TRAIL signaling (Homo sapiens)

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153, 552, 141, 9, 1610, 175, 6cytosolTNFRSF10B TNFSF10TNFRSF10DCASP10(1-521) TNFRSF10A CASP10(1-521)TNFRSF10A TNFRSF10B TNFRSF10A,TNFRSF10BFADD TNFRSF10A TNFSF10 Caspase activationvia Death Receptorsin the presence ofligandTNFRSF10B TNFSF10:TNFRSF10A,BCASP8(1-479)FADD TNFSF10:TNFRSF10A,B:FADD:CASP8(1-479)TNFRSF10B CFLAR(1-376)FADDTNFSF10 TNFSF10 TNFRSF10A TNFRSF10A TNFSF10 TNFRSF10A TNFRSF10B FADD TNFSF10:TNFRSF10A,B:FADD:CASP10(1-521)TNFRSF10B TNFRSF10A TNFRSF10B TNFSF10 TNFRSF10D CASP8(1-479) TNFSF10:TNFRSF10A,B:FADDTNFRSF10A,B:TNFRSF10DTNFSF10:TNFRSF10A,BTrimer884, 7, 11, 12, 1881, 9, 165, 1310, 1785, 63, 5


Description

Tumor necrosis factor-related apoptosis-inducing ligand or Apo 2 ligand (TRAIL/Apo2L) is a member of the tumor necrosis factor (TNF) family. This group of apoptosis induction pathways all work through protein interactions mediated by the intracellular death domain (DD), encoded within the cytoplasmic domain of the receptor. TRAIL selectively induces apoptosis through its interaction with the Fas-associated death domain protein (FADD) and caspase-8/10 (Wang S & el-Deiry WS 2003; Sprick MR et al. 2002). TRAIL and its receptors, TRAIL-R1 and TRAIL-R2, were shown to be rapidly endocytosed via clathrin-dependent and -independent manner in human Burkitt's lymphoma B cells (BJAB) (Kohlhaas SL et al. 2007). However, FADD and caspase-8 were able to bind TRAIL-R1/R2 in TRAIL-stimulated BJAB cells at 4oC (at which membrane trafficking is inhibited), suggesting that the endocytosis was not required for an assembly of the functional TRAIL DISC complex. Moreover, blocking of clathrin-dependent endocytosis did not interfere with the capacity of TRAIL to promote apoptosis (Kohlhaas SL et al. 2007).
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Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 75158
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: Gillespie, Marc E

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Bibliography

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  1. Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N, Timour MS, Gerhart MJ, Schooley KA, Smith CA, Goodwin RG, Rauch CT.; ''TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL.''; PubMed Europe PMC Scholia
  2. Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM.; ''An antagonist decoy receptor and a death domain-containing receptor for TRAIL.''; PubMed Europe PMC Scholia
  3. Reis CR, van Assen AH, Quax WJ, Cool RH.; ''Unraveling the binding mechanism of trivalent tumor necrosis factor ligands and their receptors.''; PubMed Europe PMC Scholia
  4. Boatright KM, Renatus M, Scott FL, Sperandio S, Shin H, Pedersen IM, Ricci JE, Edris WA, Sutherlin DP, Green DR, Salvesen GS.; ''A unified model for apical caspase activation.''; PubMed Europe PMC Scholia
  5. Sprick MR, Weigand MA, Rieser E, Rauch CT, Juo P, Blenis J, Krammer PH, Walczak H.; ''FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2.''; PubMed Europe PMC Scholia
  6. Kohlhaas SL, Craxton A, Sun XM, Pinkoski MJ, Cohen GM.; ''Receptor-mediated endocytosis is not required for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis.''; PubMed Europe PMC Scholia
  7. Boatright KM, Salvesen GS.; ''Mechanisms of caspase activation.''; PubMed Europe PMC Scholia
  8. Chinnaiyan AM, O'Rourke K, Tewari M, Dixit VM.; ''FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis.''; PubMed Europe PMC Scholia
  9. Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA.; ''Identification and characterization of a new member of the TNF family that induces apoptosis.''; PubMed Europe PMC Scholia
  10. Sprick MR, Rieser E, Stahl H, Grosse-Wilde A, Weigand MA, Walczak H.; ''Caspase-10 is recruited to and activated at the native TRAIL and CD95 death-inducing signalling complexes in a FADD-dependent manner but can not functionally substitute caspase-8.''; PubMed Europe PMC Scholia
  11. Oberst A, Pop C, Tremblay AG, Blais V, Denault JB, Salvesen GS, Green DR.; ''Inducible dimerization and inducible cleavage reveal a requirement for both processes in caspase-8 activation.''; PubMed Europe PMC Scholia
  12. Donepudi M, Mac Sweeney A, Briand C, Grütter MG.; ''Insights into the regulatory mechanism for caspase-8 activation.''; PubMed Europe PMC Scholia
  13. Harper N, Hughes M, MacFarlane M, Cohen GM.; ''Fas-associated death domain protein and caspase-8 are not recruited to the tumor necrosis factor receptor 1 signaling complex during tumor necrosis factor-induced apoptosis.''; PubMed Europe PMC Scholia
  14. Neumann S, Hasenauer J, Pollak N, Scheurich P.; ''Dominant negative effects of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptor 4 on TRAIL receptor 1 signaling by formation of heteromeric complexes.''; PubMed Europe PMC Scholia
  15. Wang S, El-Deiry WS.; ''TRAIL and apoptosis induction by TNF-family death receptors.''; PubMed Europe PMC Scholia
  16. Pan G, O'Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, Dixit VM.; ''The receptor for the cytotoxic ligand TRAIL.''; PubMed Europe PMC Scholia
  17. Wang J, Chun HJ, Wong W, Spencer DM, Lenardo MJ.; ''Caspase-10 is an initiator caspase in death receptor signaling.''; PubMed Europe PMC Scholia
  18. Keller N, Grütter MG, Zerbe O.; ''Studies of the molecular mechanism of caspase-8 activation by solution NMR.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114841view16:34, 25 January 2021ReactomeTeamReactome version 75
113287view11:35, 2 November 2020ReactomeTeamReactome version 74
112498view15:45, 9 October 2020ReactomeTeamReactome version 73
101410view11:29, 1 November 2018ReactomeTeamreactome version 66
100948view21:05, 31 October 2018ReactomeTeamreactome version 65
100485view19:40, 31 October 2018ReactomeTeamreactome version 64
100030view16:23, 31 October 2018ReactomeTeamreactome version 63
99583view14:55, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99205view12:43, 31 October 2018ReactomeTeamreactome version 62
93883view13:42, 16 August 2017ReactomeTeamreactome version 61
93451view11:24, 9 August 2017ReactomeTeamreactome version 61
87130view18:48, 18 July 2016EgonwOntology Term : 'signaling pathway' added !
86543view09:20, 11 July 2016ReactomeTeamreactome version 56
83412view11:09, 18 November 2015ReactomeTeamVersion54
81609view13:09, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
CASP10(1-521) ProteinQ92851 (Uniprot-TrEMBL)
CASP10(1-521)ProteinQ92851 (Uniprot-TrEMBL)
CASP8(1-479) ProteinQ14790 (Uniprot-TrEMBL)
CASP8(1-479)ProteinQ14790 (Uniprot-TrEMBL)
CFLAR(1-376)ProteinO15519 (Uniprot-TrEMBL)
Caspase activation

via Death Receptors in the presence of

ligand		PathwayR-HSA-140534 (Reactome) Caspase-8 is synthesized as zymogen (procaspase-8) and is formed from procaspase-8 as a cleavage product. However, the cleavage itself appears not to be sufficient for the formation of an active caspase-8. Only the coordinated dimerization and cleavage of the zymogen produce efficient activation in vitro and apoptosis in cellular systems [Boatright KM and Salvesen GS 2003; Keller N et al 2010; Oberst A et al 2010].

The caspase-8 zymogens are present in the cells as inactive monomers, which are recruited to the death-inducing signaling complex (DISC) by homophilic interactions with the DED domain of FADD. The monomeric zymogens undergo dimerization and the subsequent conformational changes at the receptor complex, which results in the formation of catalytically active form of procaspase-8.[Boatright KM et al 2003; Donepudi M et al 2003; Keller N et al 2010; Oberst A et al 2010].

FADD ProteinQ13158 (Uniprot-TrEMBL)
FADDProteinQ13158 (Uniprot-TrEMBL)
TNFRSF10A ProteinO00220 (Uniprot-TrEMBL)
TNFRSF10A,B:TNFRSF10DComplexR-HSA-5635735 (Reactome)
TNFRSF10A,TNFRSF10BComplexR-HSA-5634815 (Reactome)
TNFRSF10B ProteinO14763 (Uniprot-TrEMBL)
TNFRSF10D ProteinQ9UBN6 (Uniprot-TrEMBL)
TNFRSF10DProteinQ9UBN6 (Uniprot-TrEMBL)
TNFSF10 ProteinP50591 (Uniprot-TrEMBL)
TNFSF10:TNFRSF10A,B TrimerComplexR-HSA-5637469 (Reactome)
TNFSF10:TNFRSF10A,B:FADD:CASP10(1-521)ComplexR-HSA-5637463 (Reactome)
TNFSF10:TNFRSF10A,B:FADD:CASP8(1-479)ComplexR-HSA-5637468 (Reactome)
TNFSF10:TNFRSF10A,B:FADDComplexR-HSA-5637464 (Reactome)
TNFSF10:TNFRSF10A,BComplexR-HSA-5637465 (Reactome)
TNFSF10ProteinP50591 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
CASP10(1-521)R-HSA-141316 (Reactome)
CASP8(1-479)R-HSA-75146 (Reactome)
CFLAR(1-376)TBarR-HSA-75187 (Reactome)
FADDR-HSA-75187 (Reactome)
R-HSA-141139 (Reactome) The complex of TRAIL (TNFSF10) and TRAIL receptor-1 (TNFRSF10A) or TRAIL receptor-2 (TNFRSF10B) trimerizes (Sprick et al. 2000, Reis et al. 2011).
R-HSA-141316 (Reactome) Caspase-10 precursor is recruited to the TRAIL:TRAIL receptor-2:FADD complex (TNFSF10:TNFRSF10B:FADD) as well as TRAIL:TRAIL receptor-1:FADD complex (TNFSF10:TNFRSF10A:FADD) (Sprick et al. 2002) through interaction of death effector domains of caspase-10 and FADD (Wang et al. 2001).
R-HSA-5635741 (Reactome) TNFRSF10D (also known as DcR2 or TRAILR4) inhibits pro-apoptotic signaling by TRAIL (TNFSF10) receptors TNFRSF10A (TRAILR1, DR4) and TNFRSF10B (TRAILR2, DR5). TNFRSF10D has a truncated death domain (DD) but has the motifs involved in oligomerization of TRAIL receptors. While it was initially thought that TNFRSF10D functions as a decoy receptor that competes with TNFRSF10A and TNFRSF10B for ligand binding (Pan et al. 1997), latest studies indicate that it prevents TRAIL signaling by forming heterodimers with TNFRSF10A and TNFRSF10B and thus preventing formation of functional homotrimeric TRAIL ligand:receptor complexes (Neumann et al. 2014).
R-HSA-75146 (Reactome) FADD recruits caspase-8 precursor to trimeric complex of TRAIL (TNFSF10) and TRAIL receptors (TNFRSF10A or TNFRSF10B) (Sprick et al. 2000).
R-HSA-75187 (Reactome) The trimeric complex of TRAIL and TRAIL receptor-1 (TNFSF10:TNFRSF10A) or TRAIL receptor-2 (TNFSF10:TNFRSF10B) binds FADD (Sprick et al. 2000).
R-HSA-75238 (Reactome) TRAIL (TNF-related apoptosis-inducing ligand) binds TRAIL receptor-1 (TNFRSF10A) or TRAIL receptor-2 (TNFRSF10B) (Wiley et al. 1995, Pan et al. 1997, Walczak et al. 1997).
TNFRSF10A,B:TNFRSF10DArrowR-HSA-5635741 (Reactome)
TNFRSF10A,TNFRSF10BR-HSA-5635741 (Reactome)
TNFRSF10A,TNFRSF10BR-HSA-75238 (Reactome)
TNFRSF10DR-HSA-5635741 (Reactome)
TNFSF10:TNFRSF10A,B TrimerArrowR-HSA-141139 (Reactome)
TNFSF10:TNFRSF10A,B TrimerR-HSA-75187 (Reactome)
TNFSF10:TNFRSF10A,B:FADD:CASP10(1-521)ArrowR-HSA-141316 (Reactome)
TNFSF10:TNFRSF10A,B:FADD:CASP8(1-479)ArrowR-HSA-75146 (Reactome)
TNFSF10:TNFRSF10A,B:FADDArrowR-HSA-75187 (Reactome)
TNFSF10:TNFRSF10A,B:FADDR-HSA-141316 (Reactome)
TNFSF10:TNFRSF10A,B:FADDR-HSA-75146 (Reactome)
TNFSF10:TNFRSF10A,BArrowR-HSA-75238 (Reactome)
TNFSF10:TNFRSF10A,BR-HSA-141139 (Reactome)
TNFSF10R-HSA-75238 (Reactome)
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