TNFRSF10B, also called DR5 or TRAIL receptor 2, is a type I plasma-membrane TNF receptor superfamily death receptor. Its extracellular cysteine-rich domains bind TNFSF10/TRAIL, and ligand-bound receptor trimers recruit FADD and initiator caspases through the intracellular death domain to assemble a death-inducing signaling complex and initiate TRAIL-activated extrinsic apoptosis. DR5 can also signal contextual NF-kappaB activation, can be induced by TP53, CHOP, PU.1, and therapeutic stressors, and is inhibited by decoy TRAIL receptors and viral MARCHF8-dependent down-regulation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002357 defense response to tumor cell | IDA PMID:28362429 PU.1 supports TRAIL-induced cell death by inhibiting NF-ΞΊB-m... | MODIFY | Summary: PU.1 induction of DR5 supports TRAIL-mediated tumor-cell apoptosis, but the defense-response term is too organismal for the receptor. Reason: TNFRSF10B executes the DR5 branch of TRAIL-activated apoptotic signaling in the responding tumor cell; GO:0036462 captures that receptor-proximal process better than defense response to tumor cell. Proposed replacements: TRAIL-activated apoptotic signaling pathway Supporting Evidence: PMID:28362429 PU.1 supports tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis |
| GO:0005035 death receptor activity | IEA GO_REF:0000117 | MODIFY | Summary: The automated death receptor activity row is correct but broader than the available TRAIL-specific receptor term. Reason: DR5 is a TRAIL-binding death receptor whose cytoplasmic death domain recruits FADD and initiator caspases; GO:0036463 captures the ligand specificity and receptor signaling activity. Proposed replacements: TRAIL receptor activity Supporting Evidence: PMID:10549288 Formation of a complex between Apo2L (also called TRAIL) and its signaling receptors, DR4 and DR5, triggers apoptosis PMID:10862756 FADD is required for DR4- and DR5-mediated apoptosis PMID:9430227 DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway |
| GO:0005515 protein binding | IPI PMID:10549288 Triggering cell death: the crystal structure of Apo2L/TRAIL ... | MODIFY | Summary: The TNFSF10 IPI row reflects the cognate TRAIL ligand interaction of DR5. Reason: TRAIL receptor activity is the informative molecular function for ligand-bound TNFRSF10B and is more precise than a generic TNFSF10 protein-binding edge. Proposed replacements: TRAIL receptor activity Supporting Evidence: PMID:10549288 Apo2L and the ectodomain of DR5 PMID:9373179 All three TRAIL receptors bind TRAIL with similar affinity |
| GO:0005515 protein binding | IPI PMID:18846110 Identification of an antiapoptotic protein complex at death ... | UNDECIDED | Summary: The cached record supports an anti-apoptotic protein complex at death receptors but does not expose the individual TNFRSF10B interaction. Reason: The local cache has only title-level evidence for this complex, so the DR5-specific IntAct edge cannot be accepted, removed, or replaced without the full text. 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 ... | UNDECIDED | Summary: The cached record supports an anti-apoptotic protein complex at death receptors but does not expose the individual TNFRSF10B interaction. Reason: The local cache has only title-level evidence for this complex, so the DR5-specific IntAct edge cannot be accepted, removed, or replaced without the full text. 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 ... | UNDECIDED | Summary: The cached record supports an anti-apoptotic protein complex at death receptors but does not expose the individual TNFRSF10B interaction. Reason: The local cache has only title-level evidence for this complex, so the DR5-specific IntAct edge cannot be accepted, removed, or replaced without the full text. 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 ... | UNDECIDED | Summary: The cached record supports an anti-apoptotic protein complex at death receptors but does not expose the individual TNFRSF10B interaction. Reason: The local cache has only title-level evidence for this complex, so the DR5-specific IntAct edge cannot be accepted, removed, or replaced without the full text. 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... | UNDECIDED | Summary: The cached abstract describes a TRAIL-sensitization or TRAIL-trafficking study but does not expose the exact TNFRSF10B-TNFSF10 interaction evidence. Reason: TNFSF10 is the cognate DR5 ligand, but the abstract-only local cache is not enough to adjudicate this paper-specific IntAct protein-binding import. Supporting Evidence: PMID:19427028 Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling. |
| GO:0005515 protein binding | IPI PMID:20097879 Identification of a novel proapoptotic function of resveratr... | UNDECIDED | Summary: The cached abstract describes a TRAIL-sensitization or TRAIL-trafficking study but does not expose the exact TNFRSF10B-TNFSF10 interaction evidence. Reason: TNFSF10 is the cognate DR5 ligand, but the abstract-only local cache is not enough to adjudicate this paper-specific IntAct protein-binding import. Supporting Evidence: PMID:20097879 Identification of a novel proapoptotic function of resveratrol in fat cells: SIRT1-independent sensitization to TRAIL-induced apoptosis. |
| GO:0005515 protein binding | IPI PMID:20103630 Multivalent DR5 peptides activate the TRAIL death pathway an... | UNDECIDED | Summary: The cached abstract describes a TRAIL-sensitization or TRAIL-trafficking study but does not expose the exact TNFRSF10B-TNFSF10 interaction evidence. Reason: TNFSF10 is the cognate DR5 ligand, but the abstract-only local cache is not enough to adjudicate this paper-specific IntAct protein-binding import. Supporting Evidence: PMID:20103630 Multivalent DR5 peptides activate the TRAIL death pathway and exert tumoricidal activity. |
| GO:0005515 protein binding | IPI PMID:21459798 Bortezomib primes neuroblastoma cells for TRAIL-induced apop... | UNDECIDED | Summary: The cached abstract describes a TRAIL-sensitization or TRAIL-trafficking study but does not expose the exact TNFRSF10B-TNFSF10 interaction evidence. Reason: TNFSF10 is the cognate DR5 ligand, but the abstract-only local cache is not enough to adjudicate this paper-specific IntAct protein-binding import. Supporting Evidence: PMID:21459798 Bortezomib primes neuroblastoma cells for TRAIL-induced apoptosis by linking the death receptor to the mitochondrial pathway. |
| GO:0005515 protein binding | IPI PMID:21525171 Bortezomib primes glioblastoma, including glioblastoma stem ... | UNDECIDED | Summary: The cached abstract describes a TRAIL-sensitization or TRAIL-trafficking study but does not expose the exact TNFRSF10B-TNFSF10 interaction evidence. Reason: TNFSF10 is the cognate DR5 ligand, but the abstract-only local cache is not enough to adjudicate this paper-specific IntAct protein-binding import. Supporting Evidence: PMID:21525171 Bortezomib primes glioblastoma, including glioblastoma stem cells, for TRAIL by increasing tBid stability and mitochondrial apoptosis. |
| GO:0005515 protein binding | IPI PMID:21822306 Identification of a novel pro-apoptotic role of NF-ΞΊB in the... | UNDECIDED | Summary: The cached abstract describes a TRAIL-sensitization or TRAIL-trafficking study but does not expose the exact TNFRSF10B-TNFSF10 interaction evidence. Reason: TNFSF10 is the cognate DR5 ligand, but the abstract-only local cache is not enough to adjudicate this paper-specific IntAct protein-binding import. Supporting Evidence: PMID:21822306 Identification of a novel pro-apoptotic role of NF-ΞΊB in the regulation of TRAIL- and CD95-mediated apoptosis of glioblastoma cells. |
| GO:0005515 protein binding | IPI PMID:22266862 Histone deacetylase inhibitors sensitize glioblastoma cells ... | UNDECIDED | Summary: The cached abstract describes a TRAIL-sensitization or TRAIL-trafficking study but does not expose the exact TNFRSF10B-TNFSF10 interaction evidence. Reason: TNFSF10 is the cognate DR5 ligand, but the abstract-only local cache is not enough to adjudicate this paper-specific IntAct protein-binding import. Supporting Evidence: PMID:22266862 Histone deacetylase inhibitors sensitize glioblastoma cells to TRAIL-induced apoptosis by c-myc-mediated downregulation of cFLIP. |
| GO:0005515 protein binding | IPI PMID:23678861 Inhibition of vacuolar ATPase attenuates the TRAIL-induced a... | UNDECIDED | Summary: The cached abstract describes a TRAIL-sensitization or TRAIL-trafficking study but does not expose the exact TNFRSF10B-TNFSF10 interaction evidence. Reason: TNFSF10 is the cognate DR5 ligand, but the abstract-only local cache is not enough to adjudicate this paper-specific IntAct protein-binding import. Supporting Evidence: PMID:23678861 Inhibition of vacuolar ATPase attenuates the TRAIL-induced activation of caspase-8 and modulates the trafficking of TRAIL receptosomes. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: The MUC1 row comes from the HuRI reference binary interactome screen. Reason: A systematic Y2H edge does not establish a DR5 apoptotic receptor function, so it should not be retained as a generic TNFRSF10B molecular-function annotation. Supporting Evidence: PMID:32296183 A reference map of human binary PPIs |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: The ASPH row comes from the HuRI reference binary interactome screen. Reason: A systematic Y2H edge does not establish a DR5 apoptotic receptor function, so it should not be retained as a generic TNFRSF10B molecular-function annotation. Supporting Evidence: PMID:32296183 A reference map of human binary PPIs |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: The ZDHHC15 row comes from the HuRI reference binary interactome screen. Reason: A systematic Y2H edge does not establish a DR5 apoptotic receptor function, so it should not be retained as a generic TNFRSF10B molecular-function annotation. Supporting Evidence: PMID:32296183 A reference map of human binary PPIs |
| GO:0005515 protein binding | IPI PMID:35922511 A physical wiring diagram for the human immune system. | MODIFY | Summary: The TNFSF10 IPI row reflects the cognate TRAIL ligand interaction of DR5. Reason: TRAIL receptor activity is the informative molecular function for ligand-bound TNFRSF10B and is more precise than a generic TNFSF10 protein-binding edge. Proposed replacements: TRAIL receptor activity Supporting Evidence: PMID:10549288 Apo2L and the ectodomain of DR5 PMID:9373179 All three TRAIL receptors bind TRAIL with similar affinity |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: TNFRSF10B/DR5 is a type I cell-surface death receptor for extracellular TRAIL. Reason: Plasma-membrane localization is intrinsic to DR5 TRAIL receptor activity and is directly supported by membrane-expression and ligand-binding evidence. Supporting Evidence: PMID:17462628 Membrane expression of DR4, DR5 and caspase-8 levels PMID:10549288 close to the receptor cell surface |
| GO:0005886 plasma membrane | IDA PMID:17462628 Membrane expression of DR4, DR5 and caspase-8 levels, but no... | ACCEPT | Summary: TNFRSF10B/DR5 is a type I cell-surface death receptor for extracellular TRAIL. Reason: Plasma-membrane localization is intrinsic to DR5 TRAIL receptor activity and is directly supported by membrane-expression and ligand-binding evidence. Supporting Evidence: PMID:17462628 Membrane expression of DR4, DR5 and caspase-8 levels PMID:10549288 close to the receptor cell surface |
| GO:0005886 plasma membrane | IEA GO_REF:0000117 | ACCEPT | Summary: TNFRSF10B/DR5 is a type I cell-surface death receptor for extracellular TRAIL. Reason: Plasma-membrane localization is intrinsic to DR5 TRAIL receptor activity and is directly supported by membrane-expression and ligand-binding evidence. Supporting Evidence: PMID:17462628 Membrane expression of DR4, DR5 and caspase-8 levels PMID:10549288 close to the receptor cell surface |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-139952 | ACCEPT | Summary: This Reactome event is part of the ligand-bound DR5/DISC plasma-membrane pathway. Reason: The event includes TNFRSF10B or a receptor-proximal complex built on TNFRSF10B at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-141139 | ACCEPT | Summary: This Reactome event is part of the ligand-bound DR5/DISC plasma-membrane pathway. Reason: The event includes TNFRSF10B or a receptor-proximal complex built on TNFRSF10B at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-141156 | ACCEPT | Summary: This Reactome event is part of the ligand-bound DR5/DISC plasma-membrane pathway. Reason: The event includes TNFRSF10B or a receptor-proximal complex built on TNFRSF10B at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-141316 | ACCEPT | Summary: This Reactome event is part of the ligand-bound DR5/DISC plasma-membrane pathway. Reason: The event includes TNFRSF10B or a receptor-proximal complex built on TNFRSF10B at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3371359 | MARK AS OVER ANNOTATED | Summary: This Reactome CFLAR/CASP8 event lies downstream of receptor-proximal DISC assembly. Reason: The event concerns FLIP-CASP8 checkpoint chemistry rather than the DR5 receptor itself, so exporting a TNFRSF10B plasma-membrane row here is too indirect. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3465429 | MARK AS OVER ANNOTATED | Summary: This Reactome CFLAR/CASP8 event lies downstream of receptor-proximal DISC assembly. Reason: The event concerns FLIP-CASP8 checkpoint chemistry rather than the DR5 receptor itself, so exporting a TNFRSF10B plasma-membrane row here is too indirect. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3465448 | MARK AS OVER ANNOTATED | Summary: This Reactome CFLAR/CASP8 event lies downstream of receptor-proximal DISC assembly. Reason: The event concerns FLIP-CASP8 checkpoint chemistry rather than the DR5 receptor itself, so exporting a TNFRSF10B plasma-membrane row here is too indirect. |
| 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 TNFRSF10B gene is not a cellular-component assertion about the mature DR5 receptor protein. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5635741 | KEEP AS NON CORE | Summary: This Reactome event is part of the ligand-bound DR5/DISC plasma-membrane pathway. Reason: Decoy-receptor heteromerization with DR5 is a direct plasma-membrane TRAIL-receptor complex event, but it belongs to inhibitory cross-talk rather than the core ligand-bound apoptotic route. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5675456 | MARK AS OVER ANNOTATED | Summary: This Reactome CFLAR/CASP8 event lies downstream of receptor-proximal DISC assembly. Reason: The event concerns FLIP-CASP8 checkpoint chemistry rather than the DR5 receptor itself, so exporting a TNFRSF10B plasma-membrane row here is too indirect. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-75146 | ACCEPT | Summary: This Reactome event is part of the ligand-bound DR5/DISC plasma-membrane pathway. Reason: The event includes TNFRSF10B or a receptor-proximal complex built on TNFRSF10B at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-75187 | ACCEPT | Summary: This Reactome event is part of the ligand-bound DR5/DISC plasma-membrane pathway. Reason: The event includes TNFRSF10B or a receptor-proximal complex built on TNFRSF10B at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-75238 | ACCEPT | Summary: This Reactome event is part of the ligand-bound DR5/DISC plasma-membrane pathway. Reason: The event includes TNFRSF10B or a receptor-proximal complex built on TNFRSF10B at the plasma membrane. |
| GO:0006915 apoptotic process | NAS PMID:9430227 Death receptor 5, a new member of the TNFR family, and DR4 i... | MODIFY | Summary: The broad apoptosis or signaling row can be narrowed to the TRAIL receptor pathway. Reason: TNFRSF10B specifically initiates TRAIL-activated death-receptor signaling, so GO:0036462 is more precise than this ancestor process. Proposed replacements: TRAIL-activated apoptotic signaling pathway Supporting Evidence: PMID:10862756 TRAIL receptors stably transfected into heterozygous FADD(+/-) cells or FADD(-/-) cells reconstituted with a FADD retroviral construct are sensitive to the TRAIL cytotoxic effect PMID:9430227 DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | MODIFY | Summary: The broad apoptosis or signaling row can be narrowed to the TRAIL receptor pathway. Reason: TNFRSF10B specifically initiates TRAIL-activated death-receptor signaling, so GO:0036462 is more precise than this ancestor process. Proposed replacements: TRAIL-activated apoptotic signaling pathway Supporting Evidence: PMID:10862756 TRAIL receptors stably transfected into heterozygous FADD(+/-) cells or FADD(-/-) cells reconstituted with a FADD retroviral construct are sensitive to the TRAIL cytotoxic effect PMID:9430227 DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway |
| GO:0007166 cell surface receptor signaling pathway | TAS PMID:9311998 TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. | MODIFY | Summary: The broad apoptosis or signaling row can be narrowed to the TRAIL receptor pathway. Reason: TNFRSF10B specifically initiates TRAIL-activated death-receptor signaling, so GO:0036462 is more precise than this ancestor process. Proposed replacements: TRAIL-activated apoptotic signaling pathway Supporting Evidence: PMID:10862756 TRAIL receptors stably transfected into heterozygous FADD(+/-) cells or FADD(-/-) cells reconstituted with a FADD retroviral construct are sensitive to the TRAIL cytotoxic effect PMID:9430227 DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway |
| GO:0007250 activation of NF-kappaB-inducing kinase activity | NAS PMID:11464292 CD95 and TRAIL receptor-mediated activation of protein kinas... | UNDECIDED | Summary: The cached abstract describes mixed CD95/TRAIL receptor NF-kappaB activation in pancreatic tumor cells. Reason: The abstract does not distinguish TNFRSF10B from other TRAIL receptors, so this DR5-specific NF-kappaB assertion cannot be adjudicated from local evidence alone. 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: DR5 can activate NF-kappaB in addition to FADD-dependent apoptosis. Reason: Use positive regulation of canonical NF-kappaB signal transduction for this contextual transcriptional output rather than the older NIK-activity wording. Proposed replacements: positive regulation of canonical NF-kappaB signal transduction Supporting Evidence: PMID:9430227 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 row is correct but still broader than the TRAIL-specific DR5 branch. Reason: GO:0036462 captures the ligand-specific pathway initiated by TRAIL-bound DR5. Proposed replacements: TRAIL-activated apoptotic signaling pathway Supporting Evidence: PMID:10862756 TRAIL receptors stably transfected into heterozygous FADD(+/-) cells or FADD(-/-) cells reconstituted with a FADD retroviral construct are sensitive to the TRAIL cytotoxic effect PMID:9430227 DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway |
| GO:0009986 cell surface | IBA GO_REF:0000033 | ACCEPT | Summary: Cell-surface localization is consistent with DR5 topology and function. Reason: TNFRSF10B is a type I surface receptor for soluble or membrane TNFSF10/TRAIL, and induced TRAIL-R2 surface detection also supports the component assertion. Supporting Evidence: PMID:22952982 upregulation of TRAIL-R1 and TRAIL-R2 PMID:17462628 Membrane expression of DR4, DR5 and caspase-8 levels |
| GO:0009986 cell surface | IDA PMID:22952982 N-terminal region of gelsolin induces apoptosis of activated... | ACCEPT | Summary: Cell-surface localization is consistent with DR5 topology and function. Reason: TNFRSF10B is a type I surface receptor for soluble or membrane TNFSF10/TRAIL, and induced TRAIL-R2 surface detection also supports the component assertion. Supporting Evidence: PMID:22952982 upregulation of TRAIL-R1 and TRAIL-R2 PMID:17462628 Membrane expression of DR4, DR5 and caspase-8 levels |
| GO:0009986 cell surface | IEA GO_REF:0000117 | ACCEPT | Summary: Cell-surface localization is consistent with DR5 topology and function. Reason: TNFRSF10B is a type I surface receptor for soluble or membrane TNFSF10/TRAIL, and induced TRAIL-R2 surface detection also supports the component assertion. Supporting Evidence: PMID:22952982 upregulation of TRAIL-R1 and TRAIL-R2 PMID:17462628 Membrane expression of DR4, DR5 and caspase-8 levels |
| GO:0016020 membrane | IEA GO_REF:0000044 | MODIFY | Summary: The UniProt subcellular-location mapping correctly captures membrane topology but is broader than the DR5 site of action. Reason: TNFRSF10B functions as a single-pass plasma-membrane receptor for extracellular TRAIL. Proposed replacements: plasma membrane Supporting Evidence: PMID:17462628 Membrane expression of DR4, DR5 and caspase-8 levels PMID:10549288 close to the receptor cell surface |
| GO:0034976 response to endoplasmic reticulum stress | IDA PMID:15322075 CHOP is involved in endoplasmic reticulum stress-induced apo... | MARK AS OVER ANNOTATED | Summary: ER stress can upregulate DR5 through CHOP in carcinoma cells. Reason: The cached evidence supports DR5 as an induced effector of ER-stress-triggered death, not as a gene product that executes the ER-stress response itself. Supporting Evidence: PMID:15322075 CHOP is involved in THG up-regulation of DR5, which is a critical step for ER stress-induced apoptosis in human cancer cells. |
| GO:0036462 TRAIL-activated apoptotic signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: TNFRSF10B/DR5 acts in the TRAIL-activated apoptotic signaling pathway. Reason: This term directly names the FADD- and CASP8-dependent apoptotic pathway initiated by TRAIL-bound DR5. Supporting Evidence: PMID:10862756 TRAIL receptors stably transfected into heterozygous FADD(+/-) cells or FADD(-/-) cells reconstituted with a FADD retroviral construct are sensitive to the TRAIL cytotoxic effect PMID:9430227 DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway |
| GO:0036462 TRAIL-activated apoptotic signaling pathway | IDA PMID:21785459 DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspas... | ACCEPT | Summary: TNFRSF10B/DR5 acts in the TRAIL-activated apoptotic signaling pathway. Reason: This term directly names the FADD- and CASP8-dependent apoptotic pathway initiated by TRAIL-bound DR5. Supporting Evidence: PMID:10862756 TRAIL receptors stably transfected into heterozygous FADD(+/-) cells or FADD(-/-) cells reconstituted with a FADD retroviral construct are sensitive to the TRAIL cytotoxic effect PMID:9430227 DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway |
| GO:0036462 TRAIL-activated apoptotic signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: TNFRSF10B/DR5 acts in the TRAIL-activated apoptotic signaling pathway. Reason: This term directly names the FADD- and CASP8-dependent apoptotic pathway initiated by TRAIL-bound DR5. Supporting Evidence: PMID:10862756 TRAIL receptors stably transfected into heterozygous FADD(+/-) cells or FADD(-/-) cells reconstituted with a FADD retroviral construct are sensitive to the TRAIL cytotoxic effect PMID:9430227 DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway |
| GO:0036462 TRAIL-activated apoptotic signaling pathway | IMP PMID:10862756 FADD is required for DR4- and DR5-mediated apoptosis: lack o... | ACCEPT | Summary: TNFRSF10B/DR5 acts in the TRAIL-activated apoptotic signaling pathway. Reason: This term directly names the FADD- and CASP8-dependent apoptotic pathway initiated by TRAIL-bound DR5. Supporting Evidence: PMID:10862756 TRAIL receptors stably transfected into heterozygous FADD(+/-) cells or FADD(-/-) cells reconstituted with a FADD retroviral construct are sensitive to the TRAIL cytotoxic effect PMID:9430227 DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway |
| GO:0036463 TRAIL receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: TNFRSF10B/DR5 has TRAIL receptor activity. Reason: DR5 binds TNFSF10/TRAIL through extracellular TNFR cysteine-rich domains and signals through its cytoplasmic death domain, matching GO:0036463. Supporting Evidence: PMID:10549288 Formation of a complex between Apo2L (also called TRAIL) and its signaling receptors, DR4 and DR5, triggers apoptosis PMID:10862756 FADD is required for DR4- and DR5-mediated apoptosis PMID:9430227 DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway |
| GO:0036463 TRAIL receptor activity | IDA PMID:28362429 PU.1 supports TRAIL-induced cell death by inhibiting NF-ΞΊB-m... | ACCEPT | Summary: TNFRSF10B/DR5 has TRAIL receptor activity. Reason: DR5 binds TNFSF10/TRAIL through extracellular TNFR cysteine-rich domains and signals through its cytoplasmic death domain, matching GO:0036463. Supporting Evidence: PMID:10549288 Formation of a complex between Apo2L (also called TRAIL) and its signaling receptors, DR4 and DR5, triggers apoptosis PMID:10862756 FADD is required for DR4- and DR5-mediated apoptosis PMID:9430227 DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway |
| GO:0038023 signaling receptor activity | NAS PMID:10549288 Triggering cell death: the crystal structure of Apo2L/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:10549288 Formation of a complex between Apo2L (also called TRAIL) and its signaling receptors, DR4 and DR5, triggers apoptosis PMID:10862756 FADD is required for DR4- and DR5-mediated apoptosis PMID:9430227 DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway |
| 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:10549288 Formation of a complex between Apo2L (also called TRAIL) and its signaling receptors, DR4 and DR5, triggers apoptosis PMID:10862756 FADD is required for DR4- and DR5-mediated apoptosis PMID:9430227 DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway |
| GO:0042981 regulation of apoptotic process | NAS PMID:10549288 Triggering cell death: the crystal structure of Apo2L/TRAIL ... | MODIFY | Summary: The broad apoptosis or signaling row can be narrowed to the TRAIL receptor pathway. Reason: TNFRSF10B specifically initiates TRAIL-activated death-receptor signaling, so GO:0036462 is more precise than this ancestor process. Proposed replacements: TRAIL-activated apoptotic signaling pathway Supporting Evidence: PMID:10862756 TRAIL receptors stably transfected into heterozygous FADD(+/-) cells or FADD(-/-) cells reconstituted with a FADD retroviral construct are sensitive to the TRAIL cytotoxic effect PMID:9430227 DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway |
| GO:0043065 positive regulation of apoptotic process | IBA GO_REF:0000033 | MODIFY | Summary: DR5 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 TNFRSF10B 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:10862756 TRAIL receptors stably transfected into heterozygous FADD(+/-) cells or FADD(-/-) cells reconstituted with a FADD retroviral construct are sensitive to the TRAIL cytotoxic effect PMID:9430227 DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IEP PMID:12761501 Large-scale identification and characterization of human gen... | UNDECIDED | Summary: This NF-kappaB row traces to a large-scale cDNA overexpression screen whose cached abstract does not name TNFRSF10B. Reason: Without the full hit table or full text, the screen cannot be used to verify a DR5-specific positive regulation of canonical NF-kappaB signal transduction row. Supporting Evidence: PMID:12761501 identified 299 cDNAs that activate the NF-kappaB pathway |
| 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 DR5 death domain, making it a better molecular-function term for TNFRSF10B. Proposed replacements: TRAIL receptor activity Supporting Evidence: PMID:10549288 Apo2L and the ectodomain of DR5 PMID:9373179 All three TRAIL receptors bind TRAIL with similar affinity |
| 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 DR5 death domain, making it a better molecular-function term for TNFRSF10B. Proposed replacements: TRAIL receptor activity Supporting Evidence: PMID:10549288 Apo2L and the ectodomain of DR5 PMID:9373179 All three TRAIL receptors bind TRAIL with similar affinity |
| GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress | IMP PMID:15322075 CHOP is involved in endoplasmic reticulum stress-induced apo... | MARK AS OVER ANNOTATED | Summary: ER stress can use CHOP-dependent DR5 induction to trigger apoptosis in tumor cells. Reason: DR5 is an induced death receptor that can engage the mitochondrial arm downstream; the evidence does not make TNFRSF10B an intrinsic-apoptosis effector for ER stress. Supporting Evidence: PMID:15322075 CHOP is involved in THG up-regulation of DR5, which is a critical step for ER stress-induced apoptosis in human cancer cells. |
| GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress | TAS PMID:22934019 The endoplasmic reticulum stress response in aging and age-r... | MARK AS OVER ANNOTATED | Summary: ER stress can use CHOP-dependent DR5 induction to trigger apoptosis in tumor cells. Reason: DR5 is an induced death receptor that can engage the mitochondrial arm downstream; the evidence does not make TNFRSF10B an intrinsic-apoptosis effector for ER stress. Supporting Evidence: PMID:15322075 CHOP is involved in THG up-regulation of DR5, which is a critical step for ER stress-induced apoptosis in human cancer cells. |
| GO:0071260 cellular response to mechanical stimulus | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: The mechanical-stimulus row is an expression-pattern over-annotation from a prostate-cancer BAD study. Reason: Expression change under cyclic stretch does not show that DR5 performs the cellular response to mechanical stimulus. 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: The mechanical-stimulus row is an expression-pattern over-annotation from a prostate-cancer BAD study. Reason: Expression change under cyclic stretch does not show that DR5 performs the cellular response to mechanical stimulus. Supporting Evidence: PMID:19593445 BAD, a pro-apoptotic protein of the Bcl-2 family |
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Download this section (compressed HTML)Q: Should InterPro2GO and ARBA mappings for TNFRSF10A and TNFRSF10B use GO:0036463 TRAIL receptor activity rather than the broader death receptor activity or the ligand-binding subactivity alone?
Q: Should Reactome-to-GOA restrict TNFRSF10B cellular-component exports to ligand-bound DR5/DISC events and avoid c-FLIP/CASP8 downstream checkpoints and TP53 transcriptional events?
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