FasL/ CD95L signaling (Homo sapiens)

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8136, 79112cytosolLigand-dependentcaspase activationFAS FASLG(1-281) FASLG(1-281) FAS FASL:FAStrimer:FADD:CASP8(1-479)FASL:FAS ReceptorTrimerFASLG(1-281) FAS FAS CASP8(1-479)CASP8(1-479) FADDFASL:FASReceptorTrimer:FADD:pro-Caspase-10CASP10(1-521) FADD FAS FASLG(1-281) FADD FASL:FAS ReceptormonomerFASLG(1-281) FASLG(1-281)CASP10(1-521)FASL:FAS ReceptorTrimer:FADDFADD FAS143, 42, 5, 10, 11, 15143, 41414


Description

The Fas family of cell surface receptors initiate the apototic pathway through interaction with the external ligand, FasL. The cytoplasmic domain of Fas interacts with a number of molecules in the transduction of the external signal to the cytoplasmic side of the cell membrane. The most notable cytoplasmic domain is the Death Domain (DD) that is involved in recruiting the FAS-associating death domain-containing protein (FADD). This interaction drives downstream events. View original pathway at:Reactome.

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Ontology Terms

 

Bibliography

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  1. 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
  2. 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
  3. Boatright KM, Salvesen GS.; ''Mechanisms of caspase activation.''; PubMed Europe PMC Scholia
  4. 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
  5. 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
  6. Keller N, Grütter MG, Zerbe O.; ''Studies of the molecular mechanism of caspase-8 activation by solution NMR.''; PubMed Europe PMC Scholia
  7. Brunner T, Mogil RJ, LaFace D, Yoo NJ, Mahboubi A, Echeverri F, Martin SJ, Force WR, Lynch DH, Ware CF.; ''Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas.''; PubMed Europe PMC Scholia
  8. Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter ME.; ''Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor.''; PubMed Europe PMC Scholia
  9. Boldin MP, Goncharov TM, Goltsev YV, Wallach D.; ''Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death.''; PubMed Europe PMC Scholia
  10. 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
  11. Wang J, Chun HJ, Wong W, Spencer DM, Lenardo MJ.; ''Caspase-10 is an initiator caspase in death receptor signaling.''; 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. Boldin MP, Varfolomeev EE, Pancer Z, Mett IL, Camonis JH, Wallach D.; ''A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain.''; PubMed Europe PMC Scholia
  14. Sharma V, Tewari R, Sk UH, Joseph C, Sen E.; ''Ebselen sensitizes glioblastoma cells to Tumor Necrosis Factor (TNFalpha)-induced apoptosis through two distinct pathways involving NF-kappaB downregulation and Fas-mediated formation of death inducing signaling complex.''; PubMed Europe PMC Scholia
  15. Hengartner MO.; ''The biochemistry of apoptosis.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114842view16:34, 25 January 2021ReactomeTeamReactome version 75
113288view11:35, 2 November 2020ReactomeTeamReactome version 74
112500view15:45, 9 October 2020ReactomeTeamReactome version 73
101412view11:29, 1 November 2018ReactomeTeamreactome version 66
100950view21:06, 31 October 2018ReactomeTeamreactome version 65
100487view19:40, 31 October 2018ReactomeTeamreactome version 64
100032view16:23, 31 October 2018ReactomeTeamreactome version 63
99585view14:57, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99207view12:43, 31 October 2018ReactomeTeamreactome version 62
94026view13:52, 16 August 2017ReactomeTeamreactome version 61
93646view11:29, 9 August 2017ReactomeTeamreactome version 61
87150view18:56, 18 July 2016MkutmonOntology Term : 'FasL mediated signaling pathway' added !
86762view09:25, 11 July 2016ReactomeTeamreactome version 56
83458view12:27, 18 November 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)
FADD ProteinQ13158 (Uniprot-TrEMBL)
FADDProteinQ13158 (Uniprot-TrEMBL)
FAS ProteinP25445 (Uniprot-TrEMBL)
FASL:FAS

Receptor

Trimer:FADD:pro-Caspase-10		ComplexR-HSA-141315 (Reactome)
FASL:FAS trimer:FADD:CASP8(1-479)ComplexR-HSA-75114 (Reactome)
FASL:FAS Receptor Trimer:FADDComplexR-HSA-43124 (Reactome)
FASL:FAS Receptor TrimerComplexR-HSA-76195 (Reactome)
FASL:FAS Receptor monomerComplexR-HSA-76564 (Reactome)
FASLG(1-281) ProteinP48023 (Uniprot-TrEMBL)
FASLG(1-281)ProteinP48023 (Uniprot-TrEMBL)
FASProteinP25445 (Uniprot-TrEMBL)
Ligand-dependent caspase activationPathwayR-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].

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
CASP10(1-521)R-HSA-141310 (Reactome)
CASP8(1-479)R-HSA-83586 (Reactome)
FADDR-HSA-83650 (Reactome)
FASL:FAS

Receptor

Trimer:FADD:pro-Caspase-10		ArrowR-HSA-141310 (Reactome)
FASL:FAS trimer:FADD:CASP8(1-479)ArrowR-HSA-83586 (Reactome)
FASL:FAS Receptor Trimer:FADDArrowR-HSA-83650 (Reactome)
FASL:FAS Receptor Trimer:FADDR-HSA-141310 (Reactome)
FASL:FAS Receptor Trimer:FADDR-HSA-83586 (Reactome)
FASL:FAS Receptor TrimerArrowR-HSA-71050 (Reactome)
FASL:FAS Receptor TrimerR-HSA-83650 (Reactome)
FASL:FAS Receptor monomerArrowR-HSA-75244 (Reactome)
FASL:FAS Receptor monomerR-HSA-71050 (Reactome)
FASLG(1-281)R-HSA-75244 (Reactome)
FASR-HSA-75244 (Reactome)
R-HSA-141310 (Reactome) FADD recruits caspase-10 precursor (pro-caspase-10) to FASL:FAS receptor trimer (Wang et al. 2001, Sprick et al. 2002).
R-HSA-71050 (Reactome) The complex of FASL (FAS antigen ligand) and FAS receptor (CD95) trimerizes (Kischkel et al. 1995).
R-HSA-75244 (Reactome) FASL (FAS antigen ligand) binds FAS receptor (CD95) (Brunner et al. 1995).
R-HSA-83586 (Reactome) Caspase-8 precursor (Pro-Caspase-8, also known as MACH) binds the complex of FADD and FASL:FAS receptor trimer (Boldin et al. 1996).
R-HSA-83650 (Reactome) FADD (FAS-associating death domain-containing) protein binds FASL:FAS receptor trimer through interaction of death domains of FADD and FAS (Boldin et al. 1995).
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