TNFRSF10A, also called DR4 or TRAIL receptor 1, is a type I plasma-membrane TNF receptor superfamily member with extracellular cysteine-rich TRAIL-binding domains and an intracellular death domain. Binding of TNFSF10/TRAIL to cell-surface TNFRSF10A promotes receptor oligomerization in plasma-membrane rafts and assembly of a FADD- and CASP8/CASP10-containing death-inducing signaling complex that initiates TRAIL-activated extrinsic apoptosis. DR4 trafficking and raft partitioning are regulated by ARAP1 and ZDHHC3/GODZ, decoy TRAIL receptors can restrain DR4 signaling, and ligand-bound DR4 can also produce contextual NF-kappaB outputs.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002020 protease binding | IPI PMID:21785459 DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspas... | MODIFY | Summary: The CASP8/protease-binding row reflects DISC assembly during TRAIL signaling rather than a direct protease-binding activity of TNFRSF10A. Reason: FADD is the adaptor that recruits pro-caspase-8 to ligand-bound TRAIL receptors, so this co-complex edge should be narrowed to the TRAIL-activated apoptotic signaling pathway. Proposed replacements: TRAIL-activated apoptotic signaling pathway Supporting Evidence: PMID:21785459 DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspase-8 recruitment to FADD. |
| GO:0005035 death receptor activity | IEA GO_REF:0000117 | MODIFY | Summary: The death receptor activity row matches the established TNFRSF10A/DR4 role but can be stated with the TRAIL-specific receptor term. Reason: TNFRSF10A is the TRAIL-binding death receptor whose cytoplasmic death domain nucleates FADD- and CASP8-containing DISC assembly; GO:0036463 captures that receptor specificity better than the parent death receptor term. Proposed replacements: TRAIL receptor activity Supporting Evidence: PMID:9082980 designated death receptor-4, DR4 PMID:9430228 TRAIL induces apoptosis through two closely related receptors PMID:19090789 palmitoylation is required for its raft localization and its ability to |
| GO:0005035 death receptor activity | TAS PMID:9082980 The receptor for the cytotoxic ligand TRAIL. | MODIFY | Summary: The death receptor activity row matches the established TNFRSF10A/DR4 role but can be stated with the TRAIL-specific receptor term. Reason: TNFRSF10A is the TRAIL-binding death receptor whose cytoplasmic death domain nucleates FADD- and CASP8-containing DISC assembly; GO:0036463 captures that receptor specificity better than the parent death receptor term. Proposed replacements: TRAIL receptor activity Supporting Evidence: PMID:9082980 designated death receptor-4, DR4 PMID:9430228 TRAIL induces apoptosis through two closely related receptors |
| GO:0005515 protein binding | IPI PMID:17047155 Caspase-8 prevents sustained activation of NF-kappaB in mono... | REMOVE | Summary: The monocyte differentiation paper does not support retaining a generic TNFRSF10A-CASP8 protein-binding function. Reason: Even if CASP8 was recovered with TNFRSF10A in a complex, GO:0005515 is an uninformative and likely indirect DISC co-complex assertion rather than a direct DR4 function. Supporting Evidence: PMID:9430228 TRAIL induces apoptosis through two closely related receptors |
| GO:0005515 protein binding | IPI PMID:18165900 Arf and Rho GAP adapter protein ARAP1 participates in the mo... | REMOVE | Summary: ARAP1 binds the DR4 intracellular region and affects DR4 trafficking to the cell surface. Reason: The ARAP1 interaction regulates receptor trafficking and surface delivery in a specific context; bare protein binding is not an informative molecular-function annotation for DR4. Supporting Evidence: PMID:18165900 regulation of the cell-specific trafficking of DR4 |
| GO:0005515 protein binding | IPI PMID:18846110 Identification of an antiapoptotic protein complex at death ... | REMOVE | Summary: GSK3B was reported in an anti-apoptotic complex at stimulated death receptors. Reason: The anti-apoptotic complex is context-specific and the generic interaction should not be elevated to a TNFRSF10A molecular-function annotation. Supporting Evidence: PMID:18846110 Identification of an antiapoptotic protein complex at death receptors. |
| GO:0005515 protein binding | IPI PMID:18846110 Identification of an antiapoptotic protein complex at death ... | REMOVE | Summary: BIRC2 was reported in an anti-apoptotic complex at stimulated death receptors. Reason: This context-specific anti-apoptotic complex is not the ligand-binding or death-domain signaling activity of TNFRSF10A, and GO:0005515 adds no mechanistic precision. Supporting Evidence: PMID:18846110 Identification of an antiapoptotic protein complex at death receptors. |
| GO:0005515 protein binding | IPI PMID:19427028 Cullin3-based polyubiquitination and p62-dependent aggregati... | MODIFY | Summary: This TNFSF10 IPI row reflects the ligand interaction of the DR4 receptor. Reason: TRAIL receptor activity captures extracellular ligand recognition and death-receptor signaling more precisely than a bare TNFSF10 protein-binding edge. Proposed replacements: TRAIL receptor activity Supporting Evidence: PMID:9082980 designated death receptor-4, DR4 PMID:9373179 All three TRAIL receptors bind TRAIL with similar affinity |
| GO:0005515 protein binding | IPI PMID:19427028 Cullin3-based polyubiquitination and p62-dependent aggregati... | MODIFY | Summary: The CASP8 edge is downstream DISC biology from a CUL3/caspase-8 aggregation study. Reason: TNFRSF10A nucleates the TRAIL DISC through FADD, while the CUL3-dependent aggregation of caspase-8 is a downstream activation step; the pathway term is a better representation than direct DR4-CASP8 binding. Proposed replacements: TRAIL-activated apoptotic signaling pathway Supporting Evidence: PMID:19427028 Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling. |
| GO:0005515 protein binding | IPI PMID:20103630 Multivalent DR5 peptides activate the TRAIL death pathway an... | UNDECIDED | Summary: The cached record for this DR5 agonist-peptide study is abstract-only and does not verify the TNFRSF10A interaction imported by IntAct. Reason: The title and abstract focus on multivalent DR5 peptides; without the full text, the DR4-specific TNFSF10/CASP8 interaction evidence cannot be adjudicated confidently. Supporting Evidence: PMID:20103630 Multivalent DR5 peptides activate the TRAIL death pathway and exert tumoricidal activity. |
| GO:0005515 protein binding | IPI PMID:20103630 Multivalent DR5 peptides activate the TRAIL death pathway an... | UNDECIDED | Summary: The cached record for this DR5 agonist-peptide study is abstract-only and does not verify the TNFRSF10A interaction imported by IntAct. Reason: The title and abstract focus on multivalent DR5 peptides; without the full text, the DR4-specific TNFSF10/CASP8 interaction evidence cannot be adjudicated confidently. Supporting Evidence: PMID:20103630 Multivalent DR5 peptides activate the TRAIL death pathway and exert tumoricidal activity. |
| GO:0005515 protein binding | IPI PMID:21785459 DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspas... | MODIFY | Summary: The FADD IPI row reflects the death-domain adaptor step in the TRAIL DISC. Reason: TRAIL receptor activity is the informative receptor function; FADD is recruited to the activated receptor to bridge DR4 to initiator caspases. Proposed replacements: TRAIL receptor activity Supporting Evidence: PMID:21785459 DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspase-8 recruitment to FADD. PMID:9430228 TRAIL induces apoptosis through two closely related receptors |
| GO:0005515 protein binding | IPI PMID:21785459 DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspas... | MODIFY | Summary: CASP8 is recruited into the TRAIL DISC through FADD rather than by a direct TNFRSF10A protease-binding activity. Reason: The co-complex evidence supports receptor-proximal TRAIL pathway signaling, but the molecular function should not be a generic DR4-CASP8 protein-binding edge. Proposed replacements: TRAIL-activated apoptotic signaling pathway Supporting Evidence: PMID:21785459 DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspase-8 recruitment to FADD. |
| GO:0005515 protein binding | IPI PMID:21785459 DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspas... | REMOVE | Summary: DJ-1/PARK7 inhibits TRAIL-induced apoptosis by binding FADD, not by providing a core DR4 activity. Reason: The cached evidence supports DJ-1 competition with pro-caspase-8 for FADD and regulation of DISC assembly, so importing a TNFRSF10A-PARK7 protein-binding row over-scopes the receptor. Supporting Evidence: PMID:21785459 DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspase-8 recruitment to FADD. |
| GO:0005515 protein binding | IPI PMID:30833792 A protein-interaction network of interferon-stimulated genes... | UNDECIDED | Summary: The LGALS3BP row comes from a broad AP-MS survey of interferon-stimulated-gene interactions. Reason: The cached abstract describes a broad interferon-stimulated AP-MS network and does not contain enough TNFRSF10A/LGALS3BP-specific detail to accept or reject the imported edge. Supporting Evidence: PMID:30833792 mass-spectrometry-based survey |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: The BioPlex CASP8 row is a proteome-scale AP-MS interaction edge. Reason: A BioPlex co-purification does not improve on curated death-receptor/DISC annotations and should not be kept as generic TNFRSF10A protein binding. Supporting Evidence: PMID:33961781 mass spectrometry, we have created two proteome-scale, cell-line-specific |
| GO:0005515 protein binding | IPI PMID:35922511 A physical wiring diagram for the human immune system. | MODIFY | Summary: This surface-protein screen recovered the extracellular TNFSF10-TNFRSF10A interaction. Reason: TRAIL receptor activity captures the direct receptor-ligand molecular function represented by this surface-protein-screen import. Proposed replacements: TRAIL receptor activity Supporting Evidence: PMID:35922511 we systematically mapped the direct protein PMID:9082980 designated death receptor-4, DR4 |
| GO:0005794 Golgi apparatus | IDA PMID:22240897 Regulation in the targeting of TRAIL receptor 1 to cell surf... | KEEP AS NON CORE | Summary: GODZ/ZDHHC3-dependent trafficking places a pool of TNFRSF10A in the Golgi before delivery to the plasma membrane. Reason: Golgi localization is part of receptor maturation and trafficking, not the core cell-surface death receptor activity. Supporting Evidence: PMID:22240897 GODZ binds to DR4, but not to DR5 |
| GO:0005829 cytosol | IDA PMID:22240897 Regulation in the targeting of TRAIL receptor 1 to cell surf... | KEEP AS NON CORE | Summary: The cytosol row reflects mistargeted or membrane-associated trafficking pools in the GODZ study. Reason: TNFRSF10A is a single-pass membrane receptor and functions at the cell surface, but intracellular trafficking and the cytosolic death domain make this a defensible non-core localization rather than a core site of TRAIL signaling. Supporting Evidence: PMID:22240897 GODZ binds to DR4, but not to DR5 |
| GO:0005829 cytosol | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The automated UniProtKB-SubCell cytosol mapping is too broad for a single-pass death receptor. Reason: TNFRSF10A is a single-pass membrane receptor and functions at the cell surface, but intracellular trafficking and the cytosolic death domain make this a defensible non-core localization rather than a core site of TRAIL signaling. Supporting Evidence: PMID:22240897 GODZ binds to DR4, but not to DR5 |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT propagates the conserved membrane localization of the TRAIL receptor family. Reason: Cell-surface or plasma-membrane localization is intrinsic to TNFRSF10A death receptor signaling and is experimentally supported in human DR4. Supporting Evidence: PMID:22240897 GODZ binds to DR4, but not to DR5 PMID:19090789 palmitoylation is required for its raft localization and its ability to |
| GO:0005886 plasma membrane | IDA PMID:22240897 Regulation in the targeting of TRAIL receptor 1 to cell surf... | ACCEPT | Summary: GODZ-dependent DR4 targeting supports plasma-membrane localization of TNFRSF10A. Reason: TNFRSF10A must reach the plasma membrane to bind extracellular TNFSF10/TRAIL and signal apoptosis. Supporting Evidence: PMID:22240897 GODZ binds to DR4, but not to DR5 |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Automated plasma-membrane localization is consistent with the type I membrane death-receptor topology of TNFRSF10A. Reason: The core receptor is a plasma membrane protein that engages extracellular TRAIL and recruits intracellular FADD/CASP8 through its death domain. Supporting Evidence: PMID:9082980 designated death receptor-4, DR4 PMID:22240897 GODZ binds to DR4, but not to DR5 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-139952 | ACCEPT | Summary: TNFRSF10A remains part of the plasma-membrane DISC during CASP8 recruitment and processing. Reason: The Reactome event is downstream of receptor ligation but still occurs at a DISC assembled by ligand-bound DR4 or DR5 at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-141139 | ACCEPT | Summary: The Reactome trimerization event explicitly includes TNFSF10 bound to TNFRSF10A or TNFRSF10B. Reason: This is a proximal ligand-receptor step in which TNFRSF10A acts at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-141156 | ACCEPT | Summary: True: entailed by plasma membrane raft, kept in this review. Reason: The claim is true: plasma membrane raft, kept in this review, entails this term. Other rows for this term are ACCEPTed. This row's reference does not establish it; that is recorded in source_defects, not grounds for REMOVE, which judges the claim. Supporting Evidence: PMID:22240897 GODZ binds to DR4, but not to DR5 PMID:19090789 palmitoylation is required for its raft localization and its ability to |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-141316 | ACCEPT | Summary: The Reactome CASP10 recruitment event explicitly allows a TNFSF10:TNFRSF10A:FADD complex. Reason: TNFRSF10A is still part of the plasma-membrane DISC that recruits initiator caspases. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3371359 | MARK AS OVER ANNOTATED | Summary: This c-FLIP/CASP8 heterodimer event is downstream of receptor-proximal TNFRSF10A ligand binding. Reason: TNFRSF10A builds the TRAIL DISC, but a FLIP(L)-CASP8 regulatory event should not be used as independent evidence for receptor plasma-membrane localization. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3465429 | MARK AS OVER ANNOTATED | Summary: This FLIP(S)/CASP8 event is a downstream regulator of death-receptor signaling. Reason: The event summary concerns CFLAR and CASP8 rather than the DR4 receptor itself, so exporting a TNFRSF10A location here is too indirect. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3465448 | MARK AS OVER ANNOTATED | Summary: This CASP8/FLIP(L) processing event is downstream of receptor-proximal DISC assembly. Reason: The event does not add direct TNFRSF10A localization evidence beyond the upstream TRAIL receptor complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5633441 | MARK AS OVER ANNOTATED | Summary: This Reactome event describes TP53-driven transcription of TRAIL receptor genes. Reason: A transcriptional event for the TNFRSF10A gene is not a cellular-component assertion about the mature TNFRSF10A receptor protein. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5635741 | ACCEPT | Summary: TNFRSF10D/DcR2 can heteromerize with TNFRSF10A or TNFRSF10B at the plasma membrane. Reason: Decoy-receptor heteromerization with DR4/DR5 is a direct plasma-membrane TRAIL-receptor complex event, even though it belongs to an inhibitory receptor context rather than the core apoptotic route. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5675456 | MARK AS OVER ANNOTATED | Summary: This FLIP(L)/CASP8 heterodimer event belongs to the downstream CASP8-CFLAR apoptosis/necroptosis checkpoint. Reason: The event is too far downstream to serve as a TNFRSF10A-specific plasma-membrane assertion. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-75146 | ACCEPT | Summary: FADD recruitment to a TNFSF10:TNFRSF10A/B receptor trimer is a receptor-proximal plasma-membrane DISC step. Reason: Ligand-bound TNFRSF10A is still a component of this plasma-membrane receptor complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-75187 | ACCEPT | Summary: TRAIL receptor trimers recruit FADD at the plasma membrane. Reason: This is the immediate adaptor-recruitment step downstream of TNFRSF10A ligand binding. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-75238 | ACCEPT | Summary: TNFSF10 binding to TNFRSF10A or TNFRSF10B is a plasma-membrane receptor event. Reason: The Reactome event names TNFRSF10A as a TRAIL receptor in the initial ligand-binding step. |
| GO:0006915 apoptotic process | NAS PMID:9311998 TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. | MODIFY | Summary: The top-level apoptosis row is correct but too broad for DR4. Reason: TNFRSF10A specifically initiates the TRAIL-activated branch of death-receptor apoptosis, so GO:0036462 is the better process term. Proposed replacements: TRAIL-activated apoptotic signaling pathway Supporting Evidence: PMID:9082980 designated death receptor-4, DR4 PMID:9430228 TRAIL induces apoptosis through two closely related receptors |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | MODIFY | Summary: A death-domain signature maps to signaling, but TNFRSF10A supports the TRAIL death-receptor pathway specifically. Reason: Use the TRAIL-specific apoptotic signaling process rather than top-level signal transduction. Proposed replacements: TRAIL-activated apoptotic signaling pathway Supporting Evidence: PMID:9082980 designated death receptor-4, DR4 PMID:9430228 TRAIL induces apoptosis through two closely related receptors |
| GO:0007165 signal transduction | TAS PMID:9082980 The receptor for the cytotoxic ligand TRAIL. | MODIFY | Summary: The original DR4 paper supports TRAIL-triggered death-receptor signaling rather than generic signal transduction. Reason: GO:0036462 names the ligand-specific apoptotic signaling route mediated by DR4. Proposed replacements: TRAIL-activated apoptotic signaling pathway Supporting Evidence: PMID:9082980 designated death receptor-4, DR4 PMID:9430228 TRAIL induces apoptosis through two closely related receptors |
| GO:0007250 activation of NF-kappaB-inducing kinase activity | NAS PMID:11464292 CD95 and TRAIL receptor-mediated activation of protein kinas... | MODIFY | Summary: TRAIL receptor ligation can activate NF-kappaB in pancreatic tumor cells. Reason: GO:0007250 is an older NIK-activity wording; positive regulation of canonical NF-kappaB signal transduction better describes this contextual DR4/DR5 output. Proposed replacements: positive regulation of canonical NF-kappaB signal transduction Supporting Evidence: PMID:11464292 or TRAIL resulted in activation of protein kinase C and NF-kappaB |
| GO:0007250 activation of NF-kappaB-inducing kinase activity | NAS PMID:9430227 Death receptor 5, a new member of the TNFR family, and DR4 i... | MODIFY | Summary: DR4 can activate NF-kappaB in addition to FADD-dependent apoptosis. Reason: Use positive regulation of canonical NF-kappaB signal transduction for this non-core transcriptional output. Proposed replacements: positive regulation of canonical NF-kappaB signal transduction Supporting Evidence: PMID:9430227 both receptors can activate NF-kappaB |
| GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors | NAS PMID:9311998 TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. | MODIFY | Summary: The death-domain receptor process term is correct but still broader than the TRAIL-specific branch. Reason: TNFRSF10A mediates the TNFSF10/TRAIL arm, so GO:0036462 is more precise than the parent death-domain-receptor pathway. Proposed replacements: TRAIL-activated apoptotic signaling pathway Supporting Evidence: PMID:9082980 designated death receptor-4, DR4 PMID:9430228 TRAIL induces apoptosis through two closely related receptors |
| GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors | TAS PMID:9082980 The receptor for the cytotoxic ligand TRAIL. | MODIFY | Summary: The original DR4 row to death-domain-receptor apoptotic signaling can be tightened to the TRAIL branch. Reason: GO:0036462 captures the specific ligand/receptor pathway initiated by TRAIL-bound DR4. Proposed replacements: TRAIL-activated apoptotic signaling pathway Supporting Evidence: PMID:9082980 designated death receptor-4, DR4 |
| GO:0009986 cell surface | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT assigns cell-surface activity to the experimentally supported TRAIL receptors TNFRSF10A and TNFRSF10B. Reason: TNFRSF10A acts as a cell-surface death receptor for the extracellular TNFSF10 ligand. Supporting Evidence: PMID:22240897 GODZ binds to DR4, but not to DR5 PMID:35922511 we systematically mapped the direct protein |
| GO:0009986 cell surface | IDA PMID:22952982 N-terminal region of gelsolin induces apoptosis of activated... | ACCEPT | Summary: N-terminal gelsolin fragments upregulated TRAIL-R1 on the surface of activated LX2 cells. Reason: The experiment directly detected induced TNFRSF10A/TRAIL-R1 at the cell surface of activated LX2 cells; the context is not a canonical DR4 signaling paper, but it still supports the cellular-component assertion. Supporting Evidence: PMID:22952982 modulation of cell death using this fragment involved upregulation of TRAIL-R1 |
| GO:0009986 cell surface | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA cell-surface localization is consistent with the receptor topology and curated cell-surface experiments. Reason: TNFRSF10A is a type I surface receptor for soluble or membrane TNFSF10/TRAIL. Supporting Evidence: PMID:9082980 designated death receptor-4, DR4 PMID:22240897 GODZ binds to DR4, but not to DR5 |
| GO:0036462 TRAIL-activated apoptotic signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: The PAINT TRAIL-activated apoptotic signaling row is correct for DR4. Reason: This inherited annotation is placed on the DR4/DR5 signaling node rather than on decoy TRAIL receptors and matches the GO-CAM TRAIL/TRAILR1 model. Supporting Evidence: PMID:9082980 designated death receptor-4, DR4 PMID:9430228 TRAIL induces apoptosis through two closely related receptors PMID:19090789 palmitoylation is required for its raft localization and its ability to |
| GO:0036462 TRAIL-activated apoptotic signaling pathway | IDA PMID:21785459 DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspas... | ACCEPT | Summary: TNFRSF10A acts in TRAIL-induced DISC formation in the DJ-1/FADD/CASP8 study. Reason: Although the paper focuses on DJ-1 inhibition, its FADD and pro-caspase-8 recruitment assays probe the TRAIL-activated apoptotic pathway downstream of DR4/DR5. Supporting Evidence: PMID:21785459 DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspase-8 recruitment to FADD. |
| GO:0036462 TRAIL-activated apoptotic signaling pathway | IDA PMID:9430228 TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent ap... | ACCEPT | Summary: DR4 and DR5 signal FADD-dependent TRAIL apoptosis. Reason: The evidence directly supports a TRAIL-specific apoptotic pathway for TNFRSF10A/DR4. Supporting Evidence: PMID:9430228 TRAIL induces apoptosis through two closely related receptors |
| GO:0036462 TRAIL-activated apoptotic signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: The ARBA TRAIL-activated apoptotic signaling row matches the experimentally established DR4 function. Reason: TNFRSF10A is the signaling TRAIL receptor DR4 and should carry the TRAIL-specific pathway term. Supporting Evidence: PMID:9082980 designated death receptor-4, DR4 PMID:9430228 TRAIL induces apoptosis through two closely related receptors |
| GO:0036462 TRAIL-activated apoptotic signaling pathway | IMP PMID:19090789 Palmitoylation of the TRAIL receptor DR4 confers an efficien... | ACCEPT | Summary: DR4 palmitoylation is required for raft localization, oligomerization, and efficient TRAIL-induced death signaling. Reason: This directly tests DR4 in the TRAIL-activated apoptotic pathway. Supporting Evidence: PMID:19090789 palmitoylation is required for its raft localization and its ability to |
| GO:0038023 signaling receptor activity | NAS PMID:19090789 Palmitoylation of the TRAIL receptor DR4 confers an efficien... | MODIFY | Summary: The signaling receptor activity row can be narrowed to the TRAIL-specific death-receptor activity. Reason: GO:0036463 names the TNFSF10/TRAIL receptor activity that couples ligand binding to death-domain apoptotic signaling. Proposed replacements: TRAIL receptor activity Supporting Evidence: PMID:9082980 designated death receptor-4, DR4 PMID:9430228 TRAIL induces apoptosis through two closely related receptors PMID:19090789 palmitoylation is required for its raft localization and its ability to |
| GO:0038023 signaling receptor activity | NAS PMID:9311998 TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. | MODIFY | Summary: The signaling receptor activity row can be narrowed to the TRAIL-specific death-receptor activity. Reason: GO:0036463 names the TNFSF10/TRAIL receptor activity that couples ligand binding to death-domain apoptotic signaling. Proposed replacements: TRAIL receptor activity Supporting Evidence: PMID:9430228 TRAIL induces apoptosis through two closely related receptors PMID:9430227 both receptors can activate NF-kappaB |
| GO:0042802 identical protein binding | IDA PMID:19090789 Palmitoylation of the TRAIL receptor DR4 confers an efficien... | MODIFY | Summary: Palmitoylation promotes DR4 raft localization and oligomerization. Reason: Self-association is part of DR4 activation, but TRAIL receptor activity is the receptor-level molecular function that combines ligand binding, oligomerization, and death-domain signaling. Proposed replacements: TRAIL receptor activity Supporting Evidence: PMID:19090789 palmitoylation is required for its raft localization and its ability to |
| GO:0043065 positive regulation of apoptotic process | IBA GO_REF:0000033 | MODIFY | Summary: DR4 positively drives apoptosis through the TRAIL death-receptor pathway. Reason: GO:0036462 is more precise than generic positive regulation of apoptotic process for a signaling TRAIL receptor. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN002923102 SUPPORTS TRANSFER PAINT correctly places TRAIL-receptor apoptotic signaling on DR4/DR5 descendants, but GO:0036462 is a more precise process term for TNFRSF10A than the generic regulation parent. ZFIN:ZDB-GENE-010802-1 SUPPORTS TRANSFER Zebrafish trail receptor evidence supports an inherited pro-apoptotic TRAIL receptor role; the issue is term specificity rather than a bad source annotation. Proposed replacements: TRAIL-activated apoptotic signaling pathway Supporting Evidence: PMID:9082980 designated death receptor-4, DR4 PMID:9430228 TRAIL induces apoptosis through two closely related receptors |
| GO:0044853 plasma membrane raft | IDA PMID:19090789 Palmitoylation of the TRAIL receptor DR4 confers an efficien... | ACCEPT | Summary: DR4 palmitoylation targets the receptor to plasma-membrane rafts for efficient TRAIL signaling. Reason: GO-CAM also places the TNFRSF10A TRAIL/TRAILR1 activity in plasma membrane raft, matching this experimental evidence. Supporting Evidence: PMID:19090789 palmitoylation is required for its raft localization and its ability to |
| GO:0045121 membrane raft | EXP PMID:22240897 Regulation in the targeting of TRAIL receptor 1 to cell surf... | MODIFY | Summary: GODZ/ZDHHC3-dependent palmitoylation places DR4 in a plasma-membrane raft signaling pool. Reason: Plasma membrane raft is more precise than the generic membrane raft term for TRAIL receptor death signaling. Proposed replacements: plasma membrane raft Supporting Evidence: PMID:22240897 GODZ binds to DR4, but not to DR5 PMID:19090789 palmitoylation is required for its raft localization and its ability to |
| GO:0045121 membrane raft | IDA PMID:19090789 Palmitoylation of the TRAIL receptor DR4 confers an efficien... | MODIFY | Summary: DR4 palmitoylation is required for raft localization during TRAIL signaling. Reason: Use plasma membrane raft to capture the receptor-proximal surface microdomain rather than a generic membrane raft. Proposed replacements: plasma membrane raft Supporting Evidence: PMID:19090789 palmitoylation is required for its raft localization and its ability to |
| GO:0045121 membrane raft | IEA GO_REF:0000044 | MODIFY | Summary: The automated membrane-raft mapping is consistent with DR4 palmitoylation-dependent surface raft localization. Reason: Plasma membrane raft is the more precise site for TNFRSF10A-mediated TRAIL signaling. Proposed replacements: plasma membrane raft Supporting Evidence: PMID:19090789 palmitoylation is required for its raft localization and its ability to |
| GO:0045569 TRAIL binding | IEA GO_REF:0000002 | MODIFY | Summary: The TRAIL binding row captures ligand recognition but can be folded into the complete TRAIL receptor activity term. Reason: GO:0036463 includes binding the TNFSF10/TRAIL ligand and signaling through the death-receptor cytoplasmic domain, making it a better molecular-function term for TNFRSF10A/DR4. Proposed replacements: TRAIL receptor activity Supporting Evidence: PMID:9373179 All three TRAIL receptors bind TRAIL with similar affinity PMID:9082980 designated death receptor-4, DR4 |
| GO:0045569 TRAIL binding | NAS PMID:9373179 Characterization of two receptors for TRAIL. | MODIFY | Summary: The TRAIL binding row captures ligand recognition but can be folded into the complete TRAIL receptor activity term. Reason: GO:0036463 includes binding the TNFSF10/TRAIL ligand and signaling through the death-receptor cytoplasmic domain, making it a better molecular-function term for TNFRSF10A/DR4. Proposed replacements: TRAIL receptor activity Supporting Evidence: PMID:9373179 All three TRAIL receptors bind TRAIL with similar affinity PMID:9082980 designated death receptor-4, DR4 |
| GO:0071260 cellular response to mechanical stimulus | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: The ARBA mechanical-stimulus row is not part of core TNFRSF10A biology. Reason: The linked experimental row is only expression-pattern evidence from a prostate-cancer BAD study and should not be propagated as a DR4 apoptotic function. Supporting Evidence: PMID:19593445 BAD, a pro-apoptotic protein of the Bcl-2 family |
| GO:0071260 cellular response to mechanical stimulus | IEP PMID:19593445 Expression of the Bcl-2 protein BAD promotes prostate cancer... | MARK AS OVER ANNOTATED | Summary: This IEP row only reports TNFRSF10A expression changes in a mechanical-stress experiment. Reason: Expression change under cyclic stretch does not show that DR4 performs the cellular response to mechanical stimulus. Supporting Evidence: PMID:19593445 BAD, a pro-apoptotic protein of the Bcl-2 family |
| GO:0097191 extrinsic apoptotic signaling pathway | IDA PMID:21785459 DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspas... | MODIFY | Summary: The broad extrinsic apoptotic signaling row can be tightened to the TRAIL branch. Reason: TNFRSF10A is a TRAIL receptor; GO:0036462 is the specific extrinsic pathway initiated by DR4 ligand binding. Proposed replacements: TRAIL-activated apoptotic signaling pathway Supporting Evidence: PMID:21785459 DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspase-8 recruitment to FADD. PMID:9430228 TRAIL induces apoptosis through two closely related receptors |
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Q: Should Reactome-to-GOA restrict TNFRSF10A cellular-component exports to ligand-bound DR4/DISC events and avoid DR5-only CASP8 events, c-FLIP/CASP8 downstream checkpoints, and TP53 transcriptional events?
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