CASP9 encodes the apoptosome-associated initiator caspase of the intrinsic mitochondrial apoptosis pathway. After cytochrome c release, APAF1 recruits procaspase-9 through CARD-CARD interactions and assembles an apoptosome platform that activates caspase-9, allowing the enzyme to cleave and mature executioner procaspases such as CASP3 and CASP7. Proteolytic activity resides in the full-length Caspase-9L isoform, whereas the shorter Caspase-9S isoform retains the recruitment domain but lacks the central catalytic domain and can antagonize intrinsic apoptosis by interfering with productive APAF1-caspase-9 complex formation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Procaspase-9 is a cytoplasmic apoptotic initiator. Reason: The inactive zymogen is cytoplasmic before apoptotic activation and the IBA localization agrees with experimental CASP9 localization evidence. Supporting Evidence: PMID:12782307 caspase-9 is in the cytoplasm of non-apoptotic pituitary cells |
| GO:0006915 apoptotic process | IBA GO_REF:0000033 | MODIFY | Summary: CASP9 acts as the apoptosome-associated initiator caspase in intrinsic apoptosis; the top-level apoptotic-process term can be tightened. Reason: The inherited top-level apoptosis assertion is directionally correct, but CASP9 acts at the apoptosome in intrinsic apoptotic signaling rather than as an undifferentiated apoptosis participant. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000047947 SUPPORTS SOURCE BUT NOT TARGET The PAINT node supports inherited caspase apoptosis biology, but CASP9 is the intrinsic initiator and the top-level apoptotic-process term can be tightened. Proposed replacements: intrinsic apoptotic signaling pathway Supporting Evidence: PMID:9390557 Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains |
| GO:0004197 cysteine-type endopeptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Cysteine-type endopeptidase activity is the catalytic activity of full-length CASP9. Reason: The PAINT assertion is sound for catalytically active caspase-9 orthologs; the human full-length protein cleaves and activates executioner procaspases after apoptosome recruitment. Supporting Evidence: PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: The apoptosome-associated intrinsic pathway activates CASP9 in the cytosol. Reason: Cytochrome c and APAF1 assemble the apoptosome in the cytosol, matching this inferred CASP9 localization. Supporting Evidence: PMID:12782307 caspase-9 is in the cytoplasm of non-apoptotic pituitary cells |
| GO:0043525 positive regulation of neuron apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Neuronal apoptosis is a well-known developmental outcome of the CASP9 pathway, but it is not a separate core activity of the enzyme. Reason: CASP9 executes the same intrinsic initiator-caspase chemistry in neurons as in other apoptosis contexts; the neuron-specific term should not be treated as its core molecular role. |
| GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage | IBA GO_REF:0000033 | MODIFY | Summary: The inherited DNA-damage-specific intrinsic-apoptosis row overstates the trigger specificity for CASP9. Reason: CASP9 is the intrinsic initiator downstream of MOMP and APAF1; DNA damage is only one upstream route into that pathway, so the parent intrinsic apoptotic signaling term is more appropriate. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000047947 SUPPORTS SOURCE BUT NOT TARGET CASP9 participates broadly in apoptotic signaling, but the DNA-damage-specific child term overstates trigger specificity for an inherited initiator-caspase assertion. Proposed replacements: intrinsic apoptotic signaling pathway Supporting Evidence: PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 |
| GO:0004197 cysteine-type endopeptidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Cysteine-type endopeptidase activity is the catalytic activity of full-length CASP9. Reason: The IEA row is consistent with the directly supported CASP9 cysteine endopeptidase activity. Supporting Evidence: PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 |
| GO:0006508 proteolysis | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: This is a true but broad ancestor of CASP9 cysteine endopeptidase activity. Reason: CASP9 is a cysteine-aspartyl protease, but this parent term is less informative than cysteine-type endopeptidase activity and protein maturation of executioner procaspases. |
| GO:0006915 apoptotic process | IEA GO_REF:0000120 | MODIFY | Summary: CASP9 is better described by intrinsic apoptotic signaling than by the top-level apoptotic-process parent. Reason: The automated assertion should be tightened to the apoptosome-dependent intrinsic pathway supported for CASP9. Proposed replacements: intrinsic apoptotic signaling pathway Supporting Evidence: PMID:9390557 Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains |
| GO:0006974 DNA damage response | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: This automated stress-response row is too indirect for CASP9 core curation. Reason: DNA damage and UV can signal into the intrinsic mitochondrial pathway, but an automated stimulus-response term turns a common upstream trigger into an asserted CASP9 biological process. |
| GO:0008233 peptidase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: This is a true but broad ancestor of CASP9 cysteine endopeptidase activity. Reason: CASP9 is a cysteine-aspartyl protease, but this parent term is less informative than cysteine-type endopeptidase activity and protein maturation of executioner procaspases. |
| GO:0008234 cysteine-type peptidase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: This is a true but broad ancestor of CASP9 cysteine endopeptidase activity. Reason: CASP9 is a cysteine-aspartyl protease, but this parent term is less informative than cysteine-type endopeptidase activity and protein maturation of executioner procaspases. |
| GO:0009411 response to UV | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: This automated stress-response row is too indirect for CASP9 core curation. Reason: DNA damage and UV can signal into the intrinsic mitochondrial pathway, but an automated stimulus-response term turns a common upstream trigger into an asserted CASP9 biological process. |
| GO:0016787 hydrolase activity | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: This is a true but broad ancestor of CASP9 cysteine endopeptidase activity. Reason: CASP9 is a cysteine-aspartyl protease, but this parent term is less informative than cysteine-type endopeptidase activity and protein maturation of executioner procaspases. |
| GO:0042981 regulation of apoptotic process | IEA GO_REF:0000002 | MODIFY | Summary: The positive regulatory consequence of full-length CASP9 is activation of executioner-caspase maturation. Reason: The broad apoptosis-regulation parent is avoidably imprecise for CASP9L, whose direct pro-apoptotic role is proteolytic activation of executioner caspases upstream of apoptotic execution. Proposed replacements: positive regulation of execution phase of apoptosis Supporting Evidence: PMID:16916640 Our study demonstrates the efficiency by which the executioner caspases are activated in vivo |
| GO:0051604 protein maturation | IEA GO_REF:0000117 | ACCEPT | Summary: CASP9 proteolytically matures executioner procaspases downstream of the apoptosome. Reason: Protein maturation is the correct biological-process term for the direct cleavage/activation of procaspase-7 and other effector procaspases by CASP9. Supporting Evidence: PMID:16352606 directly cleaves/activates procaspase-7 |
| GO:0005515 protein binding | IPI PMID:10206961 An APAF-1.cytochrome c multimeric complex is a functional ap... | MODIFY | Summary: The APF1-procaspase-9 CARD interaction is real, but generic protein binding is too vague. Reason: This row should capture the homotypic CARD-domain contact that recruits CASP9 to the apoptosome rather than an uninformative protein-binding parent. Proposed replacements: CARD domain binding |
| GO:0005515 protein binding | IPI PMID:10376594 Structural basis of procaspase-9 recruitment by the apoptoti... | MODIFY | Summary: The APF1-procaspase-9 CARD interaction is real, but generic protein binding is too vague. Reason: This row should capture the homotypic CARD-domain contact that recruits CASP9 to the apoptosome rather than an uninformative protein-binding parent. Proposed replacements: CARD domain binding |
| GO:0005515 protein binding | IPI PMID:11024045 Livin, a novel inhibitor of apoptosis protein family member. | REMOVE | Summary: Generic protein binding is not an informative CASP9 molecular-function annotation. Reason: The interaction may be real, but GO:0005515 does not describe a specific CASP9 activity. Apoptosome CARD binding, effector-procaspase maturation, and direct inhibitor relationships capture the informative biology where a suitable term exists. |
| GO:0005515 protein binding | IPI PMID:11084335 ML-IAP, a novel inhibitor of apoptosis that is preferentiall... | UNDECIDED | Summary: The local abstract does not expose enough CASP9-specific interaction evidence to review this generic binding row. Reason: This publication is abstract-only locally or foregrounds another pathway component; because a full-text interaction assay could underlie the IntAct row, defer rather than removing it from incomplete evidence. |
| GO:0005515 protein binding | IPI PMID:11230124 Recruitment, activation and retention of caspases-9 and -3 b... | MODIFY | Summary: CASP9 directly activates cysteine-type endopeptidases (caspases); the row is modified to cysteine-type endopeptidase activator activity, with the apoptotic context carried by the module and core functions. Reason: The replacement is the genus rather than the precomposed GO:0008656 (projects/INVOLVED_IN_PRECOMPOSITION.md); the apoptotic context is carried by the module intrinsic_apoptotic_signaling#casp9_caspase_9_initiator_protease and the core functions. Earlier reasoning, retained for its evidence (its term id updated to the genus): The informative activity is the apoptosome-associated activation of effector caspases, not a generic physical interaction edge. Proposed replacements: cysteine-type endopeptidase activator activity |
| GO:0005515 protein binding | IPI PMID:11242052 A conserved XIAP-interaction motif in caspase-9 and Smac/DIA... | REMOVE | Summary: Generic protein binding is not an informative CASP9 molecular-function annotation. Reason: The interaction may be real, but GO:0005515 does not describe a specific CASP9 activity. Apoptosome CARD binding, effector-procaspase maturation, and direct inhibitor relationships capture the informative biology where a suitable term exists. |
| GO:0005515 protein binding | IPI PMID:11801603 SMAC negatively regulates the anti-apoptotic activity of mel... | UNDECIDED | Summary: The local abstract does not expose enough CASP9-specific interaction evidence to review this generic binding row. Reason: This publication is abstract-only locally or foregrounds another pathway component; because a full-text interaction assay could underlie the IntAct row, defer rather than removing it from incomplete evidence. |
| GO:0005515 protein binding | IPI PMID:11821383 CARD-8 protein, a new CARD family member that regulates casp... | UNDECIDED | Summary: The local abstract does not expose enough CASP9-specific interaction evidence to review this generic binding row. Reason: This publication is abstract-only locally or foregrounds another pathway component; because a full-text interaction assay could underlie the IntAct row, defer rather than removing it from incomplete evidence. |
| GO:0005515 protein binding | IPI PMID:12620238 Mechanism of XIAP-mediated inhibition of caspase-9. | REMOVE | Summary: Generic protein binding is not an informative CASP9 molecular-function annotation. Reason: The interaction may be real, but GO:0005515 does not describe a specific CASP9 activity. Apoptosome CARD binding, effector-procaspase maturation, and direct inhibitor relationships capture the informative biology where a suitable term exists. |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | REMOVE | Summary: Generic protein binding is not an informative CASP9 molecular-function annotation. Reason: The interaction may be real, but GO:0005515 does not describe a specific CASP9 activity. Apoptosome CARD binding, effector-procaspase maturation, and direct inhibitor relationships capture the informative biology where a suitable term exists. |
| GO:0005515 protein binding | IPI PMID:16537496 The dependence receptor DCC requires lipid raft localization... | REMOVE | Summary: Generic protein binding is not an informative CASP9 molecular-function annotation. Reason: The interaction may be real, but GO:0005515 does not describe a specific CASP9 activity. Apoptosome CARD binding, effector-procaspase maturation, and direct inhibitor relationships capture the informative biology where a suitable term exists. |
| GO:0005515 protein binding | IPI PMID:16936772 Integrin-linked kinase interacts with caspase-9 and -8 in an... | REMOVE | Summary: Generic protein binding is not an informative CASP9 molecular-function annotation. Reason: The interaction may be real, but GO:0005515 does not describe a specific CASP9 activity. Apoptosome CARD binding, effector-procaspase maturation, and direct inhibitor relationships capture the informative biology where a suitable term exists. |
| GO:0005515 protein binding | IPI PMID:18022362 IAP antagonists induce autoubiquitination of c-IAPs, NF-kapp... | UNDECIDED | Summary: The local abstract does not expose enough CASP9-specific interaction evidence to review this generic binding row. Reason: This publication is abstract-only locally or foregrounds another pathway component; because a full-text interaction assay could underlie the IntAct row, defer rather than removing it from incomplete evidence. |
| GO:0005515 protein binding | IPI PMID:18723680 Executioner caspase-3 and caspase-7 are functionally distinc... | UNDECIDED | Summary: The local abstract does not expose enough CASP9-specific interaction evidence to review this generic binding row. Reason: This publication is abstract-only locally or foregrounds another pathway component; because a full-text interaction assay could underlie the IntAct row, defer rather than removing it from incomplete evidence. |
| GO:0005515 protein binding | IPI PMID:19153467 The structure of the BIR3 domain of cIAP1 in complex with th... | REMOVE | Summary: Generic protein binding is not an informative CASP9 molecular-function annotation. Reason: The interaction may be real, but GO:0005515 does not describe a specific CASP9 activity. Apoptosome CARD binding, effector-procaspase maturation, and direct inhibitor relationships capture the informative biology where a suitable term exists. |
| GO:0005515 protein binding | IPI PMID:19494828 The Apaf-1*procaspase-9 apoptosome complex functions as a pr... | MODIFY | Summary: The APF1-procaspase-9 CARD interaction is real, but generic protein binding is too vague. Reason: This row should capture the homotypic CARD-domain contact that recruits CASP9 to the apoptosome rather than an uninformative protein-binding parent. Proposed replacements: CARD domain binding |
| GO:0005515 protein binding | IPI PMID:19721007 Netrin-1 up-regulation in inflammatory bowel diseases is req... | UNDECIDED | Summary: The local abstract does not expose enough CASP9-specific interaction evidence to review this generic binding row. Reason: This publication is abstract-only locally or foregrounds another pathway component; because a full-text interaction assay could underlie the IntAct row, defer rather than removing it from incomplete evidence. |
| GO:0005515 protein binding | IPI PMID:20462491 Structure of an apoptosome-procaspase-9 CARD complex. | MODIFY | Summary: The APF1-procaspase-9 CARD interaction is real, but generic protein binding is too vague. Reason: This row should capture the homotypic CARD-domain contact that recruits CASP9 to the apoptosome rather than an uninformative protein-binding parent. Proposed replacements: CARD domain binding |
| GO:0005515 protein binding | IPI PMID:21827945 The holo-apoptosome: activation of procaspase-9 and interact... | MODIFY | Summary: The APF1-procaspase-9 CARD interaction is real, but generic protein binding is too vague. Reason: This row should capture the homotypic CARD-domain contact that recruits CASP9 to the apoptosome rather than an uninformative protein-binding parent. Proposed replacements: CARD domain binding |
| GO:0005515 protein binding | IPI PMID:23516580 The E. coli effector protein NleF is a caspase inhibitor. | REMOVE | Summary: Generic protein binding is not an informative CASP9 molecular-function annotation. Reason: The interaction may be real, but GO:0005515 does not describe a specific CASP9 activity. Apoptosome CARD binding, effector-procaspase maturation, and direct inhibitor relationships capture the informative biology where a suitable term exists. |
| GO:0005515 protein binding | IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ... | REMOVE | Summary: Generic protein binding is not an informative CASP9 molecular-function annotation. Reason: The interaction may be real, but GO:0005515 does not describe a specific CASP9 activity. Apoptosome CARD binding, effector-procaspase maturation, and direct inhibitor relationships capture the informative biology where a suitable term exists. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Generic protein binding is not an informative CASP9 molecular-function annotation. Reason: The interaction may be real, but GO:0005515 does not describe a specific CASP9 activity. Apoptosome CARD binding, effector-procaspase maturation, and direct inhibitor relationships capture the informative biology where a suitable term exists. |
| GO:0005515 protein binding | IPI PMID:25502805 A massively parallel pipeline to clone DNA variants and exam... | REMOVE | Summary: Generic protein binding is not an informative CASP9 molecular-function annotation. Reason: The interaction may be real, but GO:0005515 does not describe a specific CASP9 activity. Apoptosome CARD binding, effector-procaspase maturation, and direct inhibitor relationships capture the informative biology where a suitable term exists. |
| GO:0005515 protein binding | IPI PMID:25519916 The EHEC-host interactome reveals novel targets for the tran... | REMOVE | Summary: Generic protein binding is not an informative CASP9 molecular-function annotation. Reason: The interaction may be real, but GO:0005515 does not describe a specific CASP9 activity. Apoptosome CARD binding, effector-procaspase maturation, and direct inhibitor relationships capture the informative biology where a suitable term exists. |
| GO:0005515 protein binding | IPI PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusi... | REMOVE | Summary: Generic protein binding is not an informative CASP9 molecular-function annotation. Reason: The interaction may be real, but GO:0005515 does not describe a specific CASP9 activity. Apoptosome CARD binding, effector-procaspase maturation, and direct inhibitor relationships capture the informative biology where a suitable term exists. |
| GO:0005515 protein binding | IPI PMID:29997244 LuTHy: a double-readout bioluminescence-based two-hybrid tec... | REMOVE | Summary: Generic protein binding is not an informative CASP9 molecular-function annotation. Reason: The interaction may be real, but GO:0005515 does not describe a specific CASP9 activity. Apoptosome CARD binding, effector-procaspase maturation, and direct inhibitor relationships capture the informative biology where a suitable term exists. |
| GO:0005515 protein binding | IPI PMID:31467278 Maximizing binary interactome mapping with a minimal number ... | REMOVE | Summary: Generic protein binding is not an informative CASP9 molecular-function annotation. Reason: The interaction may be real, but GO:0005515 does not describe a specific CASP9 activity. Apoptosome CARD binding, effector-procaspase maturation, and direct inhibitor relationships capture the informative biology where a suitable term exists. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: Generic protein binding is not an informative CASP9 molecular-function annotation. Reason: The interaction may be real, but GO:0005515 does not describe a specific CASP9 activity. Apoptosome CARD binding, effector-procaspase maturation, and direct inhibitor relationships capture the informative biology where a suitable term exists. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding is not an informative CASP9 molecular-function annotation. Reason: The interaction may be real, but GO:0005515 does not describe a specific CASP9 activity. Apoptosome CARD binding, effector-procaspase maturation, and direct inhibitor relationships capture the informative biology where a suitable term exists. |
| GO:0005515 protein binding | IPI PMID:9390557 Cytochrome c and dATP-dependent formation of Apaf-1/caspase-... | MODIFY | Summary: The APF1-procaspase-9 CARD interaction is real, but generic protein binding is too vague. Reason: This row should capture the homotypic CARD-domain contact that recruits CASP9 to the apoptosome rather than an uninformative protein-binding parent. Proposed replacements: CARD domain binding |
| GO:0005515 protein binding | IPI PMID:9922454 Ordering the cytochrome c-initiated caspase cascade: hierarc... | MODIFY | Summary: The APF1-procaspase-9 CARD interaction is real, but generic protein binding is too vague. Reason: This row should capture the homotypic CARD-domain contact that recruits CASP9 to the apoptosome rather than an uninformative protein-binding parent. Proposed replacements: CARD domain binding |
| GO:0001666 response to hypoxia | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The Ensembl-transferred condition response is a downstream readout context, not a CASP9 core function. Reason: These hypoxia, ischemia, toxicological, hormone, and pharmacological terms are experimental or physiological contexts in which the intrinsic caspase cascade can be engaged; they should not be promoted to direct CASP9 activities without proximal evidence for CASP9 doing work in the named response. |
| GO:0001822 kidney development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: This ortholog-transferred tissue or cell-type apoptosis row is downstream of the general intrinsic CASP9 cascade. Reason: CASP9 is required for apoptosis in many developmental contexts, but this Ensembl transfer annotates a tissue outcome rather than a distinct direct function of the gene product. |
| GO:0002931 response to ischemia | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The Ensembl-transferred condition response is a downstream readout context, not a CASP9 core function. Reason: These hypoxia, ischemia, toxicological, hormone, and pharmacological terms are experimental or physiological contexts in which the intrinsic caspase cascade can be engaged; they should not be promoted to direct CASP9 activities without proximal evidence for CASP9 doing work in the named response. |
| GO:0005634 nucleus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Nuclear localization of caspase-9 is less well-established than cytosolic localization. Some reports suggest translocation during apoptosis. Reason: Caspase-9 is primarily cytosolic. Nuclear localization may occur in specific contexts but is not the primary site of function. The annotation is from ortholog transfer and should be viewed with caution. Supporting Evidence: PMID:12782307 caspase-9 is in the cytoplasm of non-apoptotic pituitary cells |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | ACCEPT | Summary: Cytoplasmic localization is well-established. Redundant with IBA annotation. Reason: Consistent with IBA annotation and experimental evidence. Caspase-9 is predominantly cytoplasmic. Supporting Evidence: PMID:12782307 caspase-9 is in the cytoplasm of non-apoptotic pituitary cells |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: Cytosolic localization confirmed. Redundant with IBA and TAS annotations. Reason: Consistent with other annotations and experimental evidence. Supporting Evidence: PMID:12782307 caspase-9 is in the cytoplasm of non-apoptotic pituitary cells |
| GO:0016485 protein processing | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: This is a true but broad ancestor of CASP9 cysteine endopeptidase activity. Reason: CASP9 is a cysteine-aspartyl protease, but this parent term is less informative than cysteine-type endopeptidase activity and protein maturation of executioner procaspases. |
| GO:0032025 response to cobalt ion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The Ensembl-transferred condition response is a downstream readout context, not a CASP9 core function. Reason: These hypoxia, ischemia, toxicological, hormone, and pharmacological terms are experimental or physiological contexts in which the intrinsic caspase cascade can be engaged; they should not be promoted to direct CASP9 activities without proximal evidence for CASP9 doing work in the named response. |
| GO:0032355 response to estradiol | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The Ensembl-transferred condition response is a downstream readout context, not a CASP9 core function. Reason: These hypoxia, ischemia, toxicological, hormone, and pharmacological terms are experimental or physiological contexts in which the intrinsic caspase cascade can be engaged; they should not be promoted to direct CASP9 activities without proximal evidence for CASP9 doing work in the named response. |
| GO:0032496 response to lipopolysaccharide | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The Ensembl-transferred condition response is a downstream readout context, not a CASP9 core function. Reason: These hypoxia, ischemia, toxicological, hormone, and pharmacological terms are experimental or physiological contexts in which the intrinsic caspase cascade can be engaged; they should not be promoted to direct CASP9 activities without proximal evidence for CASP9 doing work in the named response. |
| GO:0034349 glial cell apoptotic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: This ortholog-transferred tissue or cell-type apoptosis row is downstream of the general intrinsic CASP9 cascade. Reason: CASP9 is required for apoptosis in many developmental contexts, but this Ensembl transfer annotates a tissue outcome rather than a distinct direct function of the gene product. |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000120 | MODIFY | Summary: The positive regulatory consequence of full-length CASP9 is activation of executioner-caspase maturation. Reason: The broad apoptosis-regulation parent is avoidably imprecise for CASP9L, whose direct pro-apoptotic role is proteolytic activation of executioner caspases upstream of apoptotic execution. Proposed replacements: positive regulation of execution phase of apoptosis Supporting Evidence: PMID:16916640 Our study demonstrates the efficiency by which the executioner caspases are activated in vivo |
| GO:0045471 response to ethanol | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The Ensembl-transferred condition response is a downstream readout context, not a CASP9 core function. Reason: These hypoxia, ischemia, toxicological, hormone, and pharmacological terms are experimental or physiological contexts in which the intrinsic caspase cascade can be engaged; they should not be promoted to direct CASP9 activities without proximal evidence for CASP9 doing work in the named response. |
| GO:0071549 cellular response to dexamethasone stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The Ensembl-transferred condition response is a downstream readout context, not a CASP9 core function. Reason: These hypoxia, ischemia, toxicological, hormone, and pharmacological terms are experimental or physiological contexts in which the intrinsic caspase cascade can be engaged; they should not be promoted to direct CASP9 activities without proximal evidence for CASP9 doing work in the named response. |
| GO:0071680 response to indole-3-methanol | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The Ensembl-transferred condition response is a downstream readout context, not a CASP9 core function. Reason: These hypoxia, ischemia, toxicological, hormone, and pharmacological terms are experimental or physiological contexts in which the intrinsic caspase cascade can be engaged; they should not be promoted to direct CASP9 activities without proximal evidence for CASP9 doing work in the named response. |
| GO:0071887 leukocyte apoptotic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: This ortholog-transferred tissue or cell-type apoptosis row is downstream of the general intrinsic CASP9 cascade. Reason: CASP9 is required for apoptosis in many developmental contexts, but this Ensembl transfer annotates a tissue outcome rather than a distinct direct function of the gene product. |
| GO:0072347 response to anesthetic | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The Ensembl-transferred condition response is a downstream readout context, not a CASP9 core function. Reason: These hypoxia, ischemia, toxicological, hormone, and pharmacological terms are experimental or physiological contexts in which the intrinsic caspase cascade can be engaged; they should not be promoted to direct CASP9 activities without proximal evidence for CASP9 doing work in the named response. |
| GO:0004197 cysteine-type endopeptidase activity | TAS Reactome:R-HSA-114259 | ACCEPT | Summary: Reactome correctly captures CASP9 catalytic activity in the apoptosome-processing event. Reason: CASP9 remains an active cysteine endopeptidase in this modeled apoptosome reaction even though proteolytic processing tunes rather than creates its catalytic activity. Supporting Evidence: Reactome:R-HSA-114259 Procaspase‑9 is processed in an ATP‑dependent manner following association with APAF1 and cytochrome c (CYCS) within the apoptosome complex |
| GO:0097193 intrinsic apoptotic signaling pathway | NAS PMID:10206961 An APAF-1.cytochrome c multimeric complex is a functional ap... | ACCEPT | Summary: CASP9 recruitment and activation on the APAF1 apoptosome are core intrinsic apoptotic signaling steps. Reason: PMID:10206961 directly supports the apoptosome as a complex that recruits and activates procaspase-9 downstream of cytochrome c. Supporting Evidence: PMID:10206961 Such a complex can be isolated using gel filtration chromatography and is by itself sufficient to recruit and activate procaspase-9 |
| GO:0004197 cysteine-type endopeptidase activity | IDA PMID:16352606 Caspase-7 is directly activated by the approximately 700-kDa... | ACCEPT | Summary: PMID:16352606 demonstrates caspase-9 directly cleaving and activating caspase-7 in the apoptosome. This is direct experimental evidence for the catalytic activity (isoform 1 only). Reason: Direct experimental demonstration of caspase-9 enzymatic activity in processing caspase-7. Supporting Evidence: PMID:16352606 Apaf-1 oligomerizes to produce approximately 1.4-MDa and approximately 700-kDa apoptosome complexes, and the latter complex directly cleaves/activates procaspase-7 |
| GO:0004197 cysteine-type endopeptidase activity | IDA PMID:16916640 Engineered hybrid dimers: tracking the activation pathway of... | ACCEPT | Summary: PMID:16916640 uses engineered hybrid dimers to track caspase-7 activation by caspase-9, demonstrating the endopeptidase activity (isoform 1). Reason: Direct experimental demonstration of caspase-9 enzymatic activity in processing caspase-7 using sophisticated biochemical approaches. Supporting Evidence: PMID:16916640 A transient intermediate of singly cleaved dimeric caspase-7 can be found in a cell-free model of apoptosis induction |
| GO:0043065 positive regulation of apoptotic process | IMP PMID:11821383 CARD-8 protein, a new CARD family member that regulates casp... | UNDECIDED | Summary: The visible CARD8 abstract does not verify the CASP9 perturbation behind this row. Reason: The cached record is abstract-only and foregrounds CARD8 regulation of caspase-1, NF-kappaB, and apoptosis. It does not expose the CASP9-specific mutant evidence used for the GOA row, so defer to curator/full-text review. |
| GO:0006974 DNA damage response | IMP PMID:15657060 c-Abl tyrosine kinase regulates caspase-9 autocleavage in th... | UNDECIDED | Summary: The c-Abl/Tyr-153 DNA-damage mechanism is contradicted by later phosphorylation work. Reason: PMID:15657060 reported that c-Abl activates CASP9 through Tyr-153 after genotoxic stress, but PMID:29066624 reported no evidence for Tyr-153 phosphorylation by c-Abl and instead identified inhibitory Tyr-397 phosphorylation. The full CASP9 DNA-damage role needs curator review before this row is retained or narrowed. Supporting Evidence: PMID:15657060 Caspase-9(Y153F) also attenuated DNA damage-induced processing of caspase-9 to p35, activation of caspase-3, and apoptosis PMID:29066624 we observed no evidence for Tyr-153 phosphorylation of caspase-9 in vitro or in cells |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9627089 | KEEP AS NON CORE | Summary: The Reactome event projects CASP9 to the cytosol for a specific modeled apoptosome or regulation event. Reason: CASP9 is cytosolic, but the review should not count every Reactome event projection as a separate core localization assertion. Supporting Evidence: Reactome:R-HSA-9627089 R-HSA-9627089 |
| GO:0097193 intrinsic apoptotic signaling pathway | IDA PMID:35446120 Calmodulin Binding Activates Chromobacterium CopC Effector t... | ACCEPT | Summary: Chromobacterium CopC directly targets CASP9 to block host intrinsic apoptotic signaling. Reason: The pathogen effector assay directly modifies and inhibits host CASP9 in the intrinsic apoptosis branch, matching the GO-CAM representation of this model. |
| GO:0005739 mitochondrion | IDA PMID:12782307 Apoptosis triggered redistribution of caspase-9 from cytopla... | ACCEPT | Summary: PMID:12782307 shows caspase-9 redistributes from cytoplasm to mitochondria during apoptosis. Reason: Direct experimental evidence of caspase-9 mitochondrial localization during apoptosis. The paper shows "activation of apoptosis with rotenone triggers the redistribution of caspase-9 to mitochondria." Supporting Evidence: PMID:12782307 The activation of apoptosis with rotenone triggers the redistribution of caspase-9 to mitochondria |
| GO:0004197 cysteine-type endopeptidase activity | IDA PMID:27889207 Dual Site Phosphorylation of Caspase-7 by PAK2 Blocks Apopto... | ACCEPT | Summary: PMID:27889207 demonstrates PAK2 phosphorylation of caspase-7 blocks its activation by caspase-9, providing evidence for caspase-9 enzymatic activity (isoform 1). Reason: The study demonstrates caspase-9's enzymatic activity in caspase-7 activation. Supporting Evidence: PMID:27889207 Dual Site Phosphorylation of Caspase-7 by PAK2 Blocks Apoptotic Activity by Two Distinct Mechanisms |
| GO:0051604 protein maturation | IDA PMID:16352606 Caspase-7 is directly activated by the approximately 700-kDa... | ACCEPT | Summary: CASP9 proteolytically matures executioner procaspases downstream of the apoptosome. Reason: Protein maturation is the correct biological-process term for the direct cleavage/activation of procaspase-7 and other effector procaspases by CASP9. Supporting Evidence: PMID:16352606 directly cleaves/activates procaspase-7 |
| GO:0051604 protein maturation | IDA PMID:16916640 Engineered hybrid dimers: tracking the activation pathway of... | ACCEPT | Summary: CASP9 proteolytically matures executioner procaspases downstream of the apoptosome. Reason: Protein maturation is the correct biological-process term for the direct cleavage/activation of procaspase-7 and other effector procaspases by CASP9. Supporting Evidence: PMID:16352606 directly cleaves/activates procaspase-7 |
| GO:1900119 positive regulation of execution phase of apoptosis | IDA PMID:16916640 Engineered hybrid dimers: tracking the activation pathway of... | ACCEPT | Summary: CASP9 positively regulates apoptotic execution by activating effector caspases. Reason: This regulatory term captures the consequence of CASP9-mediated procaspase-7 maturation for the execution phase of apoptosis. Supporting Evidence: PMID:16916640 Our study demonstrates the efficiency by which the executioner caspases are activated in vivo |
| GO:0004197 cysteine-type endopeptidase activity | IMP PMID:21980415 Identification of a conserved anti-apoptotic protein that mo... | UNDECIDED | Summary: The CAAP paper uses CASP9 activity as a readout of mitochondrial apoptosis rather than visibly assaying CASP9 catalytic function itself. Reason: The full text measures LEHD-pNA activity during CAAP knockdown, but the curated IMP row to CASP9 catalytic activity needs a curator check because CAAP modulates the pathway upstream of caspase activation. |
| GO:0006915 apoptotic process | IMP PMID:15069058 BRCC2, a novel BH3-like domain-containing protein, induces a... | UNDECIDED | Summary: The BRCC2 abstract shows caspase-9 activation during BRCC2-induced apoptosis but not a CASP9 perturbation. Reason: From the local abstract, CASP9 appears to be a pathway readout downstream of BRCC2 expression; the full text is needed to decide whether an IMP annotation to CASP9 apoptotic process is supported. |
| GO:0004197 cysteine-type endopeptidase activity | IDA PMID:16920334 Protective role of Cop in Rip2/caspase-1/caspase-4-mediated ... | UNDECIDED | Summary: The COP abstract is centered on caspase-1/caspase-4-mediated cell death and does not verify the CASP9 assay. Reason: The cached record is abstract-only and does not mention CASP9, so the specific CASP9 catalytic-activity row cannot be checked locally. |
| GO:0005515 protein binding | IPI PMID:11821383 CARD-8 protein, a new CARD family member that regulates casp... | UNDECIDED | Summary: The local abstract does not expose enough CASP9-specific interaction evidence to review this generic binding row. Reason: This publication is abstract-only locally or foregrounds another pathway component; because a full-text interaction assay could underlie the IntAct row, defer rather than removing it from incomplete evidence. |
| GO:0032991 protein-containing complex | IDA PMID:11821383 CARD-8 protein, a new CARD family member that regulates casp... | UNDECIDED | Summary: The cached CARD8 abstract does not verify the generic CASP9 protein-complex assertion. Reason: The local abstract mentions CARD8 binding to ICEBERG and pseudo-ICE but not CASP9 complex membership; full-text evidence is needed before this row can be retained. |
| GO:0008233 peptidase activity | IDA PMID:19740745 A truncated form of p23 down-regulates telomerase activity v... | UNDECIDED | Summary: The p23 abstract names caspases generically and does not verify a CASP9 peptidase assay. Reason: The cached p23/telomerase record is abstract-only and does not mention CASP9, so this broad experimental peptidase row should be deferred. |
| GO:0005515 protein binding | IPI PMID:19255499 HIP1R interacts with a member of Bcl-2 family, BCL2L10, and ... | UNDECIDED | Summary: The local abstract does not expose enough CASP9-specific interaction evidence to review this generic binding row. Reason: This publication is abstract-only locally or foregrounds another pathway component; because a full-text interaction assay could underlie the IntAct row, defer rather than removing it from incomplete evidence. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-114252 | KEEP AS NON CORE | Summary: The Reactome event projects CASP9 to the cytosol for a specific modeled apoptosome or regulation event. Reason: CASP9 is cytosolic, but the review should not count every Reactome event projection as a separate core localization assertion. Supporting Evidence: Reactome:R-HSA-114252 R-HSA-114252 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-114259 | KEEP AS NON CORE | Summary: The Reactome event projects CASP9 to the cytosol for a specific modeled apoptosome or regulation event. Reason: CASP9 is cytosolic, but the review should not count every Reactome event projection as a separate core localization assertion. Supporting Evidence: Reactome:R-HSA-114259 R-HSA-114259 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-114261 | KEEP AS NON CORE | Summary: The Reactome event projects CASP9 to the cytosol for a specific modeled apoptosome or regulation event. Reason: CASP9 is cytosolic, but the review should not count every Reactome event projection as a separate core localization assertion. Supporting Evidence: Reactome:R-HSA-114261 R-HSA-114261 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-373700 | KEEP AS NON CORE | Summary: The Reactome event projects CASP9 to the cytosol for a specific modeled apoptosome or regulation event. Reason: CASP9 is cytosolic, but the review should not count every Reactome event projection as a separate core localization assertion. Supporting Evidence: Reactome:R-HSA-373700 R-HSA-373700 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-418845 | KEEP AS NON CORE | Summary: The Reactome event projects CASP9 to the cytosol for a specific modeled apoptosome or regulation event. Reason: CASP9 is cytosolic, but the review should not count every Reactome event projection as a separate core localization assertion. Supporting Evidence: Reactome:R-HSA-418845 R-HSA-418845 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6804596 | KEEP AS NON CORE | Summary: The Reactome event projects CASP9 to the cytosol for a specific modeled apoptosome or regulation event. Reason: CASP9 is cytosolic, but the review should not count every Reactome event projection as a separate core localization assertion. Supporting Evidence: Reactome:R-HSA-6804596 R-HSA-6804596 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6805426 | KEEP AS NON CORE | Summary: The Reactome event projects CASP9 to the cytosol for a specific modeled apoptosome or regulation event. Reason: CASP9 is cytosolic, but the review should not count every Reactome event projection as a separate core localization assertion. Supporting Evidence: Reactome:R-HSA-6805426 R-HSA-6805426 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9627056 | KEEP AS NON CORE | Summary: The Reactome event projects CASP9 to the cytosol for a specific modeled apoptosome or regulation event. Reason: CASP9 is cytosolic, but the review should not count every Reactome event projection as a separate core localization assertion. Supporting Evidence: Reactome:R-HSA-9627056 R-HSA-9627056 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9627078 | KEEP AS NON CORE | Summary: The Reactome event projects CASP9 to the cytosol for a specific modeled apoptosome or regulation event. Reason: CASP9 is cytosolic, but the review should not count every Reactome event projection as a separate core localization assertion. Supporting Evidence: Reactome:R-HSA-9627078 R-HSA-9627078 |
| GO:0005829 cytosol | IDA PMID:17167422 Hsp70 regulates erythropoiesis by preventing caspase-3-media... | UNDECIDED | Summary: The HSP70/GATA1 abstract foregrounds caspase-3 and does not expose a CASP9 cytosol assay. Reason: The cached record is abstract-only. Because the abstract does not mention CASP9, defer this experimental localization row to full-text review. |
| GO:0030220 platelet formation | TAS PMID:18309324 No death without life: vital functions of apoptotic effector... | KEEP AS NON CORE | Summary: PMID:18309324 reviews non-apoptotic functions of apoptotic effectors, including roles in platelet formation. Reason: Non-apoptotic function of caspases in platelet formation is documented. This represents a specialized function distinct from core apoptotic role. Supporting Evidence: PMID:18309324 multiple studies indicate that the mammalian orthologs of these C. elegans proteins (i.e. caspases, Apaf-1 and multidomain proteins of the Bcl-2 family) participate in cell death-unrelated processes |
| GO:0005829 cytosol | TAS Reactome:R-HSA-114256 | KEEP AS NON CORE | Summary: The Reactome event projects CASP9 to the cytosol for a specific modeled apoptosome or regulation event. Reason: CASP9 is cytosolic, but the review should not count every Reactome event projection as a separate core localization assertion. Supporting Evidence: Reactome:R-HSA-114256 R-HSA-114256 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-198621 | KEEP AS NON CORE | Summary: The Reactome event projects CASP9 to the cytosol for a specific modeled apoptosome or regulation event. Reason: CASP9 is cytosolic, but the review should not count every Reactome event projection as a separate core localization assertion. Supporting Evidence: Reactome:R-HSA-198621 R-HSA-198621 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2399985 | KEEP AS NON CORE | Summary: The Reactome event projects CASP9 to the cytosol for a specific modeled apoptosome or regulation event. Reason: CASP9 is cytosolic, but the review should not count every Reactome event projection as a separate core localization assertion. Supporting Evidence: Reactome:R-HSA-2399985 R-HSA-2399985 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6804596 | KEEP AS NON CORE | Summary: The Reactome event projects CASP9 to the cytosol for a specific modeled apoptosome or regulation event. Reason: CASP9 is cytosolic, but the review should not count every Reactome event projection as a separate core localization assertion. Supporting Evidence: Reactome:R-HSA-6804596 R-HSA-6804596 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6805426 | KEEP AS NON CORE | Summary: The Reactome event projects CASP9 to the cytosol for a specific modeled apoptosome or regulation event. Reason: CASP9 is cytosolic, but the review should not count every Reactome event projection as a separate core localization assertion. Supporting Evidence: Reactome:R-HSA-6805426 R-HSA-6805426 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9627056 | KEEP AS NON CORE | Summary: The Reactome event projects CASP9 to the cytosol for a specific modeled apoptosome or regulation event. Reason: CASP9 is cytosolic, but the review should not count every Reactome event projection as a separate core localization assertion. Supporting Evidence: Reactome:R-HSA-9627056 R-HSA-9627056 |
| GO:0005515 protein binding | IPI PMID:15657060 c-Abl tyrosine kinase regulates caspase-9 autocleavage in th... | REMOVE | Summary: Generic protein binding is not an informative CASP9 molecular-function annotation. Reason: The interaction may be real, but GO:0005515 does not describe a specific CASP9 activity. Apoptosome CARD binding, effector-procaspase maturation, and direct inhibitor relationships capture the informative biology where a suitable term exists. |
| GO:0006974 DNA damage response | IDA PMID:15657060 c-Abl tyrosine kinase regulates caspase-9 autocleavage in th... | UNDECIDED | Summary: The c-Abl/Tyr-153 DNA-damage mechanism is contradicted by later phosphorylation work. Reason: PMID:15657060 reported that c-Abl activates CASP9 through Tyr-153 after genotoxic stress, but PMID:29066624 reported no evidence for Tyr-153 phosphorylation by c-Abl and instead identified inhibitory Tyr-397 phosphorylation. The full CASP9 DNA-damage role needs curator review before this row is retained or narrowed. Supporting Evidence: PMID:15657060 Caspase-9(Y153F) also attenuated DNA damage-induced processing of caspase-9 to p35, activation of caspase-3, and apoptosis PMID:29066624 we observed no evidence for Tyr-153 phosphorylation of caspase-9 in vitro or in cells |
| GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage | IMP PMID:15657060 c-Abl tyrosine kinase regulates caspase-9 autocleavage in th... | UNDECIDED | Summary: The c-Abl/Tyr-153 DNA-damage mechanism is contradicted by later phosphorylation work. Reason: PMID:15657060 reported that c-Abl activates CASP9 through Tyr-153 after genotoxic stress, but PMID:29066624 reported no evidence for Tyr-153 phosphorylation by c-Abl and instead identified inhibitory Tyr-397 phosphorylation. The full DNA-damage-specific intrinsic-apoptosis row needs curator review before it is retained or narrowed. Supporting Evidence: PMID:15657060 Caspase-9(Y153F) also attenuated DNA damage-induced processing of caspase-9 to p35, activation of caspase-3, and apoptosis PMID:29066624 we observed no evidence for Tyr-153 phosphorylation of caspase-9 in vitro or in cells |
| GO:0019901 protein kinase binding | IDA PMID:15657060 c-Abl tyrosine kinase regulates caspase-9 autocleavage in th... | UNDECIDED | Summary: The reported c-Abl interaction sits in a regulatory mechanism whose activating Tyr-153 model is disputed. Reason: The original paper reported direct c-Abl binding and Tyr-153 phosphorylation of CASP9, but later work could not detect Tyr-153 phosphorylation and found inhibitory phosphorylation at Tyr-397. The physical interaction should be retained only after resolving that mechanistic discrepancy. Supporting Evidence: PMID:15657060 c-Abl binds directly to caspase-9 PMID:29066624 Tyr-397 is the dominant site of c-Abl phosphorylation both in vitro and upon c-Abl activation in cells |
| GO:0034644 cellular response to UV | IDA PMID:15657060 c-Abl tyrosine kinase regulates caspase-9 autocleavage in th... | UNDECIDED | Summary: The c-Abl/Tyr-153 DNA-damage mechanism is contradicted by later phosphorylation work. Reason: PMID:15657060 reported that c-Abl activates CASP9 through Tyr-153 after genotoxic stress, but PMID:29066624 reported no evidence for Tyr-153 phosphorylation by c-Abl and instead identified inhibitory Tyr-397 phosphorylation. The full CASP9 DNA-damage role needs curator review before this row is retained or narrowed. Supporting Evidence: PMID:15657060 Caspase-9(Y153F) also attenuated DNA damage-induced processing of caspase-9 to p35, activation of caspase-3, and apoptosis PMID:29066624 we observed no evidence for Tyr-153 phosphorylation of caspase-9 in vitro or in cells |
| GO:0042770 signal transduction in response to DNA damage | IDA PMID:15657060 c-Abl tyrosine kinase regulates caspase-9 autocleavage in th... | UNDECIDED | Summary: The c-Abl/Tyr-153 DNA-damage mechanism is contradicted by later phosphorylation work. Reason: PMID:15657060 reported that c-Abl activates CASP9 through Tyr-153 after genotoxic stress, but PMID:29066624 reported no evidence for Tyr-153 phosphorylation by c-Abl and instead identified inhibitory Tyr-397 phosphorylation. The full CASP9 DNA-damage role needs curator review before this row is retained or narrowed. Supporting Evidence: PMID:15657060 Caspase-9(Y153F) also attenuated DNA damage-induced processing of caspase-9 to p35, activation of caspase-3, and apoptosis PMID:29066624 we observed no evidence for Tyr-153 phosphorylation of caspase-9 in vitro or in cells |
| GO:0005515 protein binding | IPI PMID:11350957 Characterization of a novel proapoptotic caspase-2- and casp... | REMOVE | Summary: Generic protein binding is not an informative CASP9 molecular-function annotation. Reason: The interaction may be real, but GO:0005515 does not describe a specific CASP9 activity. Apoptosome CARD binding, effector-procaspase maturation, and direct inhibitor relationships capture the informative biology where a suitable term exists. |
| GO:0043293 apoptosome | IDA PMID:21827945 The holo-apoptosome: activation of procaspase-9 and interact... | ACCEPT | Summary: CASP9 is a CARD-recruited catalytic component of the apoptosome. Reason: Structural work places procaspase-9 CARDs in the holo-apoptosome and supports apoptosome membership for full-length CASP9. Supporting Evidence: PMID:21827945 Activation of procaspase-9 on the apoptosome is a pivotal step in the intrinsic cell death pathway |
| GO:0006915 apoptotic process | TAS PMID:8663294 ICE-LAP6, a novel member of the ICE/Ced-3 gene family, is ac... | ACCEPT | Summary: PMID:8663294 is the original paper characterizing ICE-LAP6 (caspase-9) as an apoptosis-inducing caspase. Reason: Foundational paper demonstrating caspase-9 (ICE-LAP6) induces apoptosis when overexpressed and is activated by granzyme B. Supporting Evidence: PMID:8663294 Overexpression of ICE-LAP6 induces apoptosis in MCF7 breast carcinoma cells |
| GO:0005515 protein binding | IPI PMID:11069302 Regulation of apoptosis at cell division by p34cdc2 phosphor... | REMOVE | Summary: Generic protein binding is not an informative CASP9 molecular-function annotation. Reason: The interaction may be real, but GO:0005515 does not describe a specific CASP9 activity. Apoptosome CARD binding, effector-procaspase maturation, and direct inhibitor relationships capture the informative biology where a suitable term exists. |
| GO:0004197 cysteine-type endopeptidase activity | TAS PMID:9390557 Cytochrome c and dATP-dependent formation of Apaf-1/caspase-... | ACCEPT | Summary: PMID:9390557 is the landmark paper demonstrating caspase-9 catalytic activity in the intrinsic pathway (isoform 1). Reason: Foundational paper demonstrating caspase-9 cleaves and activates caspase-3. Supporting Evidence: PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 |
| GO:0008047 enzyme activator activity | TAS PMID:9390557 Cytochrome c and dATP-dependent formation of Apaf-1/caspase-... | MODIFY | Summary: CASP9 directly activates cysteine-type endopeptidases (caspases); the row is modified to cysteine-type endopeptidase activator activity, with the apoptotic context carried by the module and core functions. Reason: The replacement is the genus rather than the precomposed GO:0008656 (projects/INVOLVED_IN_PRECOMPOSITION.md); the apoptotic context is carried by the module intrinsic_apoptotic_signaling#casp9_caspase_9_initiator_protease and the core functions. Earlier reasoning, retained for its evidence (its term id updated to the genus): CASP9 activates effector caspases by proteolytic cleavage during apoptosis; GO:0140608 captures that specific molecular activity more precisely than generic enzyme activator activity. Proposed replacements: cysteine-type endopeptidase activator activity Supporting Evidence: PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 |
| GO:2001243 negative regulation of intrinsic apoptotic signaling pathway | TAS P55211-2 PMID:10070954 Identification of an endogenous dominant-negative short isof... | NEW | Summary: The catalytically inactive Caspase-9S isoform inhibits intrinsic apoptosis by interfering with a productive APAF1-caspase-9 complex. Reason: Caspase-9b/S retains APAF1 CARD binding but lacks the central catalytic domain, so it can block cytochrome-c-dependent activation of caspase-9 and caspase-3 in a dominant-negative manner. The proposed process term should be isoform-specific for P55211-2. Supporting Evidence: PMID:10070954 Caspase-9b can interact with the caspase recruitment domain of Apaf-1 PMID:10070954 It can also block activation of caspase-9 and -3 by Apaf-1 in an in vitro cytochrome c-dependent caspase activation assay |
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Download this section (compressed HTML)Q: How do cells regulate the ratio of Caspase-9L to Caspase-9S isoforms, and what splicing factors are involved in this decision?
Q: What is the precise molecular mechanism by which Caspase-9S inhibits apoptosis - does it simply sequester Apaf-1 or does it have additional inhibitory mechanisms?
Q: What are the non-apoptotic functions of caspase-9 in autophagy, synaptic plasticity, and vascular function, and how are these regulated independently of apoptosis?
Q: Is the Tyr-153 c-Abl phosphorylation of caspase-9 originally reported in PMID:15657060 a productive in-cell event? PMID:29066624 (Serrano 2017) reported no evidence for Tyr-153 phosphorylation of caspase-9 by c-Abl in vitro or in cells, and instead identified active-site adjacent Tyr-397 as an inhibitory c-Abl site. What in-cell methods (e.g., site-directed mutants coupled to endogenous c-Abl activation in DNA damage contexts) would definitively resolve whether c-Abl's regulatory effect on caspase-9 is activating, inhibitory, or both — and in which cellular contexts?
Q: How widespread is pathogen-encoded direct phosphorylation of caspase-9 (e.g., LegK3 at Thr-102; PMID:39349471) across bacterial effector kinases, and is this a generalizable strategy to suppress host intrinsic apoptosis?
Q: To what extent is oxidative-stress-driven, reversible suppression of caspase activation (PMID:39245717) a general mechanism that gates intrinsic apoptosis in vivo beyond drug-induced liver injury?
Experiment: Isoform-specific proteomics: Develop isoform-specific antibodies or mass spectrometry methods to quantify 9L/9S ratios across tissues and disease states.
Experiment: Structural studies of Caspase-9S in the apoptosome: Determine how the truncated isoform interacts with Apaf-1 and whether it truly occupies the same binding site as 9L.
Experiment: Conditional isoform knockout: Generate mice with isoform-specific knockouts to determine the specific physiological roles of each isoform.
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