Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Caspase-3 acts in the cytoplasm/cytosol, where the procaspase resides and where it is activated and cleaves most substrates. Reason: Cytoplasmic localization is well supported as the principal site of caspase-3 activity; this is the consensus phylogenetic (IBA) cellular component and matches UniProt subcellular location. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm PMID:15003516 Caspase 3 activation is controlled by a sequence located in the N-terminus of its large subunit.
GO:0006915 apoptotic process	IBA GO_REF:0000033	ACCEPT	Summary: Caspase-3 is the principal executioner caspase of apoptosis, a deeply conserved role captured by the IBA annotation. Reason: Involvement in apoptosis is the defining biological process for caspase-3 and is supported by phylogenetic inference and extensive experimental literature. Supporting Evidence: PMID:18723680 Caspase-3 was found to be generally more promiscuous than caspase-7 and appears to be the major executioner caspase during the demolition phase of apoptosis. PMID:7596430 suggesting that apopain/CPP32 is important for the initiation of apoptotic cell death.
GO:0004197 cysteine-type endopeptidase activity	IBA GO_REF:0000033	ACCEPT	Summary: Caspase-3 is a cysteine-type endopeptidase (EC 3.4.22.56) that cleaves substrates after aspartate residues; this is its core molecular function. Reason: This is the central, well-established molecular function of caspase-3, supported by phylogenetic inference, biochemical purification, and crystal structures. It should be retained as a core function. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. It has a preferred cleavage sequence of Asp-Xaa-Xaa-Asp-\|- PMID:7596430 suggesting that apopain/CPP32 is important for the initiation of apoptotic cell death. file:human/CASP3/CASP3-deep-research-falcon.md the most proteolytically proficient executioner of programmed cell death
GO:0006508 proteolysis	IBA GO_REF:0000033	ACCEPT	Summary: Caspase-3 carries out proteolysis of many substrates; proteolysis is the biological process realization of its endopeptidase activity. Reason: Proteolysis is correct and consistent with the cysteine-type endopeptidase molecular function, although it is broad. Retained as a supporting (non-distinguishing) process term. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. It has a preferred cleavage sequence of Asp-Xaa-Xaa-Asp-\|- PMID:7596430 suggesting that apopain/CPP32 is important for the initiation of apoptotic cell death.
GO:0031264 death-inducing signaling complex	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: The death-inducing signaling complex (DISC) is the platform that activates initiator caspase-8; caspase-3 is an executioner caspase acting downstream of the DISC rather than a DISC component. Reason: Caspase-3 is activated downstream of the DISC (by caspase-8) and is not generally considered a structural part of the DISC itself. This phylogenetic part_of assignment likely reflects over-propagation across the caspase family; caspase-3's role is as an executioner, not a DISC subunit. Supporting Evidence: PMID:18723680 Caspase-3 was found to be generally more promiscuous than caspase-7 and appears to be the major executioner caspase during the demolition phase of apoptosis. file:human/CASP3/CASP3-uniprot.txt Cleavage by granzyme B, caspase-6, caspase-8 and caspase-10 generates the two active subunits
GO:0097194 execution phase of apoptosis	IBA GO_REF:0000033	ACCEPT	Summary: Caspase-3 is the major executioner caspase responsible for the demolition/execution phase of apoptosis. Reason: This is a precise and core biological process term for caspase-3, supported by phylogenetic inference and experimental evidence that caspase-3 dominates the demolition phase. Supporting Evidence: PMID:18723680 Caspase-3 was found to be generally more promiscuous than caspase-7 and appears to be the major executioner caspase during the demolition phase of apoptosis.
GO:0008047 enzyme activator activity	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Caspase-3 activates downstream enzymes by proteolytic cleavage (e.g., caspase-6, -7, -9 and gasdermin-E), but it does so via its endopeptidase activity rather than acting as a classical allosteric enzyme activator. Reason: While caspase-3 cleavage-activates other zymogens, the generic enzyme activator activity term mischaracterizes the mechanism, which is proteolysis. The cysteine-type endopeptidase activity term already captures this function more accurately. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Cleaves and activates caspase-6, -7 and -9 (CASP6, CASP7 and CASP9, respectively) PMID:28459430 GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that perforates membranes and thereby induces pyroptosis.
GO:0043525 positive regulation of neuron apoptotic process	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: As the executioner caspase, caspase-3 promotes neuronal apoptosis (e.g., developmental neuronal death), a tissue-specific instance of its general apoptotic execution role. Reason: This is a genuine but downstream, tissue-specific manifestation of the core apoptotic execution function rather than a distinct molecular activity. Retained as non-core. Supporting Evidence: PMID:18723680 Caspase-3 was found to be generally more promiscuous than caspase-7 and appears to be the major executioner caspase during the demolition phase of apoptosis.
GO:0030182 neuron differentiation	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Caspase-3 has non-apoptotic roles in neuronal differentiation/remodeling through limited substrate cleavage, captured by phylogenetic inference. Reason: Differentiation is a real but downstream, non-core role relative to caspase-3's core cysteine-protease and apoptotic-execution functions. Retained as non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Triggers cell adhesion in sympathetic neurons through RET cleavage
GO:0030216 keratinocyte differentiation	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Caspase-3 contributes to keratinocyte differentiation (cornification), a non-apoptotic tissue-specific role inferred phylogenetically. Reason: This is a genuine but downstream, tissue-specific differentiation role and not the core protease/apoptotic-execution function. Retained as non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Triggers cell adhesion in sympathetic neurons through RET cleavage
GO:0030218 erythrocyte differentiation	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Caspase-3 is activated during terminal erythroid differentiation; its activity is restrained (e.g., Hsp70 protecting GATA-1) so that differentiation proceeds without apoptosis. Reason: A genuine non-apoptotic role in erythropoiesis, supported experimentally, but downstream of and dependent on the core protease function. Retained as non-core. Supporting Evidence: PMID:17167422 Caspase-3 is activated during both terminal differentiation and erythropoietin-starvation-induced apoptosis of human erythroid precursors.
GO:0004197 cysteine-type endopeptidase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation of the core cysteine-type endopeptidase activity, consistent with experimental and phylogenetic evidence. Reason: Correct core molecular function; the IEA agrees with the IBA and IDA evidence for the same term. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. It has a preferred cleavage sequence of Asp-Xaa-Xaa-Asp-\|-
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation of cytoplasmic localization, consistent with UniProt and IBA evidence. Reason: Correct cellular component; agrees with experimental subcellular location. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0006508 proteolysis	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation of proteolysis, the process realization of caspase-3's endopeptidase activity. Reason: Correct though broad; consistent with the IBA proteolysis annotation. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. It has a preferred cleavage sequence of Asp-Xaa-Xaa-Asp-\|-
GO:0006915 apoptotic process	IEA GO_REF:0000117	ACCEPT	Summary: Electronic (ARBA) annotation of apoptotic process, the core biological process for caspase-3. Reason: Correct core process; agrees with IBA and experimental evidence. Supporting Evidence: PMID:7596430 suggesting that apopain/CPP32 is important for the initiation of apoptotic cell death.
GO:0008234 cysteine-type peptidase activity	IEA GO_REF:0000120	ACCEPT	Summary: Broader parent of cysteine-type endopeptidase activity; correct but less specific. Reason: Correct but more general than GO:0004197. Acceptable as an IEA parent term; the more specific endopeptidase term is the core function. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. It has a preferred cleavage sequence of Asp-Xaa-Xaa-Asp-\|-
GO:0051604 protein maturation	IEA GO_REF:0000117	ACCEPT	Summary: Caspase-3 matures/processes substrate proteins by limited proteolysis (e.g., activating gasdermin-E, processing cytokines). Reason: Protein maturation is a valid process realization of caspase-3 activation-by-cleavage of substrates; supported by experimental gasdermin/cytokine processing. Supporting Evidence: PMID:28459430 GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that perforates membranes and thereby induces pyroptosis.
GO:0072734 cellular response to staurosporine	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Caspase-3 is activated during staurosporine-induced apoptosis (a standard intrinsic-apoptosis trigger). Reason: A stimulus/response context term rather than a core function; caspase-3 acts as the executioner downstream of staurosporine-induced intrinsic apoptosis. Retained as non-core. Supporting Evidence: PMID:22253444 the main processing of pro-caspase-3 takes place in the cytosol of both cells lines analyzed even if caspase-3 active fragments can also be evidenced in the nuclear fractions after STP treatment
GO:0005515 protein binding	IPI PMID:11257232 Structural basis for the inhibition of caspase-3 by XIAP.	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (XIAP (BIR2 domain) binds and inhibits caspase-3 [structural].) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:11257232 Structural basis for the inhibition of caspase-3 by XIAP.
GO:0005515 protein binding	IPI PMID:16227597 A-kinase-anchoring protein 95 functions as a potential carri...	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (AKAP95 associates with active caspase-3 (nuclear translocation carrier).) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:16227597 A-kinase-anchoring protein 95 functions as a potential carrier for the nuclear translocation of active caspase 3 through an enzyme-substrate-like association.
GO:0005515 protein binding	IPI PMID:16501604 Protein kinase WNK3 increases cell survival in a caspase-3-d...	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (WNK3 kinase interaction in a caspase-3-dependent survival pathway.) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:16501604 Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway.
GO:0005515 protein binding	IPI PMID:16530191 N-myristoyltransferase 2 expression in human colon cancer: c...	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (NMT2/calpain-caspase cross-talk interaction.) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:16530191 N-myristoyltransferase 2 expression in human colon cancer: cross-talk between the calpain and caspase system.
GO:0005515 protein binding	IPI PMID:17167422 Hsp70 regulates erythropoiesis by preventing caspase-3-media...	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (GATA-1 / Hsp70 interaction context in erythroid precursors.) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:17167422 Hsp70 regulates erythropoiesis by preventing caspase-3-mediated cleavage of GATA-1.
GO:0005515 protein binding	IPI PMID:17544405 Caspase-3-mediated cleavage of Akt: involvement of non-conse...	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (AKT1 cleavage substrate interaction.) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:17544405 Caspase-3-mediated cleavage of Akt: involvement of non-consensus sites and influence of phosphorylation.
GO:0005515 protein binding	IPI PMID:17606900 Thioredoxin is required for S-nitrosation of procaspase-3 an...	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (Thioredoxin / procaspase-3 S-nitrosation interaction.) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:17606900 Thioredoxin is required for S-nitrosation of procaspase-3 and the inhibition of apoptosis in Jurkat cells.
GO:0005515 protein binding	IPI PMID:18723680 Executioner caspase-3 and caspase-7 are functionally distinc...	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (Substrate interactions (Bid, XIAP, gelsolin, caspase-6, p23).) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:18723680 Executioner caspase-3 and caspase-7 are functionally distinct proteases.
GO:0005515 protein binding	IPI PMID:19273858 S-nitrosylation of XIAP compromises neuronal survival in Par...	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (XIAP S-nitrosylation interaction context.) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:19273858 S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease.
GO:0005515 protein binding	IPI PMID:21726810 Caspase-2-mediated cleavage of Mdm2 creates a p53-induced po...	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (MDM2 cleavage interaction context.) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:21726810 Caspase-2-mediated cleavage of Mdm2 creates a p53-induced positive feedback loop.
GO:0005515 protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (High-throughput liver interactome screen.) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:21988832 Toward an understanding of the protein interaction network of the human liver.
GO:0005515 protein binding	IPI PMID:23150525 Regulation of co- and post-translational myristoylation of p...	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (N-myristoyltransferase/caspase interplay during apoptosis.) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:23150525 Regulation of co- and post-translational myristoylation of proteins during apoptosis: interplay of N-myristoyltransferases and caspases.
GO:0005515 protein binding	IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ...	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (Proximity ligation interactome profiling.) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:25241761 Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (Large-scale interactome (protein communities) screen.) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (Binary protein interactome reference map (HuRI).) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (Neurodegenerative disease interactome screen.) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (Cell-specific interactome remodeling screen.) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005515 protein binding	IPI PMID:38884001 Mapping adipocyte interactome networks by HaloTag-enrichment...	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (Adipocyte interactome HaloTag-MS screen.) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:38884001 Mapping adipocyte interactome networks by HaloTag-enrichment-mass spectrometry.
GO:0005515 protein binding	IPI PMID:7596430 Identification and inhibition of the ICE/CED-3 protease nece...	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (PARP / caspase substrate interactions (apopain).) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:7596430 Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis.
GO:0001554 luteolysis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to luteolysis. Reason: Luteolysis is a tissue-specific apoptotic process (corpus luteum regression) inferred by ortholog transfer; a downstream context of the core apoptotic-execution role. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0001666 response to hypoxia	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to hypoxia. Reason: Response to hypoxia is a stimulus/response context (ortholog-transferred), not a core caspase-3 function. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0002020 protease binding	IEA GO_REF:0000107	ACCEPT	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to protease binding. Reason: Protease binding is informative and supported because caspase-3 is bound and inhibited by XIAP (and related IAPs) and interacts with upstream proteases. This is a meaningful interaction term, unlike bare protein binding. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0004175 endopeptidase activity	IEA GO_REF:0000107	ACCEPT	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to endopeptidase activity. Reason: Endopeptidase activity is a correct parent of the cysteine-type endopeptidase activity; acceptable though less specific. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0004190 aspartic-type endopeptidase activity	IEA GO_REF:0000107	REMOVE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to aspartic-type endopeptidase activity. Reason: Aspartic-type endopeptidase activity is mechanistically incorrect because caspase-3 is a CYSTEINE protease that cleaves after aspartate residues and is not an aspartic protease. This appears to be an erroneous ortholog/keyword transfer. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0004861 cyclin-dependent protein serine/threonine kinase inhibitor activity	IEA GO_REF:0000107	REMOVE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to cyclin-dependent protein serine/threonine kinase inhibitor activity. Reason: Cyclin-dependent protein kinase inhibitor activity is not a caspase-3 molecular function; this is an implausible ortholog-transferred MF and should be removed. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0005123 death receptor binding	IEA GO_REF:0000107	REMOVE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to death receptor binding. Reason: Death receptor binding is not an established caspase-3 molecular function; caspase-3 acts downstream of death-receptor signaling (via caspase-8) rather than binding death receptors. Likely an over-propagated transfer. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0005634 nucleus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to nucleus. Reason: Active caspase-3 is found in the nucleus during apoptosis, but this is secondary to its core cytoplasmic site. Kept consistent with the IDA nucleus rows as non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0007413 axonal fasciculation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to axonal fasciculation. Reason: Axonal fasciculation is a tissue/developmental neuronal role inferred by ortholog transfer; downstream and non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0007611 learning or memory	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to learning or memory. Reason: Learning or memory is a high-level organismal phenotype (ortholog-transferred), reflecting non-apoptotic synaptic roles; non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0008233 peptidase activity	IEA GO_REF:0000107	ACCEPT	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to peptidase activity. Reason: Peptidase activity is a correct broad parent term for caspase-3's protease activity; acceptable though general. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0008627 intrinsic apoptotic signaling pathway in response to osmotic stress	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to intrinsic apoptotic signaling pathway in response to osmotic stress. Reason: Intrinsic apoptotic signaling in response to osmotic stress is a stimulus-specific apoptosis context; caspase-3 is the executioner. Non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0009410 response to xenobiotic stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to xenobiotic stimulus. Reason: Response to xenobiotic stimulus is a stimulus/response context (ortholog-transferred); non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0009749 response to glucose	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to glucose. Reason: Response to glucose is a stimulus/response context; non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0010038 response to metal ion	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to metal ion. Reason: Response to metal ion is a stimulus/response context; non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0010165 response to X-ray	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to X-ray. Reason: Response to X-ray reflects DNA-damage-induced apoptosis context; caspase-3 acts as executioner. Non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0014069 postsynaptic density	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to postsynaptic density. Reason: Postsynaptic density localization reflects non-apoptotic synaptic roles (e.g., synapse pruning) inferred by transfer; non-core relative to cytoplasmic/nuclear core localization. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0016005 phospholipase A2 activator activity	IEA GO_REF:0000107	REMOVE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to phospholipase A2 activator activity. Reason: Phospholipase A2 activator activity is not an established caspase-3 molecular function; implausible ortholog-transferred MF and should be removed. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0021766 hippocampus development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to hippocampus development. Reason: Hippocampus development is a developmental/tissue context (ortholog-transferred); non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0030163 protein catabolic process	IEA GO_REF:0000107	ACCEPT	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to protein catabolic process. Reason: Protein catabolic process is consistent with caspase-3 proteolysis of substrates; acceptable as a process term. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0030182 neuron differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to neuron differentiation. Reason: Neuron differentiation is a non-apoptotic, tissue-specific role; non-core (duplicate of the IBA neuron differentiation row). Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0031264 death-inducing signaling complex	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to death-inducing signaling complex. Reason: Caspase-3 acts downstream of the DISC as an executioner and is not a structural DISC component; this part_of assignment is an over-annotation (consistent with the IBA row). Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0031647 regulation of protein stability	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to regulation of protein stability. Reason: Regulation of protein stability reflects substrate-cleavage consequences (e.g., BACE/GGA3); a downstream effect, non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0032025 response to cobalt ion	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to cobalt ion. Reason: Response to cobalt ion is a stimulus/response context; non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0032355 response to estradiol	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to estradiol. Reason: Response to estradiol is a stimulus/response context; non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0032496 response to lipopolysaccharide	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to lipopolysaccharide. Reason: Response to lipopolysaccharide is a stimulus/response context; non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0034349 glial cell apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to glial cell apoptotic process. Reason: Glial cell apoptotic process is a cell-type-specific instance of apoptotic execution; non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0035094 response to nicotine	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to nicotine. Reason: Response to nicotine is a stimulus/response context; non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0035556 intracellular signal transduction	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to intracellular signal transduction. Reason: Intracellular signal transduction is broad; caspase-3 modulates signaling by cleaving signaling proteins, but this term is over-general. Non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0036269 swimming behavior	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to swimming behavior. Reason: Swimming behavior is a zebrafish-derived organismal phenotype transferred by orthology; non-core for human caspase-3. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0042542 response to hydrogen peroxide	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to hydrogen peroxide. Reason: Response to hydrogen peroxide (oxidative stress) is a stimulus/response context; non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0043025 neuronal cell body	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to neuronal cell body. Reason: Neuronal cell body localization reflects neuronal context; non-core relative to core cytoplasmic/nuclear localization. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0043065 positive regulation of apoptotic process	IEA GO_REF:0000120	ACCEPT	Summary: As the executioner caspase, caspase-3 positively drives the apoptotic process. Reason: Positive regulation of apoptotic process is consistent with caspase-3's executioner role; acceptable IEA, though the more precise execution-phase term is core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0043200 response to amino acid	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to amino acid. Reason: Response to amino acid is a stimulus/response context; non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0043523 regulation of neuron apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to regulation of neuron apoptotic process. Reason: Regulation of neuron apoptotic process is a tissue-specific manifestation of apoptotic execution; non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0043525 positive regulation of neuron apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to positive regulation of neuron apoptotic process. Reason: Positive regulation of neuron apoptotic process is a tissue-specific manifestation of apoptotic execution; non-core (duplicate of the IBA row). Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0044877 protein-containing complex binding	IEA GO_REF:0000107	ACCEPT	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to protein-containing complex binding. Reason: Protein-containing complex binding is supported (e.g., apoptosome-associated activation, XIAP/BIRC6 complexes); acceptable though general. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0045471 response to ethanol	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to ethanol. Reason: Response to ethanol is a stimulus/response context; non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0051146 striated muscle cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to striated muscle cell differentiation. Reason: Striated muscle cell differentiation is a non-apoptotic tissue-specific differentiation role; non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0051384 response to glucocorticoid	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to glucocorticoid. Reason: Response to glucocorticoid is a stimulus/response context (e.g., thymocyte apoptosis); non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0071887 leukocyte apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to leukocyte apoptotic process. Reason: Leukocyte apoptotic process is a cell-type-specific instance of apoptotic execution; non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0072347 response to anesthetic	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to anesthetic. Reason: Response to anesthetic is a stimulus/response context; non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0098693 regulation of synaptic vesicle cycle	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to regulation of synaptic vesicle cycle. Reason: Regulation of synaptic vesicle cycle reflects non-apoptotic synaptic roles inferred by transfer; non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0098883 synapse pruning	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to synapse pruning. Reason: Synapse pruning is a non-apoptotic neuronal role (local caspase activity); genuine but downstream/non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0098978 glutamatergic synapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to glutamatergic synapse. Reason: Glutamatergic synapse localization reflects synaptic roles inferred by transfer; non-core relative to core localization. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:1902004 positive regulation of amyloid-beta formation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to positive regulation of amyloid-beta formation. Reason: Positive regulation of amyloid-beta formation reflects substrate-cleavage effects on APP processing (BACE/GGA3); downstream, non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:1990418 response to insulin-like growth factor stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to insulin-like growth factor stimulus. Reason: Response to insulin-like growth factor stimulus is a stimulus/response context; non-core. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0032880 regulation of protein localization	IMP PMID:17559062 The most widespread desmosomal cadherin, desmoglein 2, is a ...	KEEP AS NON CORE	Summary: Caspase-3 cleaves desmoglein-2 (DSG2) and JUP at desmosomes, altering junctional protein localization during apoptosis. Reason: Regulation of protein localization here is a downstream consequence of substrate cleavage (desmosomal disassembly) rather than a core function; retained as non-core. Supporting Evidence: PMID:17559062 The most widespread desmosomal cadherin, desmoglein 2, is a novel target of caspase 3-mediated apoptotic machinery.
GO:0098883 synapse pruning	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Caspase-3 contributes to synapse pruning, a non-apoptotic local role inferred by sequence similarity. Reason: A genuine but downstream/non-core neuronal role; retained as non-core (mirrors the IEA synapse pruning row). Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
GO:0016485 protein processing	ISS GO_REF:0000024	ACCEPT	Summary: Caspase-3 processes substrate proteins by limited proteolysis (ISS). Reason: Protein processing is a valid process realization of caspase-3 substrate cleavage; consistent with IDA evidence. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins
GO:0016485 protein processing	IDA PMID:33725486 Caspase cleavage releases a nuclear protein fragment that st...	ACCEPT	Summary: Caspase-3 processes XRCC4, releasing a C-terminal fragment that activates the Xkr4 scramblase. Reason: Direct evidence of caspase-3 protein processing producing an active fragment; core-adjacent process. Supporting Evidence: PMID:33725486 Upon apoptotic stimuli, XRCC4, contained in the DNA repair complex, is cleaved by caspases, and its C-terminal fragment with an intrinsically disordered region is released into the cytoplasm.
GO:0097194 execution phase of apoptosis	IDA PMID:18723680 Executioner caspase-3 and caspase-7 are functionally distinc...	ACCEPT	Summary: Caspase-3 is the major executioner caspase of the demolition phase of apoptosis. Reason: Direct, well-supported core process term. Supporting Evidence: PMID:18723680 Caspase-3 was found to be generally more promiscuous than caspase-7 and appears to be the major executioner caspase during the demolition phase of apoptosis.
GO:0097194 execution phase of apoptosis	IDA PMID:33725486 Caspase cleavage releases a nuclear protein fragment that st...	ACCEPT	Summary: Caspase-3 executes apoptosis, including cleavage of XRCC4/scramblases driving PtdSer exposure. Reason: Direct evidence supporting the execution-phase role. Supporting Evidence: PMID:33725486 caspase-mediated cleavage releases a nuclear protein fragment for direct regulation of lipid dynamics on the plasma membrane.
GO:0005737 cytoplasm	EXP PMID:15003516 Caspase 3 activation is controlled by a sequence located in ...	ACCEPT	Summary: Caspase-3 localizes to the cytoplasm; activation is controlled by an N-terminal sequence of its large subunit. Reason: Experimental (EXP) cytoplasmic localization; core location. Supporting Evidence: PMID:15003516 Caspase 3 activation is controlled by a sequence located in the N-terminus of its large subunit.
GO:0004197 cysteine-type endopeptidase activity	IDA PMID:17823127 Cytosolic accumulation of HSP60 during apoptosis with or wit...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. HSP60 modulates caspase-3 pro/anti-apoptotic activity (cysteine protease assay). Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:17823127 Cytosolic accumulation of HSP60 during apoptosis with or without apparent mitochondrial release: evidence that its pro-apoptotic or pro-survival functions involve differential interactions with caspase-3.
GO:0097194 execution phase of apoptosis	IGI PMID:12107093 Microinjection of cathepsin d induces caspase-dependent apop...	ACCEPT	Summary: Cathepsin D microinjection induces caspase-dependent apoptosis, with caspase-3 acting in the execution phase (genetic interaction). Reason: Supports caspase-3's execution-phase role via genetic interaction evidence. Supporting Evidence: PMID:12107093 Microinjection of cathepsin d induces caspase-dependent apoptosis in fibroblasts.
GO:0004197 cysteine-type endopeptidase activity	IDA PMID:9334240 Involvement of caspase-1 and caspase-3 in the production and...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleaves pro- and mature IL-18 at Asp71/Asp76 (DEVD-inhibitable activity). Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:9334240 Involvement of caspase-1 and caspase-3 in the production and processing of mature human interleukin 18 in monocytic THP.1 cells.
GO:0016485 protein processing	IDA PMID:9334240 Involvement of caspase-1 and caspase-3 in the production and...	ACCEPT	Summary: Caspase-3 processes IL-18 (cleaving at Asp71/Asp76). Reason: Direct evidence of caspase-3 protein processing of a cytokine substrate. Supporting Evidence: PMID:9334240 the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products.
GO:0004197 cysteine-type endopeptidase activity	IDA PMID:37327784 Gasdermin D licenses MHCII induction to maintain food tolera...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 protease activity in gasdermin/IL-18 processing context. Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:37327784 Gasdermin D licenses MHCII induction to maintain food tolerance in small intestine.
GO:0001818 negative regulation of cytokine production	IMP PMID:36002459 Apoptotic caspase inhibits innate immune signaling by cleavi...	ACCEPT	Summary: Caspase-3 cleaves NF-kB members (p65/RelA, RelB, c-Rel), dampening cytokine production. Reason: Direct functional (IMP) evidence that caspase-3 negatively regulates cytokine production via NF-kB cleavage; a genuine non-apoptotic immunoregulatory role. Supporting Evidence: PMID:36002459 caspase-3 can mediate the cleavage of NF-κB members p65/RelA, RelB, and c-Rel via its protease activity
GO:0004197 cysteine-type endopeptidase activity	IDA PMID:36002459 Apoptotic caspase inhibits innate immune signaling by cleavi...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleaves NF-kB subunits p65/RelA, RelB, c-Rel via its protease activity. Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:36002459 Apoptotic caspase inhibits innate immune signaling by cleaving NF-κBs in both Mammals and Flies.
GO:0006915 apoptotic process	IDA PMID:34480022 Endotoxin stabilizes protein arginine methyltransferase 4 (P...	ACCEPT	Summary: Caspase-3 mediates apoptosis (PRMT4/endotoxin-triggered death of lung epithelia). Reason: Direct evidence of caspase-3 in the apoptotic process; core. Supporting Evidence: PMID:34480022 Endotoxin stabilizes protein arginine methyltransferase 4 (PRMT4) protein triggering death of lung epithelia.
GO:0070269 pyroptotic inflammatory response	IDA PMID:36426955 TRIM21 Regulates Virus-Induced Cell Pyroptosis through Polyu...	KEEP AS NON CORE	Summary: Caspase-3 participates in pyroptotic inflammatory responses (virus-induced pyroptosis context). Reason: Pyroptosis via gasdermin cleavage is a genuine caspase-3 role; this particular TRIM21/ISG12a context is supportive but the core pyroptosis link is the GSDME cleavage. Retained as non-core context. Supporting Evidence: PMID:36426955 TRIM21 Regulates Virus-Induced Cell Pyroptosis through Polyubiquitination of ISG12a.
GO:0004197 cysteine-type endopeptidase activity	IDA PMID:33852854 Gasdermin E permits interleukin-1 beta release in distinct s...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleaves and activates gasdermin-E (GSDME) at its linker. Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:33852854 Gasdermin E permits interleukin-1 beta release in distinct sublytic and pyroptotic phases.
GO:0004197 cysteine-type endopeptidase activity	IDA PMID:35594856 Human NLRP1 is a sensor of pathogenic coronavirus 3CL protea...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 protease activity in NLRP1/gasdermin processing context. Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:35594856 Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells.
GO:0051604 protein maturation	IDA PMID:33852854 Gasdermin E permits interleukin-1 beta release in distinct s...	ACCEPT	Summary: Caspase-3 matures gasdermin-E (GSDME) by cleavage at its activation site. Reason: Direct evidence of caspase-3 protein maturation of a substrate. Supporting Evidence: PMID:33852854 non-cleavable GSDMED270A variant (altered at the CASP3 cleavage and activation site)
GO:0051604 protein maturation	IDA PMID:35594856 Human NLRP1 is a sensor of pathogenic coronavirus 3CL protea...	ACCEPT	Summary: Caspase-3 matures gasdermin substrates in the NLRP1/coronavirus protease context. Reason: Direct evidence of caspase-3 protein maturation activity. Supporting Evidence: PMID:35594856 Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells.
GO:0140639 positive regulation of pyroptotic inflammatory response	IDA PMID:33852854 Gasdermin E permits interleukin-1 beta release in distinct s...	ACCEPT	Summary: Caspase-3 cleavage of GSDME positively regulates pyroptotic IL-1b release. Reason: Direct evidence that caspase-3-GSDME cleavage promotes the pyroptotic inflammatory response. Supporting Evidence: PMID:33852854 Gasdermin E permits interleukin-1 beta release in distinct sublytic and pyroptotic phases.
GO:0140639 positive regulation of pyroptotic inflammatory response	IDA PMID:35594856 Human NLRP1 is a sensor of pathogenic coronavirus 3CL protea...	ACCEPT	Summary: Caspase-3 promotes pyroptotic inflammatory responses via gasdermin cleavage in the NLRP1 context. Reason: Direct evidence supporting caspase-3's positive role in pyroptosis. Supporting Evidence: PMID:35594856 Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells.
GO:0004197 cysteine-type endopeptidase activity	IDA PMID:28459430 Chemotherapy drugs induce pyroptosis through caspase-3 cleav...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 specifically cleaves GSDME in its linker to generate the pore-forming N fragment. Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:28459430 Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin.
GO:0051604 protein maturation	IDA PMID:28459430 Chemotherapy drugs induce pyroptosis through caspase-3 cleav...	ACCEPT	Summary: Caspase-3 matures gasdermin-E by cleavage in its linker to generate the pore-forming fragment. Reason: Direct evidence of caspase-3 protein maturation of GSDME. Supporting Evidence: PMID:28459430 GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that perforates membranes and thereby induces pyroptosis.
GO:0097194 execution phase of apoptosis	IDA PMID:16374543 Nuclear caspase-3 and caspase-7 activation, and poly(ADP-rib...	ACCEPT	Summary: Active nuclear caspase-3 executes apoptosis (PARP cleavage) early in camptothecin-induced death. Reason: Direct evidence of caspase-3 execution-phase activity. Supporting Evidence: PMID:16374543 the activation of nuclear caspases-7 and -3, and poly(ADP-ribose) polymerase (PARP) cleavage, are early events in camptothecin-induced apoptosis
GO:0140639 positive regulation of pyroptotic inflammatory response	IDA PMID:28459430 Chemotherapy drugs induce pyroptosis through caspase-3 cleav...	ACCEPT	Summary: Caspase-3 cleavage of GSDME positively regulates pyroptosis after chemotherapy. Reason: Direct evidence that caspase-3 promotes the pyroptotic inflammatory response. Supporting Evidence: PMID:28459430 caspase-3 activation can trigger necrosis by cleaving GSDME
GO:0005737 cytoplasm	IDA PMID:17167422 Hsp70 regulates erythropoiesis by preventing caspase-3-media...	ACCEPT	Summary: Active caspase-3 acts in the cytoplasm of erythroid precursors (and nucleus on GATA-1). Reason: Cytoplasm is the core site of caspase-3 activity; consistent with experimental evidence. Supporting Evidence: PMID:17167422 Caspase-3 is activated during both terminal differentiation and erythropoietin-starvation-induced apoptosis of human erythroid precursors.
GO:0097193 intrinsic apoptotic signaling pathway	IMP PMID:15565177 A novel mitochondrial protein DIP mediates E2F1-induced apop...	ACCEPT	Summary: Caspase-3 is activated and executes the intrinsic (mitochondrial) apoptotic pathway (DIP/E2F1). Reason: Caspase-3 acts in intrinsic apoptotic signaling downstream of mitochondrial signals; supported. Supporting Evidence: PMID:15565177 typical apoptotic features such as caspase-3 activation and cleavage of poly(ADP-ribose)-polymerase
GO:0004197 cysteine-type endopeptidase activity	IDA PMID:16374543 Nuclear caspase-3 and caspase-7 activation, and poly(ADP-rib...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Active nuclear caspase-3 cleaves PARP early in camptothecin-induced apoptosis. Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:16374543 Nuclear caspase-3 and caspase-7 activation, and poly(ADP-ribose) polymerase cleavage are early events in camptothecin-induced apoptosis.
GO:0005634 nucleus	IDA PMID:16374543 Nuclear caspase-3 and caspase-7 activation, and poly(ADP-rib...	KEEP AS NON CORE	Summary: Active caspase-3 is found in the nucleus, cleaving PARP early in apoptosis. Reason: Nuclear localization of active caspase-3 is supported but secondary to its core cytoplasmic site; retained as non-core. Supporting Evidence: PMID:16374543 the activation of nuclear caspases-7 and -3, and poly(ADP-ribose) polymerase (PARP) cleavage, are early events in camptothecin-induced apoptosis
GO:0030163 protein catabolic process	IDA PMID:16374543 Nuclear caspase-3 and caspase-7 activation, and poly(ADP-rib...	ACCEPT	Summary: Caspase-3 carries out protein catabolism (PARP cleavage) during apoptosis. Reason: Protein catabolic process is consistent with caspase-3 substrate cleavage; acceptable. Supporting Evidence: PMID:16374543 poly(ADP-ribose) polymerase (PARP) cleavage, are early events in camptothecin-induced apoptosis
GO:0004197 cysteine-type endopeptidase activity	IDA PMID:20566630 Identification of functional regions defining different acti...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Functional regions defining caspase-3 vs caspase-7 cellular protease activity. Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:20566630 Identification of functional regions defining different activity in caspase-3 and caspase-7 within cells.
GO:0004197 cysteine-type endopeptidase activity	IDA PMID:23650375 Structural snapshots reveal distinct mechanisms of procaspas...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Structural snapshots of procaspase-3 activation (catalytic mechanism). Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:23650375 Structural snapshots reveal distinct mechanisms of procaspase-3 and -7 activation.
GO:0004197 cysteine-type endopeptidase activity	IDA PMID:18723680 Executioner caspase-3 and caspase-7 are functionally distinc...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleaves multiple natural substrates (Bid, XIAP, gelsolin, caspase-6, p23). Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:18723680 Executioner caspase-3 and caspase-7 are functionally distinct proteases.
GO:0004197 cysteine-type endopeptidase activity	IDA PMID:30878284 Apoptotic Caspases Suppress Type I Interferon Production via...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleaves cGAS, MAVS and IRF3 via its protease activity. Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:30878284 Apoptotic Caspases Suppress Type I Interferon Production via the Cleavage of cGAS, MAVS, and IRF3.
GO:0004197 cysteine-type endopeptidase activity	IDA PMID:33725486 Caspase cleavage releases a nuclear protein fragment that st...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleaves XRCC4 and XKR scramblases (apoptotic PtdSer exposure). Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:33725486 Caspase cleavage releases a nuclear protein fragment that stimulates phospholipid scrambling at the plasma membrane.
GO:0004197 cysteine-type endopeptidase activity	IDA PMID:24904167 Caspase-mediated cleavage of phospholipid flippase for apopt...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleaves the ATP11C phospholipid flippase for apoptotic PtdSer exposure. Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:24904167 Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure.
GO:0004197 cysteine-type endopeptidase activity	IDA PMID:19240112 Huntingtin promotes cell survival by preventing Pak2 cleavag...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleaves PAK2 (huntingtin modulates this). Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:19240112 Huntingtin promotes cell survival by preventing Pak2 cleavage.
GO:0008233 peptidase activity	IDA PMID:17167422 Hsp70 regulates erythropoiesis by preventing caspase-3-media...	ACCEPT	Summary: Caspase-3 peptidase activity cleaves GATA-1 in erythroid precursors. Reason: Peptidase activity is correct (broad parent of cysteine-type endopeptidase activity); supported. Supporting Evidence: PMID:17167422 Hsp70 prevents active caspase-3 from cleaving GATA-1 and inducing apoptosis.
GO:0005515 protein binding	IPI PMID:15246877 S-nitrosation of thioredoxin in the nitrogen monoxide/supero...	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (Thioredoxin/ASK1 S-nitrosation interaction context.) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:15246877 S-nitrosation of thioredoxin in the nitrogen monoxide/superoxide system activates apoptosis signal-regulating kinase 1.
GO:0006508 proteolysis	IDA PMID:17553422 Depletion of GGA3 stabilizes BACE and enhances beta-secretas...	ACCEPT	Summary: Caspase-3 cleaves GGA3, stabilizing BACE and enhancing beta-secretase activity (proteolysis). Reason: Proteolysis is correct and consistent with the cysteine-type endopeptidase function; this substrate cleavage is a concrete instance. Kept consistent with the other proteolysis annotations. Supporting Evidence: PMID:17553422 Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity.
GO:0031647 regulation of protein stability	IDA PMID:17553422 Depletion of GGA3 stabilizes BACE and enhances beta-secretas...	KEEP AS NON CORE	Summary: Caspase-3 cleavage of GGA3 alters BACE protein stability. Reason: Regulation of protein stability is a downstream consequence of substrate cleavage; non-core. Supporting Evidence: PMID:17553422 Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity.
GO:1902004 positive regulation of amyloid-beta formation	IDA PMID:17553422 Depletion of GGA3 stabilizes BACE and enhances beta-secretas...	KEEP AS NON CORE	Summary: Caspase-3-mediated GGA3 cleavage increases BACE/beta-secretase activity, promoting amyloid-beta formation. Reason: A downstream, disease-context effect of substrate cleavage; genuine but non-core. Supporting Evidence: PMID:17553422 Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity.
GO:0004197 cysteine-type endopeptidase activity	IMP PMID:21980415 Identification of a conserved anti-apoptotic protein that mo...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Anti-apoptotic protein modulates mitochondrial caspase-3 activation. Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:21980415 Identification of a conserved anti-apoptotic protein that modulates the mitochondrial apoptosis pathway.
GO:0006915 apoptotic process	IMP PMID:15565177 A novel mitochondrial protein DIP mediates E2F1-induced apop...	ACCEPT	Summary: Caspase-3 is activated and mediates apoptosis in the DIP/E2F1 pathway. Reason: Direct evidence of caspase-3 in the apoptotic process; core. Supporting Evidence: PMID:15565177 typical apoptotic features such as caspase-3 activation and cleavage of poly(ADP-ribose)-polymerase
GO:0004197 cysteine-type endopeptidase activity	IDA PMID:16920334 Protective role of Cop in Rip2/caspase-1/caspase-4-mediated ...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 activity in Rip2/caspase-1/-4-mediated cell death. Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:16920334 Protective role of Cop in Rip2/caspase-1/caspase-4-mediated HeLa cell death.
GO:0008233 peptidase activity	IDA PMID:19740745 A truncated form of p23 down-regulates telomerase activity v...	ACCEPT	Summary: Caspase-3 peptidase activity generates a truncated p23 that down-regulates telomerase. Reason: Peptidase activity is correct (broad); supported by substrate cleavage evidence. Supporting Evidence: PMID:19740745 A truncated form of p23 down-regulates telomerase activity via disruption of Hsp90 function.
GO:0004197 cysteine-type endopeptidase activity	IMP PMID:22253444 Apoptotic DNA degradation into oligonucleosomal fragments, b...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleaves ICAD/CAD to enable apoptotic DNA fragmentation. Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:22253444 Apoptotic DNA degradation into oligonucleosomal fragments, but not apoptotic nuclear morphology, relies on a cytosolic pool of DFF40/CAD endonuclease.
GO:0005829 cytosol	IDA PMID:22253444 Apoptotic DNA degradation into oligonucleosomal fragments, b...	ACCEPT	Summary: Caspase-3 is processed and active in the cytosol (where it cleaves ICAD/CAD). Reason: Cytosol is the core location of caspase-3 activity; directly supported. Supporting Evidence: PMID:22253444 the main processing of pro-caspase-3 takes place in the cytosol of both cells lines analyzed
GO:0072734 cellular response to staurosporine	IMP PMID:22253444 Apoptotic DNA degradation into oligonucleosomal fragments, b...	KEEP AS NON CORE	Summary: Caspase-3 is activated in response to staurosporine, cleaving ICAD to enable DNA fragmentation. Reason: A stimulus/response context (intrinsic apoptosis trigger); caspase-3 acts as executioner. Non-core. Supporting Evidence: PMID:22253444 the activation of, at least, caspase-3 is necessary for the proper cleavage of ICAD L/S
GO:0016241 regulation of macroautophagy	TAS PMID:19549685 Caspase cleavage of Atg4D stimulates GABARAP-L1 processing a...	KEEP AS NON CORE	Summary: Caspase cleavage of Atg4D stimulates GABARAP-L1 processing, linking caspase-3 to autophagy regulation. Reason: Regulation of macroautophagy is a downstream cross-talk role (TAS) via substrate cleavage; non-core. Supporting Evidence: PMID:19549685 Caspase cleavage of Atg4D stimulates GABARAP-L1 processing and triggers mitochondrial targeting and apoptosis.
GO:0048011 neurotrophin TRK receptor signaling pathway	IDA PMID:23954828 Dok5 is involved in the signaling pathway of neurotrophin-3 ...	KEEP AS NON CORE	Summary: Caspase-3 acts within neurotrophin/TrkC (Dok5) signaling, where TrkC can trigger apoptosis. Reason: A signaling-pathway context where caspase-3 acts downstream; non-core relative to the core protease/apoptosis function. Supporting Evidence: PMID:23954828 Dok5 is involved in the signaling pathway of neurotrophin-3 against TrkC-induced apoptosis.
GO:0004197 cysteine-type endopeptidase activity	IDA PMID:23729654 The human papillomavirus-16 E7 oncoprotein exerts antiapopto...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. HPV-16 E7/gelsolin context modulating caspase-3 activity. Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:23729654 The human papillomavirus-16 E7 oncoprotein exerts antiapoptotic effects via its physical interaction with the actin-binding protein gelsolin.
GO:0004197 cysteine-type endopeptidase activity	IMP PMID:10921886 The RET proto-oncogene induces apoptosis: a novel mechanism ...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. RET proto-oncogene-induced apoptosis is caspase-3-dependent. Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:10921886 The RET proto-oncogene induces apoptosis: a novel mechanism for Hirschsprung disease.
GO:0030218 erythrocyte differentiation	IDA PMID:17167422 Hsp70 regulates erythropoiesis by preventing caspase-3-media...	KEEP AS NON CORE	Summary: Caspase-3 is activated during terminal erythroid differentiation; GATA-1 is protected from cleavage by Hsp70. Reason: A genuine non-apoptotic role in erythropoiesis, but downstream of the core protease function. Non-core. Supporting Evidence: PMID:17167422 Caspase-3 is activated during both terminal differentiation and erythropoietin-starvation-induced apoptosis of human erythroid precursors.
GO:0030218 erythrocyte differentiation	TAS PMID:18309324 No death without life: vital functions of apoptotic effector...	KEEP AS NON CORE	Summary: Effector caspases including caspase-3 have vital (non-death) functions in erythroid differentiation. Reason: Non-apoptotic differentiation role (TAS review); genuine but non-core. Supporting Evidence: PMID:18309324 No death without life: vital functions of apoptotic effectors.
GO:0030220 platelet formation	TAS PMID:18309324 No death without life: vital functions of apoptotic effector...	KEEP AS NON CORE	Summary: Caspase-3 contributes to platelet formation (a non-apoptotic effector-caspase function). Reason: A genuine non-apoptotic tissue role (TAS review); non-core. Supporting Evidence: PMID:18309324 No death without life: vital functions of apoptotic effectors.
GO:0097194 execution phase of apoptosis	IMP PMID:11350920 Deficiency of caspase-3 in MCF7 cells blocks Bax-mediated nu...	ACCEPT	Summary: Caspase-3 is required for Bax-mediated nuclear fragmentation in the execution phase (MCF7 deficiency). Reason: Direct functional (IMP) evidence for caspase-3's execution-phase role in nuclear demolition. Supporting Evidence: PMID:11350920 Deficiency of caspase-3 in MCF7 cells blocks Bax-mediated nuclear fragmentation but not cell death.
GO:0004197 cysteine-type endopeptidase activity	IMP PMID:17559062 The most widespread desmosomal cadherin, desmoglein 2, is a ...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleaves desmoglein-2 (DSG2) and JUP at desmosomes. Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:17559062 The most widespread desmosomal cadherin, desmoglein 2, is a novel target of caspase 3-mediated apoptotic machinery.
GO:0097194 execution phase of apoptosis	IDA PMID:8689682 Induction of apoptotic program in cell-free extracts: requir...	ACCEPT	Summary: In cell-free extracts, cytochrome c/dATP triggers the apoptotic program that activates executioner caspase-3. Reason: Classic evidence placing caspase-3 in the execution phase downstream of cytochrome c/apoptosome. Supporting Evidence: PMID:8689682 Cells undergoing apoptosis in vivo showed increased release of cytochrome c to their cytosol, suggesting that mitochondria may function in apoptosis by releasing cytochrome c.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-211186	KEEP AS NON CORE	Summary: Reactome places caspase-3 in the nucleoplasm for nuclear substrate cleavage (e.g., DFF45/ICAD), consistent with active caspase-3 translocating to the nucleus during apoptosis. Reason: Nuclear/nucleoplasm localization of active caspase-3 is supported but secondary to its core cytoplasmic site; retained as non-core location context for nuclear substrate cleavage. Supporting Evidence: PMID:16374543 the activation of nuclear caspases-7 and -3, and poly(ADP-ribose) polymerase (PARP) cleavage, are early events in camptothecin-induced apoptosis
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-211190	KEEP AS NON CORE	Summary: Reactome places caspase-3 in the nucleoplasm for nuclear substrate cleavage (e.g., DFF45/ICAD), consistent with active caspase-3 translocating to the nucleus during apoptosis. Reason: Nuclear/nucleoplasm localization of active caspase-3 is supported but secondary to its core cytoplasmic site; retained as non-core location context for nuclear substrate cleavage. Supporting Evidence: PMID:16374543 the activation of nuclear caspases-7 and -3, and poly(ADP-ribose) polymerase (PARP) cleavage, are early events in camptothecin-induced apoptosis
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-211219	KEEP AS NON CORE	Summary: Reactome places caspase-3 in the nucleoplasm for nuclear substrate cleavage (e.g., DFF45/ICAD), consistent with active caspase-3 translocating to the nucleus during apoptosis. Reason: Nuclear/nucleoplasm localization of active caspase-3 is supported but secondary to its core cytoplasmic site; retained as non-core location context for nuclear substrate cleavage. Supporting Evidence: PMID:16374543 the activation of nuclear caspases-7 and -3, and poly(ADP-ribose) polymerase (PARP) cleavage, are early events in camptothecin-induced apoptosis
GO:0005829 cytosol	TAS Reactome:R-HSA-114252	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-201595	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-201603	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-201608	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-201611	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-201622	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-201628	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-201629	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-201630	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-201631	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-201636	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-201639	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-201640	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-2028692	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-2028697	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-202917	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-202939	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-202947	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-202960	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-202966	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-202967	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-202969	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-205117	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-211219	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-212552	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-350651	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-351849	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-351871	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-351876	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-351877	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-351901	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-351913	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-373705	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-418845	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-449073	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-9627104	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-9647632	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-9686088	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005829 cytosol	TAS Reactome:R-NUL-211643	ACCEPT	Summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity. Reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt SUBCELLULAR LOCATION; Cytoplasm
GO:0005515 protein binding	IPI PMID:9208847 Casper is a FADD- and caspase-related inducer of apoptosis.	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (Casper/c-FLIP FADD- and caspase-related interaction.) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:9208847 Casper is a FADD- and caspase-related inducer of apoptosis.
GO:0005634 nucleus	IDA PMID:17167422 Hsp70 regulates erythropoiesis by preventing caspase-3-media...	KEEP AS NON CORE	Summary: Active caspase-3 is present in the nucleus of erythroid precursors where it can cleave GATA-1. Reason: Nuclear localization of active caspase-3 is supported but secondary to its core cytoplasmic site; non-core. Supporting Evidence: PMID:17167422 Hsp70 co-localizes and interacts with GATA-1 in the nucleus of erythroid precursors undergoing terminal differentiation.
GO:0005829 cytosol	IDA PMID:17167422 Hsp70 regulates erythropoiesis by preventing caspase-3-media...	ACCEPT	Summary: Caspase-3 acts in the cytosol of erythroid precursors. Reason: Cytosol is the core site of caspase-3 activity; supported. Supporting Evidence: PMID:17167422 Caspase-3 is activated during both terminal differentiation and erythropoietin-starvation-induced apoptosis of human erythroid precursors.
GO:0004197 cysteine-type endopeptidase activity	IDA PMID:21726810 Caspase-2-mediated cleavage of Mdm2 creates a p53-induced po...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleavage activity in the MDM2/p53 feedback context. Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:21726810 Caspase-2-mediated cleavage of Mdm2 creates a p53-induced positive feedback loop.
GO:0034612 response to tumor necrosis factor	TAS PMID:10521396 Cleavage of the death domain kinase RIP by caspase-8 prompts...	KEEP AS NON CORE	Summary: Caspase-3 acts downstream of TNF-induced apoptosis (RIP cleavage by caspase-8). Reason: Response to TNF is a stimulus/response signaling context; caspase-3 is the executioner downstream. Non-core. Supporting Evidence: PMID:10521396 Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis.
GO:0097190 apoptotic signaling pathway	TAS PMID:10521396 Cleavage of the death domain kinase RIP by caspase-8 prompts...	ACCEPT	Summary: Caspase-3 acts within the apoptotic signaling pathway (TNF/death-receptor-induced apoptosis). Reason: Apoptotic signaling pathway is a valid process for caspase-3 as the executioner; supported. Supporting Evidence: PMID:10521396 Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis.
GO:0008233 peptidase activity	IDA PMID:9353287 Generation of anti-apoptotic presenilin-2 polypeptides by al...	ACCEPT	Summary: Caspase-3 peptidase activity cleaves presenilin-2 generating anti-apoptotic polypeptides. Reason: Peptidase activity is correct (broad); supported by substrate cleavage evidence. Supporting Evidence: PMID:9353287 Generation of anti-apoptotic presenilin-2 polypeptides by alternative transcription, proteolysis, and caspase-3 cleavage.
GO:0005515 protein binding	IPI PMID:17823127 Cytosolic accumulation of HSP60 during apoptosis with or wit...	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (HSP60 interaction modulating pro/anti-apoptotic functions.) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:17823127 Cytosolic accumulation of HSP60 during apoptosis with or without apparent mitochondrial release: evidence that its pro-apoptotic or pro-survival functions involve differential interactions with caspase-3.
GO:0005829 cytosol	IDA PMID:17823127 Cytosolic accumulation of HSP60 during apoptosis with or wit...	ACCEPT	Summary: Caspase-3 is present in the cytosol, where cytosolic HSP60 modulates its activity during apoptosis. Reason: Cytosol is the core location of caspase-3; directly supported. Supporting Evidence: PMID:17823127 Cytosolic accumulation of HSP60 during apoptosis with or without apparent mitochondrial release
GO:0006508 proteolysis	IDA PMID:12888622 Caspase cleavage of tau: linking amyloid and neurofibrillary...	ACCEPT	Summary: Caspase-3 cleaves tau, linking amyloid and neurofibrillary tangles (proteolysis). Reason: Proteolysis is correct and consistent with the cysteine-type endopeptidase function; this substrate cleavage is a concrete instance. Kept consistent with the other proteolysis annotations. Supporting Evidence: PMID:12888622 Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease.
GO:0005515 protein binding	IPI PMID:9736630 Tau cleavage and dephosphorylation in cerebellar granule neu...	MARK AS OVER ANNOTATED	Summary: This IPI captures a physical interaction (Tau cleavage interaction in apoptotic neurons.) but the generic protein binding term is uninformative about caspase-3's molecular function. Reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative. Supporting Evidence: PMID:9736630 Tau cleavage and dephosphorylation in cerebellar granule neurons undergoing apoptosis.
GO:0004197 cysteine-type endopeptidase activity	TAS PMID:10942389 HIV-1 gp120- and gp160-induced apoptosis in cultured endothe...	ACCEPT	Summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. HIV-1 gp120/gp160-induced endothelial apoptosis mediated by caspases including caspase-3. Reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function. Supporting Evidence: PMID:10942389 HIV-1 gp120- and gp160-induced apoptosis in cultured endothelial cells is mediated by caspases.
GO:0006915 apoptotic process	TAS PMID:7983002 CPP32, a novel human apoptotic protein with homology to Caen...	ACCEPT	Summary: CPP32 (caspase-3) is an apoptotic protein homologous to CED-3/ICE (original cloning, TAS). Reason: Foundational evidence for caspase-3's role in the apoptotic process; core. Supporting Evidence: PMID:7983002 CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme.

Core Functions

Caspase-3 is a cysteine-type endopeptidase (EC 3.4.22.56) that cleaves substrates after aspartate residues, with a strict requirement for Asp at the P1 and P4 positions of an Asp-X-X-Asp recognition motif. It is synthesized as a zymogen and activated by cleavage by initiator caspases or granzyme B into a p17/p12 heterotetramer.

Molecular Function:

cysteine-type endopeptidase activity

Directly Involved In:

proteolysis

Cellular Locations:

cytosol

Supporting Evidence:

file:human/CASP3/CASP3-uniprot.txt
Strict requirement for an Asp residue at positions P1 and P4. It has a preferred cleavage sequence of Asp-Xaa-Xaa-Asp-|-
PMID:7596430
This enzyme, named apopain, is composed of two subunits of relative molecular mass (M(r)) 17K and 12K that are derived from a common proenzyme identified as CPP32.

As the principal executioner caspase, caspase-3 carries out the demolition phase of apoptosis by cleaving many cellular substrates (e.g., PARP1; ICAD/DFF45 to release the CAD/DFF40 DNA-fragmentation nuclease; cytoskeletal, junctional and signaling proteins) and by driving phosphatidylserine exposure through cleavage of XKR scramblases and the ATP11C flippase.

Molecular Function:

cysteine-type endopeptidase activity

Directly Involved In:

execution phase of apoptosis

Cellular Locations:

cytosol

Supporting Evidence:

PMID:18723680
Caspase-3 was found to be generally more promiscuous than caspase-7 and appears to be the major executioner caspase during the demolition phase of apoptosis.
PMID:22253444
the main processing of pro-caspase-3 takes place in the cytosol of both cells lines analyzed even if caspase-3 active fragments can also be evidenced in the nuclear fractions after STP treatment

Caspase-3 cleaves and activates gasdermin-E (GSDME/DFNA5), switching apoptotic cells to pyroptosis and permitting IL-1 beta release, coupling the apoptotic protease to a pro-inflammatory lytic cell-death program.

Molecular Function:

cysteine-type endopeptidase activity

Directly Involved In:

positive regulation of pyroptotic inflammatory response

Cellular Locations:

cytosol

Supporting Evidence:

PMID:28459430
Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin.

Caspase-3 restrains innate immune and cytokine signaling by cleaving antiviral signaling proteins (cGAS, MAVS, IRF3) and NF-kB subunits (p65/RelA, RelB, c-Rel) and by processing cytokines such as IL-18, dampening cytokine production during apoptosis.

Molecular Function:

cysteine-type endopeptidase activity

Directly Involved In:

negative regulation of cytokine production

Cellular Locations:

cytosol

Supporting Evidence:

PMID:30878284
Apoptotic Caspases Suppress Type I Interferon Production via the Cleavage of cGAS, MAVS, and IRF3.
PMID:36002459
Apoptotic caspase inhibits innate immune signaling by cleaving NF-κBs in both Mammals and Flies.

References

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10521396

Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis.

PMID:10921886

The RET proto-oncogene induces apoptosis: a novel mechanism for Hirschsprung disease.

PMID:10942389

HIV-1 gp120- and gp160-induced apoptosis in cultured endothelial cells is mediated by caspases.

PMID:11257232

Structural basis for the inhibition of caspase-3 by XIAP.

PMID:11350920

Deficiency of caspase-3 in MCF7 cells blocks Bax-mediated nuclear fragmentation but not cell death.

PMID:12107093

Microinjection of cathepsin d induces caspase-dependent apoptosis in fibroblasts.

PMID:12888622

Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease.

PMID:15003516

Caspase 3 activation is controlled by a sequence located in the N-terminus of its large subunit.

PMID:15246877

S-nitrosation of thioredoxin in the nitrogen monoxide/superoxide system activates apoptosis signal-regulating kinase 1.

PMID:15565177

A novel mitochondrial protein DIP mediates E2F1-induced apoptosis independently of p53.

PMID:16227597

A-kinase-anchoring protein 95 functions as a potential carrier for the nuclear translocation of active caspase 3 through an enzyme-substrate-like association.

PMID:16374543

Nuclear caspase-3 and caspase-7 activation, and poly(ADP-ribose) polymerase cleavage are early events in camptothecin-induced apoptosis.

PMID:16501604

Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway.

PMID:16530191

N-myristoyltransferase 2 expression in human colon cancer: cross-talk between the calpain and caspase system.

PMID:16920334

Protective role of Cop in Rip2/caspase-1/caspase-4-mediated HeLa cell death.

PMID:17167422

Hsp70 regulates erythropoiesis by preventing caspase-3-mediated cleavage of GATA-1.

PMID:17544405

Caspase-3-mediated cleavage of Akt: involvement of non-consensus sites and influence of phosphorylation.

PMID:17553422

Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity.

PMID:17559062

The most widespread desmosomal cadherin, desmoglein 2, is a novel target of caspase 3-mediated apoptotic machinery.

PMID:17606900

Thioredoxin is required for S-nitrosation of procaspase-3 and the inhibition of apoptosis in Jurkat cells.

PMID:17823127

Cytosolic accumulation of HSP60 during apoptosis with or without apparent mitochondrial release: evidence that its pro-apoptotic or pro-survival functions involve differential interactions with caspase-3.

PMID:18309324

No death without life: vital functions of apoptotic effectors.

PMID:18723680

Executioner caspase-3 and caspase-7 are functionally distinct proteases.

PMID:19240112

Huntingtin promotes cell survival by preventing Pak2 cleavage.

PMID:19273858

S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease.

PMID:19549685

Caspase cleavage of Atg4D stimulates GABARAP-L1 processing and triggers mitochondrial targeting and apoptosis.

PMID:19740745

A truncated form of p23 down-regulates telomerase activity via disruption of Hsp90 function.

PMID:20566630

Identification of functional regions defining different activity in caspase-3 and caspase-7 within cells.

PMID:21726810

Caspase-2-mediated cleavage of Mdm2 creates a p53-induced positive feedback loop.

PMID:21980415

Identification of a conserved anti-apoptotic protein that modulates the mitochondrial apoptosis pathway.

PMID:21988832

Toward an understanding of the protein interaction network of the human liver.

PMID:22253444

Apoptotic DNA degradation into oligonucleosomal fragments, but not apoptotic nuclear morphology, relies on a cytosolic pool of DFF40/CAD endonuclease.

PMID:23150525

Regulation of co- and post-translational myristoylation of proteins during apoptosis: interplay of N-myristoyltransferases and caspases.

PMID:23650375

Structural snapshots reveal distinct mechanisms of procaspase-3 and -7 activation.

PMID:23729654

The human papillomavirus-16 E7 oncoprotein exerts antiapoptotic effects via its physical interaction with the actin-binding protein gelsolin.

PMID:23954828

Dok5 is involved in the signaling pathway of neurotrophin-3 against TrkC-induced apoptosis.

PMID:24904167

Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure.

PMID:25241761

Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network.

PMID:28459430

Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:30878284

Apoptotic Caspases Suppress Type I Interferon Production via the Cleavage of cGAS, MAVS, and IRF3.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33725486

Caspase cleavage releases a nuclear protein fragment that stimulates phospholipid scrambling at the plasma membrane.

PMID:33852854

Gasdermin E permits interleukin-1 beta release in distinct sublytic and pyroptotic phases.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:34480022

Endotoxin stabilizes protein arginine methyltransferase 4 (PRMT4) protein triggering death of lung epithelia.

PMID:35594856

Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells.

PMID:36002459

Apoptotic caspase inhibits innate immune signaling by cleaving NF-κBs in both Mammals and Flies.

PMID:36426955

TRIM21 Regulates Virus-Induced Cell Pyroptosis through Polyubiquitination of ISG12a.

PMID:37327784

Gasdermin D licenses MHCII induction to maintain food tolerance in small intestine.

PMID:38884001

Mapping adipocyte interactome networks by HaloTag-enrichment-mass spectrometry.

PMID:7596430

Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis.

PMID:7983002

CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme.

PMID:8689682

Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c.

PMID:9208847

Casper is a FADD- and caspase-related inducer of apoptosis.

PMID:9334240

Involvement of caspase-1 and caspase-3 in the production and processing of mature human interleukin 18 in monocytic THP.1 cells.

PMID:9353287

Generation of anti-apoptotic presenilin-2 polypeptides by alternative transcription, proteolysis, and caspase-3 cleavage.

PMID:9736630

Tau cleavage and dephosphorylation in cerebellar granule neurons undergoing apoptosis.

Reactome:R-HSA-114252

Cleavage of Procaspase-3 by the apoptosome

Reactome:R-HSA-201595

Caspase-mediated cleavage of plakophilin-1

Reactome:R-HSA-201603

Caspase-mediated cleavage of PKC theta

Reactome:R-HSA-201608

Caspase-mediated cleavage of alpha adducin

Reactome:R-HSA-201611

Caspase-mediated cleavage of Rock-1

Reactome:R-HSA-201622

Caspase-mediated cleavage of gelsolin

Reactome:R-HSA-201628

Caspase-mediated cleavage of vimentin at DSVD (85)

Reactome:R-HSA-201629

Caspase-mediated cleavage of Tau

Reactome:R-HSA-201630

Caspase-mediated cleavage of Acinus

Reactome:R-HSA-201631

Caspase-mediated cleavage of Desmoglein 3

Reactome:R-HSA-201636

Caspase-mediated cleavage of Desmoplakin

Reactome:R-HSA-201639

Caspase-mediated cleavage of GAS2

Reactome:R-HSA-201640

Caspase-mediated cleavage of farnesyltransferase/geranyl- geranyltransferase subunit alpha

Reactome:R-HSA-2028692

Cleavage of p-STK4 (p-MST1) by caspase 3

Reactome:R-HSA-2028697

Cleavage of p-STK3 (p-MST2) by caspase 3

Reactome:R-HSA-202917

Caspase-mediated cleavage of Desmoglein 1

Reactome:R-HSA-202939

Caspase-mediated cleavage of E-Cadherin

Reactome:R-HSA-202947

Caspase mediated cleavage of APC

Reactome:R-HSA-202960

Caspase mediated cleavage of C-IAP1

Reactome:R-HSA-202966

Caspase mediated cleavage of HIP-55

Reactome:R-HSA-202967

Caspase mediated cleavage of alpha-II-Fodrin

Reactome:R-HSA-202969

Caspase mediated cleavage of beta-catenin

Reactome:R-HSA-205117

p75NTR:NADE promotes caspase2/3 activation

Reactome:R-HSA-211186

Cleavage of DFF45 (224) by caspase-3

Reactome:R-HSA-211190

Caspase 3-mediated cleavage of DFF45 (117)

Reactome:R-HSA-211219

Translocation of caspase-3 to the nucleus

Reactome:R-HSA-212552

Caspase 3-mediated cleavage of PKC delta

Reactome:R-HSA-350651

Caspase-mediated cleavage of MASK

Reactome:R-HSA-351849

Caspase-mediated cleavage of Etk

Reactome:R-HSA-351871

Caspase-mediated cleavage of Z0-2

Reactome:R-HSA-351876

Caspase-mediated cleavage of occludin

Reactome:R-HSA-351877

Caspase-mediated cleavage of Desmoglein 2

Reactome:R-HSA-351901

Caspase-mediated cleavage of MST3

Reactome:R-HSA-351913

Caspase-mediated cleavage of TJP1

Reactome:R-HSA-373705

Caspase cleavage of DCC

Reactome:R-HSA-418845

Activation of caspase-3

Reactome:R-HSA-449073

Caspase-3 cleaves pro-interleukin-16

Reactome:R-HSA-9627104

XIAP binds CASP3

Reactome:R-HSA-9647632

CASP3 cleaves GSDME

Reactome:R-HSA-9686088

CASP3 cleaves GSDMD

Reactome:R-NUL-211643

Cleavage of PAK-2 at 212

file:human/CASP3/CASP3-deep-research-falcon.md

Falcon deep research report for CASP3

Falcon corroborates the review's core characterization of CASP3 as the principal executioner caspase and a cysteine protease that cleaves strictly after aspartate at the P1 position.

"Caspase-3 is a cysteine protease that cleaves peptide bonds almost exclusively C-terminal to aspartate residues at the P1 position"

Suggested Experiments

Experiment: Perform N-terminomics (e.g., TAILS/subtiligase) on cells undergoing caspase-3-dependent differentiation versus apoptosis, with caspase-3 knockout and caspase-resistant substrate mutants as controls, to map the differentiation-specific cleavage repertoire.

Hypothesis: Caspase-3 substrate cleavage during sublethal/non-apoptotic activation produces a distinct proteome from that during full apoptosis, explaining its differentiation roles.

Type: degradomics / N-terminomics

Experiment: Titrate GSDME expression and caspase-3 activation kinetics in isogenic cell lines (including non-cleavable GSDME D270A) and quantify apoptosis versus pyroptosis outcomes and IL-1 beta release.

Hypothesis: The balance between caspase-3-driven apoptosis and GSDME-driven pyroptosis is set by GSDME abundance and caspase-3 activity kinetics.

Type: cell death pathway dissection

Deep Research

Falcon

(CASP3-deep-research-falcon.md)

Comprehensive Research Report: Human CASP3 (Caspase-3) Falcon Edison Scientific Literature 20 citations 2 artifacts 2026-06-21T07:05:41.625430

Edison artifact artifact-00 (text/markdown)

Edison artifact artifact-01 (text/markdown)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: Human CASP3 (Caspase-3)

Gene and Protein Identity

The CASP3 gene encodes human caspase-3 (UniProt P42574), a pivotal executioner caspase in the caspase family of cysteine-dependent, aspartate-specific proteases (malireddi2025threedecadesof pages 1-3, araya2021deorphanizingcaspase3and pages 1-3). Caspase-3 is classified as EC 3.4.22.56 and functions as the most proteolytically proficient executioner of programmed cell death, though it also plays important roles in non-apoptotic cellular processes (malireddi2025threedecadesof pages 1-3, araya2021deorphanizingcaspase3and pages 1-3, blais2026usingabioluminescence pages 2-3). The protein is synthesized as an inactive zymogen (procaspase-3) and belongs to the peptidase C14A family (malireddi2025threedecadesof pages 1-3).

Primary Enzymatic Function and Substrate Specificity

Caspase-3 is a cysteine protease that cleaves peptide bonds almost exclusively C-terminal to aspartate residues at the P1 position (malireddi2025threedecadesof pages 1-3, araya2021deorphanizingcaspase3and pages 1-3). The enzyme catalyzes the hydrolysis of protein substrates during apoptosis and cellular stress responses, functioning as the primary executioner protease that mediates downstream substrate cleavage following activation by initiator caspases (mustafa2024apoptosisacomprehensive pages 2-4, araya2021deorphanizingcaspase3and pages 1-3, mustafa2024apoptosisacomprehensive pages 7-9).

Catalytic Mechanism and Activation

Procaspase-3 exists as an inactive homodimer that requires proteolytic cleavage at the intersubunit linker to form an active tetramer (malireddi2025threedecadesof pages 1-3, araya2021deorphanizingcaspase3and pages 1-3). Initiator caspases, particularly caspase-9 (via the intrinsic pathway) and caspase-8 (via the extrinsic pathway), cleave procaspase-3 at the intersubunit linker sequence 172-IETD↓S to generate the active enzyme (araya2021deorphanizingcaspase3and pages 1-3, soni2021caspase9activationof pages 1-3). This cleavage produces two subunits (p17 and p12) that assemble into the catalytically active tetrameric form (malireddi2025threedecadesof pages 1-3).

Substrate Recognition and Cleavage Specificity

Deep substrate profiling using subtiligase N-terminomics in native human cell lysates has revealed that caspase-3 recognizes a clear consensus motif of DEVD↓(G/S/A) for positions P4-P3-P2-P1↓P1′ (araya2021deorphanizingcaspase3and pages 4-6, blais2026usingabioluminescence pages 2-3). This motif can be more broadly summarized as DXXD↓X, though the P4 aspartate contributes importantly to substrate discrimination (araya2021deorphanizingcaspase3and pages 4-6, blais2026usingabioluminescence pages 2-3). However, substrate cleavage depends not only on sequence but also on local structural context and accessibility, as many proteins containing potential recognition motifs are not efficiently cleaved (araya2021deorphanizingcaspase3and pages 4-6, soni2021caspase9activationof pages 1-3).

Substrate Repertoire

The most comprehensive substrate profiling to date identified 906 putative protein substrates and 1,126 cleavage sites for caspase-3 in native lysates (araya2021deorphanizingcaspase3and pages 1-3, araya2021deorphanizingcaspase3and pages 4-6). Of these, 577 cleavage sites and 257 substrates had not previously been reported in the apoptosis DegraBase, revealing a pool of novel substrates that likely function in non-apoptotic contexts (araya2021deorphanizingcaspase3and pages 4-6). Caspase-3 substrates are enriched in cytoplasmic (~49%) and nuclear (~48%) proteins, with smaller fractions in mitochondria, endoplasmic reticulum, cell membrane, and secreted compartments (araya2021deorphanizingcaspase3and pages 4-6).

Key validated substrates include:
- PARP1 (poly(ADP-ribose) polymerase 1): A canonical substrate whose cleavage is widely used as a hallmark readout of caspase-3 activation during apoptosis (blais2026usingabioluminescence pages 2-3, samarasekera2025caspase3and pages 1-2, killarney2023executionercaspasesrestrict pages 1-2)
- ICAD/DFF45 (inhibitor of caspase-activated DNase): Cleavage releases CAD nuclease activity, enabling genomic DNA fragmentation (blais2026usingabioluminescence pages 2-3, zhou2024diversefunctionsof pages 1-2)
- Gasdermin E (GSDME): Cleaved by caspase-3 but not efficiently by caspase-7, demonstrating non-redundant substrate discrimination between executioner caspases (blais2026usingabioluminescence pages 2-3)
- CAD (carbamoyl-phosphate synthetase/aspartate transcarbamylase/dihydroorotase): Cleaved at Asp1371 prior to degradation, linking caspase-3 to pyrimidine synthesis control and chemosensitivity (tannous2025supersensitivechemiluminescentprobe pages 1-3)

Feature	Human CASP3 summary	Evidence
Verified identity	CASP3 encodes human caspase-3, an executioner/effector caspase in the caspase family; UniProt P42574 aligns with literature describing a cysteine-dependent, aspartate-specific protease central to apoptosis.	(mustafa2024apoptosisacomprehensive pages 2-4, malireddi2025threedecadesof pages 1-3, araya2021deorphanizingcaspase3and pages 1-3)
Enzyme classification	EC 3.4.22.56; proteolytic enzyme that hydrolyzes peptide bonds in protein substrates during apoptosis and other stress responses.	(malireddi2025threedecadesof pages 1-3, araya2021deorphanizingcaspase3and pages 1-3)
Protease type	Cysteine-dependent, aspartate-specific protease (cysteine aspartyl protease). Caspases cleave almost exclusively C-terminal to Asp at the P1 position.	(malireddi2025threedecadesof pages 1-3, araya2021deorphanizingcaspase3and pages 1-3, soni2021caspase9activationof pages 1-3)
Primary biochemical function	CASP3 is the major executioner protease that performs downstream substrate cleavage after activation by initiator caspases, thereby driving apoptotic dismantling of the cell; it also contributes to selected non-apoptotic stress-adaptation pathways.	(mustafa2024apoptosisacomprehensive pages 2-4, araya2021deorphanizingcaspase3and pages 1-3, mustafa2024apoptosisacomprehensive pages 7-9, samarasekera2025caspase3and pages 1-2)
Catalytic mechanism	Activated initiator caspases cleave procaspase-3 at the intersubunit linker to generate the active executioner enzyme; executioner caspases are inactive homodimers that require cleavage to form active tetramers that mediate downstream substrate cleavage. Proteolysis occurs at the scissile bond between P1 and P1′, with strict requirement for Asp at P1.	(malireddi2025threedecadesof pages 1-3, araya2021deorphanizingcaspase3and pages 1-3, soni2021caspase9activationof pages 1-3)
Preferred cleavage motif	Deep substrate profiling in native human cell lysates identified a clear caspase-3 consensus of DEVD↓(G/S/A) for P4-P1↓P1′; broader tolerated motifs exist, indicating cleavage depends on both sequence and local structural context.	(araya2021deorphanizingcaspase3and pages 4-6, blais2026usingabioluminescence pages 2-3)
Minimal sequence rule	Preference is often summarized as DXXD↓X, but the strongest observed motif for human caspase-3 is DEVD↓(G/A/S); P4 contributes importantly to specificity.	(araya2021deorphanizingcaspase3and pages 4-6, soni2021caspase9activationof pages 1-3, blais2026usingabioluminescence pages 2-3)
Importance of substrate context	Sequence alone is insufficient to explain cleavage; local accessibility and structural context strongly affect whether a potential motif is actually cleaved in proteins.	(araya2021deorphanizingcaspase3and pages 4-6, soni2021caspase9activationof pages 1-3)
Scale of substrate repertoire	Reverse N-terminomics identified 906 putative protein substrates and 1126 cleavage sites for caspase-3 in native lysates, representing one of the most comprehensive substrate maps reported.	(araya2021deorphanizingcaspase3and pages 1-3, araya2021deorphanizingcaspase3and pages 4-6)
Novelty of substrate map	Of the observed caspase-3 cleavage events, 577 cleavage sites had not previously been found in the apoptosis DegraBase, and 257 substrates were newly reported.	(araya2021deorphanizingcaspase3and pages 4-6)
Major substrate classes	CASP3 cleaves structural, regulatory, DNA-repair, cytoskeletal, chromatin, and signaling proteins, consistent with its role in morphological remodeling, DNA fragmentation, and apoptotic execution.	(tannous2025supersensitivechemiluminescentprobe pages 1-3, blais2026usingabioluminescence pages 2-3, mustafa2024apoptosisacomprehensive pages 7-9)
Key substrate example: PARP1	PARP1 is a canonical bona fide caspase-3 substrate and a standard readout of caspase-3 activity during apoptosis; cleavage of PARP1 is repeatedly cited as a hallmark of executioner caspase activation.	(blais2026usingabioluminescence pages 2-3, samarasekera2025caspase3and pages 1-2, killarney2023executionercaspasesrestrict pages 1-2)
Key substrate example: ICAD/DFF45	CASP3 cleaves the inhibitor of caspase-activated DNase (ICAD), enabling CAD-mediated genomic DNA fragmentation during apoptosis.	(zhou2024diversefunctionsof pages 1-2, blais2026usingabioluminescence pages 2-3)
Key substrate example: GSDME	Human GSDME contains a DxxD motif recognized by CASP3; recent work emphasizes that human GSDME is cleaved by CASP3 but not efficiently by human CASP7, illustrating non-redundant substrate discrimination between the two executioner caspases.	(blais2026usingabioluminescence pages 2-3)
Key substrate example: CAD (carbamoyl-phosphate synthetase/aspartate transcarbamylase/dihydroorotase)	Recent work shows CAD must be cleaved by caspase-3 at Asp1371 prior to degradation, linking CASP3 activity to chemosensitivity and pyrimidine synthesis control in cancer cells.	(tannous2025supersensitivechemiluminescentprobe pages 1-3)
Other validated/representative substrate themes	Caspase-3 substrates include proteins involved in apoptosis, stress adaptation, autophagy modulation, DNA-damage signaling, and inflammatory restraint; cleavage landscapes differ under lethal vs non-lethal stress.	(samarasekera2025caspase3and pages 1-2, killarney2023executionercaspasesrestrict pages 1-2)
Subcellular distribution of substrates	In the N-terminomics dataset, caspase-3 substrates were enriched in cytoplasmic and nuclear proteins: ~49% cytoplasmic and ~48% nuclear, with smaller fractions in mitochondria, ER, membrane, and secreted compartments.	(araya2021deorphanizingcaspase3and pages 4-6)
Comparison with caspase-7: shared features	CASP3 and CASP7 are closely related executioner caspases with overlapping preferences and a shared preference for DEVD-like motifs; both are activated downstream of initiator caspases in apoptosis.	(mustafa2024apoptosisacomprehensive pages 2-4, blais2026usingabioluminescence pages 2-3)
Comparison with caspase-7: key difference	Despite shared DxxD recognition, CASP3 and CASP7 are not fully redundant. Human GSDME is cleaved by CASP3 but not by human CASP7, and structural work attributes this to differences in the CASP7 p10 subunit/prime-side substrate recognition.	(blais2026usingabioluminescence pages 2-3)
Comparison with caspase-7: proteolytic breadth	Caspase-3 is described as the most proteolytically proficient executioner caspase and has a very broad substrate repertoire; some recent assay work and reviews continue to treat CASP3 as the dominant executioner enzyme.	(blais2026usingabioluminescence pages 2-3, tannous2025supersensitivechemiluminescentprobe pages 1-3)

Table: This table summarizes the primary enzymatic activity, cleavage preferences, substrate scope, and mechanism of human caspase-3, with a focused comparison to caspase-7. It is useful for quickly identifying what CASP3 cleaves, how it recognizes substrates, and why it is considered the dominant executioner caspase.

Subcellular Localization

Procaspase-3 is synthesized in the cytosol where it exists as an inactive enzyme under normal conditions (araya2021deorphanizingcaspase3and pages 4-6). Upon apoptotic stimulation, the activated caspase-3 functions primarily in the cytoplasm and nucleus, where it cleaves its broad substrate repertoire (araya2021deorphanizingcaspase3and pages 4-6). The distribution of caspase-3 substrates reflects this dual cytoplasmic-nuclear localization, with approximately equal representation in both compartments (araya2021deorphanizingcaspase3and pages 4-6). During apoptosis, active caspase-3 can also translocate to mitochondria and the nucleus to execute specific functions (mustafa2024apoptosisacomprehensive pages 7-9).

Role in Apoptotic Signaling Pathways

Caspase-3 serves as the central convergence point for both intrinsic (mitochondrial) and extrinsic (death receptor) apoptotic pathways, making it a critical integration node for diverse death stimuli (mustafa2024apoptosisacomprehensive pages 2-4, araya2021deorphanizingcaspase3and pages 1-3, mustafa2024apoptosisacomprehensive pages 5-7).

Intrinsic (Mitochondrial) Pathway

The intrinsic pathway is initiated by intracellular stress signals including DNA damage, reactive oxygen species (ROS), endoplasmic reticulum stress, growth factor withdrawal, and hypoxia (mustafa2024apoptosisacomprehensive pages 5-7, mustafa2024apoptosisacomprehensive pages 7-9). These stressors activate BH3-only proteins and p53, which either directly activate the pore-forming effectors BAX and BAK or neutralize anti-apoptotic BCL-2 family members (BCL-2, BCL-xL, MCL-1) (mustafa2024apoptosisacomprehensive pages 2-4, mustafa2024apoptosisacomprehensive pages 5-7, mustafa2024apoptosisacomprehensive pages 7-9).

BAX and BAK oligomerize to form pores in the outer mitochondrial membrane, causing mitochondrial outer membrane permeabilization (MOMP), often described as the apoptotic "point of no return" (mustafa2024apoptosisacomprehensive pages 7-9). MOMP releases cytochrome c from the mitochondrial intermembrane space into the cytosol (araya2021deorphanizingcaspase3and pages 1-3, zhou2024diversefunctionsof pages 1-2). Cytosolic cytochrome c binds to apoptotic protease activating factor-1 (APAF-1) in the presence of ATP, forming the apoptosome complex (araya2021deorphanizingcaspase3and pages 1-3, zhou2024diversefunctionsof pages 1-2, killarney2023executionercaspasesrestrict pages 1-2). Procaspase-9 associates with the apoptosome and undergoes proximity-induced auto-activation (araya2021deorphanizingcaspase3and pages 1-3, zhou2024diversefunctionsof pages 1-2). Active caspase-9 then cleaves and activates procaspase-3 and procaspase-7, initiating the downstream proteolytic cascade (araya2021deorphanizingcaspase3and pages 1-3, mustafa2024apoptosisacomprehensive pages 7-9).

Extrinsic (Death Receptor) Pathway

The extrinsic pathway is initiated by extracellular death ligands (such as FasL, TNF-α, and TRAIL) binding to their cognate death receptors (Fas/CD95, TNFR1, and death receptors 4/5) on the cell surface (mustafa2024apoptosisacomprehensive pages 2-4, araya2021deorphanizingcaspase3and pages 1-3, mustafa2024apoptosisacomprehensive pages 5-7). Ligand binding induces receptor oligomerization and assembly of the death-inducing signaling complex (DISC), which recruits and activates initiator caspases-8 and -10 through proximity-induced dimerization and autoproteolysis (mustafa2024apoptosisacomprehensive pages 2-4, araya2021deorphanizingcaspase3and pages 1-3, mustafa2024apoptosisacomprehensive pages 5-7).

Active caspase-8 can directly cleave and activate procaspase-3, providing a rapid route to apoptotic execution (mustafa2024apoptosisacomprehensive pages 2-4, araya2021deorphanizingcaspase3and pages 1-3, mustafa2024apoptosisacomprehensive pages 5-7). Alternatively, caspase-8 can cleave the BH3-only protein BID, generating truncated BID (tBID) that translocates to mitochondria and engages the intrinsic pathway, thereby amplifying the death signal through mitochondrial amplification and caspase-9 activation (araya2021deorphanizingcaspase3and pages 1-3, mustafa2024apoptosisacomprehensive pages 7-9). This cross-talk mechanism integrates extrinsic and intrinsic signaling.

Regulatory Mechanisms

Multiple regulatory mechanisms fine-tune caspase-3 activation:
- Inhibitor of apoptosis proteins (IAPs) such as XIAP suppress caspase activity by direct binding (mustafa2024apoptosisacomprehensive pages 7-9)
- Smac/DIABLO and Omi/HtrA2, released from mitochondria during MOMP, antagonize IAPs and relieve caspase inhibition (mustafa2024apoptosisacomprehensive pages 7-9)
- BCL-2 family proteins determine the apoptotic threshold upstream of caspase-3 by regulating MOMP (mustafa2024apoptosisacomprehensive pages 2-4, mustafa2024apoptosisacomprehensive pages 5-7, mustafa2024apoptosisacomprehensive pages 7-9)

Downstream Effects of Caspase-3 Activation

Once activated, caspase-3 cleaves a vast array of structural, regulatory, DNA repair, cytoskeletal, and chromatin-associated proteins, producing the hallmark biochemical and morphological features of apoptosis (malireddi2025threedecadesof pages 1-3, araya2021deorphanizingcaspase3and pages 1-3, araya2021deorphanizingcaspase3and pages 4-6, blais2026usingabioluminescence pages 2-3):

PARP1 cleavage: Marks shutdown of DNA repair and progression toward irreversible apoptotic execution (blais2026usingabioluminescence pages 2-3, samarasekera2025caspase3and pages 1-2)
DNA fragmentation: Cleavage of ICAD releases CAD nuclease activity, causing characteristic apoptotic DNA ladder formation (blais2026usingabioluminescence pages 2-3, zhou2024diversefunctionsof pages 1-2)
Cellular demolition: Proteolysis of cytoskeletal and structural proteins produces membrane blebbing, chromatin condensation, cell shrinkage, phosphatidylserine externalization, and detachment from the extracellular matrix (mustafa2024apoptosisacomprehensive pages 2-4, blais2026usingabioluminescence pages 2-3, mustafa2024apoptosisacomprehensive pages 7-9)

Pathway/component	Sequence of events involving CASP3	Key regulators / molecular details	Functional outcome	Evidence
Intrinsic (mitochondrial) apoptosis	Intracellular stress signals trigger mitochondrial outer membrane permeabilization (MOMP), releasing cytochrome c into the cytosol; cytochrome c binds APAF1 to assemble the apoptosome, which activates caspase-9, and caspase-9 then cleaves and activates procaspase-3.	Stressors include DNA damage, ROS, ER stress, loss of adhesion, growth-factor withdrawal, and hypoxia. BAX/BAK are the key pore-forming effectors that drive MOMP.	Activation of executioner caspase-3 initiates the downstream proteolytic cascade that dismantles the cell.	(mustafa2024apoptosisacomprehensive pages 5-7, mustafa2024apoptosisacomprehensive pages 7-9, zhou2024diversefunctionsof pages 1-2, killarney2023executionercaspasesrestrict pages 1-2)
MOMP as the commitment step	MOMP is described as the apoptotic “point of no return”; after membrane permeabilization, mitochondrial proteins enter the cytosol and enable caspase activation.	BH3-only proteins and p53 promote BAX/BAK activation directly or by neutralizing anti-apoptotic BCL-2 family members.	Commits the cell to apoptosis and licenses caspase-9 to activate caspase-3.	(mustafa2024apoptosisacomprehensive pages 7-9)
Cytochrome c–apoptosome axis	Released cytochrome c binds apoptotic protease activating factor-1 (APAF1), forming the apoptosome complex with procaspase-9; auto-activation of caspase-9 within this complex leads to downstream cleavage of executioner caspases-3/7.	Cytochrome c is normally in the mitochondrial intermembrane space and becomes apoptogenic upon cytosolic release.	Central biochemical route linking mitochondrial injury to CASP3 activation.	(araya2021deorphanizingcaspase3and pages 1-3, zhou2024diversefunctionsof pages 1-2, killarney2023executionercaspasesrestrict pages 1-2)
Extrinsic (death receptor) apoptosis	Extracellular death ligands bind cell-surface death receptors, leading to assembly of the death-inducing signaling complex (DISC), activation of initiator caspase-8 (and sometimes caspase-10), and direct cleavage/activation of procaspase-3.	Fas/CD95 and TNFR-family death receptors are highlighted; DISC-mediated proximity promotes initiator caspase activation.	Rapid activation of CASP3 from receptor-proximal signaling.	(mustafa2024apoptosisacomprehensive pages 2-4, araya2021deorphanizingcaspase3and pages 1-3, mustafa2024apoptosisacomprehensive pages 5-7)
Extrinsic–intrinsic cross-talk via BID	Activated caspase-8 can also cleave BID, thereby engaging mitochondrial apoptosis and caspase-9 in addition to directly activating caspase-3.	BID is a BH3-interacting death agonist linking death receptor signaling to MOMP.	Amplifies apoptotic signaling and integrates extrinsic and intrinsic pathways.	(araya2021deorphanizingcaspase3and pages 1-3, mustafa2024apoptosisacomprehensive pages 7-9)
Key upstream regulators: BCL-2 family	The balance between pro-apoptotic and anti-apoptotic BCL-2 family proteins determines whether MOMP occurs and therefore whether CASP3 can be activated through the intrinsic pathway.	Pro-apoptotic: BAX, BAK, BID, BIM, PUMA, NOXA, BIK. Anti-apoptotic: BCL-2, BCL-xL, MCL-1.	Governs apoptotic threshold upstream of CASP3.	(mustafa2024apoptosisacomprehensive pages 2-4, mustafa2024apoptosisacomprehensive pages 5-7, mustafa2024apoptosisacomprehensive pages 7-9)
Key upstream regulators: death receptors	Fas/CD95 and TNFR1-family receptors transduce extracellular apoptotic cues to initiator caspases that activate CASP3.	Ligand binding induces receptor complex assembly and initiator caspase activation at the DISC.	Couples immune/extracellular death signals to executioner caspase activation.	(mustafa2024apoptosisacomprehensive pages 2-4, mustafa2024apoptosisacomprehensive pages 5-7)
Key upstream regulators: IAPs and Smac/DIABLO	IAP proteins suppress caspase activity, while mitochondrial Smac/DIABLO released during MOMP antagonizes IAPs, thereby facilitating caspase-3 activation and function.	XIAP and related IAPs inhibit caspases; Smac/DIABLO relieves this inhibition after mitochondrial permeabilization.	Strengthens and sustains CASP3-mediated execution.	(mustafa2024apoptosisacomprehensive pages 7-9)
CASP3 as executioner protease	Initiator caspases activate CASP3, which then cleaves broad sets of structural, regulatory, DNA-repair, cytoskeletal, and chromatin-associated proteins.	CASP3 is an executioner cysteine-aspartate protease with strong DEVD-like substrate preference and a large substrate repertoire.	Produces the canonical biochemical and morphological features of apoptosis.	(malireddi2025threedecadesof pages 1-3, araya2021deorphanizingcaspase3and pages 1-3, araya2021deorphanizingcaspase3and pages 4-6, blais2026usingabioluminescence pages 2-3)
Downstream effect: PARP1 cleavage	CASP3 cleaves PARP1, a canonical hallmark substrate commonly used as a readout of executioner caspase activation.	PARP1 cleavage marks shutdown of DNA repair and progression of apoptosis.	Promotes irreversible apoptotic execution.	(blais2026usingabioluminescence pages 2-3, samarasekera2025caspase3and pages 1-2, killarney2023executionercaspasesrestrict pages 1-2)
Downstream effect: DNA fragmentation	CASP3 cleaves ICAD, releasing CAD activity and driving genomic DNA fragmentation.	Cleavage of the inhibitor of caspase-activated DNase is a core mechanism for apoptotic DNA breakdown.	Produces a defining nuclear feature of apoptosis.	(blais2026usingabioluminescence pages 2-3, zhou2024diversefunctionsof pages 1-2)
Downstream effect: cellular demolition	CASP3 activation causes membrane blebbing, chromatin condensation, cell shrinkage, phosphatidylserine exposure, and detachment from the extracellular matrix through cleavage of multiple substrates.	Executioner caspases-3/6/7 mediate the terminal demolition phase downstream of initiators.	Morphological and biochemical completion of apoptosis.	(mustafa2024apoptosisacomprehensive pages 2-4, blais2026usingabioluminescence pages 2-3, mustafa2024apoptosisacomprehensive pages 7-9)
Pathway convergence	Both intrinsic and extrinsic pathways converge on CASP3 activation, making it a central integration point for diverse death stimuli.	Caspase-8 and caspase-9 represent the main upstream initiators for extrinsic and intrinsic apoptosis, respectively.	Explains why CASP3 is widely used as a core apoptosis effector/readout.	(mustafa2024apoptosisacomprehensive pages 2-4, araya2021deorphanizingcaspase3and pages 1-3, mustafa2024apoptosisacomprehensive pages 5-7)
Additional route: granzyme B-mediated apoptosis	Cytotoxic lymphocyte granzyme B can promote caspase-dependent apoptosis by cleaving caspase-3, caspase-7, and BID.	Provides an immune-mediated apoptotic route that intersects with both direct CASP3 activation and mitochondrial amplification.	Supports target-cell killing by immune effectors.	(mustafa2024apoptosisacomprehensive pages 7-9)
Inflammatory restraint during apoptosis	During MOMP-associated apoptosis, executioner caspases-3/7 suppress mtRNA-driven type I interferon signaling, limiting inflammatory responses while cell death proceeds.	In CASP3/7-deficient settings, mtRNA activates the MDA5/MAVS/IRF3 pathway and type I IFN signaling.	Helps maintain the typically immunologically silent character of apoptosis.	(killarney2023executionercaspasesrestrict pages 1-2)

Table: This table summarizes how human caspase-3 is activated through intrinsic and extrinsic apoptosis pathways, the main upstream regulators controlling those routes, and the principal downstream consequences of caspase-3 activation. It is useful for linking CASP3's biochemical function to its pathway context and cellular effects.

Non-Apoptotic Functions of Caspase-3

Accumulating evidence from 2022-2025 demonstrates that caspase-3 plays critical roles beyond apoptosis, supporting the hypothesis that the primordial function of caspases was to regulate cellular stress adaptations rather than solely execute cell death (samarasekera2025caspase3and pages 1-2, rosa2024nonapoptoticcaspaseevents pages 1-2).

Cytoprotective Autophagy and Stress Adaptation

Recent work has established a functionally conserved role for caspase-3 and caspase-7 in promoting starvation- or proteasome inhibition-induced cytoprotective autophagy in human breast cancer cells (samarasekera2025caspase3and pages 1-2). Loss of CASP3 and CASP7 results in increased PARP1 cleavage, reduced LC3B and ATG7 transcript levels, and decreased H2AX phosphorylation, consistent with a block in autophagy and DNA damage response pathways (samarasekera2025caspase3and pages 1-2). Under non-lethal stress conditions, caspase-7 undergoes non-canonical processing at calpain cleavage sites flanking a PARP1 exosite, producing stable fragments that can rescue H2AX phosphorylation (samarasekera2025caspase3and pages 1-2). The synthetic lethality observed between CASP3/CASP7 loss and BRCA1 deficiency underscores the importance of caspases in stress adaptation (samarasekera2025caspase3and pages 1-2).

Suppression of Inflammatory Signaling During Apoptosis

During apoptosis, mitochondrial outer membrane permeabilization (MOMP) releases mitochondrial RNA (mtRNA) into the cytosol (killarney2023executionercaspasesrestrict pages 1-2). Executioner caspases-3 and -7 prevent cytoplasmic mtRNA from triggering inflammatory signaling pathways (killarney2023executionercaspasesrestrict pages 1-2). In settings where caspase-3/7 are inhibited, apoptotic insults result in mtRNA activation of the MDA5/MAVS/IRF3 pathway, driving Type I interferon (IFN) signaling (killarney2023executionercaspasesrestrict pages 1-2). This key function of caspase-3/7 helps maintain the typically immunologically silent character of apoptosis by inhibiting inflammation caused by cytoplasmic release of mtRNA (killarney2023executionercaspasesrestrict pages 1-2).

Neuronal Plasticity and Synaptic Remodeling

Non-apoptotic caspase-3 activation mediates synaptic pruning, dendritic spine loss, and long-term depression (LTD) in neurons without causing cell death (fieblinger2022nonapoptoticcaspase3activation pages 1-2). In a mouse model of Parkinson's disease, caspase-3 is transiently activated in the striatum following dopaminergic denervation, coinciding with rapid loss of dendritic spines and deficits in synaptic LTD in indirect pathway neurons (fieblinger2022nonapoptoticcaspase3activation pages 1-2). Systemic caspase inhibitor treatment prevents both spine pruning and LTD deficits without interfering with ongoing dopaminergic degeneration, identifying non-apoptotic caspase activation as a critical event in early neuroplastic changes (fieblinger2022nonapoptoticcaspase3activation pages 1-2). Similar non-apoptotic caspase-3 functions have been documented in synaptic dysfunction in Alzheimer's disease models.

Neural Stem Cell Differentiation

Non-apoptotic caspase-3/7 events occur in adult neural stem cells (NSCs) and are biased toward direct neuronal conversion under physiological conditions (rosa2024nonapoptoticcaspaseevents pages 1-2). Using an NSC-specific genetic tracer of caspase-3/7 activation in zebrafish, researchers demonstrated that non-apoptotic caspase events facilitate direct neuronal differentiation without cell division (rosa2024nonapoptoticcaspaseevents pages 1-2). The transcription factor Atf3 is necessary for this fate choice, and caspase-3/7 activation is part of the processes engaged when NSCs are recruited for neuronal regeneration (rosa2024nonapoptoticcaspaseevents pages 1-2).

Oncogenic Transformation

In certain contexts, caspase-3 can promote rather than suppress oncogene-induced malignant transformation (fieblinger2022nonapoptoticcaspase3activation pages 1-2). Active caspase-3 triggers translocation of endonuclease G (EndoG) from mitochondria to the nucleus, inducing phosphorylation of the Src-STAT3 signaling pathway to facilitate oncogenic transformation (fieblinger2022nonapoptoticcaspase3activation pages 1-2). Genetic ablation of caspase-3 significantly attenuates oncogene-induced transformation in vitro and delays breast cancer progression in mouse models, revealing a context-dependent pro-oncogenic role (fieblinger2022nonapoptoticcaspase3activation pages 1-2).

Comparison with Caspase-7

While caspase-3 and caspase-7 are closely related executioner caspases with overlapping substrate preferences and shared recognition of DEVD-like motifs, they are not fully redundant (mustafa2024apoptosisacomprehensive pages 2-4, blais2026usingabioluminescence pages 2-3). Caspase-3 is described as the most proteolytically proficient executioner caspase, and recent structural studies reveal that substrate discrimination differs between the two enzymes (blais2026usingabioluminescence pages 2-3). For example, human GSDME is efficiently cleaved by caspase-3 but not by caspase-7, a difference attributed to variations in the p10 subunit and prime-side substrate recognition architecture (blais2026usingabioluminescence pages 2-3). Caspase-7 can serve as a "backup" to caspase-3 in certain developmental contexts, though caspase-3 is considered the dominant executioner in most apoptotic settings (mustafa2024apoptosisacomprehensive pages 2-4).

Summary

Human caspase-3 (CASP3, UniProt P42574) is the central executioner caspase in programmed cell death, functioning as a cysteine-dependent, aspartate-specific protease (EC 3.4.22.56) with a preferred cleavage motif of DEVD↓(G/S/A). The enzyme is activated downstream of initiator caspases-9 and -8 in the intrinsic (mitochondrial) and extrinsic (death receptor) apoptotic pathways, respectively, and cleaves over 900 protein substrates to produce the biochemical and morphological hallmarks of apoptosis. Beyond its canonical role in cell death, recent research (2022-2025) has established important non-apoptotic functions for caspase-3, including promotion of cytoprotective autophagy, suppression of inflammatory signaling during stress, regulation of neuronal plasticity and synaptic remodeling, facilitation of neural stem cell differentiation, and context-dependent roles in oncogenic transformation. The protein functions primarily in the cytoplasm and nucleus, where the majority of its substrates are localized. Understanding caspase-3's multifaceted roles in both apoptotic and non-apoptotic contexts is essential for developing targeted therapeutic strategies in cancer, neurodegenerative diseases, and other conditions where cell fate decisions are dysregulated.

References

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(tannous2025supersensitivechemiluminescentprobe pages 1-3): Rozan Tannous, Chi Zhang, and Doron Shabat. Super-sensitive chemiluminescent probe for the detection of caspase‑3 activity. Bioconjugate Chemistry, 36:1113-1120, May 2025. URL: https://doi.org/10.1021/acs.bioconjchem.5c00151, doi:10.1021/acs.bioconjchem.5c00151. This article has 3 citations and is from a peer-reviewed journal.
(mustafa2024apoptosisacomprehensive pages 5-7): Mohd Mustafa, Rizwan Ahmad, Irfan Qadir Tantry, Waleem Ahmad, Sana Siddiqui, Mudassir Alam, Kashif Abbas, Moinuddin, Md. Imtaiyaz Hassan, Safia Habib, and Sidra Islam. Apoptosis: a comprehensive overview of signaling pathways, morphological changes, and physiological significance and therapeutic implications. Cells, 13:1838, Nov 2024. URL: https://doi.org/10.3390/cells13221838, doi:10.3390/cells13221838. This article has 545 citations.
(rosa2024nonapoptoticcaspaseevents pages 1-2): Frédéric Rosa, Nicolas Dray, and Laure Bally-Cuif. Non-apoptotic caspase events and atf3 expression underlie direct neuronal differentiation of adult neural stem cells. Development (Cambridge, England), Mar 2024. URL: https://doi.org/10.1242/dev.204381, doi:10.1242/dev.204381. This article has 6 citations.
(fieblinger2022nonapoptoticcaspase3activation pages 1-2): Tim Fieblinger, Chang Li, Elena Espa, and M. Angela Cenci. Non-apoptotic caspase-3 activation mediates early synaptic dysfunction of indirect pathway neurons in the parkinsonian striatum. International Journal of Molecular Sciences, 23:5470, May 2022. URL: https://doi.org/10.3390/ijms23105470, doi:10.3390/ijms23105470. This article has 20 citations.

Artifacts

Citations

malireddi2025threedecadesof pages 1-3
blais2026usingabioluminescence pages 2-3
tannous2025supersensitivechemiluminescentprobe pages 1-3
mustafa2024apoptosisacomprehensive pages 7-9
killarney2023executionercaspasesrestrict pages 1-2
rosa2024nonapoptoticcaspaseevents pages 1-2
mustafa2024apoptosisacomprehensive pages 2-4
zhou2024diversefunctionsof pages 1-2
mustafa2024apoptosisacomprehensive pages 5-7
https://doi.org/10.1093/hmg/ddaf106,
https://doi.org/10.1021/acschembio.1c00456,
https://doi.org/10.1042/bsr20254030,
https://doi.org/10.3390/cells13221838,
https://doi.org/10.1021/acs.biochem.1c00459,
https://doi.org/10.1371/journal.pbio.3003034,
https://doi.org/10.1038/s41467-023-37146-z,
https://doi.org/10.1038/s41418-024-01284-8,
https://doi.org/10.1021/acs.bioconjchem.5c00151,
https://doi.org/10.1242/dev.204381,
https://doi.org/10.3390/ijms23105470,

📚 Additional Documentation

Notes

(CASP3-notes.md)

CASP3 (Caspase-3) review notes

UniProt: P42574 (CASP3_HUMAN), 277 aa precursor. EC 3.4.22.56. Peptidase C14A family.
Synonyms: CPP32, Yama, apopain, SCA-1. Heterotetramer of two p17 (large) + p12 (small) subunits.

Core identity / molecular function

CASP3 is a cysteine-dependent aspartate-directed endopeptidase: cleaves substrates after Asp
with strict requirement for Asp at P1 and P4 (preferred motif DxxD-|-). [UniProt CATALYTIC ACTIVITY,
"Strict requirement for an Asp residue at positions P1 and P4. It has a preferred cleavage sequence of Asp-Xaa-Xaa-Asp-|-"]
It is the principal effector/executioner caspase of apoptosis. Purified as "apopain" responsible
for PARP cleavage, derived from proenzyme CPP32; related to ICE and C. elegans CED-3. [PMID:7596430,
"This enzyme, named apopain, is composed of two subunits ... derived from a common proenzyme identified as CPP32 ...
apopain/CPP32 is important for the initiation of apoptotic cell death"]
Activated by upstream initiator caspases (CASP8, CASP9, CASP10) and granzyme B; PTM section confirms
cleavage by granzyme B, caspase-6, -8, -10 generates the two active subunits. [UniProt PTM]
Caspase-3 is the major executioner caspase, more promiscuous than caspase-7, and "appears to be the major
executioner caspase during the demolition phase of apoptosis." PMID:18723680

Substrate cleavage / downstream demolition (all DEPEND on the same MF, mostly downstream processes)

PARP1 cleavage at 216-Asp|Gly-217 (hallmark execution substrate). [UniProt FUNCTION; PMID:16374543 nuclear
caspase-3 activation and PARP cleavage early in camptothecin apoptosis]
ICAD/DFF45 cleavage -> releases CAD/DFF40 endonuclease for oligonucleosomal DNA fragmentation. Apoptotic
DNA laddering relies on cytosolic DFF40/CAD activated by caspase processing of ICAD. PMID:22253444
GATA-1 cleavage in erythroid precursors; Hsp70 protects GATA-1 during terminal erythroid differentiation
(link to erythropoiesis). PMID:17167422
Phospholipid scramblase / PtdSer exposure: cleaves XKR8 and ATP11C flippase to drive apoptotic PtdSer "eat me"
signal; also XRCC4 cleavage releases fragment activating Xkr4 scrambling. [PMID:24904167 ATP11C flippase;
PMID:33725486 XRCC4/Xkr4]
IL-18 processing in monocytes (CASP3 contributes along with CASP1). PMID:9334240; note newer UniProt text
says CASP3 "cleaves and inactivates IL18" (context-dependent).
Pyroptosis crosstalk: cleaves/activates gasdermin-E (GSDME/DFNA5) to switch apoptosis to secondary
necrosis/pyroptosis and permit IL-1b release. [PMID:28459430 caspase-3 cleavage of a gasdermin (GSDME);
PMID:33852854 GSDME permits IL-1b release; Reactome R-HSA-9647632 CASP3 cleaves GSDME]
CASP3 also cleaves/inactivates GSDMD (Reactome R-HSA-9686088), generally inhibiting GSDMD pyroptosis.
Antiviral / innate immunity restraint: cleaves cGAS, MAVS, IRF3 to suppress type I IFN during apoptosis;
cleaves NF-kB members p65/RelA, RelB, c-Rel to dampen cytokine production. [PMID:30878284; PMID:36002459]
Tau cleavage (Alzheimer link), BACE/GGA3 -> amyloid-beta (APP processing). [PMID:12888622; PMID:9736630;
PMID:17553422]
Many additional substrates curated by Reactome (desmosomal cadherins, fodrin/spectrin, ROCK1, gelsolin,
beta-catenin, MST kinases, etc.) — these are CASP3 substrate-cleavage reactions, located in cytosol/nucleus.

Localization

Cytoplasm (UniProt SUBCELLULAR LOCATION, PMID:15003516). Procaspase cytosolic; active CASP3 also translocates
to nucleus during apoptosis (PARP, DFF45 cleavage there). Nuclear localization is functional/active-site
context (PMID:16374543 nuclear caspase-3 activation; Reactome R-HSA-211219 translocation to nucleus).

Regulation

S-nitrosylation of catalytic Cys163 keeps procaspase inactive; denitrosylated on Fas activation. [UniProt PTM;
PMID:10213689]
Inhibited by XIAP (BIR2) and ubiquitinated/inhibited by BIRC6/BRUCE (relieved by SMAC/DIABLO). [UniProt;
PMID:11257232 XIAP structure]
ADP-riboxanation at Arg207 by bacterial CopC blocks activation (microbial infection).

Curation strategy

CORE molecular function: GO:0004197 cysteine-type endopeptidase activity (many IDA + IBA) -> ACCEPT.
Broader MF parents (GO:0008234 cysteine-type peptidase, GO:0008233 peptidase, GO:0004175 endopeptidase) ->
ACCEPT as correct-but-general. GO:0004190 aspartic-type endopeptidase activity is WRONG (CASP3 is a cysteine
protease that cleaves after Asp; it is not an aspartic protease) -> REMOVE.
CORE biological process: apoptotic process (GO:0006915), execution phase of apoptosis (GO:0097194),
proteolysis (GO:0006508), protein processing/maturation -> ACCEPT.
Pyroptosis terms (GO:0070269, GO:0140639) -> ACCEPT (well supported IDA, gasdermin cleavage).
Many tissue/process annotations (neuron/erythrocyte/keratinocyte differentiation, hippocampus development,
synapse pruning, platelet formation, learning/memory, muscle differentiation) are downstream non-apoptotic or
tissue-specific roles -> KEEP_AS_NON_CORE.
Long list of IEA GO_REF:0000107 "response to X" stimulus terms (hypoxia, glucose, nicotine, ethanol, X-ray,
metal ion, etc.) are ortholog-transferred stimulus/response terms, not core; mostly KEEP_AS_NON_CORE; a few
questionable MF transfers (aspartic-type endopeptidase, CDK inhibitor, phospholipase A2 activator) -> REMOVE/
MARK_AS_OVER_ANNOTATED.
bare protein binding (GO:0005515, IPI, many) -> MARK_AS_OVER_ANNOTATED / KEEP_AS_NON_CORE (uninformative;
many from interactome screens). Do not endorse as core.
Reactome cytosol/nucleoplasm CC TAS (dozens) -> ACCEPT location, but these are substrate-cleavage reaction
contexts; cytosol/nucleus are valid.

Exact supporting quotes gathered (for supported_by)

PMID:18723680: "Caspase-3 was found to be generally more promiscuous than caspase-7 and appears to be the
major executioner caspase during the demolition phase of apoptosis."
PMID:7596430: "This enzyme, named apopain, is composed of two subunits of relative molecular mass (M(r)) 17K
and 12K that are derived from a common proenzyme identified as CPP32." / "suggesting that apopain/CPP32 is
important for the initiation of apoptotic cell death."
PMID:9334240: "the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and
Asp76-Asn77 to generate biologically inactive products."
PMID:16374543: "the activation of nuclear caspases-7 and -3, and poly(ADP-ribose) polymerase (PARP) cleavage,
are early events in camptothecin-induced apoptosis."
PMID:17167422: "Caspase-3 is activated during both terminal differentiation and erythropoietin-starvation-
induced apoptosis of human erythroid precursors." / "Hsp70 prevents active caspase-3 from cleaving GATA-1 and
inducing apoptosis."
PMID:22253444: "the activation of, at least, caspase-3 is necessary for the proper cleavage of ICAD L/S."
PMID:28459430: "GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that
perforates membranes and thereby induces pyroptosis."
PMID:30878284: "activated caspase-3 cleaved cGAS, MAVS, and IRF3 to prevent cytokine overproduction." /
"Caspase-3 was exclusively required in human cells."
PMID:36002459: "caspase-3 can mediate the cleavage of NF-κB members p65/RelA, RelB, and c-Rel via its protease
activity."
PMID:33725486: "Upon apoptotic stimuli, XRCC4, contained in the DNA repair complex, is cleaved by caspases,
and its C-terminal fragment with an intrinsically disordered region is released into the cytoplasm."
PMID:11257232: "We report the crystal structure of the second BIR domain of XIAP (BIR2) in complex with
caspase-3, at a resolution of 2.7 A, revealing the structural basis for inhibition."
PMID:8689682: "Cells undergoing apoptosis in vivo showed increased release of cytochrome c to their cytosol"
(intrinsic/apoptosome upstream of CASP3 activation).
PMID:15565177: "typical apoptotic features such as caspase-3 activation and cleavage of poly(ADP-ribose)-
polymerase" (DIP/E2F1 intrinsic apoptosis).
PMID:33852854: GSDME "cleaved by apoptosis-associated CASP3"; non-cleavable GSDME D270A "altered at the CASP3
cleavage and activation site."

Falcon deep research integration (2026-06-21)

Falcon (Edison) deep-research report is in CASP3-deep-research-falcon.md; it strongly corroborates the existing
review/annotations (executioner cysteine-aspartate protease, EC 3.4.22.56, DxxD specificity, CASP8/9 activation,
PARP1/ICAD/GSDME substrates, cytoplasmic+nuclear localization, non-apoptotic differentiation roles, IFN restraint),
adding no contradictions but a few refinements. All Falcon-sourced citations below are not yet independently verified
against full text.

New / refined points (beyond existing notes):
- Refined cleavage motif: native-lysate subtiligase N-terminomics gives a stronger CASP3 consensus DEVD↓(G/S/A) at
P4-P1↓P1' (not just generic DxxD↓), with cleavage also gated by local structural accessibility. [Araya et al.,
ACS Chem Biol 2021, doi:10.1021/acschembio.1c00456; Soni & Hardy, Biochemistry 2021, doi:10.1021/acs.biochem.1c00459]
(not yet independently verified against full text)
- Scale of substrate repertoire quantified: ~906 putative substrates / 1126 cleavage sites in native lysates, of which
577 sites and 257 substrates were novel vs the apoptosis DegraBase; substrates ~49% cytoplasmic and ~48% nuclear.
[Araya et al., ACS Chem Biol 2021, doi:10.1021/acschembio.1c00456] (not yet independently verified against full text)
- CASP3 vs CASP7 non-redundancy: human GSDME is cleaved efficiently by CASP3 but not by CASP7 (attributed to CASP7 p10
subunit / prime-side recognition differences), supporting CASP3 as the dominant/most proteolytically proficient
executioner. [Blais & Denault, Biosci Rep 2026, doi:10.1042/bsr20254030; Mustafa et al., Cells 2024,
doi:10.3390/cells13221838] (not yet independently verified against full text)
- New substrate: CAD (carbamoyl-phosphate synthetase 2/aspartate transcarbamylase/dihydroorotase, CAD enzyme of
pyrimidine synthesis) cleaved at Asp1371 prior to degradation, linking CASP3 to pyrimidine synthesis control and
chemosensitivity. [Tannous et al., Bioconjug Chem 2025, doi:10.1021/acs.bioconjchem.5c00151] (not yet independently
verified against full text) — note potential ambiguity: report's "CAD" elsewhere also denotes caspase-activated DNase.
- Non-apoptotic cytoprotective autophagy / DDR: CASP3+CASP7 promote starvation- or proteasome-inhibition-induced
cytoprotective autophagy and the DNA-damage response in breast cancer cells; loss reduces LC3B/ATG7 and H2AX
phosphorylation, and is synthetic-lethal with BRCA1 deficiency. [Samarasekera et al., PLoS Biol 2025,
doi:10.1371/journal.pbio.3003034] (not yet independently verified against full text) — relevant to existing
GO:0016241 regulation of macroautophagy annotation.
- IFN restraint mechanism specified: CASP3/7 prevent MOMP-released mtRNA from triggering the MDA5/MAVS/IRF3 type I IFN
pathway, keeping apoptosis immunologically silent. [Killarney et al., Nat Commun 2023, doi:10.1038/s41467-023-37146-z]
(not yet independently verified against full text) — consistent with existing GO:0001818 negative regulation of
cytokine production / cGAS-MAVS-IRF3 cleavage notes (PMID:30878284).
- Neural stem cell differentiation: non-apoptotic CASP3/7 events bias adult NSCs toward direct (division-independent)
neuronal conversion, requiring transcription factor Atf3 (zebrafish tracer). [Rosa et al., Development 2024,
doi:10.1242/dev.204381] (not yet independently verified against full text) — supports existing neuron-differentiation
/ non-core developmental annotations.
- Non-apoptotic synaptic role + context-dependent pro-oncogenic role: CASP3 drives synaptic pruning / dendritic-spine
loss / LTD without death (Parkinson model), and via EndoG->nucleus and Src-STAT3 can promote oncogenic transformation.
[Fieblinger et al., Int J Mol Sci 2022, doi:10.3390/ijms23105470] (not yet independently verified against full text) —
consistent with existing synapse-pruning (GO:0098883) non-core annotations.

Discrepancies / annotations to revisit:
- No direct contradictions with the existing review were found; Falcon is consistent with the curated picture.
- The execution/substrate-cleavage themes (autophagy regulation, IFN/cytokine restraint, NSC and synaptic roles) are
already captured as ACCEPT or KEEP_AS_NON_CORE, so no action implied for those. The only candidate for a possible
NEW supporting annotation is the CASP3-vs-CASP7 substrate-discrimination point, but this is a comparative-biochemistry
observation rather than a new GO term for CASP3 itself; no annotation change recommended from Falcon alone.

📄 View Raw YAML

id: P42574
gene_symbol: CASP3
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'CASP3 (caspase-3; apopain/CPP32/Yama) is the principal executioner cysteine-aspartic protease of apoptosis in human cells. Synthesized as an inactive zymogen, it is activated by proteolytic cleavage by initiator caspases (CASP8, CASP9, CASP10) and granzyme B into a heterotetramer of two p17/p12 heterodimers with a catalytic cysteine. It is a cysteine-type endopeptidase (EC 3.4.22.56) that cleaves substrates strictly after aspartate residues, with a preferred Asp-X-X-Asp recognition motif. During the execution/demolition phase of apoptosis it cleaves hundreds of cellular substrates, including PARP1, the ICAD/DFF45 inhibitor of the CAD/DFF40 DNA-fragmentation nuclease, cytoskeletal and junctional proteins, and numerous signaling proteins, thereby dismantling the dying cell and promoting phosphatidylserine exposure for efferocytosis. Beyond classical apoptosis, caspase-3 cleaves gasdermin-E (GSDME/DFNA5) to switch cells to pyroptosis, processes cytokines such as IL-18, and restrains innate antiviral signaling by cleaving cGAS, MAVS, IRF3, and NF-kB subunits. It also has non-lethal roles, contributing to differentiation programs (e.g., erythroid, keratinocyte, neuronal) through limited substrate cleavage. Caspase-3 acts mainly in the cytoplasm/cytosol but its active form is also found in the nucleus during apoptosis; its activity is restrained by inhibitors including XIAP and BIRC6 and by S-nitrosylation of the catalytic cysteine.'
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Caspase-3 acts in the cytoplasm/cytosol, where the procaspase resides and where it is activated and cleaves most substrates.
    action: ACCEPT
    reason: Cytoplasmic localization is well supported as the principal site of caspase-3 activity; this is the consensus phylogenetic (IBA) cellular component and matches UniProt subcellular location.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
    - reference_id: PMID:15003516
      supporting_text: Caspase 3 activation is controlled by a sequence located in the N-terminus of its large subunit.
      reference_section_type: TITLE
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Caspase-3 is the principal executioner caspase of apoptosis, a deeply conserved role captured by the IBA annotation.
    action: ACCEPT
    reason: Involvement in apoptosis is the defining biological process for caspase-3 and is supported by phylogenetic inference and extensive experimental literature.
    supported_by:
    - &casp3_executioner
      reference_id: PMID:18723680
      supporting_text: Caspase-3 was found to be generally more promiscuous than caspase-7 and appears to be the major executioner caspase during the demolition phase of apoptosis.
      reference_section_type: ABSTRACT
    - &apopain
      reference_id: PMID:7596430
      supporting_text: suggesting that apopain/CPP32 is important for the initiation of apoptotic cell death.
      reference_section_type: ABSTRACT
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Caspase-3 is a cysteine-type endopeptidase (EC 3.4.22.56) that cleaves substrates after aspartate residues; this is its core molecular function.
    action: ACCEPT
    reason: This is the central, well-established molecular function of caspase-3, supported by phylogenetic inference, biochemical purification, and crystal structures. It should be retained as a core function.
    supported_by:
    - &casp3_catalytic
      reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Strict requirement for an Asp residue at positions P1 and P4. It has a preferred cleavage sequence of Asp-Xaa-Xaa-Asp-|-
    - *apopain
    - reference_id: file:human/CASP3/CASP3-deep-research-falcon.md
      supporting_text: the most proteolytically proficient executioner of programmed cell death
- term:
    id: GO:0006508
    label: proteolysis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Caspase-3 carries out proteolysis of many substrates; proteolysis is the biological process realization of its endopeptidase activity.
    action: ACCEPT
    reason: Proteolysis is correct and consistent with the cysteine-type endopeptidase molecular function, although it is broad. Retained as a supporting (non-distinguishing) process term.
    supported_by:
    - *casp3_catalytic
    - *apopain
- term:
    id: GO:0031264
    label: death-inducing signaling complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: The death-inducing signaling complex (DISC) is the platform that activates initiator caspase-8; caspase-3 is an executioner caspase acting downstream of the DISC rather than a DISC component.
    action: MARK_AS_OVER_ANNOTATED
    reason: Caspase-3 is activated downstream of the DISC (by caspase-8) and is not generally considered a structural part of the DISC itself. This phylogenetic part_of assignment likely reflects over-propagation across the caspase family; caspase-3's role is as an executioner, not a DISC subunit.
    supported_by:
    - *casp3_executioner
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Cleavage by granzyme B, caspase-6, caspase-8 and caspase-10 generates the two active subunits
- term:
    id: GO:0097194
    label: execution phase of apoptosis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Caspase-3 is the major executioner caspase responsible for the demolition/execution phase of apoptosis.
    action: ACCEPT
    reason: This is a precise and core biological process term for caspase-3, supported by phylogenetic inference and experimental evidence that caspase-3 dominates the demolition phase.
    supported_by:
    - *casp3_executioner
- term:
    id: GO:0008047
    label: enzyme activator activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Caspase-3 activates downstream enzymes by proteolytic cleavage (e.g., caspase-6, -7, -9 and gasdermin-E), but it does so via its endopeptidase activity rather than acting as a classical allosteric enzyme activator.
    action: MARK_AS_OVER_ANNOTATED
    reason: While caspase-3 cleavage-activates other zymogens, the generic enzyme activator activity term mischaracterizes the mechanism, which is proteolysis. The cysteine-type endopeptidase activity term already captures this function more accurately.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Cleaves and activates caspase-6, -7 and -9 (CASP6, CASP7 and CASP9, respectively)
    - reference_id: PMID:28459430
      supporting_text: GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that perforates membranes and thereby induces pyroptosis.
      reference_section_type: ABSTRACT
- term:
    id: GO:0043525
    label: positive regulation of neuron apoptotic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: As the executioner caspase, caspase-3 promotes neuronal apoptosis (e.g., developmental neuronal death), a tissue-specific instance of its general apoptotic execution role.
    action: KEEP_AS_NON_CORE
    reason: This is a genuine but downstream, tissue-specific manifestation of the core apoptotic execution function rather than a distinct molecular activity. Retained as non-core.
    supported_by:
    - *casp3_executioner
- term:
    id: GO:0030182
    label: neuron differentiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Caspase-3 has non-apoptotic roles in neuronal differentiation/remodeling through limited substrate cleavage, captured by phylogenetic inference.
    action: KEEP_AS_NON_CORE
    reason: Differentiation is a real but downstream, non-core role relative to caspase-3's core cysteine-protease and apoptotic-execution functions. Retained as non-core.
    supported_by:
    - &nonapoptotic
      reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Triggers cell adhesion in sympathetic neurons through RET cleavage
- term:
    id: GO:0030216
    label: keratinocyte differentiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Caspase-3 contributes to keratinocyte differentiation (cornification), a non-apoptotic tissue-specific role inferred phylogenetically.
    action: KEEP_AS_NON_CORE
    reason: This is a genuine but downstream, tissue-specific differentiation role and not the core protease/apoptotic-execution function. Retained as non-core.
    supported_by:
    - *nonapoptotic
- term:
    id: GO:0030218
    label: erythrocyte differentiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Caspase-3 is activated during terminal erythroid differentiation; its activity is restrained (e.g., Hsp70 protecting GATA-1) so that differentiation proceeds without apoptosis.
    action: KEEP_AS_NON_CORE
    reason: A genuine non-apoptotic role in erythropoiesis, supported experimentally, but downstream of and dependent on the core protease function. Retained as non-core.
    supported_by:
    - &gata1
      reference_id: PMID:17167422
      supporting_text: Caspase-3 is activated during both terminal differentiation and erythropoietin-starvation-induced apoptosis of human erythroid precursors.
      reference_section_type: ABSTRACT
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic annotation of the core cysteine-type endopeptidase activity, consistent with experimental and phylogenetic evidence.
    action: ACCEPT
    reason: Correct core molecular function; the IEA agrees with the IBA and IDA evidence for the same term.
    supported_by:
    - *casp3_catalytic
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic annotation of cytoplasmic localization, consistent with UniProt and IBA evidence.
    action: ACCEPT
    reason: Correct cellular component; agrees with experimental subcellular location.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0006508
    label: proteolysis
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic annotation of proteolysis, the process realization of caspase-3's endopeptidase activity.
    action: ACCEPT
    reason: Correct though broad; consistent with the IBA proteolysis annotation.
    supported_by:
    - *casp3_catalytic
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Electronic (ARBA) annotation of apoptotic process, the core biological process for caspase-3.
    action: ACCEPT
    reason: Correct core process; agrees with IBA and experimental evidence.
    supported_by:
    - *apopain
- term:
    id: GO:0008234
    label: cysteine-type peptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Broader parent of cysteine-type endopeptidase activity; correct but less specific.
    action: ACCEPT
    reason: Correct but more general than GO:0004197. Acceptable as an IEA parent term; the more specific endopeptidase term is the core function.
    supported_by:
    - *casp3_catalytic
- term:
    id: GO:0051604
    label: protein maturation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Caspase-3 matures/processes substrate proteins by limited proteolysis (e.g., activating gasdermin-E, processing cytokines).
    action: ACCEPT
    reason: Protein maturation is a valid process realization of caspase-3 activation-by-cleavage of substrates; supported by experimental gasdermin/cytokine processing.
    supported_by:
    - &gsdme
      reference_id: PMID:28459430
      supporting_text: GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that perforates membranes and thereby induces pyroptosis.
      reference_section_type: ABSTRACT
- term:
    id: GO:0072734
    label: cellular response to staurosporine
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Caspase-3 is activated during staurosporine-induced apoptosis (a standard intrinsic-apoptosis trigger).
    action: KEEP_AS_NON_CORE
    reason: A stimulus/response context term rather than a core function; caspase-3 acts as the executioner downstream of staurosporine-induced intrinsic apoptosis. Retained as non-core.
    supported_by:
    - reference_id: PMID:22253444
      supporting_text: the main processing of pro-caspase-3 takes place in the cytosol of both cells lines analyzed even if caspase-3 active fragments can also be evidenced in the nuclear fractions after STP treatment
      reference_section_type: DISCUSSION
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11257232
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (XIAP (BIR2 domain) binds and inhibits caspase-3 [structural].) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:11257232
      supporting_text: Structural basis for the inhibition of caspase-3 by XIAP.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16227597
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (AKAP95 associates with active caspase-3 (nuclear translocation carrier).) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:16227597
      supporting_text: A-kinase-anchoring protein 95 functions as a potential carrier for the nuclear translocation of active caspase 3 through an enzyme-substrate-like association.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16501604
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (WNK3 kinase interaction in a caspase-3-dependent survival pathway.) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:16501604
      supporting_text: Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16530191
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (NMT2/calpain-caspase cross-talk interaction.) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:16530191
      supporting_text: 'N-myristoyltransferase 2 expression in human colon cancer: cross-talk between the calpain and caspase system.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17167422
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (GATA-1 / Hsp70 interaction context in erythroid precursors.) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:17167422
      supporting_text: Hsp70 regulates erythropoiesis by preventing caspase-3-mediated cleavage of GATA-1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17544405
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (AKT1 cleavage substrate interaction.) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:17544405
      supporting_text: 'Caspase-3-mediated cleavage of Akt: involvement of non-consensus sites and influence of phosphorylation.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17606900
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (Thioredoxin / procaspase-3 S-nitrosation interaction.) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:17606900
      supporting_text: Thioredoxin is required for S-nitrosation of procaspase-3 and the inhibition of apoptosis in Jurkat cells.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18723680
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (Substrate interactions (Bid, XIAP, gelsolin, caspase-6, p23).) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:18723680
      supporting_text: Executioner caspase-3 and caspase-7 are functionally distinct proteases.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19273858
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (XIAP S-nitrosylation interaction context.) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:19273858
      supporting_text: S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21726810
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (MDM2 cleavage interaction context.) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:21726810
      supporting_text: Caspase-2-mediated cleavage of Mdm2 creates a p53-induced positive feedback loop.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (High-throughput liver interactome screen.) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:21988832
      supporting_text: Toward an understanding of the protein interaction network of the human liver.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23150525
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (N-myristoyltransferase/caspase interplay during apoptosis.) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:23150525
      supporting_text: 'Regulation of co- and post-translational myristoylation of proteins during apoptosis: interplay of N-myristoyltransferases and caspases.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25241761
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (Proximity ligation interactome profiling.) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:25241761
      supporting_text: Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (Large-scale interactome (protein communities) screen.) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:28514442
      supporting_text: Architecture of the human interactome defines protein communities and disease networks.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (Binary protein interactome reference map (HuRI).) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (Neurodegenerative disease interactome screen.) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (Cell-specific interactome remodeling screen.) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:38884001
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (Adipocyte interactome HaloTag-MS screen.) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:38884001
      supporting_text: Mapping adipocyte interactome networks by HaloTag-enrichment-mass spectrometry.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:7596430
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (PARP / caspase substrate interactions (apopain).) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:7596430
      supporting_text: Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis.
- term:
    id: GO:0001554
    label: luteolysis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to luteolysis.
    action: KEEP_AS_NON_CORE
    reason: Luteolysis is a tissue-specific apoptotic process (corpus luteum regression) inferred by ortholog transfer; a downstream context of the core apoptotic-execution role.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0001666
    label: response to hypoxia
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to hypoxia.
    action: KEEP_AS_NON_CORE
    reason: Response to hypoxia is a stimulus/response context (ortholog-transferred), not a core caspase-3 function.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0002020
    label: protease binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to protease binding.
    action: ACCEPT
    reason: Protease binding is informative and supported because caspase-3 is bound and inhibited by XIAP (and related IAPs) and interacts with upstream proteases. This is a meaningful interaction term, unlike bare protein binding.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0004175
    label: endopeptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to endopeptidase activity.
    action: ACCEPT
    reason: Endopeptidase activity is a correct parent of the cysteine-type endopeptidase activity; acceptable though less specific.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0004190
    label: aspartic-type endopeptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to aspartic-type endopeptidase activity.
    action: REMOVE
    reason: Aspartic-type endopeptidase activity is mechanistically incorrect because caspase-3 is a CYSTEINE protease that cleaves after aspartate residues and is not an aspartic protease. This appears to be an erroneous ortholog/keyword transfer.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0004861
    label: cyclin-dependent protein serine/threonine kinase inhibitor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to cyclin-dependent protein serine/threonine kinase inhibitor activity.
    action: REMOVE
    reason: Cyclin-dependent protein kinase inhibitor activity is not a caspase-3 molecular function; this is an implausible ortholog-transferred MF and should be removed.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0005123
    label: death receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to death receptor binding.
    action: REMOVE
    reason: Death receptor binding is not an established caspase-3 molecular function; caspase-3 acts downstream of death-receptor signaling (via caspase-8) rather than binding death receptors. Likely an over-propagated transfer.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to nucleus.
    action: KEEP_AS_NON_CORE
    reason: Active caspase-3 is found in the nucleus during apoptosis, but this is secondary to its core cytoplasmic site. Kept consistent with the IDA nucleus rows as non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0007413
    label: axonal fasciculation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to axonal fasciculation.
    action: KEEP_AS_NON_CORE
    reason: Axonal fasciculation is a tissue/developmental neuronal role inferred by ortholog transfer; downstream and non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0007611
    label: learning or memory
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to learning or memory.
    action: KEEP_AS_NON_CORE
    reason: Learning or memory is a high-level organismal phenotype (ortholog-transferred), reflecting non-apoptotic synaptic roles; non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0008233
    label: peptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to peptidase activity.
    action: ACCEPT
    reason: Peptidase activity is a correct broad parent term for caspase-3's protease activity; acceptable though general.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0008627
    label: intrinsic apoptotic signaling pathway in response to osmotic stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to intrinsic apoptotic signaling pathway in response to osmotic stress.
    action: KEEP_AS_NON_CORE
    reason: Intrinsic apoptotic signaling in response to osmotic stress is a stimulus-specific apoptosis context; caspase-3 is the executioner. Non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0009410
    label: response to xenobiotic stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to xenobiotic stimulus.
    action: KEEP_AS_NON_CORE
    reason: Response to xenobiotic stimulus is a stimulus/response context (ortholog-transferred); non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0009749
    label: response to glucose
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to glucose.
    action: KEEP_AS_NON_CORE
    reason: Response to glucose is a stimulus/response context; non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0010038
    label: response to metal ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to metal ion.
    action: KEEP_AS_NON_CORE
    reason: Response to metal ion is a stimulus/response context; non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0010165
    label: response to X-ray
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to X-ray.
    action: KEEP_AS_NON_CORE
    reason: Response to X-ray reflects DNA-damage-induced apoptosis context; caspase-3 acts as executioner. Non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0014069
    label: postsynaptic density
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to postsynaptic density.
    action: KEEP_AS_NON_CORE
    reason: Postsynaptic density localization reflects non-apoptotic synaptic roles (e.g., synapse pruning) inferred by transfer; non-core relative to cytoplasmic/nuclear core localization.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0016005
    label: phospholipase A2 activator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to phospholipase A2 activator activity.
    action: REMOVE
    reason: Phospholipase A2 activator activity is not an established caspase-3 molecular function; implausible ortholog-transferred MF and should be removed.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0021766
    label: hippocampus development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to hippocampus development.
    action: KEEP_AS_NON_CORE
    reason: Hippocampus development is a developmental/tissue context (ortholog-transferred); non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0030163
    label: protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to protein catabolic process.
    action: ACCEPT
    reason: Protein catabolic process is consistent with caspase-3 proteolysis of substrates; acceptable as a process term.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0030182
    label: neuron differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to neuron differentiation.
    action: KEEP_AS_NON_CORE
    reason: Neuron differentiation is a non-apoptotic, tissue-specific role; non-core (duplicate of the IBA neuron differentiation row).
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0031264
    label: death-inducing signaling complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to death-inducing signaling complex.
    action: MARK_AS_OVER_ANNOTATED
    reason: Caspase-3 acts downstream of the DISC as an executioner and is not a structural DISC component; this part_of assignment is an over-annotation (consistent with the IBA row).
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0031647
    label: regulation of protein stability
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to regulation of protein stability.
    action: KEEP_AS_NON_CORE
    reason: Regulation of protein stability reflects substrate-cleavage consequences (e.g., BACE/GGA3); a downstream effect, non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0032025
    label: response to cobalt ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to cobalt ion.
    action: KEEP_AS_NON_CORE
    reason: Response to cobalt ion is a stimulus/response context; non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0032355
    label: response to estradiol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to estradiol.
    action: KEEP_AS_NON_CORE
    reason: Response to estradiol is a stimulus/response context; non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0032496
    label: response to lipopolysaccharide
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to lipopolysaccharide.
    action: KEEP_AS_NON_CORE
    reason: Response to lipopolysaccharide is a stimulus/response context; non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0034349
    label: glial cell apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to glial cell apoptotic process.
    action: KEEP_AS_NON_CORE
    reason: Glial cell apoptotic process is a cell-type-specific instance of apoptotic execution; non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0035094
    label: response to nicotine
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to nicotine.
    action: KEEP_AS_NON_CORE
    reason: Response to nicotine is a stimulus/response context; non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0035556
    label: intracellular signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to intracellular signal transduction.
    action: KEEP_AS_NON_CORE
    reason: Intracellular signal transduction is broad; caspase-3 modulates signaling by cleaving signaling proteins, but this term is over-general. Non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0036269
    label: swimming behavior
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to swimming behavior.
    action: KEEP_AS_NON_CORE
    reason: Swimming behavior is a zebrafish-derived organismal phenotype transferred by orthology; non-core for human caspase-3.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0042542
    label: response to hydrogen peroxide
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to hydrogen peroxide.
    action: KEEP_AS_NON_CORE
    reason: Response to hydrogen peroxide (oxidative stress) is a stimulus/response context; non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0043025
    label: neuronal cell body
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to neuronal cell body.
    action: KEEP_AS_NON_CORE
    reason: Neuronal cell body localization reflects neuronal context; non-core relative to core cytoplasmic/nuclear localization.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0043065
    label: positive regulation of apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: As the executioner caspase, caspase-3 positively drives the apoptotic process.
    action: ACCEPT
    reason: Positive regulation of apoptotic process is consistent with caspase-3's executioner role; acceptable IEA, though the more precise execution-phase term is core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0043200
    label: response to amino acid
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to amino acid.
    action: KEEP_AS_NON_CORE
    reason: Response to amino acid is a stimulus/response context; non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0043523
    label: regulation of neuron apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to regulation of neuron apoptotic process.
    action: KEEP_AS_NON_CORE
    reason: Regulation of neuron apoptotic process is a tissue-specific manifestation of apoptotic execution; non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0043525
    label: positive regulation of neuron apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to positive regulation of neuron apoptotic process.
    action: KEEP_AS_NON_CORE
    reason: Positive regulation of neuron apoptotic process is a tissue-specific manifestation of apoptotic execution; non-core (duplicate of the IBA row).
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to protein-containing complex binding.
    action: ACCEPT
    reason: Protein-containing complex binding is supported (e.g., apoptosome-associated activation, XIAP/BIRC6 complexes); acceptable though general.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0045471
    label: response to ethanol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to ethanol.
    action: KEEP_AS_NON_CORE
    reason: Response to ethanol is a stimulus/response context; non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0051146
    label: striated muscle cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to striated muscle cell differentiation.
    action: KEEP_AS_NON_CORE
    reason: Striated muscle cell differentiation is a non-apoptotic tissue-specific differentiation role; non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0051384
    label: response to glucocorticoid
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to glucocorticoid.
    action: KEEP_AS_NON_CORE
    reason: Response to glucocorticoid is a stimulus/response context (e.g., thymocyte apoptosis); non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0071887
    label: leukocyte apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to leukocyte apoptotic process.
    action: KEEP_AS_NON_CORE
    reason: Leukocyte apoptotic process is a cell-type-specific instance of apoptotic execution; non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0072347
    label: response to anesthetic
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to anesthetic.
    action: KEEP_AS_NON_CORE
    reason: Response to anesthetic is a stimulus/response context; non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0098693
    label: regulation of synaptic vesicle cycle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to regulation of synaptic vesicle cycle.
    action: KEEP_AS_NON_CORE
    reason: Regulation of synaptic vesicle cycle reflects non-apoptotic synaptic roles inferred by transfer; non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0098883
    label: synapse pruning
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to synapse pruning.
    action: KEEP_AS_NON_CORE
    reason: Synapse pruning is a non-apoptotic neuronal role (local caspase activity); genuine but downstream/non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to glutamatergic synapse.
    action: KEEP_AS_NON_CORE
    reason: Glutamatergic synapse localization reflects synaptic roles inferred by transfer; non-core relative to core localization.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:1902004
    label: positive regulation of amyloid-beta formation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to positive regulation of amyloid-beta formation.
    action: KEEP_AS_NON_CORE
    reason: Positive regulation of amyloid-beta formation reflects substrate-cleavage effects on APP processing (BACE/GGA3); downstream, non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:1990418
    label: response to insulin-like growth factor stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara, GO_REF:0000107) annotation to response to insulin-like growth factor stimulus.
    action: KEEP_AS_NON_CORE
    reason: Response to insulin-like growth factor stimulus is a stimulus/response context; non-core.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0032880
    label: regulation of protein localization
  evidence_type: IMP
  original_reference_id: PMID:17559062
  qualifier: involved_in
  review:
    summary: Caspase-3 cleaves desmoglein-2 (DSG2) and JUP at desmosomes, altering junctional protein localization during apoptosis.
    action: KEEP_AS_NON_CORE
    reason: Regulation of protein localization here is a downstream consequence of substrate cleavage (desmosomal disassembly) rather than a core function; retained as non-core.
    supported_by:
    - reference_id: PMID:17559062
      supporting_text: The most widespread desmosomal cadherin, desmoglein 2, is a novel target of caspase 3-mediated apoptotic machinery.
      reference_section_type: TITLE
- term:
    id: GO:0098883
    label: synapse pruning
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Caspase-3 contributes to synapse pruning, a non-apoptotic local role inferred by sequence similarity.
    action: KEEP_AS_NON_CORE
    reason: A genuine but downstream/non-core neuronal role; retained as non-core (mirrors the IEA synapse pruning row).
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Caspase-3 processes substrate proteins by limited proteolysis (ISS).
    action: ACCEPT
    reason: Protein processing is a valid process realization of caspase-3 substrate cleavage; consistent with IDA evidence.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: mediates execution of apoptosis by catalyzing cleavage of many proteins
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IDA
  original_reference_id: PMID:33725486
  qualifier: involved_in
  review:
    summary: Caspase-3 processes XRCC4, releasing a C-terminal fragment that activates the Xkr4 scramblase.
    action: ACCEPT
    reason: Direct evidence of caspase-3 protein processing producing an active fragment; core-adjacent process.
    supported_by:
    - reference_id: PMID:33725486
      supporting_text: Upon apoptotic stimuli, XRCC4, contained in the DNA repair complex, is cleaved by caspases, and its C-terminal fragment with an intrinsically disordered region is released into the cytoplasm.
      reference_section_type: ABSTRACT
- term:
    id: GO:0097194
    label: execution phase of apoptosis
  evidence_type: IDA
  original_reference_id: PMID:18723680
  qualifier: involved_in
  review:
    summary: Caspase-3 is the major executioner caspase of the demolition phase of apoptosis.
    action: ACCEPT
    reason: Direct, well-supported core process term.
    supported_by:
    - reference_id: PMID:18723680
      supporting_text: Caspase-3 was found to be generally more promiscuous than caspase-7 and appears to be the major executioner caspase during the demolition phase of apoptosis.
      reference_section_type: ABSTRACT
- term:
    id: GO:0097194
    label: execution phase of apoptosis
  evidence_type: IDA
  original_reference_id: PMID:33725486
  qualifier: involved_in
  review:
    summary: Caspase-3 executes apoptosis, including cleavage of XRCC4/scramblases driving PtdSer exposure.
    action: ACCEPT
    reason: Direct evidence supporting the execution-phase role.
    supported_by:
    - reference_id: PMID:33725486
      supporting_text: caspase-mediated cleavage releases a nuclear protein fragment for direct regulation of lipid dynamics on the plasma membrane.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:15003516
  qualifier: located_in
  review:
    summary: Caspase-3 localizes to the cytoplasm; activation is controlled by an N-terminal sequence of its large subunit.
    action: ACCEPT
    reason: Experimental (EXP) cytoplasmic localization; core location.
    supported_by:
    - reference_id: PMID:15003516
      supporting_text: Caspase 3 activation is controlled by a sequence located in the N-terminus of its large subunit.
      reference_section_type: TITLE
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:17823127
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. HSP60 modulates caspase-3 pro/anti-apoptotic activity (cysteine protease assay).
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:17823127
      supporting_text: 'Cytosolic accumulation of HSP60 during apoptosis with or without apparent mitochondrial release: evidence that its pro-apoptotic or pro-survival functions involve differential interactions with caspase-3.'
- term:
    id: GO:0097194
    label: execution phase of apoptosis
  evidence_type: IGI
  original_reference_id: PMID:12107093
  qualifier: involved_in
  review:
    summary: Cathepsin D microinjection induces caspase-dependent apoptosis, with caspase-3 acting in the execution phase (genetic interaction).
    action: ACCEPT
    reason: Supports caspase-3's execution-phase role via genetic interaction evidence.
    supported_by:
    - reference_id: PMID:12107093
      supporting_text: Microinjection of cathepsin d induces caspase-dependent apoptosis in fibroblasts.
      reference_section_type: TITLE
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:9334240
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleaves pro- and mature IL-18 at Asp71/Asp76 (DEVD-inhibitable activity).
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:9334240
      supporting_text: Involvement of caspase-1 and caspase-3 in the production and processing of mature human interleukin 18 in monocytic THP.1 cells.
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IDA
  original_reference_id: PMID:9334240
  qualifier: involved_in
  review:
    summary: Caspase-3 processes IL-18 (cleaving at Asp71/Asp76).
    action: ACCEPT
    reason: Direct evidence of caspase-3 protein processing of a cytokine substrate.
    supported_by:
    - reference_id: PMID:9334240
      supporting_text: the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products.
      reference_section_type: ABSTRACT
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:37327784
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 protease activity in gasdermin/IL-18 processing context.
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:37327784
      supporting_text: Gasdermin D licenses MHCII induction to maintain food tolerance in small intestine.
- term:
    id: GO:0001818
    label: negative regulation of cytokine production
  evidence_type: IMP
  original_reference_id: PMID:36002459
  qualifier: involved_in
  review:
    summary: Caspase-3 cleaves NF-kB members (p65/RelA, RelB, c-Rel), dampening cytokine production.
    action: ACCEPT
    reason: Direct functional (IMP) evidence that caspase-3 negatively regulates cytokine production via NF-kB cleavage; a genuine non-apoptotic immunoregulatory role.
    supported_by:
    - reference_id: PMID:36002459
      supporting_text: caspase-3 can mediate the cleavage of NF-κB members p65/RelA, RelB, and c-Rel via its protease activity
      reference_section_type: ABSTRACT
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:36002459
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleaves NF-kB subunits p65/RelA, RelB, c-Rel via its protease activity.
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:36002459
      supporting_text: Apoptotic caspase inhibits innate immune signaling by cleaving NF-κBs in both Mammals and Flies.
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: IDA
  original_reference_id: PMID:34480022
  qualifier: involved_in
  review:
    summary: Caspase-3 mediates apoptosis (PRMT4/endotoxin-triggered death of lung epithelia).
    action: ACCEPT
    reason: Direct evidence of caspase-3 in the apoptotic process; core.
    supported_by:
    - reference_id: PMID:34480022
      supporting_text: Endotoxin stabilizes protein arginine methyltransferase 4 (PRMT4) protein triggering death of lung epithelia.
      reference_section_type: TITLE
- term:
    id: GO:0070269
    label: pyroptotic inflammatory response
  evidence_type: IDA
  original_reference_id: PMID:36426955
  qualifier: involved_in
  review:
    summary: Caspase-3 participates in pyroptotic inflammatory responses (virus-induced pyroptosis context).
    action: KEEP_AS_NON_CORE
    reason: Pyroptosis via gasdermin cleavage is a genuine caspase-3 role; this particular TRIM21/ISG12a context is supportive but the core pyroptosis link is the GSDME cleavage. Retained as non-core context.
    supported_by:
    - reference_id: PMID:36426955
      supporting_text: TRIM21 Regulates Virus-Induced Cell Pyroptosis through Polyubiquitination of ISG12a.
      reference_section_type: TITLE
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:33852854
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleaves and activates gasdermin-E (GSDME) at its linker.
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:33852854
      supporting_text: Gasdermin E permits interleukin-1 beta release in distinct sublytic and pyroptotic phases.
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:35594856
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 protease activity in NLRP1/gasdermin processing context.
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:35594856
      supporting_text: Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells.
- term:
    id: GO:0051604
    label: protein maturation
  evidence_type: IDA
  original_reference_id: PMID:33852854
  qualifier: involved_in
  review:
    summary: Caspase-3 matures gasdermin-E (GSDME) by cleavage at its activation site.
    action: ACCEPT
    reason: Direct evidence of caspase-3 protein maturation of a substrate.
    supported_by:
    - reference_id: PMID:33852854
      supporting_text: non-cleavable GSDMED270A variant (altered at the CASP3 cleavage and activation site)
      reference_section_type: RESULTS
- term:
    id: GO:0051604
    label: protein maturation
  evidence_type: IDA
  original_reference_id: PMID:35594856
  qualifier: involved_in
  review:
    summary: Caspase-3 matures gasdermin substrates in the NLRP1/coronavirus protease context.
    action: ACCEPT
    reason: Direct evidence of caspase-3 protein maturation activity.
    supported_by:
    - reference_id: PMID:35594856
      supporting_text: Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells.
      reference_section_type: TITLE
- term:
    id: GO:0140639
    label: positive regulation of pyroptotic inflammatory response
  evidence_type: IDA
  original_reference_id: PMID:33852854
  qualifier: involved_in
  review:
    summary: Caspase-3 cleavage of GSDME positively regulates pyroptotic IL-1b release.
    action: ACCEPT
    reason: Direct evidence that caspase-3-GSDME cleavage promotes the pyroptotic inflammatory response.
    supported_by:
    - reference_id: PMID:33852854
      supporting_text: Gasdermin E permits interleukin-1 beta release in distinct sublytic and pyroptotic phases.
      reference_section_type: INTRODUCTION
- term:
    id: GO:0140639
    label: positive regulation of pyroptotic inflammatory response
  evidence_type: IDA
  original_reference_id: PMID:35594856
  qualifier: involved_in
  review:
    summary: Caspase-3 promotes pyroptotic inflammatory responses via gasdermin cleavage in the NLRP1 context.
    action: ACCEPT
    reason: Direct evidence supporting caspase-3's positive role in pyroptosis.
    supported_by:
    - reference_id: PMID:35594856
      supporting_text: Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells.
      reference_section_type: TITLE
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:28459430
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 specifically cleaves GSDME in its linker to generate the pore-forming N fragment.
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:28459430
      supporting_text: Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin.
- term:
    id: GO:0051604
    label: protein maturation
  evidence_type: IDA
  original_reference_id: PMID:28459430
  qualifier: involved_in
  review:
    summary: Caspase-3 matures gasdermin-E by cleavage in its linker to generate the pore-forming fragment.
    action: ACCEPT
    reason: Direct evidence of caspase-3 protein maturation of GSDME.
    supported_by:
    - reference_id: PMID:28459430
      supporting_text: GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that perforates membranes and thereby induces pyroptosis.
      reference_section_type: ABSTRACT
- term:
    id: GO:0097194
    label: execution phase of apoptosis
  evidence_type: IDA
  original_reference_id: PMID:16374543
  qualifier: involved_in
  review:
    summary: Active nuclear caspase-3 executes apoptosis (PARP cleavage) early in camptothecin-induced death.
    action: ACCEPT
    reason: Direct evidence of caspase-3 execution-phase activity.
    supported_by:
    - reference_id: PMID:16374543
      supporting_text: the activation of nuclear caspases-7 and -3, and poly(ADP-ribose) polymerase (PARP) cleavage, are early events in camptothecin-induced apoptosis
      reference_section_type: ABSTRACT
- term:
    id: GO:0140639
    label: positive regulation of pyroptotic inflammatory response
  evidence_type: IDA
  original_reference_id: PMID:28459430
  qualifier: involved_in
  review:
    summary: Caspase-3 cleavage of GSDME positively regulates pyroptosis after chemotherapy.
    action: ACCEPT
    reason: Direct evidence that caspase-3 promotes the pyroptotic inflammatory response.
    supported_by:
    - reference_id: PMID:28459430
      supporting_text: caspase-3 activation can trigger necrosis by cleaving GSDME
      reference_section_type: ABSTRACT
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:17167422
  qualifier: is_active_in
  review:
    summary: Active caspase-3 acts in the cytoplasm of erythroid precursors (and nucleus on GATA-1).
    action: ACCEPT
    reason: Cytoplasm is the core site of caspase-3 activity; consistent with experimental evidence.
    supported_by:
    - reference_id: PMID:17167422
      supporting_text: Caspase-3 is activated during both terminal differentiation and erythropoietin-starvation-induced apoptosis of human erythroid precursors.
      reference_section_type: ABSTRACT
- term:
    id: GO:0097193
    label: intrinsic apoptotic signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:15565177
  qualifier: involved_in
  review:
    summary: Caspase-3 is activated and executes the intrinsic (mitochondrial) apoptotic pathway (DIP/E2F1).
    action: ACCEPT
    reason: Caspase-3 acts in intrinsic apoptotic signaling downstream of mitochondrial signals; supported.
    supported_by:
    - reference_id: PMID:15565177
      supporting_text: typical apoptotic features such as caspase-3 activation and cleavage of poly(ADP-ribose)-polymerase
      reference_section_type: ABSTRACT
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:16374543
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Active nuclear caspase-3 cleaves PARP early in camptothecin-induced apoptosis.
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:16374543
      supporting_text: Nuclear caspase-3 and caspase-7 activation, and poly(ADP-ribose) polymerase cleavage are early events in camptothecin-induced apoptosis.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:16374543
  qualifier: is_active_in
  review:
    summary: Active caspase-3 is found in the nucleus, cleaving PARP early in apoptosis.
    action: KEEP_AS_NON_CORE
    reason: Nuclear localization of active caspase-3 is supported but secondary to its core cytoplasmic site; retained as non-core.
    supported_by:
    - reference_id: PMID:16374543
      supporting_text: the activation of nuclear caspases-7 and -3, and poly(ADP-ribose) polymerase (PARP) cleavage, are early events in camptothecin-induced apoptosis
      reference_section_type: ABSTRACT
- term:
    id: GO:0030163
    label: protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:16374543
  qualifier: involved_in
  review:
    summary: Caspase-3 carries out protein catabolism (PARP cleavage) during apoptosis.
    action: ACCEPT
    reason: Protein catabolic process is consistent with caspase-3 substrate cleavage; acceptable.
    supported_by:
    - reference_id: PMID:16374543
      supporting_text: poly(ADP-ribose) polymerase (PARP) cleavage, are early events in camptothecin-induced apoptosis
      reference_section_type: ABSTRACT
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:20566630
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Functional regions defining caspase-3 vs caspase-7 cellular protease activity.
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:20566630
      supporting_text: Identification of functional regions defining different activity in caspase-3 and caspase-7 within cells.
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:23650375
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Structural snapshots of procaspase-3 activation (catalytic mechanism).
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:23650375
      supporting_text: Structural snapshots reveal distinct mechanisms of procaspase-3 and -7 activation.
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:18723680
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleaves multiple natural substrates (Bid, XIAP, gelsolin, caspase-6, p23).
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:18723680
      supporting_text: Executioner caspase-3 and caspase-7 are functionally distinct proteases.
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:30878284
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleaves cGAS, MAVS and IRF3 via its protease activity.
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:30878284
      supporting_text: Apoptotic Caspases Suppress Type I Interferon Production via the Cleavage of cGAS, MAVS, and IRF3.
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:33725486
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleaves XRCC4 and XKR scramblases (apoptotic PtdSer exposure).
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:33725486
      supporting_text: Caspase cleavage releases a nuclear protein fragment that stimulates phospholipid scrambling at the plasma membrane.
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:24904167
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleaves the ATP11C phospholipid flippase for apoptotic PtdSer exposure.
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:24904167
      supporting_text: Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure.
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:19240112
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleaves PAK2 (huntingtin modulates this).
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:19240112
      supporting_text: Huntingtin promotes cell survival by preventing Pak2 cleavage.
- term:
    id: GO:0008233
    label: peptidase activity
  evidence_type: IDA
  original_reference_id: PMID:17167422
  qualifier: enables
  review:
    summary: Caspase-3 peptidase activity cleaves GATA-1 in erythroid precursors.
    action: ACCEPT
    reason: Peptidase activity is correct (broad parent of cysteine-type endopeptidase activity); supported.
    supported_by:
    - reference_id: PMID:17167422
      supporting_text: Hsp70 prevents active caspase-3 from cleaving GATA-1 and inducing apoptosis.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15246877
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (Thioredoxin/ASK1 S-nitrosation interaction context.) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:15246877
      supporting_text: S-nitrosation of thioredoxin in the nitrogen monoxide/superoxide system activates apoptosis signal-regulating kinase 1.
- term:
    id: GO:0006508
    label: proteolysis
  evidence_type: IDA
  original_reference_id: PMID:17553422
  qualifier: involved_in
  review:
    summary: Caspase-3 cleaves GGA3, stabilizing BACE and enhancing beta-secretase activity (proteolysis).
    action: ACCEPT
    reason: Proteolysis is correct and consistent with the cysteine-type endopeptidase function; this substrate cleavage is a concrete instance. Kept consistent with the other proteolysis annotations.
    supported_by:
    - reference_id: PMID:17553422
      supporting_text: Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity.
      reference_section_type: TITLE
- term:
    id: GO:0031647
    label: regulation of protein stability
  evidence_type: IDA
  original_reference_id: PMID:17553422
  qualifier: involved_in
  review:
    summary: Caspase-3 cleavage of GGA3 alters BACE protein stability.
    action: KEEP_AS_NON_CORE
    reason: Regulation of protein stability is a downstream consequence of substrate cleavage; non-core.
    supported_by:
    - reference_id: PMID:17553422
      supporting_text: Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity.
      reference_section_type: TITLE
- term:
    id: GO:1902004
    label: positive regulation of amyloid-beta formation
  evidence_type: IDA
  original_reference_id: PMID:17553422
  qualifier: involved_in
  review:
    summary: Caspase-3-mediated GGA3 cleavage increases BACE/beta-secretase activity, promoting amyloid-beta formation.
    action: KEEP_AS_NON_CORE
    reason: A downstream, disease-context effect of substrate cleavage; genuine but non-core.
    supported_by:
    - reference_id: PMID:17553422
      supporting_text: Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity.
      reference_section_type: TITLE
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IMP
  original_reference_id: PMID:21980415
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Anti-apoptotic protein modulates mitochondrial caspase-3 activation.
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:21980415
      supporting_text: Identification of a conserved anti-apoptotic protein that modulates the mitochondrial apoptosis pathway.
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: IMP
  original_reference_id: PMID:15565177
  qualifier: involved_in
  review:
    summary: Caspase-3 is activated and mediates apoptosis in the DIP/E2F1 pathway.
    action: ACCEPT
    reason: Direct evidence of caspase-3 in the apoptotic process; core.
    supported_by:
    - reference_id: PMID:15565177
      supporting_text: typical apoptotic features such as caspase-3 activation and cleavage of poly(ADP-ribose)-polymerase
      reference_section_type: ABSTRACT
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:16920334
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 activity in Rip2/caspase-1/-4-mediated cell death.
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:16920334
      supporting_text: Protective role of Cop in Rip2/caspase-1/caspase-4-mediated HeLa cell death.
- term:
    id: GO:0008233
    label: peptidase activity
  evidence_type: IDA
  original_reference_id: PMID:19740745
  qualifier: enables
  review:
    summary: Caspase-3 peptidase activity generates a truncated p23 that down-regulates telomerase.
    action: ACCEPT
    reason: Peptidase activity is correct (broad); supported by substrate cleavage evidence.
    supported_by:
    - reference_id: PMID:19740745
      supporting_text: A truncated form of p23 down-regulates telomerase activity via disruption of Hsp90 function.
      reference_section_type: TITLE
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IMP
  original_reference_id: PMID:22253444
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleaves ICAD/CAD to enable apoptotic DNA fragmentation.
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:22253444
      supporting_text: Apoptotic DNA degradation into oligonucleosomal fragments, but not apoptotic nuclear morphology, relies on a cytosolic pool of DFF40/CAD endonuclease.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:22253444
  qualifier: located_in
  review:
    summary: Caspase-3 is processed and active in the cytosol (where it cleaves ICAD/CAD).
    action: ACCEPT
    reason: Cytosol is the core location of caspase-3 activity; directly supported.
    supported_by:
    - reference_id: PMID:22253444
      supporting_text: the main processing of pro-caspase-3 takes place in the cytosol of both cells lines analyzed
      reference_section_type: DISCUSSION
- term:
    id: GO:0072734
    label: cellular response to staurosporine
  evidence_type: IMP
  original_reference_id: PMID:22253444
  qualifier: involved_in
  review:
    summary: Caspase-3 is activated in response to staurosporine, cleaving ICAD to enable DNA fragmentation.
    action: KEEP_AS_NON_CORE
    reason: A stimulus/response context (intrinsic apoptosis trigger); caspase-3 acts as executioner. Non-core.
    supported_by:
    - reference_id: PMID:22253444
      supporting_text: the activation of, at least, caspase-3 is necessary for the proper cleavage of ICAD L/S
      reference_section_type: DISCUSSION
- term:
    id: GO:0016241
    label: regulation of macroautophagy
  evidence_type: TAS
  original_reference_id: PMID:19549685
  qualifier: involved_in
  review:
    summary: Caspase cleavage of Atg4D stimulates GABARAP-L1 processing, linking caspase-3 to autophagy regulation.
    action: KEEP_AS_NON_CORE
    reason: Regulation of macroautophagy is a downstream cross-talk role (TAS) via substrate cleavage; non-core.
    supported_by:
    - reference_id: PMID:19549685
      supporting_text: Caspase cleavage of Atg4D stimulates GABARAP-L1 processing and triggers mitochondrial targeting and apoptosis.
      reference_section_type: TITLE
- term:
    id: GO:0048011
    label: neurotrophin TRK receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:23954828
  qualifier: acts_upstream_of_or_within
  review:
    summary: Caspase-3 acts within neurotrophin/TrkC (Dok5) signaling, where TrkC can trigger apoptosis.
    action: KEEP_AS_NON_CORE
    reason: A signaling-pathway context where caspase-3 acts downstream; non-core relative to the core protease/apoptosis function.
    supported_by:
    - reference_id: PMID:23954828
      supporting_text: Dok5 is involved in the signaling pathway of neurotrophin-3 against TrkC-induced apoptosis.
      reference_section_type: TITLE
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:23729654
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. HPV-16 E7/gelsolin context modulating caspase-3 activity.
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:23729654
      supporting_text: The human papillomavirus-16 E7 oncoprotein exerts antiapoptotic effects via its physical interaction with the actin-binding protein gelsolin.
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IMP
  original_reference_id: PMID:10921886
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. RET proto-oncogene-induced apoptosis is caspase-3-dependent.
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:10921886
      supporting_text: 'The RET proto-oncogene induces apoptosis: a novel mechanism for Hirschsprung disease.'
- term:
    id: GO:0030218
    label: erythrocyte differentiation
  evidence_type: IDA
  original_reference_id: PMID:17167422
  qualifier: involved_in
  review:
    summary: Caspase-3 is activated during terminal erythroid differentiation; GATA-1 is protected from cleavage by Hsp70.
    action: KEEP_AS_NON_CORE
    reason: A genuine non-apoptotic role in erythropoiesis, but downstream of the core protease function. Non-core.
    supported_by:
    - reference_id: PMID:17167422
      supporting_text: Caspase-3 is activated during both terminal differentiation and erythropoietin-starvation-induced apoptosis of human erythroid precursors.
      reference_section_type: ABSTRACT
- term:
    id: GO:0030218
    label: erythrocyte differentiation
  evidence_type: TAS
  original_reference_id: PMID:18309324
  qualifier: involved_in
  review:
    summary: Effector caspases including caspase-3 have vital (non-death) functions in erythroid differentiation.
    action: KEEP_AS_NON_CORE
    reason: Non-apoptotic differentiation role (TAS review); genuine but non-core.
    supported_by:
    - reference_id: PMID:18309324
      supporting_text: 'No death without life: vital functions of apoptotic effectors.'
      reference_section_type: TITLE
- term:
    id: GO:0030220
    label: platelet formation
  evidence_type: TAS
  original_reference_id: PMID:18309324
  qualifier: involved_in
  review:
    summary: Caspase-3 contributes to platelet formation (a non-apoptotic effector-caspase function).
    action: KEEP_AS_NON_CORE
    reason: A genuine non-apoptotic tissue role (TAS review); non-core.
    supported_by:
    - reference_id: PMID:18309324
      supporting_text: 'No death without life: vital functions of apoptotic effectors.'
      reference_section_type: TITLE
- term:
    id: GO:0097194
    label: execution phase of apoptosis
  evidence_type: IMP
  original_reference_id: PMID:11350920
  qualifier: involved_in
  review:
    summary: Caspase-3 is required for Bax-mediated nuclear fragmentation in the execution phase (MCF7 deficiency).
    action: ACCEPT
    reason: Direct functional (IMP) evidence for caspase-3's execution-phase role in nuclear demolition.
    supported_by:
    - reference_id: PMID:11350920
      supporting_text: Deficiency of caspase-3 in MCF7 cells blocks Bax-mediated nuclear fragmentation but not cell death.
      reference_section_type: TITLE
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IMP
  original_reference_id: PMID:17559062
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleaves desmoglein-2 (DSG2) and JUP at desmosomes.
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:17559062
      supporting_text: The most widespread desmosomal cadherin, desmoglein 2, is a novel target of caspase 3-mediated apoptotic machinery.
- term:
    id: GO:0097194
    label: execution phase of apoptosis
  evidence_type: IDA
  original_reference_id: PMID:8689682
  qualifier: involved_in
  review:
    summary: In cell-free extracts, cytochrome c/dATP triggers the apoptotic program that activates executioner caspase-3.
    action: ACCEPT
    reason: Classic evidence placing caspase-3 in the execution phase downstream of cytochrome c/apoptosome.
    supported_by:
    - reference_id: PMID:8689682
      supporting_text: Cells undergoing apoptosis in vivo showed increased release of cytochrome c to their cytosol, suggesting that mitochondria may function in apoptosis by releasing cytochrome c.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-211186
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 in the nucleoplasm for nuclear substrate cleavage (e.g., DFF45/ICAD), consistent with active caspase-3 translocating to the nucleus during apoptosis.
    action: KEEP_AS_NON_CORE
    reason: Nuclear/nucleoplasm localization of active caspase-3 is supported but secondary to its core cytoplasmic site; retained as non-core location context for nuclear substrate cleavage.
    supported_by:
    - reference_id: PMID:16374543
      supporting_text: the activation of nuclear caspases-7 and -3, and poly(ADP-ribose) polymerase (PARP) cleavage, are early events in camptothecin-induced apoptosis
      reference_section_type: ABSTRACT
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-211190
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 in the nucleoplasm for nuclear substrate cleavage (e.g., DFF45/ICAD), consistent with active caspase-3 translocating to the nucleus during apoptosis.
    action: KEEP_AS_NON_CORE
    reason: Nuclear/nucleoplasm localization of active caspase-3 is supported but secondary to its core cytoplasmic site; retained as non-core location context for nuclear substrate cleavage.
    supported_by:
    - reference_id: PMID:16374543
      supporting_text: the activation of nuclear caspases-7 and -3, and poly(ADP-ribose) polymerase (PARP) cleavage, are early events in camptothecin-induced apoptosis
      reference_section_type: ABSTRACT
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-211219
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 in the nucleoplasm for nuclear substrate cleavage (e.g., DFF45/ICAD), consistent with active caspase-3 translocating to the nucleus during apoptosis.
    action: KEEP_AS_NON_CORE
    reason: Nuclear/nucleoplasm localization of active caspase-3 is supported but secondary to its core cytoplasmic site; retained as non-core location context for nuclear substrate cleavage.
    supported_by:
    - reference_id: PMID:16374543
      supporting_text: the activation of nuclear caspases-7 and -3, and poly(ADP-ribose) polymerase (PARP) cleavage, are early events in camptothecin-induced apoptosis
      reference_section_type: ABSTRACT
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-114252
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-201595
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-201603
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-201608
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-201611
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-201622
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-201628
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-201629
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-201630
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-201631
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-201636
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-201639
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-201640
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2028692
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2028697
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-202917
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-202939
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-202947
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-202960
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-202966
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-202967
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-202969
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-205117
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-211219
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-212552
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-350651
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-351849
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-351871
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-351876
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-351877
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-351901
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-351913
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-373705
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-418845
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-449073
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9627104
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9647632
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9686088
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-211643
  qualifier: located_in
  review:
    summary: Reactome places caspase-3 (and its substrate-cleavage reactions) in the cytosol, the principal compartment of caspase-3 activity.
    action: ACCEPT
    reason: Cytosol is the core, well-supported location of caspase-3. These Reactome rows are substrate-cleavage reaction contexts; the cytosolic cellular component is correct.
    supported_by:
    - reference_id: file:human/CASP3/CASP3-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION; Cytoplasm
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9208847
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (Casper/c-FLIP FADD- and caspase-related interaction.) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:9208847
      supporting_text: Casper is a FADD- and caspase-related inducer of apoptosis.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:17167422
  qualifier: located_in
  review:
    summary: Active caspase-3 is present in the nucleus of erythroid precursors where it can cleave GATA-1.
    action: KEEP_AS_NON_CORE
    reason: Nuclear localization of active caspase-3 is supported but secondary to its core cytoplasmic site; non-core.
    supported_by:
    - reference_id: PMID:17167422
      supporting_text: Hsp70 co-localizes and interacts with GATA-1 in the nucleus of erythroid precursors undergoing terminal differentiation.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:17167422
  qualifier: located_in
  review:
    summary: Caspase-3 acts in the cytosol of erythroid precursors.
    action: ACCEPT
    reason: Cytosol is the core site of caspase-3 activity; supported.
    supported_by:
    - reference_id: PMID:17167422
      supporting_text: Caspase-3 is activated during both terminal differentiation and erythropoietin-starvation-induced apoptosis of human erythroid precursors.
      reference_section_type: ABSTRACT
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:21726810
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. Caspase-3 cleavage activity in the MDM2/p53 feedback context.
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:21726810
      supporting_text: Caspase-2-mediated cleavage of Mdm2 creates a p53-induced positive feedback loop.
- term:
    id: GO:0034612
    label: response to tumor necrosis factor
  evidence_type: TAS
  original_reference_id: PMID:10521396
  qualifier: involved_in
  review:
    summary: Caspase-3 acts downstream of TNF-induced apoptosis (RIP cleavage by caspase-8).
    action: KEEP_AS_NON_CORE
    reason: Response to TNF is a stimulus/response signaling context; caspase-3 is the executioner downstream. Non-core.
    supported_by:
    - reference_id: PMID:10521396
      supporting_text: Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis.
      reference_section_type: TITLE
- term:
    id: GO:0097190
    label: apoptotic signaling pathway
  evidence_type: TAS
  original_reference_id: PMID:10521396
  qualifier: involved_in
  review:
    summary: Caspase-3 acts within the apoptotic signaling pathway (TNF/death-receptor-induced apoptosis).
    action: ACCEPT
    reason: Apoptotic signaling pathway is a valid process for caspase-3 as the executioner; supported.
    supported_by:
    - reference_id: PMID:10521396
      supporting_text: Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis.
      reference_section_type: TITLE
- term:
    id: GO:0008233
    label: peptidase activity
  evidence_type: IDA
  original_reference_id: PMID:9353287
  qualifier: enables
  review:
    summary: Caspase-3 peptidase activity cleaves presenilin-2 generating anti-apoptotic polypeptides.
    action: ACCEPT
    reason: Peptidase activity is correct (broad); supported by substrate cleavage evidence.
    supported_by:
    - reference_id: PMID:9353287
      supporting_text: Generation of anti-apoptotic presenilin-2 polypeptides by alternative transcription, proteolysis, and caspase-3 cleavage.
      reference_section_type: TITLE
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17823127
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (HSP60 interaction modulating pro/anti-apoptotic functions.) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:17823127
      supporting_text: 'Cytosolic accumulation of HSP60 during apoptosis with or without apparent mitochondrial release: evidence that its pro-apoptotic or pro-survival functions involve differential interactions with caspase-3.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:17823127
  qualifier: located_in
  review:
    summary: Caspase-3 is present in the cytosol, where cytosolic HSP60 modulates its activity during apoptosis.
    action: ACCEPT
    reason: Cytosol is the core location of caspase-3; directly supported.
    supported_by:
    - reference_id: PMID:17823127
      supporting_text: Cytosolic accumulation of HSP60 during apoptosis with or without apparent mitochondrial release
      reference_section_type: TITLE
- term:
    id: GO:0006508
    label: proteolysis
  evidence_type: IDA
  original_reference_id: PMID:12888622
  qualifier: involved_in
  review:
    summary: Caspase-3 cleaves tau, linking amyloid and neurofibrillary tangles (proteolysis).
    action: ACCEPT
    reason: Proteolysis is correct and consistent with the cysteine-type endopeptidase function; this substrate cleavage is a concrete instance. Kept consistent with the other proteolysis annotations.
    supported_by:
    - reference_id: PMID:12888622
      supporting_text: 'Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer''s disease.'
      reference_section_type: TITLE
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9736630
  qualifier: enables
  review:
    summary: This IPI captures a physical interaction (Tau cleavage interaction in apoptotic neurons.) but the generic protein binding term is uninformative about caspase-3's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) does not describe a distinct caspase-3 molecular activity; the functionally meaningful interactions (substrate cleavage, inhibitor binding) are better represented by the endopeptidase activity and protease binding terms. Retained but flagged as uninformative.
    supported_by:
    - reference_id: PMID:9736630
      supporting_text: Tau cleavage and dephosphorylation in cerebellar granule neurons undergoing apoptosis.
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: TAS
  original_reference_id: PMID:10942389
  qualifier: enables
  review:
    summary: Direct evidence of caspase-3 cysteine-type endopeptidase activity. HIV-1 gp120/gp160-induced endothelial apoptosis mediated by caspases including caspase-3.
    action: ACCEPT
    reason: This is the core molecular function of caspase-3, repeatedly demonstrated experimentally on diverse substrates. Retained as a core function.
    supported_by:
    - reference_id: PMID:10942389
      supporting_text: HIV-1 gp120- and gp160-induced apoptosis in cultured endothelial cells is mediated by caspases.
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: TAS
  original_reference_id: PMID:7983002
  qualifier: involved_in
  review:
    summary: CPP32 (caspase-3) is an apoptotic protein homologous to CED-3/ICE (original cloning, TAS).
    action: ACCEPT
    reason: Foundational evidence for caspase-3's role in the apoptotic process; core.
    supported_by:
    - reference_id: PMID:7983002
      supporting_text: CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme.
      reference_section_type: TITLE
core_functions:
- description: Caspase-3 is a cysteine-type endopeptidase (EC 3.4.22.56) that cleaves substrates after aspartate residues, with a strict requirement for Asp at the P1 and P4 positions of an Asp-X-X-Asp recognition motif. It is synthesized as a zymogen and activated by cleavage by initiator caspases or granzyme B into a p17/p12 heterotetramer.
  molecular_function:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  directly_involved_in:
  - id: GO:0006508
    label: proteolysis
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/CASP3/CASP3-uniprot.txt
    supporting_text: Strict requirement for an Asp residue at positions P1 and P4. It has a preferred cleavage sequence of Asp-Xaa-Xaa-Asp-|-
  - reference_id: PMID:7596430
    supporting_text: This enzyme, named apopain, is composed of two subunits of relative molecular mass (M(r)) 17K and 12K that are derived from a common proenzyme identified as CPP32.
    reference_section_type: ABSTRACT
- description: As the principal executioner caspase, caspase-3 carries out the demolition phase of apoptosis by cleaving many cellular substrates (e.g., PARP1; ICAD/DFF45 to release the CAD/DFF40 DNA-fragmentation nuclease; cytoskeletal, junctional and signaling proteins) and by driving phosphatidylserine exposure through cleavage of XKR scramblases and the ATP11C flippase.
  molecular_function:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  directly_involved_in:
  - id: GO:0097194
    label: execution phase of apoptosis
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:18723680
    supporting_text: Caspase-3 was found to be generally more promiscuous than caspase-7 and appears to be the major executioner caspase during the demolition phase of apoptosis.
    reference_section_type: ABSTRACT
  - reference_id: PMID:22253444
    supporting_text: the main processing of pro-caspase-3 takes place in the cytosol of both cells lines analyzed even if caspase-3 active fragments can also be evidenced in the nuclear fractions after STP treatment
    reference_section_type: DISCUSSION
- description: Caspase-3 cleaves and activates gasdermin-E (GSDME/DFNA5), switching apoptotic cells to pyroptosis and permitting IL-1 beta release, coupling the apoptotic protease to a pro-inflammatory lytic cell-death program.
  molecular_function:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  directly_involved_in:
  - id: GO:0140639
    label: positive regulation of pyroptotic inflammatory response
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:28459430
    supporting_text: Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin.
    reference_section_type: TITLE
- description: Caspase-3 restrains innate immune and cytokine signaling by cleaving antiviral signaling proteins (cGAS, MAVS, IRF3) and NF-kB subunits (p65/RelA, RelB, c-Rel) and by processing cytokines such as IL-18, dampening cytokine production during apoptosis.
  molecular_function:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  directly_involved_in:
  - id: GO:0001818
    label: negative regulation of cytokine production
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:30878284
    supporting_text: Apoptotic Caspases Suppress Type I Interferon Production via the Cleavage of cGAS, MAVS, and IRF3.
    reference_section_type: TITLE
  - reference_id: PMID:36002459
    supporting_text: Apoptotic caspase inhibits innate immune signaling by cleaving NF-κBs in both Mammals and Flies.
    reference_section_type: TITLE
proposed_new_terms: []
suggested_questions:
- question: To what extent are caspase-3 non-apoptotic roles (erythroid/keratinocyte differentiation, synapse pruning, platelet formation) driven by spatially or temporally restricted sublethal caspase-3 activity, and can substrate repertoires be defined that distinguish lethal from non-lethal activation?
  experts:
  - Salvesen GS
  - Martin SJ
- question: Which GO_REF:0000107 ortholog-transferred stimulus/response and tissue terms on CASP3 represent genuine direct roles versus over-propagation across the caspase family, and should questionable molecular-function transfers (aspartic-type endopeptidase, CDK inhibitor, phospholipase A2 activator) be removed upstream?
  experts:
  - Thornberry NA
suggested_experiments:
- hypothesis: Caspase-3 substrate cleavage during sublethal/non-apoptotic activation produces a distinct proteome from that during full apoptosis, explaining its differentiation roles.
  description: Perform N-terminomics (e.g., TAILS/subtiligase) on cells undergoing caspase-3-dependent differentiation versus apoptosis, with caspase-3 knockout and caspase-resistant substrate mutants as controls, to map the differentiation-specific cleavage repertoire.
  experiment_type: degradomics / N-terminomics
- hypothesis: The balance between caspase-3-driven apoptosis and GSDME-driven pyroptosis is set by GSDME abundance and caspase-3 activity kinetics.
  description: Titrate GSDME expression and caspase-3 activation kinetics in isogenic cell lines (including non-cleavable GSDME D270A) and quantify apoptosis versus pyroptosis outcomes and IL-1 beta release.
  experiment_type: cell death pathway dissection
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10521396
  title: Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced
    apoptosis.
  findings: []
- id: PMID:10921886
  title: 'The RET proto-oncogene induces apoptosis: a novel mechanism for Hirschsprung
    disease.'
  findings: []
- id: PMID:10942389
  title: HIV-1 gp120- and gp160-induced apoptosis in cultured endothelial cells is
    mediated by caspases.
  findings: []
- id: PMID:11257232
  title: Structural basis for the inhibition of caspase-3 by XIAP.
  findings: []
- id: PMID:11350920
  title: Deficiency of caspase-3 in MCF7 cells blocks Bax-mediated nuclear fragmentation
    but not cell death.
  findings: []
- id: PMID:12107093
  title: Microinjection of cathepsin d induces caspase-dependent apoptosis in fibroblasts.
  findings: []
- id: PMID:12888622
  title: 'Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in
    Alzheimer''s disease.'
  findings: []
- id: PMID:15003516
  title: Caspase 3 activation is controlled by a sequence located in the N-terminus
    of its large subunit.
  findings: []
- id: PMID:15246877
  title: S-nitrosation of thioredoxin in the nitrogen monoxide/superoxide system activates
    apoptosis signal-regulating kinase 1.
  findings: []
- id: PMID:15565177
  title: A novel mitochondrial protein DIP mediates E2F1-induced apoptosis independently
    of p53.
  findings: []
- id: PMID:16227597
  title: A-kinase-anchoring protein 95 functions as a potential carrier for the nuclear
    translocation of active caspase 3 through an enzyme-substrate-like association.
  findings: []
- id: PMID:16374543
  title: Nuclear caspase-3 and caspase-7 activation, and poly(ADP-ribose) polymerase
    cleavage are early events in camptothecin-induced apoptosis.
  findings: []
- id: PMID:16501604
  title: Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway.
  findings: []
- id: PMID:16530191
  title: 'N-myristoyltransferase 2 expression in human colon cancer: cross-talk between
    the calpain and caspase system.'
  findings: []
- id: PMID:16920334
  title: Protective role of Cop in Rip2/caspase-1/caspase-4-mediated HeLa cell death.
  findings: []
- id: PMID:17167422
  title: Hsp70 regulates erythropoiesis by preventing caspase-3-mediated cleavage
    of GATA-1.
  findings: []
- id: PMID:17544405
  title: 'Caspase-3-mediated cleavage of Akt: involvement of non-consensus sites and
    influence of phosphorylation.'
  findings: []
- id: PMID:17553422
  title: Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity.
  findings: []
- id: PMID:17559062
  title: The most widespread desmosomal cadherin, desmoglein 2, is a novel target
    of caspase 3-mediated apoptotic machinery.
  findings: []
- id: PMID:17606900
  title: Thioredoxin is required for S-nitrosation of procaspase-3 and the inhibition
    of apoptosis in Jurkat cells.
  findings: []
- id: PMID:17823127
  title: 'Cytosolic accumulation of HSP60 during apoptosis with or without apparent
    mitochondrial release: evidence that its pro-apoptotic or pro-survival functions
    involve differential interactions with caspase-3.'
  findings: []
- id: PMID:18309324
  title: 'No death without life: vital functions of apoptotic effectors.'
  findings: []
- id: PMID:18723680
  title: Executioner caspase-3 and caspase-7 are functionally distinct proteases.
  findings: []
- id: PMID:19240112
  title: Huntingtin promotes cell survival by preventing Pak2 cleavage.
  findings: []
- id: PMID:19273858
  title: S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease.
  findings: []
- id: PMID:19549685
  title: Caspase cleavage of Atg4D stimulates GABARAP-L1 processing and triggers mitochondrial
    targeting and apoptosis.
  findings: []
- id: PMID:19740745
  title: A truncated form of p23 down-regulates telomerase activity via disruption
    of Hsp90 function.
  findings: []
- id: PMID:20566630
  title: Identification of functional regions defining different activity in caspase-3
    and caspase-7 within cells.
  findings: []
- id: PMID:21726810
  title: Caspase-2-mediated cleavage of Mdm2 creates a p53-induced positive feedback
    loop.
  findings: []
- id: PMID:21980415
  title: Identification of a conserved anti-apoptotic protein that modulates the mitochondrial
    apoptosis pathway.
  findings: []
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
- id: PMID:22253444
  title: Apoptotic DNA degradation into oligonucleosomal fragments, but not apoptotic
    nuclear morphology, relies on a cytosolic pool of DFF40/CAD endonuclease.
  findings: []
- id: PMID:23150525
  title: 'Regulation of co- and post-translational myristoylation of proteins during
    apoptosis: interplay of N-myristoyltransferases and caspases.'
  findings: []
- id: PMID:23650375
  title: Structural snapshots reveal distinct mechanisms of procaspase-3 and -7 activation.
  findings: []
- id: PMID:23729654
  title: The human papillomavirus-16 E7 oncoprotein exerts antiapoptotic effects via
    its physical interaction with the actin-binding protein gelsolin.
  findings: []
- id: PMID:23954828
  title: Dok5 is involved in the signaling pathway of neurotrophin-3 against TrkC-induced
    apoptosis.
  findings: []
- id: PMID:24904167
  title: Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine
    exposure.
  findings: []
- id: PMID:25241761
  title: Using an in situ proximity ligation assay to systematically profile endogenous
    protein-protein interactions in a pathway network.
  findings: []
- id: PMID:28459430
  title: Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
- id: PMID:30878284
  title: Apoptotic Caspases Suppress Type I Interferon Production via the Cleavage
    of cGAS, MAVS, and IRF3.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33725486
  title: Caspase cleavage releases a nuclear protein fragment that stimulates phospholipid
    scrambling at the plasma membrane.
  findings: []
- id: PMID:33852854
  title: Gasdermin E permits interleukin-1 beta release in distinct sublytic and pyroptotic
    phases.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:34480022
  title: Endotoxin stabilizes protein arginine methyltransferase 4 (PRMT4) protein
    triggering death of lung epithelia.
  findings: []
- id: PMID:35594856
  title: Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial
    cells.
  findings: []
- id: PMID:36002459
  title: Apoptotic caspase inhibits innate immune signaling by cleaving NF-κBs in
    both Mammals and Flies.
  findings: []
- id: PMID:36426955
  title: TRIM21 Regulates Virus-Induced Cell Pyroptosis through Polyubiquitination
    of ISG12a.
  findings: []
- id: PMID:37327784
  title: Gasdermin D licenses MHCII induction to maintain food tolerance in small
    intestine.
  findings: []
- id: PMID:38884001
  title: Mapping adipocyte interactome networks by HaloTag-enrichment-mass spectrometry.
  findings: []
- id: PMID:7596430
  title: Identification and inhibition of the ICE/CED-3 protease necessary for mammalian
    apoptosis.
  findings: []
- id: PMID:7983002
  title: CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans
    cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme.
  findings: []
- id: PMID:8689682
  title: 'Induction of apoptotic program in cell-free extracts: requirement for dATP
    and cytochrome c.'
  findings: []
- id: PMID:9208847
  title: Casper is a FADD- and caspase-related inducer of apoptosis.
  findings: []
- id: PMID:9334240
  title: Involvement of caspase-1 and caspase-3 in the production and processing of
    mature human interleukin 18 in monocytic THP.1 cells.
  findings: []
- id: PMID:9353287
  title: Generation of anti-apoptotic presenilin-2 polypeptides by alternative transcription,
    proteolysis, and caspase-3 cleavage.
  findings: []
- id: PMID:9736630
  title: Tau cleavage and dephosphorylation in cerebellar granule neurons undergoing
    apoptosis.
  findings: []
- id: Reactome:R-HSA-114252
  title: Cleavage of Procaspase-3 by the apoptosome
  findings: []
- id: Reactome:R-HSA-201595
  title: Caspase-mediated cleavage of plakophilin-1
  findings: []
- id: Reactome:R-HSA-201603
  title: Caspase-mediated cleavage of PKC theta
  findings: []
- id: Reactome:R-HSA-201608
  title: Caspase-mediated cleavage of alpha adducin
  findings: []
- id: Reactome:R-HSA-201611
  title: Caspase-mediated cleavage of Rock-1
  findings: []
- id: Reactome:R-HSA-201622
  title: Caspase-mediated cleavage of gelsolin
  findings: []
- id: Reactome:R-HSA-201628
  title: Caspase-mediated cleavage of vimentin at DSVD (85)
  findings: []
- id: Reactome:R-HSA-201629
  title: Caspase-mediated cleavage of Tau
  findings: []
- id: Reactome:R-HSA-201630
  title: Caspase-mediated cleavage of Acinus
  findings: []
- id: Reactome:R-HSA-201631
  title: Caspase-mediated cleavage of Desmoglein 3
  findings: []
- id: Reactome:R-HSA-201636
  title: Caspase-mediated cleavage of Desmoplakin
  findings: []
- id: Reactome:R-HSA-201639
  title: Caspase-mediated cleavage of GAS2
  findings: []
- id: Reactome:R-HSA-201640
  title: Caspase-mediated cleavage of farnesyltransferase/geranyl- geranyltransferase
    subunit alpha
  findings: []
- id: Reactome:R-HSA-2028692
  title: Cleavage of p-STK4 (p-MST1) by caspase 3
  findings: []
- id: Reactome:R-HSA-2028697
  title: Cleavage of p-STK3 (p-MST2) by caspase 3
  findings: []
- id: Reactome:R-HSA-202917
  title: Caspase-mediated cleavage of Desmoglein 1
  findings: []
- id: Reactome:R-HSA-202939
  title: Caspase-mediated cleavage of E-Cadherin
  findings: []
- id: Reactome:R-HSA-202947
  title: Caspase mediated cleavage of APC
  findings: []
- id: Reactome:R-HSA-202960
  title: Caspase mediated cleavage of C-IAP1
  findings: []
- id: Reactome:R-HSA-202966
  title: Caspase mediated cleavage of HIP-55
  findings: []
- id: Reactome:R-HSA-202967
  title: Caspase mediated cleavage of alpha-II-Fodrin
  findings: []
- id: Reactome:R-HSA-202969
  title: Caspase mediated cleavage of beta-catenin
  findings: []
- id: Reactome:R-HSA-205117
  title: p75NTR:NADE promotes caspase2/3 activation
  findings: []
- id: Reactome:R-HSA-211186
  title: Cleavage of DFF45 (224) by caspase-3
  findings: []
- id: Reactome:R-HSA-211190
  title: Caspase 3-mediated cleavage of DFF45 (117)
  findings: []
- id: Reactome:R-HSA-211219
  title: Translocation of caspase-3 to the nucleus
  findings: []
- id: Reactome:R-HSA-212552
  title: Caspase 3-mediated cleavage of PKC delta
  findings: []
- id: Reactome:R-HSA-350651
  title: Caspase-mediated cleavage of MASK
  findings: []
- id: Reactome:R-HSA-351849
  title: Caspase-mediated cleavage of Etk
  findings: []
- id: Reactome:R-HSA-351871
  title: Caspase-mediated cleavage of Z0-2
  findings: []
- id: Reactome:R-HSA-351876
  title: Caspase-mediated cleavage of occludin
  findings: []
- id: Reactome:R-HSA-351877
  title: Caspase-mediated cleavage of Desmoglein 2
  findings: []
- id: Reactome:R-HSA-351901
  title: Caspase-mediated cleavage of MST3
  findings: []
- id: Reactome:R-HSA-351913
  title: Caspase-mediated cleavage of TJP1
  findings: []
- id: Reactome:R-HSA-373705
  title: Caspase cleavage of DCC
  findings: []
- id: Reactome:R-HSA-418845
  title: Activation of caspase-3
  findings: []
- id: Reactome:R-HSA-449073
  title: Caspase-3 cleaves pro-interleukin-16
  findings: []
- id: Reactome:R-HSA-9627104
  title: XIAP binds CASP3
  findings: []
- id: Reactome:R-HSA-9647632
  title: CASP3 cleaves GSDME
  findings: []
- id: Reactome:R-HSA-9686088
  title: CASP3 cleaves GSDMD
  findings: []
- id: Reactome:R-NUL-211643
  title: Cleavage of PAK-2 at 212
  findings: []
- id: file:human/CASP3/CASP3-deep-research-falcon.md
  title: Falcon deep research report for CASP3
  findings:
  - statement: Falcon corroborates the review's core characterization of CASP3 as the
      principal executioner caspase and a cysteine protease that cleaves strictly after
      aspartate at the P1 position.
    supporting_text: Caspase-3 is a cysteine protease that cleaves peptide bonds almost
      exclusively C-terminal to aspartate residues at the P1 position

CASP3

Gene Description

Existing Annotations Review

Core Functions

Caspase-3 cleaves and activates gasdermin-E (GSDME/DFNA5), switching apoptotic cells to pyroptosis and permitting IL-1 beta release, coupling the apoptotic protease to a pro-inflammatory lytic cell-death program.

Caspase-3 restrains innate immune and cytokine signaling by cleaving antiviral signaling proteins (cGAS, MAVS, IRF3) and NF-kB subunits (p65/RelA, RelB, c-Rel) and by processing cytokines such as IL-18, dampening cytokine production during apoptosis.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: Human CASP3 (Caspase-3)

Gene and Protein Identity

Primary Enzymatic Function and Substrate Specificity

Catalytic Mechanism and Activation

Substrate Recognition and Cleavage Specificity

Substrate Repertoire

Subcellular Localization

Role in Apoptotic Signaling Pathways

Intrinsic (Mitochondrial) Pathway

Extrinsic (Death Receptor) Pathway

Regulatory Mechanisms

Downstream Effects of Caspase-3 Activation

Non-Apoptotic Functions of Caspase-3

Cytoprotective Autophagy and Stress Adaptation

Suppression of Inflammatory Signaling During Apoptosis

Neuronal Plasticity and Synaptic Remodeling

Neural Stem Cell Differentiation

Oncogenic Transformation

Comparison with Caspase-7

Summary

Artifacts

Citations

📚 Additional Documentation

Notes

CASP3 (Caspase-3) review notes

Core identity / molecular function

Substrate cleavage / downstream demolition (all DEPEND on the same MF, mostly downstream processes)

Localization

Regulation

Curation strategy

Exact supporting quotes gathered (for supported_by)

Falcon deep research integration (2026-06-21)

📄 View Raw YAML