-5621356 (Reactome) Phospholipase C-gamma (PLCG) binds to phosphorylated Tyr-348 (Tyr-342 in mouse) and Tyr-352 (Tyr-346 in mouse) in SYK with its C-terminal SH2 domain (Law et al. 1996). PLCG2 functions downstream of CLEC6A/Dectin-2 and triggers cytokine production in response to the infection by Candida albicans. PLCG2 deficiency results in the defective production of NF-kB and significantly reduced production of reactive oxygen species (ROS) following infection (Gorjestani et al. 2011).
R-HSA-5621363 (Reactome) Activation of SYK triggers multiple cascades, which induces NF-kB activation through a CARD9-dependent pathway. Phospholipase C-gamma 2 (PLCG2) is one of the key signaling components of the CLEC4E (Mincle)/CLEC6A (Dectin-2) pathway that connects SYK activation to CARD9 recruitment. PLCG2 is activated upon CLEC4E (Mincle)/CLEC6A (Dectin-2) engagement and triggers an intracellular Ca2+ flux. SYK and Src family kinases are upstream of PLCG2. SYK phosphorylates PLCG2 on Y753 and Y759, enhancing the activity of PLCG2 (Gorjestani et al. 2011, Suzuki-Inoue et al. 2004).
R-HSA-5621366 (Reactome) SYK is a cytoplasmic tyrosine kinase related to ZAP70 that is expressed in all hematopoietic cells and coimmunoprecipitates with the gamma chain associated with FCGRIIIA in macrophages and with FCERI in mast cells. Tyrosine phosphorylation of the FCER1G ITAM recruits SYK and initiates a signaling cascade, leading to the activation of transcription factors such as NF-kB via CARD9-BCL10-MALT1 (Kerscher et al. 2013).
R-HSA-5621367 (Reactome) CLEC4A (C-type lectin domain family 4 member A/Dendritic cell immunoreceptor (DCIR)) is expressed by all CD14+ monocytes, CD15+ granulocytes, all dendrite cell (DC) subsets and B cells in peripheral blood. The extracellular domain of CLEC4A has an EPS motif which recognises carbohydrates but the definitive carbohydrate ligands have not been defined. However, it has been identified as an attachment factor for HIV on DCs and hepatitis C virus (HCV) glycoprotein E2 on plasmacytoid dendritic cells (pDCs) (Lambert et al. 2008, Florentin et al. 2012, Kerscher et al. 2013).
Unlike the other Dectin-2 family members, CLEC4A has a long cytoplasmic tail with a classical immunoreceptor tyrosine based inhibitory signalling motif (ITIMs) (Flornes et al. 2004). CLEC4A with its ITIM motif mediates inhibitory signalling through activation of the phosphatases SHP1 and SHP2 (Kanazawa et al 2003, Meyer-Wentrup et al. 2009). Activation of CLEC4A on DCs or pDCs leads to inhibition of TLR8-mediated IL12 and TNF production, and TLR9-induced IFN-alpha production (Lambert et al. 2011, Meyer-Wentrup et al. 2008).
In humans, polymorphisms of CLEC4A have been associated with susceptibility to rheumatoid arthritis (Lorentzen et al. 2007).
R-HSA-5621370 (Reactome) SYK can autophosphorylate and autophosphorylation increases its activity. It is more readily activated by autophosphorylation although it is rapidly activated by Src family kinases. SYK has multiple sites of phosphorylation which both regulate its activity and serve as docking sites for other proteins (Sada et al. 2001). Some of these sites include Y131 of interdomain A, Y323, Y348, and Y352 of interdomain B, and Y525 and Y526 within the activation loop of the kinase domain and Y630 in the C-terminus (Zhang et al. 2002, Lupher et al. 1998, Furlong et al. 1997).
R-HSA-5621371 (Reactome) CLEC4C (C-type lectin domain family 4 member C/Blood dendritic cell antigen 2 (BDCA2)) is a member of the Dectin-2 family expressed exclusively on plasmacytoid dendritic cells (pDCs). CLEC4C is capable of binding certain CD14+ monocytes, monocyte-derived DCs and several tumour cell lines by recognising sugars asialo-galactosyl-oligosaccharides with terminal beta1-4- and beta1-3-galactose residues. CLEC4C has also been shown to bind the HIV-1 envelope glycoprotein gp120 and hepatitis C virus (HCV) glycoprotein E2 (Kerscher et al. 2013, Riboldi et al. 2011, Florentin et al. 2011).
CLEC4C lacks signalling motif in its cytoplasmic tail and associates with transmembrane adapter FCERG (High affinity immunoglobulin epsilon receptor subunit gamma) to induce intracellular signal transduction in a B-cell receptor (BCR)-like fashion employing SYK to regulate the immune functions of pDCs. The FCERG-SYK signalling pathway interferes with TLR9-induced activation of pDC, inhibiting type I IFN secretion (Cao et al. 2007, Dzionek et al. 2001, Rock et al. 2007, Riboldi et al. 2011).
R-HSA-5621571 (Reactome) CD209 (DC-SIGN) acts as an adhesion molecule and besides foreign antigens (Ags), it binds to a number of endogenous ligands, particularly to intracellular adhesion molecule 2 (ICAM2) on endothelial cells. This CD209-ICAM2 interaction regulates chemokine-induced transmigration of dendritic cells across both resting and activated endothelium (Geijtenbeek et al. 2000).
R-HSA-5621573 (Reactome) Both CLEC7A (Dectin-1) and CD209 (DC-SIGN) modulates Toll-like receptor signalling by activating RAF1 which in turn induces the phosphorylation of p65 (RELA) subunit leading to the modification of p50/p65 NF-kB dimer (Gringhuis et al. 2007 & 2009). Gringhuis et al. demonstrated that CD209 (DC-SIGN) stimulated by ManLAM (lipoarabinomannan) activates the small GTPase RAS. Immunoblotting detected active RAS in dendritic cells when induced by ManLAM (Gringhuis et al. 2007). RAF1 is recruited to the membrane through an interaction with the active form of RAS.
R-HSA-5621606 (Reactome) CD209 (DC-SIGN) interacts with pathogens through either mannose or fucose containing glycans. It interacts with mannose capped cell-wall component of Mycobacterium tuberculosis ManLAM (lipoarabinomannan). The carbohydrate recognition domain (CRD) of CD209 recognizes Man-LAM and lipomannans and the amount of Man-LAM determines the binding strength. The interaction of ManLAM and CD209 leads to the activation of serine/threonine kinase RAF1 and increases the production of the immunosuppressive cytokine interleukin 6 (IL6), IL10 and IL12 in the presence of Toll like receptor stimulation (Geijtenbeek et al. 2003, Gringhuis et al. 2007 & 2009).
R-HSA-5621615 (Reactome) Contact between dendritic cells (DC) and resting T cells is essential to initiate a primary immune response. CD209 binds the intracellular adhesion molecule 3 (ICAM3) with very high affinity. CD209 interacts primarily with the immunoglobulin (Ig)-like second domain of ICAM2 and ICAM3. CD209-ICAM3 interaction mediates clustering of DCs with naive T cells forming a DC-T cell synapse (Geijtenbeek et al. 2000). CD209 binding to ICAM3 is calcium dependent, and CD209 CRD (carbohydrate recognition domain) binds two Ca2+ ions, one essential for tertiary structure and the other for coordinating ligand binding (Feinberg et al. 2001, Svajger et al. 2010).
R-HSA-5624473 (Reactome) Protein kinase A (PKA/PRKACA) and Ribosomal protein S6 kinase alpha-5 (RPS6KA5/MSK1/SAPK1) phosphorylate serine 276 (S276) in the Rel homology domain (RHD) of nuclear p65 subunit RELA (Yoon et al. 2008, Reber et al. 2009). Few other phosphorylation sites (S311, S529 and S536) have also been proposed in RELA (Duran et al. 2003) note: in this reaction we are showing only S276 phosphorylation)). Phosphorylation of RELA subunit enhances the association of RELA with p300 and this is a prerequisite for later NF-kB modification by histone acetyltransferases (HATs) p300/CBP. Phosphorylation of RELA also cross-regulates CLEC7A (dectin-1) mediated non-canonical NF-kB pathway by forming inactive p65 and RELB dimers, that cannot bind DNA.
R-HSA-5624486 (Reactome) Phosphorylation of tyrosine 340, 341 (Y340,341) on RAF1 in response to CD209 (DC-SIGN) signalling depends on yet unidentified members of the Src family of tyrosine kinases (SFKs). In imunoprecipitation studies, CD209 from lipid rafts of dendritic cells was found to co-precipitate with LYN, a member of the SFK, as well as with SYK tyrosine kinase, indicating their possible involvement in DC-SIGN signalling (Caparros et al. 2006, Svajger et al. 2010).
R-HSA-5624492 (Reactome) RAF regulation is highly complex and is not solely mediated by conformational changes but also requires phosphorylation. Several phosphorylation sites on RAF1 have been identified that are involved in its kinase activity. Two of these phosphorylation sites are serine 338 (S338) and tyrosine 340 and 341 (Y340/341). Gringhuis et al. demonstrated that ManLAM activation of CD209 (DC-SIGN) results in induced phosphorylation of RAF1 on S338 and Y340/341. The phosphorylation of S338 is mediated by p21-activated kinases (PAK). Inhibition of Rho GTPases with toxin B blocks CD209 induced phosphorylation of RAF1on S338 (Gringhuis et al. 2007, Wellbrock et al. 2004).
R-HSA-5624494 (Reactome) Upon CLEC7A (Dectin-1) and CD209 (DC-SIGN) activation, RAF1 translocates to the membrane through interaction with the active form of RAS. This interaction induces a conformational change in RAF1 and is required for RAF1 activation (Gringhuis et al. 2007, Wellbrock et al. 2004).
R-HSA-5660622 (Reactome) NK-kB transcription factor binds to the DNA and promotes the transcription of proinflammatory cytokine interleukin 1-beta (IL1B).
R-HSA-5660660 (Reactome) Acetylation of RELA/p65 subunit differentially regulates distinct biological activities of the NF-kB transcription factor complex. The acetylation enables increased DNA binding and transcriptional activity by NF-kB, leading to up-regulated IL6 (interleukin 6), IL10, IL12p35, IL12p40 and IL23p19 production (Geijtenbeek and Gringhuis 2009). Acetyltransferases p300 and CBP are involved in the acetylation of RELA on multiple sites including lysines 122, 123, 218, 221 and 310. Acetylation of lysine 221 by p300/CBP increases the DNA binding affinity of RELA for the IkB enhancer and, together with acetylation of lysine 218, impairs assembly of RELA with newly synthesized IkBalpha, which shuttles in and out of the nucleus. Acetylation of lysine 310 does not modulate DNA binding or IkBalpha assembly but markedly enhances the transcriptional activity of NF-kB (Chen et al. 2002, 2005).
R-HSA-5660662 (Reactome) ASC (adaptor protein apoptosis-associated speck-like protein containing a CARD) is a pro-apoptotic protein containing a pyrin domain (PD) and a caspase-recruitment domain (CARD). ASC with its PD domain physically interacts with caspase-8. Formation of the MALT1–caspase-8 complex is a prerequisite for the association of caspase-8 with ASC. ASC is necessary for the recruitment of pro-IL1B into the proximity of activated caspase-8 (Gringhuis et al. 2012).
R-HSA-5660663 (Reactome) Interleukin-1beta (IL1B) is secreted as inactive precursor, and the processing of pro-IL1B depends on cleavage by proteases. Active caspase-8 inflammasome is capable of cleaving the 31-kDa inactive IL1B precursor form into the bioactive 17-kDa IL1B.
R-HSA-5660665 (Reactome) After CLEC7A (dectin-1) triggering, MALT1 and caspase-8 associate to form BCL10-MALT1-Caspase-8 complex. MALT1 has a crucial dual role in the expression of IL1B by CLEC7A. It is involved in the transcription of IL1B by activating NF-kB and the other role in processing of pro-IL1B by mediating the formation and activation of a MALT1-caspase8-ASC (adaptor protein apoptosis-associated speck-like protein containing a CARD) complex (Gringhuis et al. 2012). The paracaspase domain of MALT1, in a protease-independent manner, induces caspase-8 activation through direct association (Kawadler et al. 2008).
R-HSA-5660666 (Reactome) The phosphorylation of p65 subunit has been shown to be important for RELA transcriptional activity. Once phosphorylated RELA/p65 has been shown to recruit transcriptional coactivators CREB binding protein (CBP) and p300 (Chen at al. 2002). The association between CBP/p300 and NF-kB p65 occurs through RHD (Rel homology domain) and C-terminal transactivation domain (Zong et al. 1998). Both p300 and CBP contain a histone acetyltransferase (HAT) enzymatic activity that regulates gene expression through acetylation of RELA, and promoter proximal nucleosomal histones, resulting in increased accessibility of the DNA for other essential regulators (Kalkhoven 2004).
R-HSA-5660965 (Reactome) RELB-p52 NF-kB complex binds to DNA and mediate the expression of chemokines (CCL17) and CCL22 after CLEC7A (dectin-1) triggering.
R-HSA-5660980 (Reactome) Phosphorylated RELA besides undergoing further acetylation by the histone acetyltransferases (HATs) CBP and p300 also forms a complex with RELB to form inactive RELA-RELB dimers that cannot bind DNA. Because RELB requires p50 or p52 as a dimerization partner to bind DNA, it is possible that sequestration of RELB from its complex partners p50 and p52 by RELA might account for the lack of RELB DNA binding. RELA-RELB dimers have important regulatory consequences on dectin-1 mediated non-canonical NF-kB pathway. Inactive p65-RELB dimers blocks binding of RELB-p52 to the promoters of the chemokine genes CCL17 (CC-chemokine ligand 17) and CCL22, thereby blocking chemokine expression (Gringhuis et al. 2009).
R-HSA-74448 (Reactome) Upon increase in calcium concentration, calmodulin (CaM) is activated by binding to four calcium ions.
RAF1R-HSA-5624494 (Reactome)
RELBR-HSA-5660980 (Reactome)
RPS6KA5(MSK1/SAPK1):PKA catalytic subunitsmim-catalysisR-HSA-5624473 (Reactome)
SCF-beta-TRCPArrowR-HSA-5607725 (Reactome)
SCF-beta-TRCPArrowR-HSA-5607728 (Reactome)
SCF-beta-TRCPR-HSA-5607723 (Reactome)
SCF-beta-TRCPR-HSA-5607728 (Reactome)
SCF-beta-TRCPmim-catalysisR-HSA-5607728 (Reactome)
SRC-1mim-catalysisR-HSA-5607750 (Reactome)
SYKR-HSA-5607738 (Reactome)
SYKR-HSA-5621366 (Reactome)
TAB1:TAB2,TAB3:TAK1R-HSA-5607759 (Reactome)
TDM,alpha-mannanR-HSA-5621354 (Reactome)
TDMR-HSA-5621353 (Reactome)
TRAF6R-HSA-5607747 (Reactome)
TRAF6R-HSA-5607751 (Reactome)
UBA3ArrowR-HSA-5607725 (Reactome)
UBA3R-HSA-5607725 (Reactome)
UBE2D2,UBE2D1,(CDC34)ArrowR-HSA-5607728 (Reactome)
UBE2D2,UBE2D1,(CDC34)R-HSA-5607728 (Reactome)
Ub-TRAF6 trimer

bound to CBM

complex		mim-catalysisR-HSA-202534 (Reactome)
UbArrowR-HSA-5607731 (Reactome)
Ubc13:UBE2V1ArrowR-HSA-202534 (Reactome)
Ubc13:UBE2V1ArrowR-HSA-5607756 (Reactome)
Ubc13:UBE2V1ArrowR-HSA-5607757 (Reactome)
Ubc13:UBE2V1R-HSA-202534 (Reactome)
Ubc13:UBE2V1R-HSA-5607756 (Reactome)
Ubc13:UBE2V1R-HSA-5607757 (Reactome)
active caspase-8R-HSA-5660665 (Reactome)
alpha-mannanR-HSA-5621352 (Reactome)
p-S177,S181-IKKB:IKKA:NEMOArrowR-HSA-5607742 (Reactome)
p-S177,S181-IKKB:IKKA:NEMOR-HSA-202534 (Reactome)
p-S177,S181-IKKB:IKKA:pUb-NEMOArrowR-HSA-202534 (Reactome)
p-S177,S181-IKKB:IKKA:pUb-NEMOmim-catalysisR-HSA-202541 (Reactome)
p-S276-RELA:RELBArrowR-HSA-5660980 (Reactome)
p-S276-RELA:RELBTBarR-HSA-5660965 (Reactome)
p-S276-RELAR-HSA-5660980 (Reactome)
p-S32,36-IkB-alpha:NF-kB complexArrowR-HSA-202541 (Reactome)
p-S32,36-IkB-alpha:NF-kB complexR-HSA-5607728 (Reactome)
p-T231-CARD9 oligomer:BCL10ArrowR-HSA-5607733 (Reactome)
p-T231-CARD9 oligomer:BCL10R-HSA-5607737 (Reactome)
p-T231-CARD9 oligomerArrowR-HSA-5607753 (Reactome)
p-T231-CARD9 oligomerR-HSA-5607733 (Reactome)
p-T231-CARD9:BCL10 oligomers:MALT1ArrowR-HSA-5607744 (Reactome)
p-T231-CARD9:BCL10 oligomers:MALT1R-HSA-5607736 (Reactome)
p-T231-CARD9:BCL10 oligomersArrowR-HSA-5607737 (Reactome)
p-T231-CARD9:BCL10 oligomersR-HSA-5607744 (Reactome)
p-T231-CARD9:BCL10:MALT1 oligomers:TRAF6ArrowR-HSA-5607747 (Reactome)
p-T231-CARD9:BCL10:MALT1 oligomers:TRAF6R-HSA-5607751 (Reactome)
p-T231-CARD9:BCL10:MALT1 oligomersArrowR-HSA-5607736 (Reactome)
p-T231-CARD9:BCL10:MALT1 oligomersR-HSA-5607747 (Reactome)
p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TAB1:TAB2/TAB3:K63polyUb-34,158-TAK1ArrowR-HSA-5607757 (Reactome)
p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TAB1:TAB2/TAB3:K63polyUb-34,158-TAK1R-HSA-5607732 (Reactome)
p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TAB1:TAB2/TAB3:K63polyUb-34,158-TAK1mim-catalysisR-HSA-5607732 (Reactome)
p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TAB1:TAB2/TAB3:K63polyUb-34,158-p3Y,1S-TAK1ArrowR-HSA-5607732 (Reactome)
p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TAB1:TAB2/TAB3:K63polyUb-34,158-p3Y,1S-TAK1mim-catalysisR-HSA-5607742 (Reactome)
p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TRIKA2ArrowR-HSA-5607759 (Reactome)
p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TRIKA2R-HSA-5607757 (Reactome)
p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomers:TRIKA2mim-catalysisR-HSA-5607757 (Reactome)
p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomersArrowR-HSA-5607756 (Reactome)
p-T231-CARD9:BCL10:MALT1:K63polyUb-TRAF6 oligomersR-HSA-5607759 (Reactome)
p-T231-CARD9:BCL10:MALT1:TRAF6 oligomersArrowR-HSA-5607751 (Reactome)
p-T231-CARD9:BCL10:MALT1:TRAF6 oligomersR-HSA-5607756 (Reactome)
p-T231-CARD9:BCL10:MALT1:TRAF6 oligomersmim-catalysisR-HSA-5607756 (Reactome)
p-T231-CARD9ArrowR-HSA-5607740 (Reactome)
p-T231-CARD9R-HSA-5607753 (Reactome)
p-T507,S645,S664-PRKCDR-HSA-5607734 (Reactome)
p-Y753,Y759-PLCG2ArrowR-HSA-5607745 (Reactome)
p-Y753,Y759-PLCG2ArrowR-HSA-5607755 (Reactome)
p-Y753,Y759-PLCG2ArrowR-HSA-5621347 (Reactome)
p-Y753,Y759-PLCG2R-HSA-5607755 (Reactome)
p-Y753,Y759-PLCG2mim-catalysisR-HSA-5607735 (Reactome)
p100:RELBR-HSA-5607720 (Reactome)
p21 RAS:GTP:p-S338,Y340,Y341-RAF1ArrowR-HSA-5624486 (Reactome)
p21 RAS:GTP:p-S338-RAF1ArrowR-HSA-5624492 (Reactome)
p21 RAS:GTP:p-S338-RAF1R-HSA-5624486 (Reactome)
p21 RAS:GDPR-HSA-5621573 (Reactome)
p21 RAS:GTP:RAF1ArrowR-HSA-5624494 (Reactome)
p21 RAS:GTP:RAF1R-HSA-5624492 (Reactome)
p21 RAS:GTPArrowR-HSA-5621573 (Reactome)
p21 RAS:GTPR-HSA-5624494 (Reactome)
p52:RELBArrowR-HSA-5607731 (Reactome)
p52:RELBArrowR-HSA-5607741 (Reactome)
p52:RELBArrowR-HSA-5660965 (Reactome)
p52:RELBR-HSA-5607741 (Reactome)
pathogens:CLEC6A,CLEC4E:FCER1G dimerR-HSA-5621355 (Reactome)
pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer:SYKArrowR-HSA-5621366 (Reactome)
pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer:SYKR-HSA-5621370 (Reactome)
pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer:SYKmim-catalysisR-HSA-5621370 (Reactome)
pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer:p-6Y-SYK:PLCG2ArrowR-HSA-5621356 (Reactome)
pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer:p-6Y-SYK:PLCG2R-HSA-5621363 (Reactome)
pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer:p-6Y-SYK:PLCG2mim-catalysisR-HSA-5621363 (Reactome)
pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer:p-6Y-SYK:p-Y753,Y759-PLCG2ArrowR-HSA-5621363 (Reactome)
pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer:p-6Y-SYK:p-Y753,Y759-PLCG2R-HSA-5621347 (Reactome)
pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer:p-6Y-SYKArrowR-HSA-5621347 (Reactome)
pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer:p-6Y-SYKArrowR-HSA-5621370 (Reactome)
pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimer:p-6Y-SYKR-HSA-5621356 (Reactome)
pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimerArrowR-HSA-5621355 (Reactome)
pathogens:CLEC6A,CLEC4E:p-Y65,Y76-FCER1G dimerR-HSA-5621366 (Reactome)
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