Caspase activation via death receptors in the presence of ligand (Homo sapiens)

From WikiPathways

Revision as of 10:55, 18 November 2015 by ReactomeTeam (Talk | contribs)
Jump to: navigation, search
5, 8, 23, 24, 2919, 33, 374, 9, 13, 351, 5, 11, 12, 22...4, 25, 31, 343, 235, 28, 385, 22, 245, 16, 21, 26, 382, 14, 17, 22, 31...endosomecytosolFASLG(1-281) FASLG(1-281) activatedTLR3/TLR4:TRIF:RIP1:FADD:pro-caspase-8viral dsRNA CFLAR(377-480)CASP8(1-479) CASP8(385-479) TRADD TLR4 CASP8(1-479) FAS FADD TNFRSF10A FASL:FASreceptortrimer:FADD:procaspase-8-dimerCASP8(1-479) TRADD FADD TNFSF10:TNFRSF10A,B:FADD:2xCASP8(1-479)TLR3 TICAM1 TNFRSF10B FADD TICAM1 FAS FADD TICAM1 LY96 FASL:FASReceptorTrimer:FADD:pro-Caspase-8:FLIP(L)TNFRSF10A active caspase-8CASP8(1-479) FADD FADD FADD GPIN-CD14(20-345) CASP8(1-479) LY96 RIPK1 FAS RIPK1 CFLAR(1-480) TRAF2 TNFRSF10A TRAF2 TICAM1 TRADD TNFRSF10B TRAF2:TRADD:RIP1:FADD:2xCASP8(1-479)RIPK1 TNFRSF10A CASP8(1-479) CASP8(1-479) FAS TNFSF10 FASLG(1-281) FAS CFLAR(1-480) DISC:procaspase-8:FLIP(L)FADD TLR3 FADD LPS DISC:procaspase-8-dimerCFLAR(1-480)TNFRSF10B TNFRSF10B TNFSF10 FAS FADD TNFSF10 MyrG-p-S16-TICAM2 CASP8(217-374) TNFSF10 RIPK1 TNFSF10 CFLAR(1-376) FADD TLR4 TRAF2 TNFSF10:TNFRSF10A,B:FADD:CASP8(1-479):CFLARFADD MyD88-independentTLR3/TLR4 cascade TRADD TNFRSF10B CASP8(1-479) viral dsRNA TNFRSF10A RIPK1 RIPK1(325-671) MC159 CASP8(1-479)TNFRSF10B FAS MyrG-p-S16-TICAM2 TRADD DISC:p43/p41CASP8:p43 FLIP(L)TNFSF10 CASP8(1-479) TRADD TRADD:TRAF2:RIP1:FADD:procaspase-8:FLIP(L)FASLG(1-281) CASP8(1-479) TNFRSF10B FADD ORF71 viral c-FLIPhomologueFASLG(1-281) CFLAR(1-480) CASP8(1-479) Death ReceptorSignallingFLIP(S)LPS TNFRSF10A TRAF2 TNFSF10:TNFRSF10A,B:FADD:CASP8(1-479)CASP8(1-479) FASLG(1-281) CASP8(1-374) TRADD:TRAF2:RIP1:FADD:CASP8(1-479)RIPK1 TNFSF10 FADD RIPK1 TNFRSF10A RIPK1 TRADD activatedTLR3/TLR4:TRIF:RIP1:FADDDISCCFLAR(1-480) FASL:FAStrimer:FADD:CASP8(1-479)FADD TRAF2 GPIN-CD14(20-345) FASLG(1-281) TRAF2 TRAF2 101010101032206, 3010107, 203, 1828101, 11, 12, 151010361010101, 121010


Description

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]. View original pathway at:Reactome.</div>

Try the New WikiPathways

View approved pathways at the new wikipathways.org.

Quality Tags

Ontology Terms

 

Bibliography

View all...
  1. Boatright KM, Salvesen GS.; ''Mechanisms of caspase activation.''; PubMed Europe PMC Scholia
  2. Kataoka T, Budd RC, Holler N, Thome M, Martinon F, Irmler M, Burns K, Hahne M, Kennedy N, Kovacsovics M, Tschopp J.; ''The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways.''; PubMed Europe PMC Scholia
  3. 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
  4. Gangloff M, Gay NJ.; ''MD-2: the Toll 'gatekeeper' in endotoxin signalling.''; PubMed Europe PMC Scholia
  5. Micheau O, Thome M, Schneider P, Holler N, Tschopp J, Nicholson DW, Briand C, Grütter MG.; ''The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex.''; PubMed Europe PMC Scholia
  6. 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
  7. Cusson-Hermance N, Khurana S, Lee TH, Fitzgerald KA, Kelliher MA.; ''Rip1 mediates the Trif-dependent toll-like receptor 3- and 4-induced NF-{kappa}B activation but does not contribute to interferon regulatory factor 3 activation.''; PubMed Europe PMC Scholia
  8. Chang DW, Xing Z, Capacio VL, Peter ME, Peter ME, Yang X.; ''Interdimer processing mechanism of procaspase-8 activation.''; PubMed Europe PMC Scholia
  9. Pop C, Oberst A, Drag M, Van Raam BJ, Riedl SJ, Green DR, Salvesen GS.; ''FLIP(L) induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity.''; PubMed Europe PMC Scholia
  10. Hughes MA, Harper N, Butterworth M, Cain K, Cohen GM, MacFarlane M.; ''Reconstitution of the death-inducing signaling complex reveals a substrate switch that determines CD95-mediated death or survival.''; PubMed Europe PMC Scholia
  11. Vittori D, Vota D, Callero M, Chamorro ME, Nesse A.; ''c-FLIP is involved in erythropoietin-mediated protection of erythroid-differentiated cells from TNF-alpha-induced apoptosis.''; PubMed Europe PMC Scholia
  12. 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
  13. Scaffidi C, Schmitz I, Krammer PH, Peter ME.; ''The role of c-FLIP in modulation of CD95-induced apoptosis.''; PubMed Europe PMC Scholia
  14. 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
  15. Fricker N, Beaudouin J, Richter P, Eils R, Krammer PH, Lavrik IN.; ''Model-based dissection of CD95 signaling dynamics reveals both a pro- and antiapoptotic role of c-FLIPL.''; PubMed Europe PMC Scholia
  16. Seal S, Hockenbery DM, Spaulding EY, Kiem HP, Abbassi N, Deeg HJ.; ''Differential responses of FLIPLong and FLIPShort-overexpressing human myeloid leukemia cells to TNF-alpha and TRAIL-initiated apoptotic signals.''; PubMed Europe PMC Scholia
  17. Keller N, Mares J, Zerbe O, Grütter MG.; ''Structural and biochemical studies on procaspase-8: new insights on initiator caspase activation.''; PubMed Europe PMC Scholia
  18. Yerbes R, Palacios C, Reginato MJ, López-Rivas A.; ''Cellular FLIP(L) plays a survival role and regulates morphogenesis in breast epithelial cells.''; PubMed Europe PMC Scholia
  19. 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
  20. Keller N, Grütter MG, Zerbe O.; ''Studies of the molecular mechanism of caspase-8 activation by solution NMR.''; PubMed Europe PMC Scholia
  21. Wang L, Du F, Wang X.; ''TNF-alpha induces two distinct caspase-8 activation pathways.''; PubMed Europe PMC Scholia
  22. Feoktistova M, Geserick P, Kellert B, Dimitrova DP, Langlais C, Hupe M, Cain K, MacFarlane M, Häcker G, Leverkus M.; ''cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms.''; PubMed Europe PMC Scholia
  23. Donepudi M, Mac Sweeney A, Briand C, Grütter MG.; ''Insights into the regulatory mechanism for caspase-8 activation.''; PubMed Europe PMC Scholia
  24. Watt W, Koeplinger KA, Mildner AM, Heinrikson RL, Tomasselli AG, Watenpaugh KD.; ''The atomic-resolution structure of human caspase-8, a key activator of apoptosis.''; PubMed Europe PMC Scholia
  25. Kreuz S, Siegmund D, Rumpf JJ, Samel D, Leverkus M, Janssen O, Häcker G, Dittrich-Breiholz O, Kracht M, Scheurich P, Wajant H.; ''NFkappaB activation by Fas is mediated through FADD, caspase-8, and RIP and is inhibited by FLIP.''; PubMed Europe PMC Scholia
  26. Siegmund D, Mauri D, Peters N, Juo P, Thome M, Reichwein M, Blenis J, Scheurich P, Tschopp J, Wajant H.; ''Fas-associated death domain protein (FADD) and caspase-8 mediate up-regulation of c-Fos by Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) via a FLICE inhibitory protein (FLIP)-regulated pathway.''; PubMed Europe PMC Scholia
  27. Ashkenazi A, Dixit VM.; ''Death receptors: signaling and modulation.''; PubMed Europe PMC Scholia
  28. 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
  29. Kataoka T, Tschopp J.; ''N-terminal fragment of c-FLIP(L) processed by caspase 8 specifically interacts with TRAF2 and induces activation of the NF-kappaB signaling pathway.''; PubMed Europe PMC Scholia
  30. Kalai M, Van Loo G, Vanden Berghe T, Meeus A, Burm W, Saelens X, Vandenabeele P.; ''Tipping the balance between necrosis and apoptosis in human and murine cells treated with interferon and dsRNA.''; PubMed Europe PMC Scholia
  31. 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
  32. Kaiser WJ, Offermann MK.; ''Apoptosis induced by the toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motif.''; PubMed Europe PMC Scholia
  33. Micheau O, Tschopp J.; ''Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.''; PubMed Europe PMC Scholia
  34. Yu JW, Jeffrey PD, Shi Y.; ''Mechanism of procaspase-8 activation by c-FLIPL.''; PubMed Europe PMC Scholia
  35. 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
  36. Rushworth SA, Taylor A, Langa S, MacEwan DJ.; ''TNF signaling gets FLIPped off: TNF-induced regulation of FLIP.''; PubMed Europe PMC Scholia
  37. Sharp DA, Lawrence DA, Ashkenazi A.; ''Selective knockdown of the long variant of cellular FLICE inhibitory protein augments death receptor-mediated caspase-8 activation and apoptosis.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
117671view11:59, 22 May 2021EweitzModified title
114773view16:26, 25 January 2021ReactomeTeamReactome version 75
113217view11:28, 2 November 2020ReactomeTeamReactome version 74
112441view15:38, 9 October 2020ReactomeTeamReactome version 73
101346view11:23, 1 November 2018ReactomeTeamreactome version 66
100884view20:57, 31 October 2018ReactomeTeamreactome version 65
100425view19:31, 31 October 2018ReactomeTeamreactome version 64
99974view16:15, 31 October 2018ReactomeTeamreactome version 63
99529view14:51, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93835view13:39, 16 August 2017ReactomeTeamreactome version 61
93390view11:22, 9 August 2017ReactomeTeamreactome version 61
87868view12:09, 25 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86476view09:19, 11 July 2016ReactomeTeamreactome version 56
83347view10:55, 18 November 2015ReactomeTeamVersion54
81505view13:02, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
CASP8(1-374) ProteinQ14790 (Uniprot-TrEMBL)
CASP8(1-479) ProteinQ14790 (Uniprot-TrEMBL)
CASP8(1-479)ProteinQ14790 (Uniprot-TrEMBL)
CASP8(217-374) ProteinQ14790 (Uniprot-TrEMBL)
CASP8(385-479) ProteinQ14790 (Uniprot-TrEMBL)
CFLAR(1-376) ProteinO15519-1 (Uniprot-TrEMBL)
CFLAR(1-480) ProteinO15519-1 (Uniprot-TrEMBL)
CFLAR(1-480)ProteinO15519-1 (Uniprot-TrEMBL)
CFLAR(377-480)ProteinO15519-1 (Uniprot-TrEMBL)
DISC:p43/p41CASP8:p43 FLIP(L)ComplexR-HSA-3465431 (Reactome)
DISC:procaspase-8-dimerComplexR-HSA-2671813 (Reactome)
DISC:procaspase-8:FLIP(L)ComplexR-HSA-3371381 (Reactome)
DISCComplexR-HSA-2671814 (Reactome)
Death Receptor SignallingPathwayR-HSA-73887 (Reactome) The death receptors, all cell-surface receptors, begin the process of caspase activation. The common feature of these type 1 transmembrane proteins is the "death-domain" a conserved cytoplasmic motif found on all of the three receptors (FAS/CD95, TNF-receptor, and TRAIL-receptor) that binds the Fas-associated protein with death domain (FADD). Ligand binding to death receptors (DR) results in receptor oligomerization and recruitment of adaptor proteins via homophilic interaction of death domains. This project describes an assembly of the death-inducing signaling complex (DISC) and shows protein composition and stoichiometry within the DISC. It also provides the appropriate literature references if available. However, the DISC signaling complex may vary in its components stoichiometry. DR signaling may trigger formation of higher order receptor structures or signaling through rearrangement of receptor chains, which is not reflected here.
FADD ProteinQ13158 (Uniprot-TrEMBL)
FAS ProteinP25445 (Uniprot-TrEMBL)
FASL:FAS

Receptor

Trimer:FADD:pro-Caspase-8:FLIP(L)		ComplexR-HSA-3465499 (Reactome)
FASL:FAS

receptor

trimer:FADD:procaspase-8-dimer		ComplexR-HSA-2671811 (Reactome)
FASL:FAS trimer:FADD:CASP8(1-479)ComplexR-HSA-75114 (Reactome)
FASLG(1-281) ProteinP48023 (Uniprot-TrEMBL)
FLIP(S)ProteinO15519-2 (Uniprot-TrEMBL)
GPIN-CD14(20-345) ProteinP08571 (Uniprot-TrEMBL)
LPS MetaboliteCHEBI:16412 (ChEBI)
LY96 ProteinQ9Y6Y9 (Uniprot-TrEMBL)
MC159 ProteinQ98325 (Uniprot-TrEMBL)
MyD88-independent TLR3/TLR4 cascade PathwayR-HSA-166166 (Reactome) MyD88-independent signaling pathway is shared by TLR3 and TLR4 cascades. TIR-domain-containing adapter-inducing interferon-beta (TRIF or TICAM1) is a key adapter molecule in transducing signals from TLR3 and TLR4 in a MyD88-independent manner (Yamamoto M et al. 2003a). TRIF is recruited to ligand-stimulated TLR3 or 4 complex via its TIR domain. TLR3 directly binds TRIF (Oshiumi H et al 2003). In contrast, TLR4-mediated signaling pathway requires two adapter molecules, TRAM (TRIF-related adapter molecule or TICAM2) and TRIF. TRAM(TICAM2) is thought to bridge between the activated TLR4 complex and TRIF (Yamamoto M et al. 2003b, Tanimura N et al. 2008, Kagan LC et al. 2008).

TRIF recruitment to TLR complex stimulates distinct pathways leading to production of type 1 interferons (IFNs), pro-inflammatory cytokines and induction of programmed cell death.

MyrG-p-S16-TICAM2 ProteinQ86XR7 (Uniprot-TrEMBL)
ORF71 ProteinQ76RF1 (Uniprot-TrEMBL)
RIPK1 ProteinQ13546 (Uniprot-TrEMBL)
RIPK1(325-671) ProteinQ13546 (Uniprot-TrEMBL)
TICAM1 ProteinQ8IUC6 (Uniprot-TrEMBL)
TLR3 ProteinO15455 (Uniprot-TrEMBL)
TLR4 ProteinO00206 (Uniprot-TrEMBL)
TNFRSF10A ProteinO00220 (Uniprot-TrEMBL)
TNFRSF10B ProteinO14763 (Uniprot-TrEMBL)
TNFSF10 ProteinP50591 (Uniprot-TrEMBL)
TNFSF10:TNFRSF10A,B:FADD:2xCASP8(1-479)ComplexR-HSA-2671816 (Reactome)
TNFSF10:TNFRSF10A,B:FADD:CASP8(1-479):CFLARComplexR-HSA-3371390 (Reactome)
TNFSF10:TNFRSF10A,B:FADD:CASP8(1-479)ComplexR-HSA-5637468 (Reactome)
TRADD ProteinQ15628 (Uniprot-TrEMBL)
TRADD:TRAF2:RIP1:FADD:CASP8(1-479)ComplexR-HSA-140976 (Reactome)
TRADD:TRAF2:RIP1:FADD:procaspase-8:FLIP(L)ComplexR-HSA-3465532 (Reactome)
TRAF2 ProteinQ12933 (Uniprot-TrEMBL)
TRAF2:TRADD:RIP1:FADD:2xCASP8(1-479)ComplexR-HSA-2671812 (Reactome)
activated TLR3/TLR4:TRIF:RIP1:FADD:pro-caspase-8ComplexR-HSA-2562542 (Reactome)
activated TLR3/TLR4:TRIF:RIP1:FADDComplexR-HSA-2562577 (Reactome)
active caspase-8ComplexR-HSA-2562550 (Reactome)
viral c-FLIP homologueComplexR-HSA-R-MCV-2671796 (Reactome)
viral dsRNA R-VIR-6790593 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
CASP8(1-479)R-HSA-141156 (Reactome)
CASP8(1-479)R-HSA-141159 (Reactome)
CASP8(1-479)R-HSA-73945 (Reactome)
CFLAR(1-480)R-HSA-3371359 (Reactome)
CFLAR(1-480)R-HSA-3371360 (Reactome)
CFLAR(1-480)R-HSA-3465459 (Reactome)
CFLAR(377-480)ArrowR-HSA-3465448 (Reactome)
DISC:p43/p41CASP8:p43 FLIP(L)ArrowR-HSA-3465448 (Reactome)
DISC:procaspase-8-dimerR-HSA-139952 (Reactome)
DISC:procaspase-8:FLIP(L)R-HSA-3465448 (Reactome)
DISCArrowR-HSA-139952 (Reactome)
FASL:FAS

Receptor

Trimer:FADD:pro-Caspase-8:FLIP(L)		ArrowR-HSA-3465459 (Reactome)
FASL:FAS

receptor

trimer:FADD:procaspase-8-dimer		ArrowR-HSA-73945 (Reactome)
FASL:FAS trimer:FADD:CASP8(1-479)R-HSA-3465459 (Reactome)
FASL:FAS trimer:FADD:CASP8(1-479)R-HSA-73945 (Reactome)
FLIP(S)TBarR-HSA-141156 (Reactome)
FLIP(S)TBarR-HSA-141159 (Reactome)
FLIP(S)TBarR-HSA-73945 (Reactome)
R-HSA-139952 (Reactome) Caspase-8 zymogens are present in the cells as inactive monomers, containing a large N-terminal prodomain with two death effector domains (DED), and a C-terminal catalytic subunit composed of small and a large domains separated by a smaller linker region [Donepudi M et al 2003; Keller N et al 2009]. Dimerization is required for the caspase-8 activation [Donepudi M et al 2003]. Once dimerized, caspase-8 zymogen undergoes a series of autoproteolytic cleavage events at aspartic acid residues in their interdomain linker regions. A second cleavage event between the the N-terminal prodomain and the catalytic domain releases the active caspase from the activation complex into the cytosol. The resulting fully active enzyme is a homodimer of catalytic domains, where each domain is composed of a large p18 and a small p10 subunit [Keller N et al 2009; Oberst A et al 2010].
R-HSA-141156 (Reactome) Monomeric caspase-8 zymogens undergo dimerization and subsequent conformational changes at the TRAIL:TRAIL receptor-2:FADD receptor complex leading to the formation of the catalytically active form of procaspase-8.
R-HSA-141159 (Reactome) Monomeric caspase-8 zymogens undergo dimerization and subsequent conformational changes at the TRADD:TRAF2:RIP1:FADD:Capase-8 receptor complex leading to the formation of the catalytically active form of procaspase-8.
R-HSA-2562564 (Reactome) TLR3/4 signaling component were shown to mediate apoptosis in various human cell lines in the FADD:caspasse-8-dependent manner [Kalai M et al 2002; Kaiser WJ and Offermann MK 2005; Estornes Y et al 2012]. Caspase-8 zymogens (procaspase-8) are present in the cells as inactive monomers, containing a large N-terminal prodomain with two death effector domains (DED), and a C-terminal catalytic subunit composed of small and a large domains separated by a smaller linker region [Donepudi M et al 2003; Keller N et al 2009]. Dimerization is required for caspase-8 activation [Donepudi M et al 2003]. The dimerization event occurs at the receptor signaling complex. Once dimerized, caspase-8 zymogen undergoes a series of autoproteolytic cleavage events at aspartic acid residues in their interdomain linker regions. A second cleavage event between the the N-terminal prodomain and the catalytic domain releases the active caspase from the activation complex into the cytosol. The resulting fully active enzyme is a homodimer of catalytic domains, where each domain is compsed of a large p18 and a small p10 subunit [Keller N et al 2009; Oberst A et al 2010].
R-HSA-3371359 (Reactome) Pro-caspase-8 and FLIP(L) are recruited to the DISC. Following recruitment to the DISC, FLIP-L forms a heterodimer with caspase-8 through both death effector domain (DED) and caspase-like domain (CLD). In addition, FLIP(L) can also regulate signaling via interaction with the DED of FADD. The regulatory function of FLIP(L) has been found to differ depending on its expression levels. FLIP(L) was shown to inhibit death receptor (DR)-mediated apoptosis only when expressed at high levels, while low cell levels of FLIP(L) enhanced DR signaling to apoptosis (Sharp DA et al. 2005; Siegmund D et al. 2002; Boatright KM et al. 2004; Okano H et al. 2003; Yerbes R et al. 2011). The expression levels of c-FLIP proteins were shown to be regulated by NFkappaB signaling pathway (Micheau O et a. 2001; Kreuz S et al 2001).
R-HSA-3371360 (Reactome) Following recruitment to the DISC, FLIP(L) forms a heterodimer with caspase-8 through both death effector domain (DED) and caspase-like domain (CLD). In addition, FLIP-L can also regulate TNF-R1 signaling via interaction with the DED of FADD. The regulatory function of FLIP(L) has been found to differ depending on its expression levels. c-FLIP was shown to inhibit death receptor (DR)-mediated apoptosis only when expressed at high levels, while low cell levels of FLIP(L) enhanced DR signaling to apoptosis (Boatright KM et al. 2004; Okano H et al. 2003; Yerbes R et al. 2011). The expression levels of c-FLIP proteins were shown to be regulated by NFkappaB signaling pathway (Micheau O et a. 2001; Kreuz S et al 2001).
R-HSA-3465448 (Reactome) In the presence of FLIP(L), both caspase-8 and FLIP(L) are recruited and partially processed at the death-inducing signaling complex (DISC). The partially processed proteins stay bound to the DISC.

The long cellular FLIP (FLIP(L) or c-FLIPL) has two death effector domains (DED) and a caspase-like domain that lacks catalytic activity due to absence of a cysteine residue. Processing of FLIP(L) occurs at the DISC and depends on caspase-8 activity (zymogen and mature form). Upon activation FLIP(L) is cleaved to generate N-terminal FLIP(p43) and C-terminal FLIP(p12)(Irmler M et al. 1997; Jong WY et al. 2009). Processed FLIP(L) can enhance the proteolytic activity of procaspase-8 (Chang DW et al. 2002; Jong WY et al. 2009; Pop C et al. 2011). However, the increased FLIP(L) protein levels in cells have been found to limit caspase-8 activity and inhibit apoptotic signaling pathway,

R-HSA-3465459 (Reactome) Pro-caspase-8 and FLIP(L) are recruited to FAS/CD95 receptor complex where FLIP(L) forms a heterodimer with caspase-8 through both death effector domain (DED) and caspase-like domain (CLD). In addition, FLIP(L) can also regulate signaling via interaction with the DED of FADD. The regulatory function of FLIP(L) has been found to differ depending on its expression levels. FLIP(L) was shown to inhibit death receptor (DR)-mediated apoptosis only when expressed at high levels, while low cell levels of FLIP-L enhanced DR signaling to apoptosis (Chang DW et al. 2002; Fricker N et al. 2010; Toivonen HT et al. 2011; Boatright KM et al. 2004; Okano H et al. 2003). The expression levels of c-FLIP proteins were shown to be regulated by NFkappaB signaling pathway (Micheau O et a. 2001; Kreuz S et al 2001).
R-HSA-73945 (Reactome) Monomeric caspase-8 zymogens undergo dimerization and subsequent conformational changes at the FASL:FAS Receptor Trimer:FADD:procaspase-8 receptor complex leading to the formation of the catalytically active form of procaspase-8.
TNFSF10:TNFRSF10A,B:FADD:2xCASP8(1-479)ArrowR-HSA-141156 (Reactome)
TNFSF10:TNFRSF10A,B:FADD:CASP8(1-479):CFLARArrowR-HSA-3371359 (Reactome)
TNFSF10:TNFRSF10A,B:FADD:CASP8(1-479)R-HSA-141156 (Reactome)
TNFSF10:TNFRSF10A,B:FADD:CASP8(1-479)R-HSA-3371359 (Reactome)
TRADD:TRAF2:RIP1:FADD:CASP8(1-479)R-HSA-141159 (Reactome)
TRADD:TRAF2:RIP1:FADD:CASP8(1-479)R-HSA-3371360 (Reactome)
TRADD:TRAF2:RIP1:FADD:procaspase-8:FLIP(L)ArrowR-HSA-3371360 (Reactome)
TRAF2:TRADD:RIP1:FADD:2xCASP8(1-479)ArrowR-HSA-141159 (Reactome)
activated TLR3/TLR4:TRIF:RIP1:FADD:pro-caspase-8R-HSA-2562564 (Reactome)
activated TLR3/TLR4:TRIF:RIP1:FADD:pro-caspase-8mim-catalysisR-HSA-2562564 (Reactome)
activated TLR3/TLR4:TRIF:RIP1:FADDArrowR-HSA-2562564 (Reactome)
active caspase-8ArrowR-HSA-139952 (Reactome)
active caspase-8ArrowR-HSA-2562564 (Reactome)
active caspase-8mim-catalysisR-HSA-139952 (Reactome)
active caspase-8mim-catalysisR-HSA-3465448 (Reactome)
viral c-FLIP homologueTBarR-HSA-139952 (Reactome)

Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP3358"
Personal tools