CFLAR encodes c-FLIP, a catalytically inactive caspase-8-like regulator of death-effector-domain signaling complexes. Tandem death effector domains recruit c-FLIP isoforms to FADD-, CASP8-, and CASP10-containing death-inducing signaling complexes, TNFR1 complex II, and ripoptosomes, where c-FLIP sets the amount and substrate selectivity of initiator-caspase activity. Long c-FLIP(L) additionally carries a pseudo-caspase domain that heterodimerizes with CASP8 or CASP10 to permit limited catalytic activity such as RIPK1 cleavage, whereas short c-FLIP isoforms cap DED filaments and block full CASP8 activation. Through these interactions, CFLAR restrains FAS, TNF, and TRAIL extrinsic apoptosis and modulates the switch between CASP8-dependent apoptosis and RIPK1/RIPK3/MLKL-dependent necroptosis.
Curated functional classes representing distinct biological activities. These may be splice variants, cleavage products, or other forms with different functions.
CFLAR_FLIPLCFLAR_FLIPS| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001666 response to hypoxia | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The hypoxia-response row is a rat Compara transfer and describes a distal stimulus phenotype, not a direct human c-FLIP activity. Reason: CFLAR may change or be required under stress contexts, but the supported molecular role is DED-mediated control of CASP8-containing death complexes. |
| GO:0002020 protease binding | IEA GO_REF:0000107 | MODIFY | Summary: The Compara row captures c-FLIP binding to caspase-like partners but the informative activity is DED-mediated recruitment of CASP8/CASP10 into death-effector assemblies. Reason: CFLAR binds initiator caspases through tandem death effector domains rather than acting as a generic protease-binding factor. Proposed replacements: death effector domain binding |
| GO:0002020 protease binding | IPI PMID:9208847 Casper is a FADD- and caspase-related inducer of apoptosis. | KEEP AS NON CORE | Summary: The original Casper paper reports a direct CASP3 interaction, but that executioner-caspase interaction is not the core receptor-proximal c-FLIP activity. Reason: CASP3 lacks a DED, so GO:0002020 is imprecise but not safely replaceable by death effector domain binding. |
| GO:0002020 protease binding | IPI PMID:9208847 Casper is a FADD- and caspase-related inducer of apoptosis. | MODIFY | Summary: The CASP8 protease-binding row should be narrowed to DED-mediated binding of an initiator caspase. Reason: CASP8 and c-FLIP assemble through tandem death effector domains in DISC and complex-II platforms. Proposed replacements: death effector domain binding Supporting Evidence: PMID:9217161 interact with the adaptor protein FADD PMID:38710704 human FADD-procaspase-8-cFLIP complexes |
| GO:0004197 cysteine-type endopeptidase activity | IBA GO_REF:0000033 | REMOVE | Summary: The PAINT cysteine endopeptidase activity row propagates active-caspase catalysis across a family that includes the catalytically inactive c-FLIP paralog. Reason: Human c-FLIP retains a caspase-like domain but lacks the catalytic active-site residues required for cysteine endopeptidase activity. Current PAINT places an IRD (NOT) for this term at PTN000047958 (2026-08-28), the mammalian CFLAR clade, so this IBA is no longer propagated by PAINT and remains only in the cached GOA file. The IRD agrees with this verdict. Propagation Review Root cause: PROPAGATION BAD Failure modes: PSEUDO OR SUBACTIVITY LOSS Sources checked: PANTHER:PTN000047947 SUPPORTS SOURCE BUT NOT TARGET Active-caspase cysteine endopeptidase activity was placed above catalytically dead CFLAR. Supporting Evidence: PMID:9208847 Casper is not a caspase |
| GO:0004197 cysteine-type endopeptidase activity | IEA GO_REF:0000002 | REMOVE | Summary: The InterPro2GO peptidase mapping follows the caspase fold and misses the CFLAR-specific loss of catalytic residues. Reason: CFLAR is a pseudocaspase-like regulator and should not inherit cysteine endopeptidase activity from active C14-family caspases. Supporting Evidence: PMID:9208847 Casper is not a caspase |
| GO:0005123 death receptor binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: c-FLIP is recruited to death-receptor complexes through FADD and CASP8/CASP10 DED interactions rather than direct death-domain receptor binding. Reason: The row is transferred from the rodent ortholog, annotated from a physical-interaction experiment in a study showing that Fas ligand, Fas and death-inducing signaling complex proteins are recruited to membrane rafts after spinal cord injury (IPI, PMID:17518537). Recovery of c-FLIP with Fas in such a complex is a real observation, but c-FLIP is recruited to the DISC through death effector domain interactions with FADD and caspase-8 rather than by contacting the receptor itself, and no direct binding to FAS, TNFR1, DR4 or DR5 has been shown. Death receptor binding therefore over-reads co-recruitment into the complex. |
| GO:0005515 protein binding | IPI PMID:11741985 Identification and characterization of DEDD2, a death effect... | REMOVE | Summary: The DEDD2-FLIP paper supports a physical interaction but not a useful c-FLIP molecular-function annotation. Reason: The abstract does not show that the DEDD2 edge is a core CFLAR function or expose the interaction domain, so the generic GO:0005515 import should be removed. |
| GO:0005515 protein binding | IPI PMID:12887920 Induction of TNF receptor I-mediated apoptosis via two seque... | MODIFY | Summary: TNFR1 complex II contains FADD, CASP8, and c-FLIP(L); the generic CASP8 protein-binding edge is better represented as DED binding. Reason: The cached abstract supports c-FLIP(L) in the CASP8-containing TNFR1 complex II, and DED binding is the specific activity used to assemble this complex. Proposed replacements: death effector domain binding Supporting Evidence: PMID:9217161 interact with the adaptor protein FADD PMID:38710704 human FADD-procaspase-8-cFLIP complexes |
| GO:0005515 protein binding | IPI PMID:12887920 Induction of TNF receptor I-mediated apoptosis via two seque... | UNDECIDED | Summary: The cached TNFR1 complex-II abstract exposes FLIP(L) and CASP8 but not the individual CASP10-cFLIP interaction imported by IntAct. Reason: Without the full text, the CASP10 edge cannot be confidently accepted, rejected, or narrowed. |
| GO:0005515 protein binding | IPI PMID:17047155 Caspase-8 prevents sustained activation of NF-kappaB in mono... | MODIFY | Summary: The M-CSF-induced monocyte complex contains CASP8, FADD, RIPK1, and long FLIP; the direct c-FLIP molecular function is DED binding. Reason: This is a noncanonical differentiation-associated CASP8 complex rather than the core death-receptor DISC, but the partner-specific interaction is compatible with DED-mediated CASP8 binding. Proposed replacements: death effector domain binding |
| GO:0005515 protein binding | IPI PMID:23541952 Control of autophagic cell death by caspase-10 in multiple m... | MODIFY | Summary: In myeloma, CASP10 and cFLIP(L) form a survival protease complex; the CASP10 edge is better captured as DED binding than bare protein binding. Reason: The row is not apoptosis-specific, but it reflects the same tandem-DED initiator-caspase binding mechanism. Proposed replacements: death effector domain binding |
| GO:0005515 protein binding | IPI PMID:24438025 Involvement of caspase 8 and c-FLIPL in the proangiogenic ef... | UNDECIDED | Summary: The TRAIL/HUVEC abstract mentions c-FLIP(L) expression and CASP8 processing but does not expose a specific CFLAR-CASP8 IPI assay. Reason: The full text or IntAct details are needed before replacing or rejecting this partner edge. |
| GO:0005515 protein binding | IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ... | UNDECIDED | Summary: The in situ proximity-ligation paper is a pathway-scale PPI survey; the cached abstract does not expose the individual CFLAR-CASP10 assay. Reason: The IntAct row may be valid, but the local evidence is too generic to adjudicate it. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: The Rolland interactome row is an uninformative high-throughput TRAF1 protein-binding edge. Reason: TRAF1 binding is not the core c-FLIP DED scaffold activity and the proteome-scale Y2H paper does not provide mechanistic CFLAR support in the cached text. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: The HuRI import is a generic high-throughput TRAF1 protein-binding edge with no mechanistic CFLAR support in the paper body. Reason: A broad interactome screen is not enough to keep a bare GO:0005515 assertion for c-FLIP. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: The BioPlex AP-MS import is a high-throughput CASP8 co-complex edge and should not be kept as bare protein binding. Reason: CASP8 binding is real c-FLIP biology, but this screen row adds no mechanistic detail beyond GO:0005515 and is redundant with direct FADD/CASP8/c-FLIP complex evidence. |
| GO:0005515 protein binding | IPI PMID:9208847 Casper is a FADD- and caspase-related inducer of apoptosis. | REMOVE | Summary: The original Casper abstract reports TRAF1 binding, but this peripheral generic PPI row adds no CFLAR molecular function. Reason: TRAF1 binding should not be kept as an unqualified GO:0005515 assertion in an apoptosis checkpoint review. |
| GO:0005515 protein binding | IPI PMID:9208847 Casper is a FADD- and caspase-related inducer of apoptosis. | MODIFY | Summary: FADD binding is mediated by death effector domain interactions and should not remain as unqualified protein binding. Reason: FADD-CASP8-cFLIP DED assembly is the central molecular interaction that positions c-FLIP in death-inducing signaling complexes. Proposed replacements: death effector domain binding Supporting Evidence: PMID:9217161 interact with the adaptor protein FADD PMID:38710704 human FADD-procaspase-8-cFLIP complexes |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: The HPA immunofluorescence row reports nucleoplasmic staining, a context outside the canonical cytosolic DISC/ripoptosome role. Reason: Cytosolic receptor-proximal complexes are c-FLIP core sites; the nucleoplasmic localization is kept as a non-core localization observation. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT cytoplasm transfer is consistent with cytosolic pools of c-FLIP that are recruited into FADD/CASP8 complexes. Reason: The row captures the major pre-recruitment compartment of CFLAR. |
| GO:0005737 cytoplasm | IDA PMID:18073330 NF-kappaB-dependent expression of the antiapoptotic factor c... | ACCEPT | Summary: The CAPN3/NF-kappaB paper is skeletal-muscle regulatory context, and the cytoplasmic localization itself is compatible with c-FLIP biology. Reason: Keep the cytoplasm localization as a true cellular-component assertion while treating the CAPN3/NF-kappaB muscle-expression biology as peripheral. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: The automated cytoplasm row from mouse c-FLIP agrees with the established cytosolic localization of human CFLAR. Reason: c-FLIP acts from the cytoplasm/cytosol before and during recruitment to DISC and complex-II assemblies. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: The HPA cytosol row matches the compartment where c-FLIP encounters FADD, CASP8, CASP10, and RIPK1-containing complexes. Reason: Cytosol is a core location for CFLAR function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3371359 | ACCEPT | Summary: Reactome places FLIP(L):CASP8 heterodimer formation in TRAIL signaling in the cytosol. Reason: This is a direct receptor-proximal c-FLIP complex relevant to extrinsic apoptosis. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3371360 | ACCEPT | Summary: Reactome places FLIP(L):CASP8 heterodimer formation in TNFR1 signaling in the cytosol. Reason: This is a direct c-FLIP checkpoint in TNFR1 complex-II signaling. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3465429 | ACCEPT | Summary: Reactome places the DED-only FLIP(S):CASP8 heterodimer in the cytosol. Reason: FLIP(S) is a core c-FLIP isoform that blocks DISC-dependent CASP8 activation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3465448 | ACCEPT | Summary: Reactome models CASP8-dependent FLIP(L) processing at the DISC in the cytosol. Reason: This captures the direct cleavage and retention of p43-FLIP(L) in the DISC. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3465459 | ACCEPT | Summary: Reactome places FLIP(L):CASP8 heterodimer formation in FAS/CD95 signaling in the cytosol. Reason: This is a direct c-FLIP complex in the FAS branch of extrinsic apoptosis. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5675456 | ACCEPT | Summary: Reactome models the generic cytosolic FLIP(L):CASP8 heterodimer that balances apoptosis and necroptosis. Reason: The event captures the shared c-FLIP/CASP8 checkpoint outside one receptor-specific branch. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9697747 | ACCEPT | Summary: Reactome places CASP8:FLIP(L) processing at the TNFR signaling complex in the cytosol. Reason: This event reflects direct c-FLIP regulation of CASP8 and RIPK1 signaling downstream of TNFR1. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9697750 | ACCEPT | Summary: Reactome models RIPK1 cleavage by the CASP8:FLIP(L) heterodimer in the cytosol. Reason: RIPK1 cleavage by the limited-activity CASP8:FLIP(L) complex restrains necroptosis. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9793988 | ACCEPT | Summary: Reactome places cytosolic CFLAR in CFLAR ubiquitination by LUBAC, a stability-control input rather than CFLAR execution of DISC signaling. Reason: The imported assertion is only cytosol, which is correct for this direct CFLAR regulatory event. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9794008 | ACCEPT | Summary: Reactome places cytosolic CFLAR in LUBAC binding to CFLAR, a regulatory interaction that stabilizes c-FLIP. Reason: The imported assertion is only cytosol, which is correct for this direct CFLAR regulatory event. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9796617 | ACCEPT | Summary: Reactome places cytosolic CFLAR in MIB2 binding to FLIP(L), a ubiquitin-ligase interaction that tunes c-FLIP stability. Reason: The imported assertion is only cytosol, which is correct for this direct CFLAR regulatory event. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9796626 | ACCEPT | Summary: Reactome places cytosolic CFLAR in MIB2-mediated CFLAR ubiquitination. Reason: The imported assertion is only cytosol, which is correct for this direct CFLAR regulatory event. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA plasma-membrane staining is compatible with c-FLIP recruitment to membrane-proximal DISCs but CFLAR is not a resident transmembrane receptor. Reason: Keep the localization as non-core while centering c-FLIP function on cytosolic DED assemblies. |
| GO:0006508 proteolysis | IEA GO_REF:0000002 | REMOVE | Summary: The InterPro proteolysis mapping is a false positive for catalytically inactive human c-FLIP. Reason: The caspase-like domain lacks the catalytic residues needed for endopeptidase-driven proteolysis. Supporting Evidence: PMID:9208847 Casper is not a caspase |
| GO:0006915 apoptotic process | IBA GO_REF:0000033 | MODIFY | Summary: The PAINT apoptotic-process row is too broad and inherits active-caspase family biology; CFLAR specifically regulates receptor-proximal extrinsic apoptosis. Reason: c-FLIP is a catalytically inactive DED scaffold that restrains and tunes FAS/TNF/TRAIL death-receptor signaling rather than directly executing generic apoptosis. Propagation Review Root cause: PROPAGATION BAD Failure modes: REGULATORY SIGN INVERSION ROLE CONFLATION Sources checked: PANTHER:PTN000047947 SUPPORTS SOURCE BUT NOT TARGET The node mixes active apoptotic caspases with the catalytically dead c-FLIP regulator. Proposed replacements: negative regulation of extrinsic apoptotic signaling pathway via death domain receptors |
| GO:0007519 skeletal muscle tissue development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Skeletal muscle tissue development is a distal mouse Cflar phenotype, not a direct human CFLAR pathway step. Reason: CFLAR may be required for muscle homeostasis through survival signaling, but the gene product itself acts at CASP8-containing death complexes. |
| GO:0007519 skeletal muscle tissue development | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: The ISS row transfers a mouse skeletal-muscle phenotype onto human CFLAR. Reason: This is too distal from the direct DED-mediated CASP8 checkpoint to keep as a core human process annotation. |
| GO:0008047 enzyme activator activity | IDA PMID:9208847 Casper is a FADD- and caspase-related inducer of apoptosis. | UNDECIDED | Summary: The original Casper abstract verifies binding and apoptotic effects but not a defined allosteric enzyme-activator activity. Reason: Because cached evidence is abstract-only and the original report used overexpression and mutant constructs, the GO:0008047 row should wait for full-text review rather than being mapped to FLIP(L)-specific CASP8 activation. |
| GO:0008047 enzyme activator activity | IEA GO_REF:0000117 | MODIFY | Summary: The ARBA row captures the CASP8-activating side of c-FLIP(L) but should name the relevant caspase class. Reason: FLIP(L) can promote limited initiator-caspase activation in heterodimers, so GO:0140608 is more specific than generic enzyme activator activity. Proposed replacements: cysteine-type endopeptidase activator activity |
| GO:0008234 cysteine-type peptidase activity | IEA GO_REF:0000002 | REMOVE | Summary: The InterPro cysteine-type peptidase mapping follows peptidase domains and should not apply to the inactive c-FLIP pseudoenzyme. Reason: CFLAR does not enable cysteine-type peptidase activity because its caspase-like domain is catalytically inactive. Supporting Evidence: PMID:9208847 Casper is not a caspase |
| GO:0008303 caspase complex | IPI PMID:38710704 Deciphering DED assembly mechanisms in FADD-procaspase-8-cFL... | ACCEPT | Summary: The 2024 structural work supports c-FLIP as a component of CASP8-containing DED complexes. Reason: ComplexPortal correctly captures CFLAR in a CASP8/FADD/c-FLIP caspase complex. |
| GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors | IBA GO_REF:0000033 | MODIFY | Summary: The PAINT extrinsic-apoptosis row should be directionally narrowed for c-FLIP. Reason: Unlike active CASP8, CFLAR is best curated as a DED scaffold that negatively regulates death-domain receptor apoptosis and helps gate CASP8 activation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: REGULATORY SIGN INVERSION ROLE CONFLATION Sources checked: PANTHER:PTN000047971 SUPPORTS SOURCE BUT NOT TARGET The CASP8-like source biology supports death-domain receptor complexes, but CFLAR is the regulatory c-FLIP pseudoenzyme rather than the active initiator caspase. Proposed replacements: negative regulation of extrinsic apoptotic signaling pathway via death domain receptors |
| GO:0010667 negative regulation of cardiac muscle cell apoptotic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The cardiac apoptotic row is a rodent Compara tissue phenotype downstream of c-FLIP survival functions. Reason: It does not name a direct human CFLAR biochemical step. |
| GO:0010976 positive regulation of neuron projection development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Neuron-projection development is a distal transferred phenotype and not a direct c-FLIP function. Reason: CFLAR should not be annotated to this developmental output without a proximal DED-complex mechanism. |
| GO:0014732 skeletal muscle atrophy | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Skeletal muscle atrophy is a distal mouse Cflar phenotype. Reason: The direct CFLAR function is receptor-proximal control of CASP8, not execution of muscle atrophy. |
| GO:0014732 skeletal muscle atrophy | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: The ISS skeletal muscle atrophy row transfers a mouse phenotype rather than a direct human c-FLIP process. Reason: This is outside the core apoptosis checkpoint mechanism. |
| GO:0014842 regulation of skeletal muscle satellite cell proliferation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Skeletal muscle satellite-cell proliferation is a downstream mouse phenotype. Reason: The row overstates a direct human CFLAR role in the proliferation process. |
| GO:0014842 regulation of skeletal muscle satellite cell proliferation | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: The ISS satellite-cell row is transferred from mouse Cflar phenotyping. Reason: The evidence is too distal for direct human CFLAR process annotation. |
| GO:0014866 skeletal myofibril assembly | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Skeletal myofibril assembly is a distal mouse phenotype. Reason: CFLAR does not assemble myofibrils directly. |
| GO:0014866 skeletal myofibril assembly | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: The ISS myofibril row transfers a downstream Cflar muscle phenotype to human CFLAR. Reason: This is an over-annotation relative to c-FLIP molecular function. |
| GO:0016504 peptidase activator activity | IEA GO_REF:0000107 | MODIFY | Summary: The mouse-derived peptidase-activator row should be narrowed to c-FLIP control of cysteine-type initiator caspases. Reason: The useful assertion is that c-FLIP can promote limited CASP8-family endopeptidase activity in heterodimers. Proposed replacements: cysteine-type endopeptidase activator activity |
| GO:0030225 macrophage differentiation | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: The PAINT macrophage-differentiation row appears to follow the active CASP8 subfamily and is not a core CFLAR process. Reason: c-FLIP can participate in atypical CASP8 complexes, but macrophage differentiation is too distal for CFLAR as a direct process annotation. Current PAINT places an IRD (NOT) for this term at PTN000047958 (2026-06-16), the mammalian CFLAR clade, so this IBA is no longer propagated by PAINT and remains only in the cached GOA file. The IRD agrees with this verdict. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION CONTEXT OR TISSUE MISMATCH Sources checked: PANTHER:PTN000047971 SUPPORTS SOURCE BUT NOT TARGET The active CASP8 macrophage-differentiation node should not be projected as a core process of catalytically inactive CFLAR. |
| GO:0031264 death-inducing signaling complex | IDA PMID:21803845 PMLRARΞ± binds to Fas and suppresses Fas-mediated apoptosis t... | ACCEPT | Summary: PML-RARA recruits c-FLIP(L/S) to a FAS death signaling complex. Reason: This supports CFLAR as part of a death-inducing signaling complex. |
| GO:0031264 death-inducing signaling complex | IEA GO_REF:0000107 | ACCEPT | Summary: The rat Compara death-inducing signaling complex row is consistent with conserved c-FLIP recruitment to FADD/CASP8 receptor complexes. Reason: DISC membership is a direct c-FLIP cellular component. |
| GO:0031265 CD95 death-inducing signaling complex | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT CD95 DISC membership is consistent with c-FLIP recruitment to the FAS death-inducing signaling complex. Reason: c-FLIP is a component of the CD95 death-inducing signaling complex: the CD95/TRAILR-FADD DISC assembles by DED assembly with procaspase-8 and cFLIP (PMID:38710704), and FAS/CD95 signaling is one of the core death-receptor branches c-FLIP regulates. Current PAINT places an IRD (NOT) for this term at PTN000047958 (2026-06-16), the mammalian CFLAR clade, so this IBA is no longer propagated by PAINT and remains only in the cached GOA file. The DISC evidence contradicts the IRD, so the ACCEPT stands and the IRD is listed in projects/IRD_EVIDENCE/PAINT_REPORT.md. Propagation Review Root cause: NO FAILURE CORE Supporting Evidence: PMID:38710704 The CD95/TRAILR-FADD receptor complex assembles the death-inducing signaling complex (DISC), or complex I, by homotypic death-effector domain (DED) assembly with procaspase-8 (Casp-8) and antiapoptotic cellular FLICE-inhibitory proteins (cFLIP) |
| GO:0031265 CD95 death-inducing signaling complex | IEA GO_REF:0000107 | ACCEPT | Summary: The Compara CD95 DISC row correctly transfers c-FLIP membership in FAS receptor-proximal DISCs. Reason: This is a direct complex annotation rather than a downstream survival phenotype. |
| GO:0032869 cellular response to insulin stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The insulin-stimulus row is a distal rat Compara transfer. Reason: It is not a direct human c-FLIP apoptotic checkpoint term. |
| GO:0033574 response to testosterone | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The testosterone-response row is a distal rat Compara transfer. Reason: The row does not identify direct CFLAR activity at a named receptor or CASP8 complex. |
| GO:0042981 regulation of apoptotic process | IEA GO_REF:0000002 | MODIFY | Summary: The InterPro DED-driven apoptosis row is too broad for human c-FLIP. Reason: CFLAR uses tandem DEDs to regulate the extrinsic branch rather than apoptosis in general. Proposed replacements: negative regulation of extrinsic apoptotic signaling pathway via death domain receptors |
| GO:0043066 negative regulation of apoptotic process | IEA GO_REF:0000107 | MODIFY | Summary: The Compara negative-apoptosis row is directionally correct but too generic. Reason: For c-FLIP the supported anti-apoptotic activity is receptor-proximal inhibition of extrinsic death-receptor signaling. Proposed replacements: negative regulation of extrinsic apoptotic signaling pathway via death domain receptors |
| GO:0043066 negative regulation of apoptotic process | TAS PMID:9217161 Inhibition of death receptor signals by cellular FLIP. | MODIFY | Summary: The original cellular FLIP paper specifically established inhibition of human death-receptor signals. Reason: GO:2001237 is more informative than the broad negative regulation of apoptotic process parent. Proposed replacements: negative regulation of extrinsic apoptotic signaling pathway via death domain receptors Supporting Evidence: PMID:9217161 potently inhibit apoptosis induced by all known human death PMID:22266862 overexpression of cFLIP(L) or cFLIP(S) significantly reduces MS275- |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IEP PMID:12761501 Large-scale identification and characterization of human gen... | KEEP AS NON CORE | Summary: CFLAR activated an NF-kappaB reporter in a large-scale cDNA screen, but this is not its core FADD/CASP8 checkpoint function. Reason: Retain the screen-backed signaling output as non-core pending receptor-specific mechanistic evidence. |
| GO:0043403 skeletal muscle tissue regeneration | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Skeletal muscle tissue regeneration is a distal mouse Cflar phenotype. Reason: The ISS/Compara muscle rows should not be treated as direct human CFLAR functions. |
| GO:0043403 skeletal muscle tissue regeneration | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: The ISS regeneration row transfers a mouse tissue phenotype to human CFLAR. Reason: This is downstream of survival signaling and outside direct c-FLIP function. |
| GO:0043525 positive regulation of neuron apoptotic process | IBA GO_REF:0000033 | REMOVE | Summary: The PAINT neuron-apoptosis row leaks active-caspase and neuronal outcome biology onto catalytically inactive c-FLIP. Reason: This sign- and context-mismatched transfer conflicts with CFLAR's principal death-receptor inhibitory role and is not supported by local human c-FLIP evidence. Current PAINT places an IRD (NOT) for this term at PTN000047958 (2026-06-16), the mammalian CFLAR clade, so this IBA is no longer propagated by PAINT and remains only in the cached GOA file. The IRD agrees with this verdict. Propagation Review Root cause: PROPAGATION BAD Failure modes: REGULATORY SIGN INVERSION ROLE CONFLATION CONTEXT OR TISSUE MISMATCH Sources checked: PANTHER:PTN000047947 SUPPORTS SOURCE BUT NOT TARGET The active-caspase neuronal-apoptosis assertion should not propagate to c-FLIP. |
| GO:0044877 protein-containing complex binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The protein-containing complex binding row is a generic rat Compara transfer. Reason: The row is transferred from the rodent ortholog, where it rests on a physical-interaction experiment showing c-FLIP recovered with the Fas death-inducing signaling complex (IPI, PMID:17518537). The claim is true of CFLAR, which joins the DISC and the ripoptosome through its death effector domains. The term is generic and the specific content is carried by the complex-membership and death effector domain binding annotations, so it is kept as non-core rather than removed. Supporting Evidence: PMID:17518537 forming a death-inducing signaling complex (DISC) |
| GO:0060544 regulation of necroptotic process | IEA GO_REF:0000117 | ACCEPT | Summary: Automated regulation of necroptosis agrees with c-FLIP isoforms gating RIPK1/CASP8/ripoptosome outcomes. Reason: FLIP(L) and FLIP(S) can push ripoptosome outputs in opposite directions, so the unsigned parent term is appropriate. Supporting Evidence: PMID:21737330 It contains RIP1, FADD, caspase-8, caspase-10 PMID:21737330 cFLIP(L) prevents Ripoptosome formation |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The ERK cascade row is a distal rat Compara transfer. Reason: CFLAR is not a core ERK activator in the death-receptor checkpoint module. |
| GO:0071364 cellular response to epidermal growth factor stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The EGF response row is a distal rat Compara transfer. Reason: The row is too far from c-FLIP DED-complex activity. |
| GO:0071392 cellular response to estradiol stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The estradiol response row is a distal rat Compara transfer. Reason: The direct human CFLAR function is not execution of estrogen-response signaling. |
| GO:0071456 cellular response to hypoxia | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The cellular hypoxia-response row is a rat Compara stimulus phenotype. Reason: It does not connect CFLAR to a proximal apoptotic step. |
| GO:0071549 cellular response to dexamethasone stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The dexamethasone-response row is a distal rat Compara transfer. Reason: CFLAR should not be directly annotated to this hormone response from indirect survival readouts. |
| GO:0071550 death-inducing signaling complex assembly | NAS PMID:38710704 Deciphering DED assembly mechanisms in FADD-procaspase-8-cFL... | ACCEPT | Summary: The 2024 structural paper directly supports DED assembly of FADD, procaspase-8, and c-FLIP complexes. Reason: c-FLIP is one of the DED components that orchestrate assembly of CASP8-containing death-inducing complexes. Supporting Evidence: PMID:9217161 interact with the adaptor protein FADD PMID:38710704 human FADD-procaspase-8-cFLIP complexes |
| GO:0071732 cellular response to nitric oxide | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The nitric-oxide response row is a distal rat Compara transfer. Reason: It does not describe the direct DED scaffold or CASP8 regulatory function of human c-FLIP. |
| GO:0072126 positive regulation of glomerular mesangial cell proliferation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The mesangial-cell proliferation row is a distal rat Compara phenotype. Reason: It should not be promoted to a direct human CFLAR process annotation. |
| GO:0097342 ripoptosome | IDA PMID:21737330 cIAPs block Ripoptosome formation, a RIP1/caspase-8 containi... | ACCEPT | Summary: The ripoptosome paper directly identified cFLIP isoforms in the RIP1/FADD/CASP8/CASP10 intracellular death complex. Reason: CFLAR is a bona fide ripoptosome component and controls whether the complex drives apoptosis or necroptosis. Supporting Evidence: PMID:21737330 It contains RIP1, FADD, caspase-8, caspase-10 PMID:21737330 cFLIP(L) prevents Ripoptosome formation |
| GO:1901740 negative regulation of myoblast fusion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Negative regulation of myoblast fusion is a distal mouse Cflar phenotype. Reason: The row is outside direct CFLAR action at CASP8-containing complexes. |
| GO:1901740 negative regulation of myoblast fusion | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: The ISS myoblast-fusion row transfers a downstream muscle-development phenotype. Reason: It over-annotates human CFLAR from mouse tissue phenotyping. |
| GO:1902042 negative regulation of extrinsic apoptotic signaling pathway via death domain receptors | IDA PMID:26582200 Lifeguard Inhibits Fas Ligand-mediated Endoplasmic Reticulum... | UNDECIDED | Summary: The cached Lifeguard abstract does not mention CFLAR or c-FLIP even though the GOA row is experimental. Reason: Do not overrule the MGI curator from the abstract alone; full-text verification is needed. |
| GO:1902042 negative regulation of extrinsic apoptotic signaling pathway via death domain receptors | IMP PMID:18202225 HO-1 underlies resistance of AML cells to TNF-induced apopto... | UNDECIDED | Summary: The cached HO-1 abstract does not expose the CFLAR perturbation that supports this IMP row. Reason: The annotation is plausible for c-FLIP, but the local evidence is incomplete. |
| GO:1903055 positive regulation of extracellular matrix organization | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The extracellular-matrix organization row is a distal rat Compara transfer. Reason: No proximal CFLAR mechanism for ECM organization is provided. |
| GO:1903427 negative regulation of reactive oxygen species biosynthetic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The ROS-biosynthesis row is a distal rat Compara transfer. Reason: It does not describe direct c-FLIP molecular work. |
| GO:1903845 negative regulation of cellular response to transforming growth factor beta stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The TGF-beta-response row is a distal rat Compara transfer. Reason: This should not be treated as a core CFLAR biological process. |
| GO:1903944 negative regulation of hepatocyte apoptotic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The hepatocyte-apoptosis row is a tissue-specific rat Compara transfer. Reason: CFLAR directly gates death-receptor CASP8 activity rather than specifically executing a hepatocyte process. |
| GO:1904036 negative regulation of epithelial cell apoptotic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The epithelial-cell apoptosis row is a rat Compara phenotype transfer. Reason: The tissue-specific descendant hides the direct, receptor-proximal c-FLIP function. |
| GO:2000347 positive regulation of hepatocyte proliferation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The hepatocyte-proliferation row is a distal rat Compara phenotype. Reason: It should not be kept as a direct human CFLAR annotation. |
| GO:2001237 negative regulation of extrinsic apoptotic signaling pathway | IDA PMID:9208847 Casper is a FADD- and caspase-related inducer of apoptosis. | UNDECIDED | Summary: The original Casper abstract describes wild-type overexpression and a C-terminal deletion mutant with opposite effects on cell death. Reason: The negative extrinsic-apoptosis annotation is plausible for c-FLIP, but the locally cached abstract is insufficient to sort WT versus mutant support for this IDA row. Supporting Evidence: PMID:9217161 potently inhibit apoptosis induced by all known human death PMID:22266862 overexpression of cFLIP(L) or cFLIP(S) significantly reduces MS275- |
| GO:2001237 negative regulation of extrinsic apoptotic signaling pathway | IEA GO_REF:0000117 | MODIFY | Summary: The ARBA row is directionally right but can be narrowed to death-domain receptor extrinsic apoptosis. Reason: The canonical inhibitory activity of c-FLIP is at FAS, TNFR1, and TRAIL receptor complexes, making GO:1902042 more informative than the broader extrinsic-apoptosis parent. Proposed replacements: negative regulation of extrinsic apoptotic signaling pathway via death domain receptors |
| GO:2001237 negative regulation of extrinsic apoptotic signaling pathway | IMP PMID:22266862 Histone deacetylase inhibitors sensitize glioblastoma cells ... | ACCEPT | Summary: c-FLIP(L/S) overexpression reduces HDAC-inhibitor/TRAIL-induced apoptosis in glioblastoma cells. Reason: MS275 down-regulates c-FLIP and sensitizes cells to TRAIL-induced apoptosis, while c-FLIP(L/S) overexpression reduces that response; the existing negative extrinsic-apoptosis term captures this c-FLIP checkpoint. Supporting Evidence: PMID:9217161 potently inhibit apoptosis induced by all known human death PMID:22266862 overexpression of cFLIP(L) or cFLIP(S) significantly reduces MS275- |
| GO:0004869 cysteine-type endopeptidase inhibitor activity | IDA PMID:9217161 Inhibition of death receptor signals by cellular FLIP. | NEW | Summary: Proposed explicit c-FLIP inhibitor activity for FLIP(S/L)-mediated restraint of death-receptor caspase activation. Reason: Existing GOA rows capture c-FLIP binding and broad negative apoptosis regulation but miss the molecular inhibitor activity implied by FLIP(S/L) blockade of FLICE/CASP8-dependent death-receptor apoptosis. Supporting Evidence: PMID:9217161 potently inhibit apoptosis induced by all known human death Reactome:R-HSA-3465429 FLIP(S) blocks DISC-dependent procaspase-8 activation |
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Download this section (compressed HTML)Q: Should GO or Reactome represent FLIP(L)-CASP8 limited heterodimers and FLIP(S) DED caps as separate complex variants so that c-FLIP activator, inhibitor, apoptosis, and necroptosis annotations can be made isoform-specifically?
Q: Should Reactome-to-GOA suppress catalytic peptidase exports for CFLAR while retaining death-effector-domain and CASP8-regulator assertions for the same CASP8-like family?
Experiment: Use endogenous replacement of c-FLIP(L) and c-FLIP(S) DED-interface or pseudo-caspase-domain mutants to measure FAS, TRAIL, and TNF DISC recruitment, CASP8 p18/p10 production, RIPK1 cleavage, effector-caspase activation, and MLKL phosphorylation in the same cellular background.
Type: isoform-specific DISC/ripoptosome structure-function assay
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