Fas (TNFRSF6, CD95, APO-1) is a single-pass type I transmembrane death receptor of the TNF receptor superfamily. Its extracellular region carries three cysteine-rich domains that bind the trimeric ligand FasL (FASLG/TNFSF6); its cytoplasmic death domain recruits the adaptor FADD, which brings in caspase-8 (and cFLIP) to form the CD95 death-inducing signaling complex (DISC) at the plasma membrane, often within membrane rafts. DISC-mediated caspase-8 activation initiates extrinsic apoptosis. In rat, Fas-dependent apoptosis has been shown in hepatocytes, cortical neurons, oligodendrocytes, alveolar epithelial and nucleus pulposus cells, and after spinal cord injury and brain ischemia. Depending on context, Fas engagement can instead activate non-apoptotic outputs such as AP-1, JNK-dependent neurite regrowth, or ERK/NF-kB proliferative signaling. Soluble forms arise by ectodomain shedding and alternative splicing. Physiologically, Fas-mediated deletion is central to lymphocyte homeostasis and peripheral tolerance.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001552 ovarian follicle atresia | IEP PMID:8612534 Fas/APO-1/CD95 system as a mediator of granulosa cell apopto... | KEEP AS NON CORE | Summary: Fas expressed in granulosa cells of early atretic follicles; IFN-gamma-primed granulosa cells undergo oocyte (FasL)-induced apoptosis. Reason: Beyond expression, the paper links Fas-FasL co-localization to granulosa apoptosis and shows FasL-bearing oocytes induce apoptosis of Fas-up-regulated granulosa cells, supporting a Fas-mediated contribution to follicle atresia. Physiological context, non-core. Supporting Evidence: PMID:8612534 Colocalization of Fas and Fas ligand in certain follicles intimately correlated with granulosa cell apoptosis |
| GO:0001666 response to hypoxia | IEP PMID:16870148 IL-6 protects enterocytes from hypoxia-induced apoptosis by ... | MARK AS OVER ANNOTATED | Summary: Reduced fas expression in IL-6-rescued hypoxic IEC-6 cells. Reason: Expression-change (IEP) evidence only: the paper shows Fas mRNA/protein levels change but does not test whether Fas performs or is required for the process. Regulation of a death receptor's expression is not participation in the process; marked as over-annotation. Supporting Evidence: PMID:16870148 IEC-6 cells that were resistant to apoptosis showed reduced fas expression and increased bcl-2 expression after co-culture with LPS+IL-6 |
| GO:0002020 protease binding | IPI PMID:17518537 FasL, Fas, and death-inducing signaling complex (DISC) prote... | MARK AS OVER ANNOTATED | Summary: Protease binding from co-precipitation of Fas with caspase-8 (and caspase-3) in the spinal-cord DISC after injury. Reason: The paper shows Fas in a raft-associated DISC containing FADD, caspase-8, cFLIP-L and caspase-3. Caspase-8 binds FADD, not Fas, so the Fas-caspase association is indirect complex co-membership. That is captured by the CD95 death-inducing signaling complex (part_of) annotation from the same paper; a protease-binding MF over-states a direct interaction. Supporting Evidence: PMID:17518537 SCI resulted in FasL and Fas translocation into membrane raft microdomains where Fas associates with the adaptor proteins Fas-associated death domain (FADD), caspase-8, cellular FLIP long form (cFLIPL ), and caspase-3, forming a death-inducing signaling complex (DISC). |
| GO:0002931 response to ischemia | IEP PMID:30301943 Intranasal delivery of a Fas-blocking peptide attenuates Fas... | KEEP AS NON CORE | Summary: Fas up-regulated in the ischemic rat brain; a Fas-blocking peptide reduced apoptosis and infarct. Reason: In addition to expression, Fas blockade by intranasal FBP attenuated Fas-mediated apoptosis after MCAO, so Fas participates in the apoptotic response to ischemia. Non-core. Supporting Evidence: PMID:30301943 FBP, upon intranasal administration, specifically binds Fas-expressing apoptotic regions in the brain in a rat ischemia model and effectively blocks Fas-mediated apoptosis resulting in recovery from ischemic stroke. |
| GO:0004888 transmembrane signaling receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: Transmembrane signaling receptor activity for rat Fas, from the InterPro Fas receptor family mapping (IEA) or a statement in the rat variant-transcript paper (NAS). Reason: Fas is a single-pass type I receptor that transmits a FASLG signal across the membrane, so the term is correct but less specific than warranted. The specific supported activity is death receptor activity (GO:0005035), a descendant term; Fas binds FASLG and recruits FADD through its death domain. PMID:7507668 itself only describes a truncated soluble variant transcript, so it adds no functional evidence beyond the family assignment. Proposed replacements: death receptor activity Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Receptor for TNFSF6/FASLG. The adapter molecule FADD recruits caspase CASP8 to the activated receptor. file:rat/Fas/Fas-uniprot.txt Contains a death domain involved in the binding of FADD, and maybe to other cytosolic adapter proteins. |
| GO:0004888 transmembrane signaling receptor activity | NAS PMID:7507668 A variant mRNA species encoding a truncated form of Fas anti... | MODIFY | Summary: Transmembrane signaling receptor activity for rat Fas, from the InterPro Fas receptor family mapping (IEA) or a statement in the rat variant-transcript paper (NAS). Reason: Fas is a single-pass type I receptor that transmits a FASLG signal across the membrane, so the term is correct but less specific than warranted. The specific supported activity is death receptor activity (GO:0005035), a descendant term; Fas binds FASLG and recruits FADD through its death domain. PMID:7507668 itself only describes a truncated soluble variant transcript, so it adds no functional evidence beyond the family assignment. Proposed replacements: death receptor activity Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Receptor for TNFSF6/FASLG. The adapter molecule FADD recruits caspase CASP8 to the activated receptor. file:rat/Fas/Fas-uniprot.txt Contains a death domain involved in the binding of FADD, and maybe to other cytosolic adapter proteins. |
| GO:0005031 tumor necrosis factor receptor activity | IBA GO_REF:0000033 | MODIFY | Summary: Phylogenetic inference of tumor necrosis factor receptor activity across the TNFRSF6 clade. Reason: GO:0005031 is defined as combining with tumor necrosis factor. Fas does not bind TNF; its ligand is FASLG (TNFSF6). The PAINT node correctly captures that the clade has a ligand-activated death-receptor activity, so the claim is sound in essence but uses a ligand-specific term for the wrong ligand. Replace with death receptor activity (GO:0005035), as in the human FAS review. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN002930185 SUPPORTS SOURCE BUT NOT TARGET Source supports a ligand-activated death-receptor activity, but the TNF-specific term names the wrong ligand for Fas (FASLG receptor). UniProtKB:P25445 SUPPORTS SOURCE BUT NOT TARGET Source supports a ligand-activated death-receptor activity, but the TNF-specific term names the wrong ligand for Fas (FASLG receptor). Proposed replacements: death receptor activity Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Receptor for TNFSF6/FASLG. The adapter molecule FADD recruits caspase CASP8 to the activated receptor. |
| GO:0005031 tumor necrosis factor receptor activity | IMP PMID:16154149 Nuclear factor-kappaB mediates Kupffer cell apoptosis throug... | MODIFY | Summary: IMP for TNF receptor activity from rat Kupffer cells, where NF-kB blockade attenuated elastase-induced Fas/FasL up-regulation and apoptosis. Reason: The abstract shows NF-kB-dependent regulation of Fas/FasL expression and Kupffer cell apoptosis; it does not test TNF binding by Fas (TNF production was unaffected), so GO:0005031 is the wrong ligand-specific term. The experiment is consistent with Fas acting as a death receptor in these cells, so the row is kept in modified form as death receptor activity (GO:0005035), consistent with the other GO:0005031 rows. Proposed replacements: death receptor activity Supporting Evidence: PMID:16154149 Inhibition of NF-kappaB DNA binding down-regulates Fas/FasL and attenuates elastase-induced apoptosis; however, it has no effect on TNF production, suggesting that regulation of Fas/FasL and TNF may occur via different pathways. file:rat/Fas/Fas-uniprot.txt Receptor for TNFSF6/FASLG. The adapter molecule FADD recruits caspase CASP8 to the activated receptor. |
| GO:0005031 tumor necrosis factor receptor activity | ISO GO_REF:0000121 | MODIFY | Summary: Tumor necrosis factor receptor activity transferred from human FAS (P25445). Reason: Same reasoning as the IBA row: Fas is the receptor for FASLG, not TNF, and GO:0005031 requires TNF binding. The receptor-activity claim is right and should be expressed as death receptor activity (GO:0005035). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P25445 SUPPORTS SOURCE BUT NOT TARGET Source supports a ligand-activated death-receptor activity, but the TNF-specific term names the wrong ligand for Fas (FASLG receptor). Proposed replacements: death receptor activity Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Receptor for TNFSF6/FASLG. The adapter molecule FADD recruits caspase CASP8 to the activated receptor. |
| GO:0005516 calmodulin binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Calmodulin binding transferred from human FAS. Reason: Human FAS binds calmodulin through the N-terminal part of the death domain (UniProt region 219-243 for rat, by similarity), a modulatory interaction rather than the receptor activity itself. Kept as a non-core binding activity; no rat-specific data. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Interacts with CALM (By similarity). |
| GO:0005516 calmodulin binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Calmodulin binding transferred from human FAS. Reason: Human FAS binds calmodulin through the N-terminal part of the death domain (UniProt region 219-243 for rat, by similarity), a modulatory interaction rather than the receptor activity itself. Kept as a non-core binding activity; no rat-specific data. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Interacts with CALM (By similarity). |
| GO:0005576 extracellular region | IDA PMID:12522536 Shedding of Fas ectodomain that affects apoptosis of hepatoc... | KEEP AS NON CORE | Summary: Shed Fas ectodomain detected after partial hepatectomy. Reason: Ectodomain shedding releases soluble Fas into the extracellular space (also observed as soluble Fas from prostate epithelium, PMID:11332701). This is a real but secondary form of the protein that can modulate ligand availability; the core receptor acts at the plasma membrane. Supporting Evidence: PMID:12522536 Fas protein ectodomain shedding occurred at 2, 12, and 36 h after partial hepatectomy |
| GO:0005576 extracellular region | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Extracellular region from mouse soluble Fas. Reason: Soluble Fas forms (shed ectodomain and splice variants lacking the TM segment) exist in rodents; kept as non-core. Supporting Evidence: PMID:12522536 Fas protein ectodomain shedding occurred at 2, 12, and 36 h after partial hepatectomy |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Plasma membrane localization from the UniProt subcellular location mapping. Reason: Fas is a single-pass type I cell-surface receptor (signal peptide, extracellular CRDs, single TM helix, cytoplasmic death domain); in rat hepatocytes, ligand engagement targets intracellular CD95 to the plasma membrane where the DISC forms. Plasma membrane is where the core activity is executed. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Cell membrane {ECO:0000250|UniProtKB:P51867}; Single-pass type I membrane protein {ECO:0000250|UniProtKB:P51867}. PMID:18045865 the addition of CD95-ligand (CD95L) induces hepatocyte apoptosis, which is preceded by a targeting and activation of intracellularly localized CD95 to the plasma membrane including formation of the death-inducing signaling complex. |
| GO:0005886 plasma membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Plasma membrane localization from human/mouse Fas. Reason: Fas is a single-pass type I cell-surface receptor (signal peptide, extracellular CRDs, single TM helix, cytoplasmic death domain); in rat hepatocytes, ligand engagement targets intracellular CD95 to the plasma membrane where the DISC forms. Plasma membrane is where the core activity is executed. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Cell membrane {ECO:0000250|UniProtKB:P51867}; Single-pass type I membrane protein {ECO:0000250|UniProtKB:P51867}. PMID:18045865 the addition of CD95-ligand (CD95L) induces hepatocyte apoptosis, which is preceded by a targeting and activation of intracellularly localized CD95 to the plasma membrane including formation of the death-inducing signaling complex. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Plasma membrane localization from human FAS. Reason: Fas is a single-pass type I cell-surface receptor (signal peptide, extracellular CRDs, single TM helix, cytoplasmic death domain); in rat hepatocytes, ligand engagement targets intracellular CD95 to the plasma membrane where the DISC forms. Plasma membrane is where the core activity is executed. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Cell membrane {ECO:0000250|UniProtKB:P51867}; Single-pass type I membrane protein {ECO:0000250|UniProtKB:P51867}. PMID:18045865 the addition of CD95-ligand (CD95L) induces hepatocyte apoptosis, which is preceded by a targeting and activation of intracellularly localized CD95 to the plasma membrane including formation of the death-inducing signaling complex. |
| GO:0006915 apoptotic process | IEA GO_REF:0000002 | MODIFY | Summary: Apoptotic process. Reason: True but general: Fas contributes to apoptosis as the receptor initiating the extrinsic death-domain receptor pathway. Refine to GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors, which the gene already carries. Proposed replacements: extrinsic apoptotic signaling pathway via death domain receptors Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0006915 apoptotic process | ISO GO_REF:0000121 | MODIFY | Summary: Apoptotic process. Reason: True but general: Fas contributes to apoptosis as the receptor initiating the extrinsic death-domain receptor pathway. Refine to GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors, which the gene already carries. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:95484 SUPPORTS TRANSFER Source claim is true for Fas; the transferred term is more general than the specific term already carried by the gene. Proposed replacements: extrinsic apoptotic signaling pathway via death domain receptors Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0006915 apoptotic process | ISO GO_REF:0000121 | MODIFY | Summary: Apoptotic process. Reason: True but general: Fas contributes to apoptosis as the receptor initiating the extrinsic death-domain receptor pathway. Refine to GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors, which the gene already carries. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:95484 SUPPORTS TRANSFER Source claim is true for Fas; the transferred term is more general than the specific term already carried by the gene. Proposed replacements: extrinsic apoptotic signaling pathway via death domain receptors Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0006924 activation-induced cell death of T cells | IBA GO_REF:0000033 | ACCEPT | Summary: Activation-induced cell death of T cells (phylogenetic / orthology based). Reason: Activation-induced death of T cells is the best-established physiological role of Fas (lpr mice, human ALPS). Accepted as a core physiological process for the clade; no rat-specific test. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt FAS-mediated apoptosis may have a role in the induction of peripheral tolerance |
| GO:0006924 activation-induced cell death of T cells | ISO GO_REF:0000121 | ACCEPT | Summary: Activation-induced cell death of T cells (phylogenetic / orthology based). Reason: Activation-induced death of T cells is the best-established physiological role of Fas (lpr mice, human ALPS). Accepted as a core physiological process for the clade; no rat-specific test. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt FAS-mediated apoptosis may have a role in the induction of peripheral tolerance |
| GO:0006925 inflammatory cell apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Inflammatory cell apoptotic process, transferred by orthology. Reason: Fas mediates apoptosis of inflammatory cells (mouse lpr data); cell-type instance of Fas-mediated apoptosis, non-core. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0006955 immune response | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Immune response from InterPro mapping. Reason: Fas-mediated apoptosis contributes to immune homeostasis and peripheral tolerance (T-cell activation-induced death, lpr phenotypes), but the receptor is not an effector of immune responses per se. Kept as a broad, non-core process. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt FAS-mediated apoptosis may have a role in the induction of peripheral tolerance |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | MODIFY | Summary: Signal transduction from InterPro mapping. Reason: Correct but uninformative; the specific pathway that Fas initiates is the Fas signaling pathway (GO:0036337), a descendant already on the gene. Proposed replacements: Fas signaling pathway Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Receptor for TNFSF6/FASLG. The adapter molecule FADD recruits caspase CASP8 to the activated receptor. |
| GO:0007283 spermatogenesis | IEP PMID:17195944 Up-regulation of CD95 (Apo-1/Fas) is associated with spermat... | MARK AS OVER ANNOTATED | Summary: Fas up-regulated in a subset of spermatocytes in juvenile rat testis. Reason: Expression evidence; Fas-mediated germ-cell apoptosis may cull spermatocytes, but spermatogenesis as a whole is too broad and is not shown to require Fas here. Over-annotation. Supporting Evidence: PMID:17195944 Fas levels increased significantly in a group of germ cell in 25 d old rats |
| GO:0007623 circadian rhythm | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Circadian rhythm, from mouse. Reason: No evidence that Fas is a clock component or contributes to rhythm generation; at most Fas expression or Fas-dependent apoptosis varies with time of day. Over-annotation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:95484 SUPPORTS SOURCE BUT NOT TARGET Source is a mouse phenotype-derived annotation; the transferred term describes a downstream or unrelated consequence rather than a process Fas carries out. |
| GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors | ISO GO_REF:0000121 | ACCEPT | Summary: Extrinsic apoptotic signaling pathway via death domain receptors, from human/mouse Fas. Reason: The defining process of Fas: FASLG binding, FADD recruitment through the death domain, DISC formation and caspase-8 activation. Rat data show ligand- or agonist-triggered, caspase-8-dependent apoptosis that is blocked by antagonist antibodies. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Receptor for TNFSF6/FASLG. The adapter molecule FADD recruits caspase CASP8 to the activated receptor. file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. PMID:23940767 Anti-Fas antibody prevents caspase-8 and caspase-3 activation by phenylalanine. |
| GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors | ISO GO_REF:0000121 | ACCEPT | Summary: Extrinsic apoptotic signaling pathway via death domain receptors, from human/mouse Fas. Reason: The defining process of Fas: FASLG binding, FADD recruitment through the death domain, DISC formation and caspase-8 activation. Rat data show ligand- or agonist-triggered, caspase-8-dependent apoptosis that is blocked by antagonist antibodies. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Receptor for TNFSF6/FASLG. The adapter molecule FADD recruits caspase CASP8 to the activated receptor. file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. PMID:23940767 Anti-Fas antibody prevents caspase-8 and caspase-3 activation by phenylalanine. |
| GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors | ISO GO_REF:0000121 | ACCEPT | Summary: Extrinsic apoptotic signaling pathway via death domain receptors, from human/mouse Fas. Reason: The defining process of Fas: FASLG binding, FADD recruitment through the death domain, DISC formation and caspase-8 activation. Rat data show ligand- or agonist-triggered, caspase-8-dependent apoptosis that is blocked by antagonist antibodies. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Receptor for TNFSF6/FASLG. The adapter molecule FADD recruits caspase CASP8 to the activated receptor. file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. PMID:23940767 Anti-Fas antibody prevents caspase-8 and caspase-3 activation by phenylalanine. |
| GO:0009410 response to xenobiotic stimulus | IEP PMID:16687611 Multiple actions of pifithrin-alpha on doxorubicin-induced a... | MARK AS OVER ANNOTATED | Summary: Fas protein increased in doxorubicin-treated H9c2 cells. Reason: Expression-change (IEP) evidence only: the paper shows Fas mRNA/protein levels change but does not test whether Fas performs or is required for the process. Regulation of a death receptor's expression is not participation in the process; marked as over-annotation. Supporting Evidence: PMID:16687611 H9c2 cells treated with Dox for 16 h had marked increase in the levels of caspases-2, -3, -8, -9, -12, Fas, and cleaved poly(ADP ribose) polymerase (PARP). |
| GO:0009636 response to toxic substance | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Response to toxic substance. Reason: Based on changes in Fas expression after toxicant exposure (Huwentoxin-I in ischemic hippocampus, p,p'-DDE in testis) or ARBA/mouse transfer. Changed expression of a death receptor during toxic injury does not show that Fas performs the response; an uninformative, over-broad process for this receptor. |
| GO:0009636 response to toxic substance | IEP PMID:17900647 Effect of Huwentoxin-I on the Fas and TNF apoptosis pathway ... | MARK AS OVER ANNOTATED | Summary: Response to toxic substance. Reason: Based on changes in Fas expression after toxicant exposure (Huwentoxin-I in ischemic hippocampus, p,p'-DDE in testis) or ARBA/mouse transfer. Changed expression of a death receptor during toxic injury does not show that Fas performs the response; an uninformative, over-broad process for this receptor. |
| GO:0009636 response to toxic substance | IEP PMID:21384494 p,p'-DDE induces apoptosis and mRNA expression of apoptosis-... | MARK AS OVER ANNOTATED | Summary: Response to toxic substance. Reason: Based on changes in Fas expression after toxicant exposure (Huwentoxin-I in ischemic hippocampus, p,p'-DDE in testis) or ARBA/mouse transfer. Changed expression of a death receptor during toxic injury does not show that Fas performs the response; an uninformative, over-broad process for this receptor. Supporting Evidence: PMID:21384494 Significant elevations in the mRNA levels of Fas, FasL, calpain-1, cytochrome c, Bax, Bak, and caspase-3, -8, -9, -12 were observed in testis of rat treated with p,p'-DDE. |
| GO:0009636 response to toxic substance | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Response to toxic substance. Reason: Based on changes in Fas expression after toxicant exposure (Huwentoxin-I in ischemic hippocampus, p,p'-DDE in testis) or ARBA/mouse transfer. Changed expression of a death receptor during toxic injury does not show that Fas performs the response; an uninformative, over-broad process for this receptor. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:95484 SUPPORTS SOURCE BUT NOT TARGET Source is a mouse phenotype-derived annotation; the transferred term describes a downstream or unrelated consequence rather than a process Fas carries out. |
| GO:0009897 external side of plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: External side of plasma membrane, phylogenetically inferred. Reason: Fas is detected by non-permeabilizing antibody staining at the cell surface (e.g. rat cortical precursors, spermatocytes); its ligand-binding ectodomain faces outward. Consistent with the type I topology. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Cell membrane {ECO:0000250|UniProtKB:P51867}; Single-pass type I membrane protein {ECO:0000250|UniProtKB:P51867}. PMID:15038834 only a fraction (~1/4th) of all Fas-expressing cells actually localize Fas to the cell-surface, in vitro |
| GO:0009897 external side of plasma membrane | IDA PMID:17195944 Up-regulation of CD95 (Apo-1/Fas) is associated with spermat... | ACCEPT | Summary: Fas detected on the surface of rat spermatocytes with up-regulated Fas. Reason: Abstract-only paper; the abstract reports elevated Fas levels in spermatocytes (cell-surface detection presumably by flow cytometry in the full text). The location is fully consistent with Fas topology, so the curator call is accepted. Supporting Evidence: PMID:17195944 We show here that Fas levels increased significantly in a group of germ cell in 25 d old rats, which were identified as spermatocytes and only a few spermatogonia. |
| GO:0009897 external side of plasma membrane | ISO GO_REF:0000121 | ACCEPT | Summary: External side of plasma membrane, from mouse Fas. Reason: As for the IBA row: surface-exposed ectodomain of a type I receptor; directly supported in rat by surface staining. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Cell membrane {ECO:0000250|UniProtKB:P51867}; Single-pass type I membrane protein {ECO:0000250|UniProtKB:P51867}. |
| GO:0009986 cell surface | IDA PMID:18045865 Amplification of CD95 activation by caspase 8-induced endoso... | ACCEPT | Summary: CD95 targeted to the hepatocyte cell surface after CD95L stimulation. Reason: In rat hepatocytes CD95 is largely intracellular at rest and trafficked to the plasma membrane upon ligand, where the DISC forms. Supports cell surface localization of the active receptor. Supporting Evidence: PMID:18045865 the addition of CD95-ligand (CD95L) induces hepatocyte apoptosis, which is preceded by a targeting and activation of intracellularly localized CD95 to the plasma membrane including formation of the death-inducing signaling complex. |
| GO:0009986 cell surface | ISO GO_REF:0000121 | ACCEPT | Summary: Cell surface localization transferred from human/mouse Fas. Reason: Fas is a cell-surface death receptor; rat-specific data show surface Fas in cortical precursors and phenylalanine-treated neurons. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Cell membrane {ECO:0000250|UniProtKB:P51867}; Single-pass type I membrane protein {ECO:0000250|UniProtKB:P51867}. PMID:23940767 Phe significantly increased cell surface Fas expression |
| GO:0009986 cell surface | ISO GO_REF:0000121 | ACCEPT | Summary: Cell surface localization transferred from human/mouse Fas. Reason: Fas is a cell-surface death receptor; rat-specific data show surface Fas in cortical precursors and phenylalanine-treated neurons. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Cell membrane {ECO:0000250|UniProtKB:P51867}; Single-pass type I membrane protein {ECO:0000250|UniProtKB:P51867}. PMID:23940767 Phe significantly increased cell surface Fas expression |
| GO:0010467 gene expression | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Gene expression (acts upstream of or within), from mouse. Reason: Fas signaling can alter transcription indirectly (e.g. AP-1, NF-kB), but "gene expression" is an uninformative downstream readout and Fas is not part of the expression machinery. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:95484 SUPPORTS SOURCE BUT NOT TARGET Source is a mouse phenotype-derived annotation; the transferred term describes a downstream or unrelated consequence rather than a process Fas carries out. |
| GO:0010626 negative regulation of Schwann cell proliferation | IMP PMID:29970988 Fas Ligand Gene (Faslg) Plays an Important Role in Nerve Deg... | REMOVE | Summary: Negative regulation of Schwann cell proliferation attributed to Fas from a Faslg knockdown study. Reason: Full text read: the perturbed gene is Faslg (ligand), not Fas. No experiment in the paper manipulates the Fas receptor, so the IMP does not apply to Fas. Removed as a gene mis-attribution (source defect recorded). Supporting Evidence: PMID:29970988 Silencing of Faslg by transfection with Faslg siRNA significantly induced SC proliferation when compared to the NCs. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: Generic membrane localization from InterPro mapping. Reason: Correct but less specific than the evidence supports. Fas is a type I plasma membrane receptor; the gene already carries plasma membrane (GO:0005886) rows, which is the appropriate refinement. Proposed replacements: plasma membrane Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Cell membrane {ECO:0000250|UniProtKB:P51867}; Single-pass type I membrane protein {ECO:0000250|UniProtKB:P51867}. |
| GO:0016324 apical plasma membrane | IDA PMID:12861046 Apoptosis of tubular epithelial cells in glycogen nephrosis ... | UNDECIDED | Summary: Apical plasma membrane localization in diabetic renal tubular clear cells. Reason: The cached record is abstract-only; the abstract reports Fas positivity and Fas/FasL-mediated death of thick ascending limb and distal tubule cells but does not describe apical membrane localization. The location cannot be verified from available text; not removed, as the curator saw the full text. Supporting Evidence: PMID:12861046 Clear cells displayed apoptotic features such as Annexin V binding, nuclear TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling), and the simultaneous occurrence of Fas, Annexin V, and TUNEL positivity. |
| GO:0019724 B cell mediated immunity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: B cell mediated immunity, transferred by orthology. Reason: Mouse phenotype (autoantibody production in lpr). Indirect; non-core. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0019900 kinase binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Kinase binding transferred from human FAS. Reason: Human FAS associates with kinases such as RIPK1, HIPK3 and GSK3B (rat UniProt SUBUNIT, by similarity). These are context-dependent partner interactions, not the core receptor activity; kept as non-core. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Binds RIPK1 and FAIM2. |
| GO:0021537 telencephalon development | IEP PMID:10024361 Fas/Apo [apoptosis]-1 and associated proteins in the differe... | MARK AS OVER ANNOTATED | Summary: Transient Fas expression during the peak of cortical apoptosis. Reason: Expression timing plus in-vitro death of neuroblasts upon Fas activation; the paper does not show that Fas is required for telencephalon development. Over-annotation of a developmental process. Supporting Evidence: PMID:10024361 Fas mRNA and protein are transiently expressed in subsets of cells within the developing rat cerebral cortex during the peak period of apoptosis. |
| GO:0030141 secretory granule | IDA PMID:11332701 Intravesicular Fas localization in epithelial cells of castr... | KEEP AS NON CORE | Summary: Fas immunogold localization in secretory granules of castrated rat prostate epithelium. Reason: Directly observed by immuno-EM, and linked to secretion of soluble Fas in this tissue. A context-specific (androgen-ablation) location, not where the receptor signals. Supporting Evidence: PMID:11332701 Fas was localized mainly in secretory granules of the castrated prostate epithelial cells and some parts of their cell membranes at later stages. |
| GO:0031104 dendrite regeneration | IMP PMID:18692025 c-Jun N-terminal kinases mediate Fas-induced neurite regener... | MODIFY | Summary: Fas-Fc reduced NGF-driven neurite regrowth in injured PC12 cells. Reason: PC12 neurites are not dendrites, so "dendrite regeneration" is over-specific; the supported process is neuron projection regeneration (GO:0031102), the parent term. Note the perturbation (Fas-Fc) traps FasL rather than removing Fas, so the evidence is indirect; non-core. Proposed replacements: neuron projection regeneration Supporting Evidence: PMID:18692025 Neurite regeneration was decreased by chemical inhibition of TrkA, but not p75(NTR), and by the Fas inhibitor protein Fas-Fc. |
| GO:0031264 death-inducing signaling complex | IDA PMID:17518537 FasL, Fas, and death-inducing signaling complex (DISC) prote... | MODIFY | Summary: Fas in a death-inducing signaling complex in injured spinal cord. Reason: Correct, but the specific complex is the CD95 death-inducing signaling complex (GO:0031265), a child term that the gene already carries. Proposed replacements: CD95 death-inducing signaling complex Supporting Evidence: PMID:17518537 SCI resulted in FasL and Fas translocation into membrane raft microdomains where Fas associates with the adaptor proteins Fas-associated death domain (FADD), caspase-8, cellular FLIP long form (cFLIPL ), and caspase-3, forming a death-inducing signaling complex (DISC). |
| GO:0031264 death-inducing signaling complex | ISO GO_REF:0000121 | MODIFY | Summary: Death-inducing signaling complex, from human FAS. Reason: Refine to the Fas-specific child term GO:0031265 CD95 death-inducing signaling complex. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P25445 SUPPORTS TRANSFER Source claim is true for Fas; the transferred term is more general than the specific term already carried by the gene. Proposed replacements: CD95 death-inducing signaling complex Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Component of the death-induced signaling complex (DISC) composed of cell surface receptor FAS/CD95, adapter protein FADD and the CASP8 protease |
| GO:0031265 CD95 death-inducing signaling complex | IBA GO_REF:0000033 | ACCEPT | Summary: Membership of the CD95 death-inducing signaling complex (phylogenetic inference). Reason: Fas is the defining receptor of the CD95 DISC (Fas-FADD-caspase-8); rat DISC formation with FADD and caspase-8 is shown directly after spinal cord injury. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Component of the death-induced signaling complex (DISC) composed of cell surface receptor FAS/CD95, adapter protein FADD and the CASP8 protease PMID:17518537 SCI resulted in FasL and Fas translocation into membrane raft microdomains where Fas associates with the adaptor proteins Fas-associated death domain (FADD), caspase-8, cellular FLIP long form (cFLIPL ), and caspase-3, forming a death-inducing signaling complex (DISC). |
| GO:0031265 CD95 death-inducing signaling complex | IDA PMID:16493077 C5b-9 terminal complex protects oligodendrocytes from apopto... | ACCEPT | Summary: CD95 DISC in rat oligodendrocytes undergoing Fas-mediated apoptosis. Reason: Abstract-only; the abstract shows Fas-mediated, caspase-8-dependent oligodendrocyte apoptosis regulated by C5b-9 and cFLIP-L, and the full text presumably assays DISC components. The claim is clearly correct for Fas, so the curator call is accepted. Supporting Evidence: PMID:16493077 These data suggest that C5b-9 through PI3K signaling can rescue OLG from Fas-mediated apoptosis by regulating caspase-8 processing. PMID:17518537 SCI resulted in FasL and Fas translocation into membrane raft microdomains where Fas associates with the adaptor proteins Fas-associated death domain (FADD), caspase-8, cellular FLIP long form (cFLIPL ), and caspase-3, forming a death-inducing signaling complex (DISC). |
| GO:0031265 CD95 death-inducing signaling complex | IEA GO_REF:0000117 | ACCEPT | Summary: Membership of the CD95 death-inducing signaling complex (ARBA prediction). Reason: Fas is the defining receptor of the CD95 DISC (Fas-FADD-caspase-8); rat DISC formation with FADD and caspase-8 is shown directly after spinal cord injury. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Component of the death-induced signaling complex (DISC) composed of cell surface receptor FAS/CD95, adapter protein FADD and the CASP8 protease PMID:17518537 SCI resulted in FasL and Fas translocation into membrane raft microdomains where Fas associates with the adaptor proteins Fas-associated death domain (FADD), caspase-8, cellular FLIP long form (cFLIPL ), and caspase-3, forming a death-inducing signaling complex (DISC). |
| GO:0031265 CD95 death-inducing signaling complex | ISO GO_REF:0000121 | ACCEPT | Summary: Membership of the CD95 death-inducing signaling complex (orthology transfer from human/mouse). Reason: Fas is the defining receptor of the CD95 DISC (Fas-FADD-caspase-8); rat DISC formation with FADD and caspase-8 is shown directly after spinal cord injury. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Component of the death-induced signaling complex (DISC) composed of cell surface receptor FAS/CD95, adapter protein FADD and the CASP8 protease PMID:17518537 SCI resulted in FasL and Fas translocation into membrane raft microdomains where Fas associates with the adaptor proteins Fas-associated death domain (FADD), caspase-8, cellular FLIP long form (cFLIPL ), and caspase-3, forming a death-inducing signaling complex (DISC). |
| GO:0031265 CD95 death-inducing signaling complex | ISO GO_REF:0000121 | ACCEPT | Summary: Membership of the CD95 death-inducing signaling complex (orthology transfer from human/mouse). Reason: Fas is the defining receptor of the CD95 DISC (Fas-FADD-caspase-8); rat DISC formation with FADD and caspase-8 is shown directly after spinal cord injury. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Component of the death-induced signaling complex (DISC) composed of cell surface receptor FAS/CD95, adapter protein FADD and the CASP8 protease PMID:17518537 SCI resulted in FasL and Fas translocation into membrane raft microdomains where Fas associates with the adaptor proteins Fas-associated death domain (FADD), caspase-8, cellular FLIP long form (cFLIPL ), and caspase-3, forming a death-inducing signaling complex (DISC). |
| GO:0031334 positive regulation of protein-containing complex assembly | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of protein-containing complex assembly, transferred by orthology. Reason: Ligand-induced Fas clustering nucleates DISC assembly; mouse-derived. Kept as non-core; the complex itself is captured by GO:0031265. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0031667 response to nutrient levels | IEP PMID:19616844 Increased placental apoptosis in maternal food restricted ge... | MARK AS OVER ANNOTATED | Summary: Placental Fas increased with maternal food restriction. Reason: Expression-change (IEP) evidence only: the paper shows Fas mRNA/protein levels change but does not test whether Fas performs or is required for the process. Regulation of a death receptor's expression is not participation in the process; marked as over-annotation. Supporting Evidence: PMID:19616844 The results suggest that the increased apoptosis may be mediated, in part, via Fas pathway |
| GO:0032496 response to lipopolysaccharide | IEP PMID:17899301 Protein kinase C-zeta (PKC-zeta) regulates Kupffer cell apop... | KEEP AS NON CORE | Summary: Fas/FasL up-regulated in Kupffer cells in sepsis and after LPS. Reason: Expression evidence here, but independent rat siRNA evidence (PMID:19823951) shows Fas is required for LPS-induced alveolar epithelial apoptosis, so Fas participates in the cellular death response to LPS. Non-core. Supporting Evidence: PMID:17899301 CLP upregulated PKC-zeta protein and activity, IKKbeta, IKKgamma, NF-kappaB, Fas/FasL, Caspase-3, and increased DNA fragmentation in rat livers |
| GO:0032872 regulation of stress-activated MAPK cascade | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Regulation of stress-activated MAPK cascade. Reason: Fas signaling activates JNK (rat PC12 neurite regrowth via JNKs; Daxx-ASK1-JNK in cardiomyocytes). A secondary signaling output; non-core. Supporting Evidence: PMID:18692025 otherwise apoptotic Fas ligation supported neuronal recovery exclusively via JNKs and promoted sprouting parallel to NGF |
| GO:0032872 regulation of stress-activated MAPK cascade | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Regulation of stress-activated MAPK cascade. Reason: Fas signaling activates JNK (rat PC12 neurite regrowth via JNKs; Daxx-ASK1-JNK in cardiomyocytes). A secondary signaling output; non-core. Supporting Evidence: PMID:18692025 otherwise apoptotic Fas ligation supported neuronal recovery exclusively via JNKs and promoted sprouting parallel to NGF |
| GO:0033209 tumor necrosis factor-mediated signaling pathway | IEA GO_REF:0000108 | MODIFY | Summary: TNF-mediated signaling pathway inferred from the TNF receptor activity annotation. Reason: This inference rests on the incorrect GO:0005031 (Fas does not bind TNF). The correct pathway for a FASLG receptor is the Fas signaling pathway (GO:0036337). Proposed replacements: Fas signaling pathway Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Receptor for TNFSF6/FASLG. The adapter molecule FADD recruits caspase CASP8 to the activated receptor. |
| GO:0034097 response to cytokine | IEP PMID:17105443 The effects of interleukin-10 on the expression of Fas and F... | MARK AS OVER ANNOTATED | Summary: Fas expression in hepatic stellate cells changes with IL-10 treatment in fibrosis. Reason: Expression-change (IEP) evidence only: the paper shows Fas mRNA/protein levels change but does not test whether Fas performs or is required for the process. Regulation of a death receptor's expression is not participation in the process; marked as over-annotation. |
| GO:0034198 cellular response to amino acid starvation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cellular response to amino acid starvation, transferred by orthology. Reason: Human evidence that Fas contributes to death under amino-acid starvation; context-specific, non-core. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0036337 Fas signaling pathway | ISO GO_REF:0000121 | ACCEPT | Summary: Fas signaling pathway, from human FAS. Reason: Fas initiates the Fas signaling pathway by definition; in rat, besides apoptosis, Fas engagement drives AP-1 activation in cardiomyocytes and ERK/NF-kB signaling in gastric cells. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Receptor for TNFSF6/FASLG. The adapter molecule FADD recruits caspase CASP8 to the activated receptor. PMID:10715265 Stimulation of isolated cardiomyocytes with recombinant FasL promoted an activation of the transcription factor AP-1 |
| GO:0042127 regulation of cell population proliferation | IMP PMID:17991709 Fas Ag-FasL coupling leads to ERK1/2-mediated proliferation ... | MODIFY | Summary: Fas signaling drives ERK1/2-mediated proliferation of rat gastric mucosal cells. Reason: The direction is known: under low stimulation or blocked apoptosis, Fas signaling promotes proliferation. Modify to positive regulation of cell population proliferation (GO:0008284). Context-specific, non-core. Proposed replacements: positive regulation of cell population proliferation Supporting Evidence: PMID:17991709 Under conditions of low receptor stimulation or under conditions where apoptosis is blocked downstream of the death-inducing signal complex, Fas Ag signaling proceeds toward proliferative signaling. |
| GO:0042383 sarcolemma | IDA PMID:10715265 The cardiac Fas (APO-1/CD95) Receptor/Fas ligand system : re... | KEEP AS NON CORE | Summary: Fas immunostaining on the cardiomyocyte sarcolemma. Reason: Sarcolemma is the muscle-cell plasma membrane, consistent with the receptor topology; it is a cell-type-specific instance of the plasma membrane location and is retained as non-core. Supporting Evidence: PMID:10715265 Fas was expressed on the sarcolemma of cardiomyocytes in left ventricular tissue sections. |
| GO:0042698 ovulation cycle | IEP PMID:16461545 Estrous cycle dependent changes in expression and distributi... | MARK AS OVER ANNOTATED | Summary: Ovarian Fas protein varies across the estrous cycle. Reason: Expression-change (IEP) evidence only: the paper shows Fas mRNA/protein levels change but does not test whether Fas performs or is required for the process. Regulation of a death receptor's expression is not participation in the process; marked as over-annotation. Supporting Evidence: PMID:16461545 Fas, Bax and caspase-3 protein levels were highest at diestrus and decreased thereafter towards metestrus. |
| GO:0042802 identical protein binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Identical protein binding (self-association) transferred from human and mouse Fas. Reason: Fas receptors pre-associate and form ligand-induced oligomers, and death-domain clustering is part of DISC assembly. Self-association is a real mechanistic property but supports, rather than constitutes, the death receptor activity; kept as non-core. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Component of the death-induced signaling complex (DISC) composed of cell surface receptor FAS/CD95, adapter protein FADD and the CASP8 protease |
| GO:0042802 identical protein binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Identical protein binding (self-association) transferred from human and mouse Fas. Reason: Fas receptors pre-associate and form ligand-induced oligomers, and death-domain clustering is part of DISC assembly. Self-association is a real mechanistic property but supports, rather than constitutes, the death receptor activity; kept as non-core. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Component of the death-induced signaling complex (DISC) composed of cell surface receptor FAS/CD95, adapter protein FADD and the CASP8 protease |
| GO:0042981 regulation of apoptotic process | IMP PMID:16582846 Insulin-like growth factor-1 treatment prevents anti-Fas ant... | MODIFY | Summary: Agonist anti-Fas antibody induced apoptosis in rat endplate chondrocytes. Reason: The direction is known: Fas activation promotes apoptosis. Modify to positive regulation of apoptotic process (GO:0043065), which the gene carries. Proposed replacements: positive regulation of apoptotic process Supporting Evidence: PMID:16582846 Fas antibody induced apoptosis in endplate chondrocytes; this was confirmed by TUNEL staining. |
| GO:0043009 chordate embryonic development | IEP PMID:11331665 Expression of Fas and Fas ligand mRNA in rat and human preim... | MARK AS OVER ANNOTATED | Summary: Fas mRNA detected only at the 2-cell stage of rat embryos. Reason: Expression-change (IEP) evidence only: the paper shows Fas mRNA/protein levels change but does not test whether Fas performs or is required for the process. Regulation of a death receptor's expression is not participation in the process; marked as over-annotation. Supporting Evidence: PMID:11331665 In rat embryos, Fas mRNA was expressed at the 2-cell stage only |
| GO:0043025 neuronal cell body | IDA PMID:15038834 The extracellular matrix, p53 and estrogen compete to regula... | KEEP AS NON CORE | Summary: Fas immunoreactivity in the cytoplasm of cultured embryonic cortical neuroblasts. Reason: Full text shows most Fas immunoreactivity in permeabilized differentiating cortical cells is cytoplasmic and in proximal processes, with a minority at the surface. The cell-body pool is an intracellular reservoir rather than the signaling site; kept as non-core. Supporting Evidence: PMID:15038834 a majority of these differentiating cells localize Fas-immunoreactivity within their cytoplasm and proximal processes |
| GO:0043029 T cell homeostasis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: T cell homeostasis, transferred by orthology. Reason: Loss of Fas (lpr) disrupts T-cell homeostasis through failed deletion; a downstream organismal consequence, non-core. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0043065 positive regulation of apoptotic process | IMP PMID:19823951 Fas inhibition attenuates lipopolysaccharide-induced apoptos... | ACCEPT | Summary: Positive regulation of apoptotic process. Reason: Fas engagement promotes apoptosis; rat Fas siRNA reduces LPS-induced alveolar epithelial apoptosis (PMID:19823951) and FasL-induced nucleus pulposus apoptosis (PMID:19902128). Accepted as a true description of the receptor output; the pathway itself is captured by GO:0008625. Supporting Evidence: PMID:19823951 In conclusion, inhibition of Fas can diminish LPS-induced apoptosis and inflammatory cytokine production in type II AECs |
| GO:0043065 positive regulation of apoptotic process | IMP PMID:19902128 Double role of Fas ligand in the apoptosis of intervertebral... | ACCEPT | Summary: Positive regulation of apoptotic process. Reason: Fas engagement promotes apoptosis; rat Fas siRNA reduces LPS-induced alveolar epithelial apoptosis (PMID:19823951) and FasL-induced nucleus pulposus apoptosis (PMID:19902128). Accepted as a true description of the receptor output; the pathway itself is captured by GO:0008625. Supporting Evidence: PMID:19902128 RNA interference results indicated that the increase of Fas expression and the NP cell apoptosis described previously were inhibited by Fas siRNA |
| GO:0043065 positive regulation of apoptotic process | ISO GO_REF:0000121 | ACCEPT | Summary: Positive regulation of apoptotic process. Reason: Fas engagement promotes apoptosis; rat Fas siRNA reduces LPS-induced alveolar epithelial apoptosis (PMID:19823951) and FasL-induced nucleus pulposus apoptosis (PMID:19902128). Accepted as a true description of the receptor output; the pathway itself is captured by GO:0008625. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0043066 negative regulation of apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Negative regulation of apoptotic process. Reason: Fas can signal survival/proliferation in some contexts (e.g. cFLIP-ERK-NF-kB-survivin signaling in rat gastric mucosal cells, PMID:17991709), and the PAINT node captures this ancestral non-apoptotic output. It is context-dependent and opposite to the main output, so non-core. Supporting Evidence: PMID:17991709 NF-kappaB activation results in upregulation of the antiapoptotic protein survivin, further promoting proliferation over apoptosis. |
| GO:0043066 negative regulation of apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of apoptotic process. Reason: Fas can signal survival/proliferation in some contexts (e.g. cFLIP-ERK-NF-kB-survivin signaling in rat gastric mucosal cells, PMID:17991709), and the PAINT node captures this ancestral non-apoptotic output. It is context-dependent and opposite to the main output, so non-core. Supporting Evidence: PMID:17991709 NF-kappaB activation results in upregulation of the antiapoptotic protein survivin, further promoting proliferation over apoptosis. |
| GO:0043434 response to peptide hormone | IEP PMID:16392621 Thyrotropin releasing hormone (TRH) affects gene expression ... | MARK AS OVER ANNOTATED | Summary: TRH suppressed Fas expression in INS-1 cells (array). Reason: Expression-change (IEP) evidence only: the paper shows Fas mRNA/protein levels change but does not test whether Fas performs or is required for the process. Regulation of a death receptor's expression is not participation in the process; marked as over-annotation. Supporting Evidence: PMID:16392621 TRH suppressed the genes of proapoptotic Bcl-2-associated protein X, Bcl-xL/ Bcl-2-associated death promoter, and Fas. |
| GO:0043525 positive regulation of neuron apoptotic process | IMP PMID:23940767 The Fas/Fas ligand death receptor pathway contributes to phe... | KEEP AS NON CORE | Summary: Neutralizing anti-Fas antibody prevented phenylalanine-induced apoptosis of rat cortical neurons. Reason: Full text shows Phe-induced Fas/FasL complex formation and that blocking Fas prevents caspase-8/3 activation and apoptosis. A neuron-specific instance of the Fas apoptotic pathway; non-core. Supporting Evidence: PMID:23940767 immunoprecipitation verified formation of the Fas/FasL complex after phenylalanine treatment, consistent with Phe-induced activation of the Fas pathway PMID:23940767 Anti-Fas antibody prevents caspase-8 and caspase-3 activation by phenylalanine. |
| GO:0043627 response to estrogen | IEP PMID:16099864 Estrogens up-regulate the Fas/FasL apoptotic pathway in lact... | KEEP AS NON CORE | Summary: Estradiol up-regulates Fas in anterior pituitary lactotropes and enables Fas-induced apoptosis. Reason: Beyond expression, Fas agonist antibody induced apoptosis only in estradiol-treated cells, so Fas participates in the estrogen-dependent apoptotic response of lactotropes. Non-core. Supporting Evidence: PMID:16099864 Our results show that 17beta-estradiol up-regulates the expression of the Fas/FasL system in anterior pituitary cells and increases Fas-induced apoptosis in lactotropes |
| GO:0044877 protein-containing complex binding | IPI PMID:17518537 FasL, Fas, and death-inducing signaling complex (DISC) prote... | MARK AS OVER ANNOTATED | Summary: Protein-containing complex binding, from Fas association with the DISC after spinal cord injury. Reason: Fas is a component of the DISC it was co-precipitated with, so "complex binding" restates complex membership as an MF. The informative statement is the CD95 death-inducing signaling complex CC annotation (and FADD recruitment via the death domain), not binding to a pre-existing complex. Supporting Evidence: PMID:17518537 SCI resulted in FasL and Fas translocation into membrane raft microdomains where Fas associates with the adaptor proteins Fas-associated death domain (FADD), caspase-8, cellular FLIP long form (cFLIPL ), and caspase-3, forming a death-inducing signaling complex (DISC). |
| GO:0045060 negative thymic T cell selection | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative thymic T cell selection, transferred by orthology. Reason: Mouse-derived; Fas contribution to thymic negative selection is limited and context-dependent (strong-agonist conditions). Kept as non-core rather than core. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0045121 membrane raft | IBA GO_REF:0000033 | ACCEPT | Summary: Membrane raft localization (phylogenetic, orthology or UniProt-mapping based). Reason: Fas partitions into membrane rafts upon activation, where the DISC assembles; this is directly shown for rat Fas after spinal cord injury (PMID:17518537), so the propagated claim is supported in rat. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Membrane raft {ECO:0000250|UniProtKB:P25445}. PMID:17518537 SCI resulted in FasL and Fas translocation into membrane raft microdomains where Fas associates with the adaptor proteins Fas-associated death domain (FADD), caspase-8, cellular FLIP long form (cFLIPL ), and caspase-3, forming a death-inducing signaling complex (DISC). |
| GO:0045121 membrane raft | IEA GO_REF:0000044 | ACCEPT | Summary: Membrane raft localization (phylogenetic, orthology or UniProt-mapping based). Reason: Fas partitions into membrane rafts upon activation, where the DISC assembles; this is directly shown for rat Fas after spinal cord injury (PMID:17518537), so the propagated claim is supported in rat. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Membrane raft {ECO:0000250|UniProtKB:P25445}. PMID:17518537 SCI resulted in FasL and Fas translocation into membrane raft microdomains where Fas associates with the adaptor proteins Fas-associated death domain (FADD), caspase-8, cellular FLIP long form (cFLIPL ), and caspase-3, forming a death-inducing signaling complex (DISC). |
| GO:0045121 membrane raft | ISO GO_REF:0000121 | ACCEPT | Summary: Membrane raft localization (phylogenetic, orthology or UniProt-mapping based). Reason: Fas partitions into membrane rafts upon activation, where the DISC assembles; this is directly shown for rat Fas after spinal cord injury (PMID:17518537), so the propagated claim is supported in rat. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Membrane raft {ECO:0000250|UniProtKB:P25445}. PMID:17518537 SCI resulted in FasL and Fas translocation into membrane raft microdomains where Fas associates with the adaptor proteins Fas-associated death domain (FADD), caspase-8, cellular FLIP long form (cFLIPL ), and caspase-3, forming a death-inducing signaling complex (DISC). |
| GO:0045121 membrane raft | ISS GO_REF:0000024 | ACCEPT | Summary: Membrane raft localization (phylogenetic, orthology or UniProt-mapping based). Reason: Fas partitions into membrane rafts upon activation, where the DISC assembles; this is directly shown for rat Fas after spinal cord injury (PMID:17518537), so the propagated claim is supported in rat. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Membrane raft {ECO:0000250|UniProtKB:P25445}. PMID:17518537 SCI resulted in FasL and Fas translocation into membrane raft microdomains where Fas associates with the adaptor proteins Fas-associated death domain (FADD), caspase-8, cellular FLIP long form (cFLIPL ), and caspase-3, forming a death-inducing signaling complex (DISC). |
| GO:0045471 response to ethanol | IEP PMID:27939985 Dihydroartemisinin protects against alcoholic liver injury t... | MARK AS OVER ANNOTATED | Summary: Ethanol-related hepatic gene expression (Fas presumably among inflammation/apoptosis genes). Reason: The abstract does not mention Fas; at most an expression change in alcoholic liver. No evidence that Fas performs the response to ethanol. Over-annotation. |
| GO:0045619 regulation of lymphocyte differentiation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Regulation of lymphocyte differentiation, transferred by orthology. Reason: Mouse lpr phenotype; downstream consequence of failed lymphocyte deletion. Non-core. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0045637 regulation of myeloid cell differentiation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Regulation of myeloid cell differentiation, transferred by orthology. Reason: Mouse phenotype; indirect consequence of Fas-mediated apoptosis in haematopoietic cells. Non-core. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0046898 response to cycloheximide | IEP PMID:9253159 Rapid induction of Fas antigen mRNA expression in vivo by cy... | MARK AS OVER ANNOTATED | Summary: Fas mRNA rapidly induced in vivo by cycloheximide. Reason: Expression-change (IEP) evidence only: the paper shows Fas mRNA/protein levels change but does not test whether Fas performs or is required for the process. Regulation of a death receptor's expression is not participation in the process; marked as over-annotation. Supporting Evidence: PMID:9253159 only the expression of Fas antigen was elevated rapidly in most of the organs examined |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:17518537 FasL, Fas, and death-inducing signaling complex (DISC) prote... | KEEP AS NON CORE | Summary: Perinuclear Fas clusters in neurons and astrocytes after spinal cord injury. Reason: Directly reported in the abstract; an injury-induced intracellular pool, peripheral to the surface signaling role. Supporting Evidence: PMID:17518537 SCI induced expression of Fas in clusters around the nucleus in both neurons and astrocytes. |
| GO:0048536 spleen development | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Spleen development, from mouse lpr phenotype. Reason: Splenomegaly in Fas-deficient mice results from accumulation of undeleted lymphocytes, not from a role of Fas in building the spleen. Over-annotation of a phenotype as a developmental process. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:95484 SUPPORTS SOURCE BUT NOT TARGET Source is a mouse phenotype-derived annotation; the transferred term describes a downstream or unrelated consequence rather than a process Fas carries out. |
| GO:0050869 negative regulation of B cell activation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of B cell activation, transferred by orthology. Reason: Fas-mediated deletion of activated B cells limits B-cell responses (mouse). Non-core. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0051384 response to glucocorticoid | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Response to glucocorticoid, transferred by orthology. Reason: Mouse-derived phenotype; glucocorticoid-induced death is largely Fas-independent, so this is at most a modulatory, non-core role. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0051402 neuron apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Neuron apoptotic process, transferred by orthology. Reason: Fas mediates neuronal apoptosis in injury models (mouse source; rat phenylalanine and ischemia data concur). Non-core cell-type instance. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0060135 maternal process involved in female pregnancy | IEP PMID:10084951 Fas and Fas ligand messenger ribonucleic acid and protein ex... | MARK AS OVER ANNOTATED | Summary: Fas/FasL expression in the corpus luteum during pregnancy and postpartum. Reason: Expression evidence plus reduction of spontaneous luteal apoptosis by anti-Fas antibody in vitro; this bears on luteolysis rather than on a maternal process of pregnancy, which is far broader. Over-annotation. Supporting Evidence: PMID:10084951 These data support a role for Fas receptor and FasL in rat CL apoptosis during luteolysis. |
| GO:0070227 lymphocyte apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Lymphocyte apoptotic process, transferred by orthology. Reason: Fas-mediated lymphocyte apoptosis underlies lpr lymphoproliferation (mouse source); a cell-type instance of the core pathway, non-core. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0070301 cellular response to hydrogen peroxide | IEP PMID:12111799 H(2)O(2) induces upregulation of Fas and Fas ligand expressi... | KEEP AS NON CORE | Summary: H2O2 induces Fas mRNA and protein in NGF-differentiated PC12 cells. Reason: Oxidative stress up-regulates Fas, and in rat cardiomyocytes H2O2 sensitizes cells to Fas-mediated apoptosis (PMID:16157298), so Fas contributes to the death response to H2O2. Non-core. Supporting Evidence: PMID:12111799 concentrations of H(2)O(2) inducing apoptotic cell death rapidly trigger the expression of Fas mRNA and protein as well as FasL mRNA |
| GO:0070301 cellular response to hydrogen peroxide | IEP PMID:16157298 Hydrogen peroxide predisposes neonatal rat ventricular myocy... | KEEP AS NON CORE | Summary: H2O2 sensitizes neonatal ventricular myocytes to Fas-mediated apoptosis. Reason: Functional sensitization to rFasL after H2O2 shows Fas participates in the cellular response to H2O2 (even though Fas protein itself decreased). Non-core. Supporting Evidence: PMID:16157298 Based on these findings we concluded that H2O2 sensitizes NRVM to Fas-mediated apoptosis |
| GO:0070848 response to growth factor | IEP PMID:18692025 c-Jun N-terminal kinases mediate Fas-induced neurite regener... | MARK AS OVER ANNOTATED | Summary: NGF dose-dependently induced Fas expression in PC12 cells. Reason: Expression evidence; Fas contribution to neurite regrowth is captured by the neuron projection regeneration row. "Response to growth factor" adds no specific claim. Over-annotation. Supporting Evidence: PMID:18692025 Nerve growth factor (NGF) dose-dependently induced sprouting and the expression of the NGF receptors Trk tyrosine kinase receptor (TrkA) and p75 neurotrophin receptor (p75(NTR)) as well as Fas and Fas ligand. |
| GO:0071234 cellular response to phenylalanine | IEP PMID:23940767 The Fas/Fas ligand death receptor pathway contributes to phe... | KEEP AS NON CORE | Summary: Phenylalanine increased surface Fas and Fas/FasL complex formation in cortical neurons. Reason: Fas blockade prevents Phe-induced apoptosis, so Fas participates in the cellular response to phenylalanine (in a hyperphenylalaninemia model). Non-core. Supporting Evidence: PMID:23940767 Phe significantly increased cell surface Fas expression |
| GO:0071248 cellular response to metal ion | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Cellular response to metal ion (ARBA). Reason: An ARBA machine-learning association with no specific mechanism for Fas; the one rat metal-ion study (cobalt) is captured more precisely by GO:0071279. Over-annotation. |
| GO:0071260 cellular response to mechanical stimulus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cellular response to mechanical stimulus, transferred by orthology. Reason: Human-derived; Fas participates in mechanically induced apoptosis. Context-specific, non-core. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0071279 cellular response to cobalt ion | IEP PMID:15519734 Involvement of mitochondrial- and Fas-mediated dual mechanis... | KEEP AS NON CORE | Summary: CoCl2 up-regulated Fas/FasL; antagonist antibody blocked caspase-8 activation. Reason: Functional blocking shows Fas contributes to CoCl2-induced apoptosis. Non-core. Supporting Evidence: PMID:15519734 We showed that expression of Fas and Fas ligand was upregulated and caspase-8 was significantly activated in CoCl(2)-induced apoptotic cells. |
| GO:0071285 cellular response to lithium ion | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cellular response to lithium ion, transferred by orthology. Reason: Mouse-derived phenotype; context-specific, non-core. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0071345 cellular response to cytokine stimulus | IEP PMID:16609999 Effects of interleukin-10 on activation and apoptosis of hep... | MARK AS OVER ANNOTATED | Summary: Fas mRNA in hepatic stellate cells after IL-10 treatment in fibrosis. Reason: Expression-change (IEP) evidence only: the paper shows Fas mRNA/protein levels change but does not test whether Fas performs or is required for the process. Regulation of a death receptor's expression is not participation in the process; marked as over-annotation. |
| GO:0071346 cellular response to type II interferon | IEP PMID:10029626 Involvement of CD95 (Apo-1/Fas) ligand expressed by rat Kupf... | KEEP AS NON CORE | Summary: IFN-gamma increased transmembrane CD95 mRNA and CD95 sensitivity of hepatocytes. Reason: IFN-gamma both induces Fas and sensitizes hepatocytes to CD95-mediated apoptosis; Fas executes the death component of this response. Non-core. Supporting Evidence: PMID:10029626 In liver parenchymal cells, interferon gamma increased messenger RNA levels of the transmembrane CD95 isoform and sensitivity of these cells toward CD95-mediated apoptosis. |
| GO:0071347 cellular response to interleukin-1 | IEP PMID:10678925 Tumor necrosis factor alpha and interleukin 1beta up-regulat... | KEEP AS NON CORE | Summary: IL-1beta and TNF-alpha induce Fas Ag in gastric mucosal RGM-1 cells, priming FasL-induced death. Reason: Cytokine-induced Fas renders cells susceptible to FasL-induced death or proliferation; Fas executes the downstream part of this response. Non-core. Supporting Evidence: PMID:10678925 Of various inflammatory cytokines tested, only interleukin 1beta and tumor necrosis factor alpha induced Fas Ag expression |
| GO:0071356 cellular response to tumor necrosis factor | IEP PMID:10678925 Tumor necrosis factor alpha and interleukin 1beta up-regulat... | KEEP AS NON CORE | Summary: IL-1beta and TNF-alpha induce Fas Ag in gastric mucosal RGM-1 cells, priming FasL-induced death. Reason: Cytokine-induced Fas renders cells susceptible to FasL-induced death or proliferation; Fas executes the downstream part of this response. Non-core. Supporting Evidence: PMID:10678925 Of various inflammatory cytokines tested, only interleukin 1beta and tumor necrosis factor alpha induced Fas Ag expression |
| GO:0071391 cellular response to estrogen stimulus | IEP PMID:15038834 The extracellular matrix, p53 and estrogen compete to regula... | KEEP AS NON CORE | Summary: Estrogen decreases Fas expression in embryonic cortical precursors; sFasL alters estrogen control of cell-cycle proteins. Reason: Reciprocal Fas-estrogen interplay shown in full text, including Fas-ligand-dependent effects on estrogen-regulated p21 and PCNA. Non-core. Supporting Evidence: PMID:15038834 The numbers of neuroblasts in G0 expressing the Fas receptor declined significantly, following exposure to estradiol-17beta. |
| GO:0071455 cellular response to hyperoxia | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cellular response to hyperoxia, transferred by orthology. Reason: Human IMP evidence that Fas mediates hyperoxia-induced epithelial death; context-specific, non-core. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0071456 cellular response to hypoxia | IEP PMID:12031707 Hypoxia predisposes neonatal rat ventricular myocytes to apo... | KEEP AS NON CORE | Summary: Hypoxia up-regulates Fas and predisposes ventricular myocytes to Fas-induced apoptosis. Reason: rFasL caused apoptosis only in hypoxic myocytes, so Fas participates in the hypoxic death response. Non-core. Supporting Evidence: PMID:12031707 By upregulating Fas expression and key proapoptotic proteins, and by downregulating antiapoptotic proteins, hypoxia predisposes ventricular myocytes to Fas-induced apoptosis. |
| GO:0071464 cellular response to hydrostatic pressure | IEP PMID:16226958 Pressure and endothelial coculture upregulate myocytic Fas-F... | MARK AS OVER ANNOTATED | Summary: Pressure increased Fas expression in smooth muscle cells. Reason: Expression-change (IEP) evidence only: the paper shows Fas mRNA/protein levels change but does not test whether Fas performs or is required for the process. Regulation of a death receptor's expression is not participation in the process; marked as over-annotation. Supporting Evidence: PMID:16226958 Pressure increased Fas and FasL expression in monocultured and cocultured SMCs |
| GO:0097049 motor neuron apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Motor neuron apoptotic process. Reason: Fas-triggered motor neuron death is documented in rodents (mouse source). A cell-type instance of Fas-mediated apoptosis; non-core. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0097049 motor neuron apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Motor neuron apoptotic process. Reason: Fas-triggered motor neuron death is documented in rodents (mouse source). A cell-type instance of Fas-mediated apoptosis; non-core. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0097190 apoptotic signaling pathway | IMP PMID:16953119 Metabolic loading of guanosine induces chondrocyte apoptosis... | MODIFY | Summary: Guanosine-induced chondrocyte apoptosis depends on Fas-FasL interaction. Reason: The abstract-only report attributes guanosine-induced chondrocyte apoptosis to Fas-FasL engagement; this places Fas in the extrinsic death-receptor pathway. Refine to GO:0008625. Proposed replacements: extrinsic apoptotic signaling pathway via death domain receptors Supporting Evidence: PMID:16953119 We found that guanosine promotes Fas-Fas ligand interaction which, in turn, leads to chondrocyte apoptosis. |
| GO:0097190 apoptotic signaling pathway | ISO GO_REF:0000121 | MODIFY | Summary: Apoptotic signaling pathway, from mouse Fas. Reason: Correct but general; the specific pathway is GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:95484 SUPPORTS TRANSFER Source claim is true for Fas; the transferred term is more general than the specific term already carried by the gene. Proposed replacements: extrinsic apoptotic signaling pathway via death domain receptors Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0097191 extrinsic apoptotic signaling pathway | IEA GO_REF:0000117 | MODIFY | Summary: Extrinsic apoptotic signaling pathway. Reason: Correct; the specific child term for a death-domain receptor is GO:0008625, already on the gene. Proposed replacements: extrinsic apoptotic signaling pathway via death domain receptors Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0097191 extrinsic apoptotic signaling pathway | IMP PMID:15519734 Involvement of mitochondrial- and Fas-mediated dual mechanis... | MODIFY | Summary: Antagonistic anti-Fas antibody blocked CoCl2-induced caspase-8 activation in PC12 cells. Reason: Supports Fas participation in extrinsic apoptotic signaling; refine to the death-domain receptor child GO:0008625. Proposed replacements: extrinsic apoptotic signaling pathway via death domain receptors Supporting Evidence: PMID:15519734 ZB4, an antagonistic Fas-antibody, inhibited the activation of caspase-8 by CoCl(2), indicating that Fas receptor was involved in this pathway. |
| GO:0097191 extrinsic apoptotic signaling pathway | ISO GO_REF:0000121 | MODIFY | Summary: Extrinsic apoptotic signaling pathway. Reason: Correct; the specific child term for a death-domain receptor is GO:0008625, already on the gene. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:95484 SUPPORTS TRANSFER Source claim is true for Fas; the transferred term is more general than the specific term already carried by the gene. Proposed replacements: extrinsic apoptotic signaling pathway via death domain receptors Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0097191 extrinsic apoptotic signaling pathway | ISO GO_REF:0000121 | MODIFY | Summary: Extrinsic apoptotic signaling pathway. Reason: Correct; the specific child term for a death-domain receptor is GO:0008625, already on the gene. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:95484 SUPPORTS TRANSFER Source claim is true for Fas; the transferred term is more general than the specific term already carried by the gene. Proposed replacements: extrinsic apoptotic signaling pathway via death domain receptors Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0097192 extrinsic apoptotic signaling pathway in absence of ligand | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Extrinsic apoptotic signaling pathway in absence of ligand, from mouse. Reason: GO:0097192 is defined for dependence receptors (DCC, UNC5B) that signal death when unliganded. Fas is a ligand-activated death receptor; any ligand-independent clustering (e.g. by stress) is better captured by GO:0008625. Over-annotation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:95484 SUPPORTS SOURCE BUT NOT TARGET Source is a mouse phenotype-derived annotation; the transferred term describes a downstream or unrelated consequence rather than a process Fas carries out. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Receptor for TNFSF6/FASLG. The adapter molecule FADD recruits caspase CASP8 to the activated receptor. |
| GO:0097284 hepatocyte apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Hepatocyte apoptotic process, transferred by orthology. Reason: Fas agonist antibody causes hepatocyte apoptosis (mouse source; rat hepatocyte CD95L data concur). Non-core cell-type instance. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
| GO:0097421 liver regeneration | IEP PMID:10632538 Fas (APO-1/CD95) mRNA is down-regulated in liver regeneratio... | MARK AS OVER ANNOTATED | Summary: Fas mRNA falls after partial hepatectomy and recovers by 14 days. Reason: Expression evidence only, and a related rat study found Fas expression did not affect regeneration (PMID:12522536). Over-annotation. Supporting Evidence: PMID:10632538 Partial hepatectomy led to a significant decrease in Fas mRNA levels at 2 h, with a further gradual reduction until 18 h. |
| GO:0097440 apical dendrite | IDA PMID:10024361 Fas/Apo [apoptosis]-1 and associated proteins in the differe... | UNDECIDED | Summary: Apical dendrite localization in developing rat cerebral cortex. Reason: Abstract-only paper; the abstract reports transient Fas expression in subsets of developing cortical cells but says nothing about apical dendrites. The sub-cellular claim cannot be checked from available text. Supporting Evidence: PMID:10024361 Fas mRNA and protein are transiently expressed in subsets of cells within the developing rat cerebral cortex during the peak period of apoptosis. |
| GO:0097527 necroptotic signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Necroptotic signaling pathway. Reason: Death receptors including Fas can trigger RIPK1/RIPK3-dependent necroptosis when caspase-8 is inhibited; Fas binds RIPK1. A real but conditional output; non-core. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Binds RIPK1 and FAIM2. |
| GO:0097527 necroptotic signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Necroptotic signaling pathway. Reason: Death receptors including Fas can trigger RIPK1/RIPK3-dependent necroptosis when caspase-8 is inhibited; Fas binds RIPK1. A real but conditional output; non-core. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Binds RIPK1 and FAIM2. |
| GO:0097527 necroptotic signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Necroptotic signaling pathway. Reason: Death receptors including Fas can trigger RIPK1/RIPK3-dependent necroptosis when caspase-8 is inhibited; Fas binds RIPK1. A real but conditional output; non-core. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt Binds RIPK1 and FAIM2. |
| GO:1900148 negative regulation of Schwann cell migration | IMP PMID:29970988 Fas Ligand Gene (Faslg) Plays an Important Role in Nerve Deg... | REMOVE | Summary: Negative regulation of Schwann cell migration attributed to Fas from a Faslg knockdown study. Reason: Full text read: only Faslg was silenced or overexpressed; Fas was not perturbed. The phenotype cannot be attributed to the receptor by IMP. Removed as a gene mis-attribution (source defect recorded). Supporting Evidence: PMID:29970988 Silencing of Faslg following transfection with Faslg siRNA in SCs significantly induced SC migration when compared to (NCs). |
| GO:1902617 response to fluoride | IEP PMID:20568470 [Experimental study on fas expression of spermatogenic cell ... | MARK AS OVER ANNOTATED | Summary: Fas expression increased in spermatogenic cells of fluoride-exposed rats. Reason: Expression-change (IEP) evidence only: the paper shows Fas mRNA/protein levels change but does not test whether Fas performs or is required for the process. Regulation of a death receptor's expression is not participation in the process; marked as over-annotation. Supporting Evidence: PMID:20568470 The expression of Fas in spermatogenic cells and the sperm aberration of each fluorotic group were higher than control group |
| GO:1903428 positive regulation of reactive oxygen species biosynthetic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of reactive oxygen species biosynthetic process, transferred by orthology. Reason: CD95L induces NADPH oxidase-dependent ROS in rat hepatocytes (PMID:18045865), consistent with the human-derived annotation. Non-core signaling output. Supporting Evidence: PMID:18045865 which triggers ceramide-dependent ROS formation as an upstream event of trafficking of intra |
| GO:2001235 positive regulation of apoptotic signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of apoptotic signaling pathway, from human FAS. Reason: Fas initiates rather than regulates the death-receptor pathway, but human evidence supports a role in promoting apoptotic signaling. Kept as non-core; the core pathway is GO:0008625. Supporting Evidence: file:rat/Fas/Fas-uniprot.txt The resulting death-inducing signaling complex (DISC) performs CASP8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. |
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Download this section (compressed HTML)Q: Which rat Fas transcripts encode soluble receptor forms beyond the 65-residue variant described in PMID:7507668, and do they antagonize FasL in vivo (e.g. in castrated prostate, where secretory-granule Fas is abundant)?
Q: The IMP annotations of Schwann-cell proliferation and migration to rat Fas cite a Faslg-only knockdown study (PMID:29970988); should RGD move them to Faslg or delete them?
Q: What determines whether Fas engagement in rat cardiomyocytes, PC12 cells and gastric mucosal cells yields non-apoptotic outputs (AP-1, JNK-driven neurite regrowth, ERK proliferation) instead of apoptosis?
Experiment: Knock down Fas (siRNA or AAV-shRNA) in cultured rat Schwann cells and in the injured sciatic nerve, with Faslg knockdown as comparator, and measure EdU incorporation, transwell migration and TUNEL.
Hypothesis: Fas itself, not only its ligand, restrains Schwann cell proliferation and migration after sciatic nerve injury.
Type: Loss-of-function with ligand comparator
Experiment: Express wild-type and death-domain point-mutant rat Fas in Fas-null cells, stimulate with FasL, and immunoprecipitate receptor complexes to quantify FADD, caspase-8 and cFLIP recruitment and caspase-8 processing.
Hypothesis: Rat Fas assembles a DISC through its death domain at the plasma membrane of hepatocytes after ligand engagement.
Type: Structure-function reconstitution
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