CASP9 (Caspase-9) is the initiator caspase of the intrinsic apoptosis pathway. It is a cysteine-aspartyl protease that cleaves peptide bonds C-terminal to Asp (P1=Asp) with peptide preference for LEHD; in native lysates the cleavage motif resembles LESD↓(G/S). Mechanistically, caspase-9 is activated by recruitment onto the heptameric Apaf-1 apoptosome via CARD-CARD interactions following cytochrome c release; apoptosome assembly is required not just for dimerization but also for optimal recognition of physiologic protein substrates (notably procaspase-3) [PMID:16630893]. Its best-established physiologic substrates are procaspase-3 (cleaved at IETD↓S) and procaspase-7; notably it does NOT efficiently activate procaspase-6 because local sequence/structural context blocks productive cleavage [PMID:34472839]. CRITICAL ISOFORM BIOLOGY: Alternative splicing produces 4 isoforms with ANTAGONISTIC functions: (1) Caspase-9L (isoform 1, P55211-1, Alpha) is the full-length ACTIVE enzyme that binds Apaf-1 in the apoptosome and cleaves effector caspases to INDUCE APOPTOSIS; (2) Caspase-9S (isoform 2, P55211-2, Beta) lacks the catalytic domain and acts as a DOMINANT-NEGATIVE INHIBITOR that competes with 9L for Apaf-1 binding [PMID:10070954]. UniProt states "Isoform 2: Lacks activity is an dominant-negative inhibitor of caspase-9". All current GOA apoptosis annotations refer to the pro-apoptotic function - MISSING the anti-apoptotic isoform 2 function.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Caspase-9 is predominantly localized in the cytoplasm as an inactive monomer in non-stressed cells [PMID:12782307, deep research]. The IBA annotation from phylogenetic inference is well-supported. Both isoforms would be cytoplasmic as neither has specific targeting signals. Reason: Cytoplasmic localization is well-established for procaspase-9. The deep research confirms "In non-stressed cells, caspase-9 predominantly localizes to the cytosol as an inactive monomer lacking typical mitochondrial targeting sequences." This applies to both isoforms as the CARD domain (retained in both) does not contain targeting signals. Supporting Evidence: PMID:12782307 caspase-9 is in the cytoplasm of non-apoptotic pituitary cells file:human/CASP9/CASP9-deep-research-perplexity.md provider: perplexity |
| GO:0006915 apoptotic process | IBA GO_REF:0000033 | ACCEPT | Summary: Caspase-9 is central to the intrinsic apoptotic pathway. The IBA annotation correctly identifies involvement in apoptosis, which is the canonical function of isoform 1. However, isoform 2 (Caspase-9S) INHIBITS apoptosis as a dominant-negative. Reason: The GO term "apoptotic process" is a broad BP term that applies to proteins involved in apoptosis regardless of whether they promote or inhibit it. The term definition includes regulation. Isoform 1 induces apoptosis while isoform 2 inhibits it - both are involved in the apoptotic process. The IBA inference from phylogenetic conservation is sound for the canonical pro-apoptotic function. Supporting Evidence: PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 |
| GO:0004197 cysteine-type endopeptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Cysteine-type endopeptidase activity is the core enzymatic function of caspase-9 (isoform 1). CRITICAL: Isoform 2 (Caspase-9S) LACKS this activity as it is missing the catalytic domain (residues 140-289). UniProt explicitly states "Isoform 2: Lacks activity". Reason: This annotation is correct for the canonical isoform 1 (P55211-1). The IBA phylogenetic inference is valid because the catalytic activity is the defining feature of caspase-9 orthologs. The catalytic dyad (Cys-287 and His-237) is conserved across the family. Note that isoform 2 would NOT have this activity. Supporting Evidence: PMID:16916640 Our study demonstrates the efficiency by which the executioner caspases are activated in vivo PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 file:human/CASP9/CASP9-deep-research-falcon.md Caspases are cysteine-aspartyl proteases that cleave peptide bonds almost exclusively C-terminal to aspartate (P1 = Asp) in substrates. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Cytosolic localization is well-established for procaspase-9 in non-apoptotic cells. The apoptosome forms in the cytosol upon cytochrome c release from mitochondria. Reason: Deep research confirms cytosolic localization: "In non-stressed cells, caspase-9 predominantly localizes to the cytosol as an inactive monomer." Multiple experimental studies confirm this. The IBA annotation is phylogenetically sound. 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 | ACCEPT | Summary: Caspase-9 plays a documented role in neuronal apoptosis during development and in neurodegenerative conditions. Caspase-9 knockout mice show severe brain abnormalities due to reduced developmental neuronal apoptosis. CRITICAL: This applies to isoform 1 only. Reason: Deep research states: "mice lacking caspase-9 die perinatally with severe brain abnormalities including exencephaly, ventricular obstructions, and protrusion formations." This demonstrates caspase-9's role in neuronal apoptotic processes during CNS development. IBA inference from phylogenetic conservation is appropriate for this well-characterized function of isoform 1. Supporting Evidence: file:human/CASP9/CASP9-deep-research-perplexity.md mice lacking caspase-9 die perinatally with severe brain abnormalities including exencephaly, ventricular obstructions, and protrusion formations |
| GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage | IBA GO_REF:0000033 | ACCEPT | Summary: Caspase-9 is the initiator caspase of the intrinsic apoptotic pathway activated by DNA damage. c-Abl phosphorylates caspase-9 at Tyr-153 in response to DNA damage, promoting apoptosis. CRITICAL: This pro-apoptotic function is isoform 1 specific. Reason: DNA damage triggers the intrinsic pathway through p53-mediated transcription of pro-apoptotic Bcl-2 family members, leading to MOMP, cytochrome c release, and caspase-9 activation. PMID:15657060 demonstrates c-Abl directly phosphorylates caspase-9 in DNA damage response. IBA phylogenetic inference is sound for this core function. Supporting Evidence: PMID:15657060 c-Abl phosphorylates caspase-9 on Tyr-153 in vitro and in cells treated with DNA damaging agents |
| GO:0004197 cysteine-type endopeptidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation of cysteine-type endopeptidase activity is redundant with IBA annotation. Correct for isoform 1, but isoform 2 lacks the catalytic domain. Reason: This is a broader IEA annotation that is consistent with the IBA annotation. While less specific than IBA, it is not incorrect. The catalytic activity is confirmed by multiple experimental studies. Supporting Evidence: PMID:16916640 Caspase-7 is an obligate dimer of catalytic domains, with generation of activity requiring limited proteolysis within a region that separates the large and small chains of each domain |
| GO:0006508 proteolysis | IEA GO_REF:0000120 | ACCEPT | Summary: Proteolysis is a parent term of cysteine-type endopeptidase activity. This is a very general annotation but not incorrect for isoform 1. Reason: Caspase-9 is definitively a protease that cleaves substrates. The term is appropriately general for an IEA annotation. More specific terms are available via IBA and IDA annotations. Supporting Evidence: PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 |
| GO:0006915 apoptotic process | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation of apoptotic process is redundant with IBA annotation. Correct as caspase-9 is a key player in apoptosis, with isoform 1 promoting and isoform 2 inhibiting the process. Reason: Consistent with other evidence. The IEA provides computational support for the experimentally validated apoptotic function. Supporting Evidence: PMID:9390557 caspase-9 is the most upstream member of the apoptotic protease cascade that is triggered by cytochrome c and dATP |
| GO:0006974 DNA damage response | IEA GO_REF:0000117 | ACCEPT | Summary: Caspase-9 participates in DNA damage response primarily through its role as the executor of DNA damage-induced apoptosis. c-Abl phosphorylates caspase-9 in response to DNA damage. Reason: The deep research and PMID:15657060 confirm caspase-9's role in DNA damage response. The ARBA machine learning annotation correctly captures this function. Supporting Evidence: PMID:15657060 The c-Abl tyrosine kinase is also involved in the apoptotic response to DNA damage |
| GO:0008233 peptidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Peptidase activity is a parent term of cysteine-type endopeptidase activity. Very general but correct for isoform 1. Reason: This is a very general parent term. More specific annotations are available. Correct for the canonical catalytically active isoform. Supporting Evidence: PMID:16916640 Caspase-7 is an obligate dimer of catalytic domains, with generation of activity requiring limited proteolysis within a region that separates the large and small chains of each domain |
| GO:0008234 cysteine-type peptidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Cysteine-type peptidase activity is a parent term of the more specific cysteine-type endopeptidase activity annotation. Correct for isoform 1. Reason: Parent term of the more specific annotation. Consistent with caspase-9's function as a cysteine protease using the catalytic dyad of Cys-287 and His-237. Supporting Evidence: PMID:16916640 Caspase-7 is an obligate dimer of catalytic domains, with generation of activity requiring limited proteolysis within a region that separates the large and small chains of each domain |
| GO:0009411 response to UV | IEA GO_REF:0000117 | ACCEPT | Summary: UV irradiation causes DNA damage that can trigger caspase-9-mediated apoptosis via the intrinsic pathway. Reason: PMID:15657060 demonstrates that DNA damaging agents including UV activate caspase-9 through c-Abl-mediated phosphorylation. The annotation captures the role of caspase-9 in UV-induced apoptosis. Supporting Evidence: PMID:15657060 Caspase-9(Y153F) also attenuated DNA damage-induced processing of caspase-9 to p35, activation of caspase-3, and apoptosis |
| GO:0016787 hydrolase activity | IEA GO_REF:0000043 | ACCEPT | Summary: Hydrolase activity is a very general parent term. Caspases hydrolyze peptide bonds. Correct but uninformative for isoform 1. Reason: Very general but correct parent term. The UniProtKB keyword mapping correctly identifies caspase-9 as a hydrolase. More specific terms provide better annotation. Supporting Evidence: PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 |
| GO:0042981 regulation of apoptotic process | IEA GO_REF:0000002 | ACCEPT | Summary: Caspase-9 regulates apoptosis. Isoform 1 positively regulates (induces) apoptosis, while isoform 2 negatively regulates (inhibits) apoptosis. This general term encompasses both functions. Reason: This general regulatory term is appropriate as CASP9 is involved in apoptosis regulation through both pro-apoptotic (isoform 1) and anti-apoptotic (isoform 2) mechanisms. The InterPro association correctly identifies this function. Supporting Evidence: file:human/CASP9/CASP9-deep-research-perplexity.md The CASP9 gene generates two functionally antagonistic isoforms through alternative splicing: the pro-apoptotic caspase-9a that retains exons 3, 4, 5, and 6, and the anti-apoptotic caspase-9b |
| GO:0051604 protein maturation | IEA GO_REF:0000117 | ACCEPT | Summary: Caspase-9 (isoform 1) processes/matures other proteins including procaspase-3 and procaspase-7 by proteolytic cleavage. Reason: The annotation captures caspase-9's role in processing downstream effector caspases from their inactive proforms to active enzymes. This is a core function of initiator caspases. 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:0005515 protein binding | IPI PMID:10206961 An APAF-1.cytochrome c multimeric complex is a functional ap... | MODIFY | Summary: PMID:10206961 demonstrates caspase-9 binding to Apaf-1 in the apoptosome complex. While "protein binding" is too vague, the specific interaction with Apaf-1 is core to caspase-9 function. Reason: "Protein binding" is uninformative. The paper demonstrates CARD-CARD interaction between caspase-9 and Apaf-1 in the apoptosome. A more specific term should be used. Proposed replacements: cysteine-type endopeptidase activity 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:0005515 protein binding | IPI PMID:10376594 Structural basis of procaspase-9 recruitment by the apoptoti... | MODIFY | Summary: PMID:10376594 describes the structural basis of procaspase-9 recruitment by Apaf-1 via CARD-CARD interactions. "Protein binding" is too general. Reason: The specific interaction is CARD domain binding. A more informative term would capture the CARD-CARD interaction that recruits caspase-9 to the apoptosome. Proposed replacements: identical protein binding Supporting Evidence: PMID:10376594 Structural basis of procaspase-9 recruitment by the apoptotic protease-activating factor 1 |
| GO:0005515 protein binding | IPI PMID:11024045 Livin, a novel inhibitor of apoptosis protein family member. | KEEP AS NON CORE | Summary: PMID:11024045 describes Livin (BIRC7), an IAP family member that can bind caspases. Reason: IAP binding is part of caspase regulation but "protein binding" is too vague. The interaction with IAPs is important for regulation but not a core function annotation. Supporting Evidence: PMID:11024045 Livin, a novel inhibitor of apoptosis protein family member |
| GO:0005515 protein binding | IPI PMID:11084335 ML-IAP, a novel inhibitor of apoptosis that is preferentiall... | KEEP AS NON CORE | Summary: PMID:11084335 describes ML-IAP (BIRC7) interaction with caspases. Reason: IAP interaction is regulatory. "Protein binding" is too vague but the interaction is documented. Supporting Evidence: PMID:11084335 ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas |
| GO:0005515 protein binding | IPI PMID:11230124 Recruitment, activation and retention of caspases-9 and -3 b... | KEEP AS NON CORE | Summary: PMID:11230124 describes recruitment of caspases to Apaf-1 apoptosome and XIAP complexes. Reason: Documents apoptosome assembly and XIAP regulation. "Protein binding" is uninformative but the interactions are relevant. Supporting Evidence: PMID:11230124 Recruitment, activation and retention of caspases-9 and -3 by Apaf-1 apoptosome and associated XIAP complexes |
| GO:0005515 protein binding | IPI PMID:11242052 A conserved XIAP-interaction motif in caspase-9 and Smac/DIA... | KEEP AS NON CORE | Summary: PMID:11242052 describes the XIAP-interaction motif in caspase-9 and Smac/DIABLO. Reason: IAP binding motif documentation. The caspase-9/XIAP interaction is well-established for regulation of caspase activity. Supporting Evidence: PMID:11242052 A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis |
| GO:0005515 protein binding | IPI PMID:11801603 SMAC negatively regulates the anti-apoptotic activity of mel... | KEEP AS NON CORE | Summary: PMID:11801603 describes SMAC interaction with ML-IAP (BIRC7). Reason: Part of the IAP regulatory network affecting caspase-9 activity. Supporting Evidence: PMID:11801603 SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis |
| GO:0005515 protein binding | IPI PMID:11821383 CARD-8 protein, a new CARD family member that regulates casp... | KEEP AS NON CORE | Summary: PMID:11821383 describes CARD-8 interaction with caspase-9 via CARD domain. CARD-8 regulates caspase-1 and can interact with caspase-9. Reason: CARD-8 interaction is regulatory. The paper focuses on caspase-1 regulation with caspase-9 interaction being secondary. Supporting Evidence: PMID:11821383 CARD-8 protein, a new CARD family member that regulates caspase-1 activation and apoptosis |
| GO:0005515 protein binding | IPI PMID:12620238 Mechanism of XIAP-mediated inhibition of caspase-9. | KEEP AS NON CORE | Summary: PMID:12620238 provides structural mechanism of XIAP-mediated caspase-9 inhibition. Reason: XIAP binding is a key regulatory mechanism. The structural data confirms the interaction but "protein binding" is too vague. Supporting Evidence: PMID:12620238 Mechanism of XIAP-mediated inhibition of caspase-9 |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | KEEP AS NON CORE | Summary: PMID:16189514 is a large-scale proteome mapping study. Individual interactions may not be validated. Reason: High-throughput study. Interactions should be confirmed by directed studies. Supporting Evidence: PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network |
| GO:0005515 protein binding | IPI PMID:16537496 The dependence receptor DCC requires lipid raft localization... | KEEP AS NON CORE | Summary: PMID:16537496 describes DCC dependence receptor signaling involving caspase-9. Reason: DCC receptor signaling is a specific pathway involving caspase-9 activation. Not a core function but a documented regulatory interaction. Supporting Evidence: PMID:16537496 The dependence receptor DCC requires lipid raft localization for cell death signaling |
| GO:0005515 protein binding | IPI PMID:16936772 Integrin-linked kinase interacts with caspase-9 and -8 in an... | KEEP AS NON CORE | Summary: PMID:16936772 describes integrin-linked kinase (ILK) interaction with caspases. Reason: ILK-caspase interaction is context-specific for adhesion-dependent apoptosis in leukemia cells. Supporting Evidence: PMID:16936772 Integrin-linked kinase interacts with caspase-9 and -8 in an adhesion-dependent manner |
| GO:0005515 protein binding | IPI PMID:18022362 IAP antagonists induce autoubiquitination of c-IAPs, NF-kapp... | KEEP AS NON CORE | Summary: PMID:18022362 describes IAP antagonists inducing autoubiquitination of c-IAPs. Reason: Part of IAP regulatory network affecting caspase activity. Supporting Evidence: PMID:18022362 IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis |
| GO:0005515 protein binding | IPI PMID:18723680 Executioner caspase-3 and caspase-7 are functionally distinc... | KEEP AS NON CORE | Summary: PMID:18723680 shows caspase-3 and caspase-7 are functionally distinct, with implications for caspase-9-mediated activation. Reason: Relevant to caspase-9's substrate specificity but "protein binding" is vague. Supporting Evidence: PMID:18723680 Executioner caspase-3 and caspase-7 are functionally distinct proteases |
| GO:0005515 protein binding | IPI PMID:19153467 The structure of the BIR3 domain of cIAP1 in complex with th... | KEEP AS NON CORE | Summary: PMID:19153467 provides structural data on BIR3 domain of cIAP1 in complex with caspase-9 N-terminal peptide. Reason: Structural data on IAP-caspase interaction. Regulatory rather than core function. Supporting Evidence: PMID:19153467 The structure of the BIR3 domain of cIAP1 in complex with the N-terminal peptides of SMAC and caspase-9 |
| GO:0005515 protein binding | IPI PMID:19494828 The Apaf-1*procaspase-9 apoptosome complex functions as a pr... | ACCEPT | Summary: PMID:19494828 describes the apoptosome as a proteolytic-based molecular timer. Reason: This paper provides important mechanistic insight into caspase-9/Apaf-1 interaction dynamics in the apoptosome. The interaction is core to function though "protein binding" is uninformative. Supporting Evidence: PMID:19494828 The Apaf-1*procaspase-9 apoptosome complex functions as a proteolytic-based molecular timer |
| GO:0005515 protein binding | IPI PMID:19721007 Netrin-1 up-regulation in inflammatory bowel diseases is req... | KEEP AS NON CORE | Summary: PMID:19721007 describes Netrin-1 signaling in colorectal cancer involving dependence receptors. Reason: Netrin-1/dependence receptor signaling is a specific context for caspase activation. Supporting Evidence: PMID:19721007 Netrin-1 up-regulation in inflammatory bowel diseases is required for colorectal cancer progression |
| GO:0005515 protein binding | IPI PMID:20462491 Structure of an apoptosome-procaspase-9 CARD complex. | ACCEPT | Summary: PMID:20462491 provides structure of apoptosome-procaspase-9 CARD complex. Reason: Key structural study of the core caspase-9/Apaf-1 CARD interaction. Though "protein binding" is vague, the CARD-CARD interaction is essential for function. Supporting Evidence: PMID:20462491 Structure of an apoptosome-procaspase-9 CARD complex |
| GO:0005515 protein binding | IPI PMID:21827945 The holo-apoptosome: activation of procaspase-9 and interact... | ACCEPT | Summary: PMID:21827945 describes holo-apoptosome structure and procaspase-9 activation and interactions with caspase-3. Reason: Core structural/mechanistic study of the apoptosome. Demonstrates caspase-9 binding to apoptosome and interactions with caspase-3. Supporting Evidence: PMID:21827945 Activation of procaspase-9 on the apoptosome is a pivotal step in the intrinsic cell death pathway |
| GO:0005515 protein binding | IPI PMID:23516580 The E. coli effector protein NleF is a caspase inhibitor. | KEEP AS NON CORE | Summary: PMID:23516580 describes E. coli NleF effector as a caspase inhibitor that binds caspase-9. Reason: Pathogen effector binding is context-specific for microbial infection. Supporting Evidence: PMID:23516580 The E. coli effector protein NleF is a caspase inhibitor |
| GO:0005515 protein binding | IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ... | KEEP AS NON CORE | Summary: High-throughput proximity ligation study. Reason: Large-scale study requiring validation of individual interactions. Supporting Evidence: PMID:25241761 Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Proteome-scale interactome mapping study. Reason: High-throughput study. Individual interactions need validation. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network |
| GO:0005515 protein binding | IPI PMID:25502805 A massively parallel pipeline to clone DNA variants and exam... | KEEP AS NON CORE | Summary: Massively parallel cloning and phenotyping study. Reason: High-throughput study. Supporting Evidence: PMID:25502805 A massively parallel pipeline to clone DNA variants and examine molecular phenotypes |
| GO:0005515 protein binding | IPI PMID:25519916 The EHEC-host interactome reveals novel targets for the tran... | KEEP AS NON CORE | Summary: EHEC-host interactome study identifying translocated intimin receptor targets. Reason: Pathogen-host interaction context. Supporting Evidence: PMID:25519916 The EHEC-host interactome reveals novel targets for the translocated intimin receptor |
| GO:0005515 protein binding | IPI PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusi... | KEEP AS NON CORE | Summary: Barcode Fusion Genetics protein interaction screen. Reason: High-throughput screening method. Supporting Evidence: PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusion Genetics |
| GO:0005515 protein binding | IPI PMID:29997244 LuTHy: a double-readout bioluminescence-based two-hybrid tec... | KEEP AS NON CORE | Summary: LuTHy two-hybrid technology for protein interaction mapping. Reason: High-throughput interaction mapping study. Supporting Evidence: PMID:29997244 LuTHy: a double-readout bioluminescence-based two-hybrid technology |
| GO:0005515 protein binding | IPI PMID:31467278 Maximizing binary interactome mapping with a minimal number ... | KEEP AS NON CORE | Summary: Binary interactome mapping optimization study. Reason: Methodological study for interaction mapping. Supporting Evidence: PMID:31467278 Maximizing binary interactome mapping with a minimal number of assays |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | KEEP AS NON CORE | Summary: Study of protein interaction disruption by genetic variants. Reason: Population genetics study of interaction disruption. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Reference map of human binary protein interactome. Reason: Large-scale interactome reference study. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome |
| GO:0005515 protein binding | IPI PMID:9390557 Cytochrome c and dATP-dependent formation of Apaf-1/caspase-... | ACCEPT | Summary: PMID:9390557 is a landmark paper demonstrating caspase-9/Apaf-1 CARD-CARD interaction in apoptosome formation. Reason: Foundational paper on caspase-9 function. Demonstrates the core CARD-CARD interaction with Apaf-1 essential for apoptosome formation and caspase activation. Supporting Evidence: PMID:9390557 Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome c and dATP |
| GO:0005515 protein binding | IPI PMID:9922454 Ordering the cytochrome c-initiated caspase cascade: hierarc... | ACCEPT | Summary: PMID:9922454 describes the caspase cascade with caspase-9 dependent activation of downstream caspases. Reason: Demonstrates caspase-9 interaction with and processing of downstream caspases (caspase-2, -3, -6, -7, -8, -10). Core function of initiator caspase. Supporting Evidence: PMID:9922454 Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner |
| GO:0001666 response to hypoxia | IEA GO_REF:0000107 | ACCEPT | Summary: Caspase-9 is activated during hypoxia-induced apoptosis. Recent research shows non-apoptotic endothelial caspase-9 signaling in hypoxia-ischemia. Reason: Deep research confirms: "In a mouse model of retinal vein occlusion (RVO), pharmacological inhibition or genetic deletion of caspase-9 specifically from endothelial cells significantly reduces vascular edema." Hypoxia triggers intrinsic apoptotic pathway. Supporting Evidence: file:human/CASP9/CASP9-deep-research-perplexity.md endothelial caspase-9 activation following hypoxia-ischemia appears to occur independently of apoptosis |
| GO:0001822 kidney development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Caspase-mediated apoptosis plays roles in kidney development. This is a pleiotropic developmental process. Reason: Apoptosis is involved in kidney development but this is not a core function of caspase-9. The annotation is from ortholog transfer (Ensembl Compara). Supporting Evidence: GO_REF:0000107 Automatic transfer of experimentally verified manual GO annotation data to orthologs |
| GO:0002931 response to ischemia | IEA GO_REF:0000107 | ACCEPT | Summary: Caspase-9 is activated in ischemic injury, both through apoptotic and non-apoptotic mechanisms in endothelial cells. Reason: Deep research confirms: "In a mouse model of retinal vein occlusion (RVO), pharmacological inhibition or genetic deletion of caspase-9...significantly reduces vascular edema, restores vascular integrity, and provides robust neuroprotection." Supporting Evidence: file:human/CASP9/CASP9-deep-research-perplexity.md non-apoptotic endothelial caspase-9 signaling as a critical mediator of ischemic injury in hypoxia-ischemia models |
| 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 | ACCEPT | Summary: Caspase-9 processes procaspases-3 and -7 by proteolytic cleavage. This is a core function. Reason: Caspase-9 processes its substrates (procaspase-3, procaspase-7) to their mature forms. This is the primary enzymatic function. 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:0032025 response to cobalt ion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cobalt ions can induce hypoxia-like responses. Caspase-9 may be activated in this context. Reason: Cobalt-induced response is likely through hypoxia mimicry. Not a core function but an experimental context. Annotation from ortholog transfer. Supporting Evidence: GO_REF:0000107 Automatic transfer of experimentally verified manual GO annotation data to orthologs |
| GO:0032355 response to estradiol | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Estradiol can have anti-apoptotic effects that may involve caspase regulation. Reason: Hormone response is context-specific. Annotation from ortholog transfer. Not a core function. Supporting Evidence: GO_REF:0000107 Automatic transfer of experimentally verified manual GO annotation data to orthologs |
| GO:0032496 response to lipopolysaccharide | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: LPS can trigger apoptotic pathways in various cell types. Reason: LPS response is context-specific, particularly relevant to immune cells. Annotation from ortholog transfer. Supporting Evidence: GO_REF:0000107 Automatic transfer of experimentally verified manual GO annotation data to orthologs |
| GO:0034349 glial cell apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Caspase-9 is involved in glial cell apoptosis as part of CNS development and disease. Reason: Cell-type specific apoptotic process. Not a core function but consistent with caspase-9's role in CNS development. CRITICAL: Only isoform 1 would positively regulate this. Supporting Evidence: file:human/CASP9/CASP9-deep-research-perplexity.md mice lacking caspase-9 die perinatally with severe brain abnormalities |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000120 | ACCEPT | Summary: CRITICAL ISOFORM ANNOTATION: This annotation is ONLY true for isoform 1 (Caspase-9L/Alpha). Isoform 2 (Caspase-9S/Beta) is a DOMINANT-NEGATIVE INHIBITOR that NEGATIVELY regulates apoptosis. Reason: Isoform 1 does positively regulate apoptosis by activating effector caspases. However, the annotation should ideally be isoform-specific. The IEA annotation applies to the canonical pro-apoptotic function. Supporting Evidence: PMID:9390557 caspase-9 is the most upstream member of the apoptotic protease cascade file:human/CASP9/CASP9-deep-research-perplexity.md the pro-apoptotic caspase-9a that retains exons 3, 4, 5, and 6, and the anti-apoptotic caspase-9b |
| GO:0045471 response to ethanol | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ethanol can induce apoptosis in various tissues including liver and neurons. Reason: Toxicological response context. Annotation from ortholog transfer. Not a core function. Supporting Evidence: GO_REF:0000107 Automatic transfer of experimentally verified manual GO annotation data to orthologs |
| GO:0071549 cellular response to dexamethasone stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Dexamethasone can induce apoptosis in some cell types. Reason: Glucocorticoid response is context-specific. Annotation from ortholog transfer. Supporting Evidence: GO_REF:0000107 Automatic transfer of experimentally verified manual GO annotation data to orthologs |
| GO:0071680 response to indole-3-methanol | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Indole-3-carbinol is a phytochemical that can affect apoptotic pathways. Reason: Specific chemical response. Not a core function. Annotation from ortholog transfer. Supporting Evidence: GO_REF:0000107 Automatic transfer of experimentally verified manual GO annotation data to orthologs |
| GO:0071887 leukocyte apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Caspase-9 is involved in leukocyte apoptosis as part of immune regulation. Reason: Cell-type specific apoptotic process. The intrinsic pathway operates in leukocytes but this is not a core function annotation. CRITICAL: Only isoform 1 promotes this. Supporting Evidence: GO_REF:0000107 Automatic transfer of experimentally verified manual GO annotation data to orthologs |
| GO:0072347 response to anesthetic | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Some anesthetics can induce neuronal apoptosis involving caspase-9. Reason: Specific pharmacological context. Annotation from ortholog transfer. Supporting Evidence: GO_REF:0000107 Automatic transfer of experimentally verified manual GO annotation data to orthologs |
| GO:0004197 cysteine-type endopeptidase activity | TAS Reactome:R-HSA-114259 | ACCEPT | Summary: Reactome pathway annotation for caspase-9 cleavage. CRITICAL: This catalytic activity is ONLY present in isoform 1. Reason: Reactome correctly annotates the catalytic activity in the context of apoptosome-mediated procaspase-9 cleavage to active caspase-9. 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: PMID:10206961 demonstrates caspase-9 activation in the apoptosome as the key step in the intrinsic apoptotic pathway. CRITICAL: Isoform 1 activates while isoform 2 inhibits this pathway. Reason: Core annotation for caspase-9 function. The paper demonstrates apoptosome formation and procaspase-9 activation. 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 file:human/CASP9/CASP9-deep-research-falcon.md In intrinsic apoptosis, mitochondrial stress leads to cytochrome c release, which binds Apaf-1; Apaf-1 assembles a heptameric apoptosome that directly engages multiple procaspase-9 molecules via CARD–CARD interactions, forming an activation assembly that promotes caspase-9 activation and subsequent activation of downstream effector caspases. |
| 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 file:human/CASP9/CASP9-deep-research-falcon.md caspase-9 effectively cleaves procaspase-3 ISL at IETD↓S, but does not efficiently activate procaspase-6 despite it having ISL Asp motifs, because the local context prevents productive cleavage. |
| 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... | ACCEPT | Summary: PMID:11821383 describes CARD-8 interaction with caspase-9. The paper shows CARD-8 overexpression induces apoptosis. CRITICAL: This pro-apoptotic function is isoform 1 specific. Reason: The study demonstrates caspase-9's role in apoptosis induction through CARD-domain interactions. The mutant phenotype evidence supports positive regulation of apoptosis. Supporting Evidence: PMID:11821383 Overexpression of CARD-8 can also induce apoptosis in transfected cells |
| GO:0006974 DNA damage response | IMP PMID:15657060 c-Abl tyrosine kinase regulates caspase-9 autocleavage in th... | ACCEPT | Summary: PMID:15657060 demonstrates c-Abl phosphorylates caspase-9 in DNA damage response, with mutant phenotype evidence. Reason: Direct experimental evidence using Y153F mutant showing attenuated DNA damage-induced caspase-9 processing and apoptosis. Supporting Evidence: PMID:15657060 Caspase-9(Y153F) also attenuated DNA damage-induced processing of caspase-9 to p35, activation of caspase-3, and apoptosis |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9627089 | ACCEPT | Summary: Reactome pathway annotation for caspase-9 localization in phosphorylation reaction. Reason: Consistent with other cytosolic localization annotations. Caspase-9 is phosphorylated at T412 in the cytosol. Supporting Evidence: Reactome:R-HSA-9627089 CASP9 is phosphorylated at T412 |
| GO:0097193 intrinsic apoptotic signaling pathway | IDA PMID:35446120 Calmodulin Binding Activates Chromobacterium CopC Effector t... | ACCEPT | Summary: PMID:35446120 shows Chromobacterium CopC effector ADP-riboxanates caspase-9 to inhibit intrinsic apoptotic pathway. This demonstrates caspase-9's role in the pathway (isoform 1). Reason: The study demonstrates caspase-9's essential role in intrinsic apoptotic signaling by showing that pathogen effector modification blocks this pathway. Supporting Evidence: PMID:35446120 Calmodulin Binding Activates Chromobacterium CopC Effector to ADP-Riboxanate Host Apoptotic Caspases |
| 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: PMID:16352606 shows caspase-9 directly matures procaspase-7 to active caspase-7 (isoform 1 function). Reason: Direct experimental evidence of caspase-9 processing procaspase-7 to mature enzyme. 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 file:human/CASP9/CASP9-deep-research-falcon.md apoptosome binding strongly optimizes recognition/processing of physiologic protein substrates (notably procaspase-3). In particular, the apoptosome-bound caspase-9 holoenzyme shows much stronger functional efficiency toward procaspase-3 (lower Km) than engineered dimeric caspase-9 |
| GO:0051604 protein maturation | IDA PMID:16916640 Engineered hybrid dimers: tracking the activation pathway of... | ACCEPT | Summary: PMID:16916640 demonstrates caspase-7 maturation by caspase-9 using hybrid dimers (isoform 1 function). Reason: Direct experimental evidence using sophisticated biochemical approaches to demonstrate procaspase-7 maturation. Supporting Evidence: PMID:16916640 The processed domain of this singly cleaved zymogen has the same catalytic activity as a domain of fully active caspase-7 |
| GO:1900119 positive regulation of execution phase of apoptosis | IDA PMID:16916640 Engineered hybrid dimers: tracking the activation pathway of... | ACCEPT | Summary: PMID:16916640 demonstrates caspase-9 activates caspase-7, which executes apoptosis. CRITICAL: This is isoform 1 specific. Reason: The execution phase of apoptosis is triggered by activation of executioner caspases (caspase-3 and -7) by caspase-9. Direct experimental evidence. 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... | ACCEPT | Summary: PMID:21980415 identifies conserved anti-apoptotic protein modulating mitochondrial apoptosis pathway, using mutant phenotypes to demonstrate caspase-9 activity. Reason: Mutant phenotype evidence for caspase-9 catalytic activity in apoptosis. Supporting Evidence: PMID:21980415 Identification of a conserved anti-apoptotic protein that modulates the mitochondrial apoptosis pathway |
| GO:0006915 apoptotic process | IMP PMID:15069058 BRCC2, a novel BH3-like domain-containing protein, induces a... | ACCEPT | Summary: PMID:15069058 describes BRCC2, a BH3-domain protein that induces apoptosis in a caspase-dependent manner. Reason: Mutant phenotype evidence for caspase-9 role in apoptosis through BH3 domain protein interactions. Supporting Evidence: PMID:15069058 BRCC2, a novel BH3-like domain-containing protein, induces apoptosis in a caspase-dependent manner |
| GO:0004197 cysteine-type endopeptidase activity | IDA PMID:16920334 Protective role of Cop in Rip2/caspase-1/caspase-4-mediated ... | ACCEPT | Summary: PMID:16920334 examines Cop protective role in caspase-mediated cell death (isoform 1 function). Reason: Direct assay evidence for caspase-9 catalytic activity in cell death. Supporting Evidence: PMID:16920334 Protective role of Cop in Rip2/caspase-1/caspase-4-mediated HeLa cell death |
| GO:0005515 protein binding | IPI PMID:11821383 CARD-8 protein, a new CARD family member that regulates casp... | KEEP AS NON CORE | Summary: PMID:11821383 shows CARD-8 binds to caspase-9 via CARD domain interaction. Reason: CARD domain interaction is documented but "protein binding" is uninformative. The CARD-CARD interaction is regulatory. Supporting Evidence: PMID:11821383 CARD-8 binds also to ICEBERG and pseudo-ICE |
| GO:0032991 protein-containing complex | IDA PMID:11821383 CARD-8 protein, a new CARD family member that regulates casp... | KEEP AS NON CORE | Summary: PMID:11821383 identifies caspase-9 in protein complexes with CARD-8. Reason: Generic complex annotation. The apoptosome is the key functional complex for caspase-9. Supporting Evidence: PMID:11821383 CARD-8 interacts physically with caspase-1 |
| GO:0008233 peptidase activity | IDA PMID:19740745 A truncated form of p23 down-regulates telomerase activity v... | ACCEPT | Summary: PMID:19740745 shows truncated p23 disrupts Hsp90 function affecting telomerase. Caspase-9 peptidase activity is involved (isoform 1). Reason: Direct assay evidence for caspase-9 peptidase activity. Parent term of cysteine-type endopeptidase activity. Supporting Evidence: PMID:19740745 A truncated form of p23 down-regulates telomerase activity via disruption of Hsp90 function |
| GO:0005515 protein binding | IPI PMID:19255499 HIP1R interacts with a member of Bcl-2 family, BCL2L10, and ... | KEEP AS NON CORE | Summary: PMID:19255499 shows HIP1R interacts with BCL2L10 which affects BAK-dependent cell death. Reason: BCL2L10 interaction affects mitochondrial apoptosis pathway. Regulatory interaction. Supporting Evidence: PMID:19255499 HIP1R interacts with a member of Bcl-2 family, BCL2L10, and induces BAK-dependent cell death |
| GO:0005829 cytosol | TAS Reactome:R-HSA-114252 | ACCEPT | Summary: Reactome pathway annotation for procaspase-3 cleavage by apoptosome. Reason: Consistent with cytosolic localization of the apoptosome complex where caspase-9 cleaves procaspase-3. Supporting Evidence: Reactome:R-HSA-114252 Cleavage of Procaspase-3 by the apoptosome |
| GO:0005829 cytosol | TAS Reactome:R-HSA-114259 | ACCEPT | Summary: Reactome annotation for procaspase-9 cleavage. Reason: Consistent with cytosolic localization of the apoptosome. 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:0005829 cytosol | TAS Reactome:R-HSA-114261 | ACCEPT | Summary: Reactome annotation for procaspase-7 cleavage by apoptosome. Reason: Consistent with cytosolic localization. Supporting Evidence: Reactome:R-HSA-114261 Cleavage of Procaspase-7 by the apoptosome |
| GO:0005829 cytosol | TAS Reactome:R-HSA-373700 | ACCEPT | Summary: Reactome annotation for caspase-9 binding to DCC:DIP13alpha complex. Reason: Consistent with cytosolic localization for dependence receptor signaling. Supporting Evidence: Reactome:R-HSA-373700 Caspase-9 binds DCC:DIP13alpha complex |
| GO:0005829 cytosol | TAS Reactome:R-HSA-418845 | ACCEPT | Summary: Reactome annotation for caspase-3 activation. Reason: Consistent with cytosolic localization for caspase cascade. Supporting Evidence: Reactome:R-HSA-418845 Activation of caspase-3 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6804596 | ACCEPT | Summary: Reactome annotation for APAF1:CYCS binding APIP. Reason: Consistent with cytosolic localization of apoptosome components. Supporting Evidence: Reactome:R-HSA-6804596 APAF1:CYCS binds APIP |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6805426 | ACCEPT | Summary: Reactome annotation for CARD8 binding to CASP9(1-416). Reason: Consistent with cytosolic localization. Supporting Evidence: Reactome:R-HSA-6805426 CARD8 binds CASP9(1-416) |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9627056 | ACCEPT | Summary: Reactome annotation for procaspase-9 dimer formation. Reason: Consistent with cytosolic localization for dimerization. Supporting Evidence: Reactome:R-HSA-9627056 Procaspase 9 forms dimer |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9627078 | ACCEPT | Summary: Reactome annotation for XIAP binding CASP9. Reason: Consistent with cytosolic localization for IAP regulation. Supporting Evidence: Reactome:R-HSA-9627078 X‑linked inhibitor‑of‑apoptosis protein (XIAP) associates with the cleaved form of CASP9 |
| GO:0005829 cytosol | IDA PMID:17167422 Hsp70 regulates erythropoiesis by preventing caspase-3-media... | ACCEPT | Summary: PMID:17167422 shows Hsp70 regulates erythropoiesis by preventing caspase-3 cleavage of GATA-1 in the cytosol. Reason: Direct experimental evidence for cytosolic caspase activity during erythroid differentiation. Supporting Evidence: PMID:17167422 At the onset of caspase activation, Hsp70 co-localizes and interacts with GATA-1 in the nucleus |
| 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 | ACCEPT | Summary: Reactome annotation for CYCS:APAF1 binding procaspase-9. Reason: Consistent with cytosolic localization of apoptosome assembly. Supporting Evidence: Reactome:R-HSA-114256 CYCS:APAF1 binds procaspase-9 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-198621 | ACCEPT | Summary: Reactome annotation for AKT phosphorylates caspase-9. Reason: Consistent with cytosolic localization for AKT-mediated regulation. Supporting Evidence: Reactome:R-HSA-198621 AKT phosphorylates caspase-9 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2399985 | ACCEPT | Summary: Reactome annotation for AKT1 E17K mutant phosphorylates caspase-9. Reason: Consistent with cytosolic localization. Supporting Evidence: Reactome:R-HSA-2399985 AKT1 E17K mutant phosphorylates caspase-9 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6804596 | ACCEPT | Summary: Duplicate annotation - same as earlier entry. Reason: Consistent with cytosolic localization. Supporting Evidence: Reactome:R-HSA-6804596 APAF1:CYCS binds APIP |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6805426 | ACCEPT | Summary: Duplicate annotation - same as earlier entry. Reason: Consistent with cytosolic localization. Supporting Evidence: Reactome:R-HSA-6805426 CARD8 binds CASP9(1-416) |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9627056 | ACCEPT | Summary: Duplicate annotation - same as earlier entry. Reason: Consistent with cytosolic localization. Supporting Evidence: Reactome:R-HSA-9627056 Procaspase 9 forms dimer |
| GO:0005515 protein binding | IPI PMID:15657060 c-Abl tyrosine kinase regulates caspase-9 autocleavage in th... | ACCEPT | Summary: PMID:15657060 shows c-Abl directly binds caspase-9 via SH3 domain. Reason: c-Abl/caspase-9 interaction is functionally important for DNA damage response. Though "protein binding" is vague, the interaction is core to DNA damage-induced apoptosis. Supporting Evidence: PMID:15657060 c-Abl binds directly to caspase-9 |
| GO:0006974 DNA damage response | IDA PMID:15657060 c-Abl tyrosine kinase regulates caspase-9 autocleavage in th... | ACCEPT | Summary: PMID:15657060 provides direct assay evidence for caspase-9 in DNA damage response through c-Abl-mediated phosphorylation. Reason: Direct experimental demonstration of caspase-9 activation in DNA damage response via c-Abl phosphorylation at Tyr-153. Supporting Evidence: PMID:15657060 c-Abl phosphorylates caspase-9 on Tyr-153 in vitro and in cells treated with DNA damaging agents |
| GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage | IMP PMID:15657060 c-Abl tyrosine kinase regulates caspase-9 autocleavage in th... | ACCEPT | Summary: PMID:15657060 demonstrates Y153F mutant attenuates DNA damage-induced caspase-9 processing and apoptosis. Reason: Mutant phenotype evidence for caspase-9 role in intrinsic apoptotic signaling in response to DNA damage. Supporting Evidence: PMID:15657060 Caspase-9(Y153F) also attenuated DNA damage-induced processing of caspase-9 to p35, activation of caspase-3, and apoptosis |
| GO:0019901 protein kinase binding | IDA PMID:15657060 c-Abl tyrosine kinase regulates caspase-9 autocleavage in th... | ACCEPT | Summary: PMID:15657060 demonstrates caspase-9 binds c-Abl tyrosine kinase. Reason: Direct experimental evidence for caspase-9 binding to c-Abl kinase. This is a more informative term than generic "protein binding". Supporting Evidence: PMID:15657060 c-Abl binds directly to caspase-9 |
| GO:0034644 cellular response to UV | IDA PMID:15657060 c-Abl tyrosine kinase regulates caspase-9 autocleavage in th... | ACCEPT | Summary: PMID:15657060 demonstrates caspase-9 activation in response to UV irradiation via c-Abl. Reason: Direct experimental evidence for caspase-9 role in UV response. The Y153F mutant attenuates UV irradiation-induced apoptosis. Supporting Evidence: PMID:15657060 Caspase-9(Y153F) also attenuated DNA damage-induced processing of caspase-9 to p35, activation of caspase-3, and apoptosis |
| GO:0042770 signal transduction in response to DNA damage | IDA PMID:15657060 c-Abl tyrosine kinase regulates caspase-9 autocleavage in th... | ACCEPT | Summary: PMID:15657060 shows c-Abl-mediated signal transduction to caspase-9 in DNA damage response. Reason: Direct experimental evidence for caspase-9 role in DNA damage signal transduction through c-Abl kinase. Supporting Evidence: PMID:15657060 c-Abl tyrosine kinase regulates caspase-9 autocleavage in the apoptotic response to DNA damage |
| GO:0005515 protein binding | IPI PMID:11350957 Characterization of a novel proapoptotic caspase-2- and casp... | KEEP AS NON CORE | Summary: PMID:11350957 describes proapoptotic caspase-2 and caspase-9 binding protein. Reason: Documents a caspase-binding protein. "Protein binding" is uninformative. Supporting Evidence: PMID:11350957 Characterization of a novel proapoptotic caspase-2- and caspase-9-binding protein |
| GO:0043293 apoptosome | IDA PMID:21827945 The holo-apoptosome: activation of procaspase-9 and interact... | ACCEPT | Summary: PMID:21827945 provides structural evidence for caspase-9 as a component of the apoptosome. Reason: Key structural study demonstrating caspase-9 localization to the apoptosome. CRITICAL: Both isoforms can bind Apaf-1 in the apoptosome, but with opposite effects (isoform 1 activates cascade, isoform 2 inhibits). Supporting Evidence: PMID:21827945 Activation of procaspase-9 on the apoptosome is a pivotal step in the intrinsic cell death pathway file:human/CASP9/CASP9-deep-research-falcon.md Apoptosome (definition): a heptameric complex formed by Apaf-1 in response to mitochondrial outer membrane permeabilization (MOMP) and cytochrome c release; this platform recruits procaspase-9 through CARD–CARD interactions and promotes caspase-9 activation by proximity-driven dimerization. |
| 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... | KEEP AS NON CORE | Summary: PMID:11069302 describes survivin interaction with caspase-9. Reason: Survivin is an IAP family member that regulates caspase-9 activity. Regulatory interaction. Supporting Evidence: PMID:11069302 Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin |
| 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-... | ACCEPT | Summary: PMID:9390557 demonstrates caspase-9 activates caspase-3 (isoform 1 function). Reason: Caspase-9 functions as an enzyme activator by cleaving and activating downstream effector caspases. This captures the initiator caspase function. Supporting Evidence: PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 file:human/CASP9/CASP9-deep-research-falcon.md For caspase-9, the best-established physiological role is to proteolytically activate procaspase-3 and procaspase-7 by cleaving their intersubunit linker (ISL) between large and small catalytic subunits. |
| GO:0043066 negative regulation of apoptotic process | TAS PMID:10070954 Identification of an endogenous dominant-negative short isof... | NEW | Summary: MISSING ANNOTATION: Caspase-9S (isoform 2, P55211-2) is a dominant-negative inhibitor of apoptosis. UniProt explicitly states "Isoform 2: Lacks activity is an dominant-negative inhibitor of caspase-9." This annotation is CRITICAL for understanding CASP9 biology. Reason: Isoform 2 (Caspase-9S/Beta) lacks the catalytic domain and competes with isoform 1 for Apaf-1 binding, thereby inhibiting apoptosis. This is a dominant-negative mechanism where the 9L/9S ratio determines apoptotic sensitivity. PMID:10070954 characterizes this isoform. Cancer cells often shift ratio towards 9S to evade apoptosis. Supporting Evidence: PMID:10070954 Identification of an endogenous dominant-negative short isoform of caspase-9 that can regulate apoptosis file:human/CASP9/CASP9-deep-research-perplexity.md the anti-apoptotic caspase-9b that excludes these exons...caspase-9b lacks the core catalytic domain and functions as a dominant-negative inhibitor of caspase-9a |
| GO:0030234 enzyme regulator activity | NAS | NEW | Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:10070954 Identification of an endogenous dominant-negative short isoform of caspase-9 that can regulate apoptosis |
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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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