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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MODIFY | Summary: CASP3 acts in a soluble cytosolic pool during proteolytic signaling. Reason: CASP3 acts in a soluble cytosolic pool during proteolytic signaling. Refine the broad cytoplasm annotation to the supported cytosol compartment; nuclear or extracellular pools are represented separately. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000047947 SUPPORTS TRANSFER WITH/FROM source traced; retained conserved biology is refined to the more specific target-supported term, without changing the inferred evolutionary placement. Proposed replacements: cytosol Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Cytoplasm |
| GO:0006915 apoptotic process | IBA GO_REF:0000033 | MODIFY | Summary: CASP3 directly performs proteolytic steps of apoptotic execution. Reason: The target effector protease directly performs the controlled substrate breakdown of apoptotic execution. Refine apoptotic process to the already represented GO:0097194 execution phase, supported by target-specific substrate/nuclear-change evidence rather than C14A membership, which also includes initiator and inflammatory caspases. Human-enzyme PMID:18723680 directly compares substrate cleavage by executioner caspases. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000047947 SUPPORTS TRANSFER The conserved apoptotic-process assertion is retained; independently inspected target execution evidence supports finer stage resolution. This does not reinterpret family-wide C14A membership as an executioner-specific activity or relocate a PAINT ancestor. Proposed replacements: execution phase of apoptosis Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins 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: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: CASP3 directly catalyzes proteolysis of diverse substrates. Reason: CASP3 directly catalyzes proteolysis of diverse substrates. This process is core and spans destructive and regulatory cleavage, so no single narrower protein-processing process replaces its full scope. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Belongs to the peptidase C14A family. file:human/CASP3/CASP3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0031264 death-inducing signaling complex | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The PAINT-supported death-inducing signaling complex association need not imply an initiator-caspase role. Reason: The PAINT-supported death-inducing signaling complex association need not imply an initiator-caspase role. PMID:17518537 reports a Fas/FADD/caspase-8/c-FLIP/caspase-3 complex in rat spinal injury; retain the conserved contextual association without asserting direct binary death-receptor binding. Supporting Evidence: |
| 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 | MODIFY | Summary: Proteolytic activation of substrates is real, but GO enzyme activator activity is restricted to direct activation without covalent modification. Reason: Proteolytic activation of substrates is real, but GO enzyme activator activity is restricted to direct activation without covalent modification. Caspase cleavage belongs to cysteine-type endopeptidase activity, not noncovalent enzyme activation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN008499732 UNRESOLVED WITH/FROM source traced; the issue is proteolytic versus noncovalent activation, not loss of the caspase enzyme. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Belongs to the peptidase C14A family. file:human/CASP3/CASP3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| 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: neuron differentiation: retain with the primary study's context and species limits. Reason: The PAINT assertion traces to PANTHER:PTN002573018, with rat Casp3 experimental grounding. This is an inherited-node judgment, not a donor-count or pairwise-similarity test; no target-specific loss is inferred. The rat donor publication PMID:15248196 distinguishes active-caspase-3-positive proliferating/differentiating cerebellar cells from apoptotic cells. Independent PMID:16103108 goes beyond colocalization: caspase activity rises in nonapoptotic differentiating neuronal populations and peptide inhibition impairs neurosphere differentiation. The inhibitor experiment is not a caspase-3-specific genetic knockout, but together with the PAINT/conserved caspase context it supports a non-core neuronal differentiation role, not universal dependence of all neurons. The abstract does not specify the neurosphere species, so no direct human or mouse assay is invented. Supporting Evidence: PMID:16103108 peptide inhibition of protease activity effectively inhibits the differentiation process in a cultured neurosphere model. PMID:15248196 Proliferative (Ki67-positive) and differentiated (TUJ1-positive) cells within the EGL exhibited a cytosolic expression of caspase-3 |
| 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 | MODIFY | Summary: CASP3 acts in a soluble cytosolic pool during proteolytic signaling. Reason: CASP3 acts in a soluble cytosolic pool during proteolytic signaling. Refine the broad cytoplasm annotation to the supported cytosol compartment; nuclear or extracellular pools are represented separately. Proposed replacements: cytosol Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Cytoplasm |
| GO:0006508 proteolysis | IEA GO_REF:0000120 | ACCEPT | Summary: CASP3 directly catalyzes proteolysis of diverse substrates. Reason: CASP3 directly catalyzes proteolysis of diverse substrates. This process is core and spans destructive and regulatory cleavage, so no single narrower protein-processing process replaces its full scope. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Belongs to the peptidase C14A family. file:human/CASP3/CASP3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0006915 apoptotic process | IEA GO_REF:0000117 | MODIFY | Summary: CASP3 directly performs proteolytic steps of apoptotic execution. Reason: The target effector protease directly performs the controlled substrate breakdown of apoptotic execution. Refine apoptotic process to the already represented GO:0097194 execution phase, supported by target-specific substrate/nuclear-change evidence rather than C14A membership, which also includes initiator and inflammatory caspases. Human-enzyme PMID:18723680 directly compares substrate cleavage by executioner caspases. Proposed replacements: execution phase of apoptosis Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins 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:0008234 cysteine-type peptidase activity | IEA GO_REF:0000120 | MODIFY | Summary: CASP3 cleaves internal peptide bonds using a catalytic cysteine. Reason: CASP3 cleaves internal peptide bonds using a catalytic cysteine. Asp at the substrate cleavage site specifies recognition, not an aspartic catalytic mechanism. The supported specific activity is cysteine-type endopeptidase activity. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Belongs to the peptidase C14A family. file:human/CASP3/CASP3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| 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. | REMOVE | Summary: XIAP BIR2 binds and inhibits caspase-3, but this is inhibitor binding to CASP3 rather than a distinct CASP3 molecular function. Reason: The structure supports an XIAP-caspase-3 inhibitory complex. For CASP3, the generic protein binding row is only a physical-interaction assertion and should not be kept or converted to a partner-specific term. Supporting Evidence: 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. |
| GO:0005515 protein binding | IPI PMID:16227597 A-kinase-anchoring protein 95 functions as a potential carri... | REMOVE | Summary: AKAP95 associates with active caspase-3 during nuclear translocation, but the source presents AKAP95 as a carrier rather than identifying a new CASP3 catalytic function. Reason: This row is a bare CASP3-AKAP95 physical-interaction assertion. The interaction should not be inflated into a transport MF for CASP3, which is the cargo, or into a substrate-specific MF from binding evidence alone. Supporting Evidence: PMID:16227597 These results indicate that AKAP95 is a potential carrier protein for active caspase 3 from the cytoplasm into the nuclei in apoptotic cells. |
| GO:0005515 protein binding | IPI PMID:16501604 Protein kinase WNK3 increases cell survival in a caspase-3-d... | REMOVE | Summary: WNK3 interacts with procaspase-3 and Hsp70 in a cell-survival pathway, but this interaction does not resolve a more informative CASP3 molecular function. Reason: The cited paper supports regulation of procaspase-3 activation by WNK3, not an additional CASP3 activity. The generic protein binding row is therefore an uninformative physical-interaction assertion. Supporting Evidence: PMID:16501604 The mechanism of WNK3 action involves interaction with procaspase-3 and heat-shock protein 70. |
| GO:0005515 protein binding | IPI PMID:16530191 N-myristoyltransferase 2 expression in human colon cancer: c... | MODIFY | Summary: CASP3 interacts with NMT2, and subsequent NMT work resolves NMT2 as a caspase-3 cleavage substrate. Reason: The original NMT2 interaction is better represented by the core CASP3 cysteine-type endopeptidase activity because NMT2 is proteolytically cleaved by caspase-3. A partner-specific binding MF should not be invented from this IPI row. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: PMID:16530191 caspase-3 interacts with NMT2 PMID:23150525 cleavage of NMT1 at Asp-72 precedes the cleavage of NMT2 by caspase-3 mainly at Asp-25. |
| GO:0005515 protein binding | IPI PMID:17167422 Hsp70 regulates erythropoiesis by preventing caspase-3-media... | MODIFY | Summary: Hsp70 prevents active caspase-3 from cleaving the erythroid transcription factor GATA-1. Reason: The informative CASP3 activity in this source is GATA-1 proteolysis. Replace generic protein binding with the core cysteine-type endopeptidase activity rather than retaining an unqualified binding row. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: PMID:17167422 Hsp70 prevents active caspase-3 from cleaving GATA-1 and inducing apoptosis. |
| GO:0005515 protein binding | IPI PMID:17544405 Caspase-3-mediated cleavage of Akt: involvement of non-conse... | MODIFY | Summary: Akt1 is a direct in vitro caspase-3 cleavage substrate. Reason: The interaction represents substrate cleavage by caspase-3 and is better captured as cysteine-type endopeptidase activity than as generic protein binding. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: PMID:17544405 Akt1 is cleaved in vitro at the caspase-3 consensus site DQDD(456) downward arrow SM. |
| GO:0005515 protein binding | IPI PMID:17606900 Thioredoxin is required for S-nitrosation of procaspase-3 an... | REMOVE | Summary: Thioredoxin-1 transnitrosates procaspase-3 and inhibits apoptosis; this is modification of procaspase-3 rather than a CASP3 molecular activity. Reason: The row captures a thioredoxin-procaspase-3 physical interaction. It does not support a more specific CASP3 function, so the generic protein binding assertion should be removed. Supporting Evidence: PMID:17606900 specific transnitrosation reaction between procaspase-3 and thioredoxin-1 (Trx) occurs in cultured human T cells |
| GO:0005515 protein binding | IPI PMID:18723680 Executioner caspase-3 and caspase-7 are functionally distinc... | MODIFY | Summary: Caspase-3 cleaves several natural substrates that are differentially processed by caspase-3 versus caspase-7. Reason: The paper experimentally distinguishes caspase-3 substrate proteolysis, so cysteine-type endopeptidase activity is the informative replacement for a generic substrate-binding row. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: PMID:18723680 Here we show that caspase-3 and caspase-7 exhibit differential activity toward multiple substrate proteins, including Bid, XIAP, gelsolin, caspase-6, and cochaperone p23. |
| GO:0005515 protein binding | IPI PMID:19273858 S-nitrosylation of XIAP compromises neuronal survival in Par... | REMOVE | Summary: S-nitrosylation impairs XIAP anticaspase-3 activity by blocking XIAP binding to caspase-3. Reason: This source describes regulation of XIAP's inhibitory binding to caspase-3. The CASP3 side is only the physical target of XIAP binding, so this should not remain as generic protein binding. Supporting Evidence: PMID:19273858 XIAP S-nitrosylation compromised its antiapoptotic function by inhibiting its anticaspase-3 activity. |
| GO:0005515 protein binding | IPI PMID:21726810 Caspase-2-mediated cleavage of Mdm2 creates a p53-induced po... | REMOVE | Summary: Mdm2 is established in this paper as a caspase-2 cleavage target; the CASP3 IPI does not support a more informative CASP3 MF. Reason: The cached full text centers on caspase-2-dependent Mdm2 cleavage, not a CASP3 activity. Any CASP3-Mdm2 contact in the source is therefore only a bare interaction row. Supporting Evidence: PMID:21726810 These data establish Mdm2 as a cleavage target of Caspase-2 |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | REMOVE | Summary: This row comes from a human liver yeast two-hybrid interactome map. Reason: The source is a large interaction screen and supplies no CASP3-specific catalytic or regulatory molecular function. The generic protein binding assertion should be removed under the current policy. Supporting Evidence: PMID:21988832 In this study, we map the interactions of an unbiased selection of 5026 human liver expression proteins by a yeast two-hybrid (Y2H) technology and establish a human liver protein interaction network (HLPN) |
| GO:0005515 protein binding | IPI PMID:23150525 Regulation of co- and post-translational myristoylation of p... | MODIFY | Summary: N-myristoyltransferases are caspase substrates during apoptosis, with NMT2 cleaved mainly by caspase-3. Reason: The NMT interaction is a substrate relationship resolved by cleavage, so the informative CASP3 activity is cysteine-type endopeptidase activity rather than generic protein binding. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: PMID:23150525 cleavage of NMT1 at Asp-72 precedes the cleavage of NMT2 by caspase-3 mainly at Asp-25. |
| GO:0005515 protein binding | IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ... | REMOVE | Summary: This row comes from systematic in situ proximity-ligation profiling of pathway protein-protein interactions. Reason: A pathway-scale proximity hit is a bare interaction assertion for CASP3 and does not support a more informative CASP3 molecular function. 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... | REMOVE | Summary: This row comes from the proteome-scale BioPlex 2.0 AP-MS interaction map. Reason: The source is a broad co-complex interactome screen. It does not by itself establish an informative CASP3 molecular function beyond a physical association. 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. | REMOVE | Summary: This row comes from HuRI, a systematic human binary interactome map. Reason: A yeast-two-hybrid HuRI edge is a bare interaction assertion and does not establish a specific CASP3 molecular activity. 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 ... | REMOVE | Summary: This row comes from a systematic neurodegenerative-disease protein interactome map. Reason: The source reports a candidate physical-interaction network, not a CASP3-specific catalytic or regulatory activity. The generic protein binding annotation should be removed. 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... | REMOVE | Summary: This row comes from a proteome-scale, cell-line-specific BioPlex AP-MS interaction network. Reason: The BioPlex interaction is a generic co-complex assertion that does not resolve a CASP3 molecular function more informative than protein binding. Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks. |
| GO:0005515 protein binding | IPI PMID:38884001 Mapping adipocyte interactome networks by HaloTag-enrichment... | REMOVE | Summary: This row comes from a HaloTag AP-MS adipocyte protein-complex screen. Reason: The source is a method-driven interactome map and does not support a CASP3 catalytic function or another specific CASP3 molecular activity. 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... | MODIFY | Summary: Apopain/CPP32 was purified as the protease responsible for PARP cleavage during apoptosis. Reason: PARP binding is a substrate context for the core caspase-3 protease activity. Replace the unqualified binding term with cysteine-type endopeptidase activity. Proposed replacements: cysteine-type endopeptidase activity 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: luteolysis: retain with the primary study's context and species limits. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. The traced rat corpus-luteum study measures luteal apoptosis over regression, uses an active-caspase-3 antibody, and perturbs ER stress with TUDCA in PGF2alpha-treated luteal cells. This supports the conserved apoptotic-effector contribution to structural luteolysis. It does not establish identical upstream endocrine control in humans, a direct steroidogenic activity, or universal necessity of CASP3 for every stage of luteal regression. Supporting Evidence: PMID:25332219 the expression levels of CHOP, caspase 12, and caspase 3 were increased during the process of CL regression. |
| GO:0001666 response to hypoxia | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: response to hypoxia: retain with the primary study's context and species limits. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. The rat donor evidence is an altitude-induced hippocampal injury study measuring caspase activity, active caspase-3 and apoptotic cells; its perturbations concern p75NTR/NMDA signaling. A second traced study, PMID:24089674, measures caspase-3 in hypoxic-ischemic neonatal rat brain after miR-210 manipulation. Retain conserved execution within a hypoxic-stress response as non-core, without attributing oxygen sensing or a direct human hippocampal experiment to CASP3. Supporting Evidence: PMID:18466900 Exposure to hypobaric hypoxia was found to progressively increase the number of TUNEL positive and Hoechst positive cells along with increase in caspase activity |
| GO:0002020 protease binding | IEA GO_REF:0000107 | UNDECIDED | Summary: The specific protease binding interaction is unresolved beyond the rat DISC association. Reason: Provenance: GO_REF:0000107 from UniProtKB:P55213, traced to PMID:17518537 in adult female Fischer rat spinal cord after injury. The rat donor annotation identifies a protease partner (RGD:620945, Casp8). The abstract places caspase-8 and caspase-3 in the SCI-associated DISC but does not expose a pair-specific binding assay that separates protease-substrate encounter from a stable interaction. Normal force retrieval remains abstract-only. The exact experimental distinction cannot be settled from that abstract, and no binding absence, wrong-protein error, or target-species loss is inferred. The source association is genuine; this uncertainty is about the molecular claim and its transfer, not the general apoptotic role of CASP3. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P55213 UNRESOLVED The rat donor annotation identifies a protease partner (RGD:620945, Casp8). The abstract places caspase-8 and caspase-3 in the SCI-associated DISC but does not expose a pair-specific binding assay that separates protease-substrate encounter from a stable interaction. Full assay details remain inaccessible in the normally fetched source. Supporting Evidence: PMID:17518537 SCI resulted in FasL and Fas translocation into membrane raft microdomains where Fas associates with the adaptor proteins Fas-associated death domain (FADD), caspase-8, cellular FLIP long form (cFLIPL ), and caspase-3, forming a death-inducing signaling complex (DISC). |
| GO:0004175 endopeptidase activity | IEA GO_REF:0000107 | MODIFY | Summary: CASP3 cleaves internal peptide bonds using a catalytic cysteine. Reason: CASP3 cleaves internal peptide bonds using a catalytic cysteine. Asp at the substrate cleavage site specifies recognition, not an aspartic catalytic mechanism. The supported specific activity is cysteine-type endopeptidase activity. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Belongs to the peptidase C14A family. file:human/CASP3/CASP3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0004190 aspartic-type endopeptidase activity | IEA GO_REF:0000107 | MODIFY | Summary: CASP3 cleaves internal peptide bonds using a catalytic cysteine. Reason: CASP3 cleaves internal peptide bonds using a catalytic cysteine. Asp at the substrate cleavage site specifies recognition, not an aspartic catalytic mechanism. The supported specific activity is cysteine-type endopeptidase activity. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Belongs to the peptidase C14A family. file:human/CASP3/CASP3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| 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 | UNDECIDED | Summary: The specific death receptor binding interaction is unresolved beyond the rat DISC association. Reason: Provenance: GO_REF:0000107 from UniProtKB:P55213, traced to PMID:17518537 in adult female Fischer rat spinal cord after injury. The rat donor evidence concerns Fas/CD95 association after spinal cord injury. Its abstract describes a DISC containing Fas, FADD, caspase-8, cFLIP and caspase-3, but does not distinguish a caspase-3/Fas binding interaction from association bridged through the complex. Normal force retrieval remains abstract-only. The exact experimental distinction cannot be settled from that abstract, and no binding absence, wrong-protein error, or target-species loss is inferred. The source association is genuine; this uncertainty is about the molecular claim and its transfer, not the general apoptotic role of CASP3. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P55213 UNRESOLVED The rat donor evidence concerns Fas/CD95 association after spinal cord injury. Its abstract describes a DISC containing Fas, FADD, caspase-8, cFLIP and caspase-3, but does not distinguish a caspase-3/Fas binding interaction from association bridged through the complex. Full assay details remain inaccessible in the normally fetched source. Supporting Evidence: PMID:17518537 SCI resulted in FasL and Fas translocation into membrane raft microdomains where Fas associates with the adaptor proteins Fas-associated death domain (FADD), caspase-8, cellular FLIP long form (cFLIPL ), and caspase-3, forming a death-inducing signaling complex (DISC). |
| GO:0005634 nucleus | IEA GO_REF:0000107 | ACCEPT | Summary: CASP3 has a supported nuclear pool and cleaves nuclear substrates. Reason: CASP3 has a supported nuclear pool and cleaves nuclear substrates. Retain nucleus because the available localization evidence is not uniformly resolved to a single nuclear subcompartment. Supporting Evidence: PMID:22253444 caspase-3 active fragments can also be evidenced in the nuclear fractions after STP treatment |
| GO:0007413 axonal fasciculation | IEA GO_REF:0000107 | UNDECIDED | Summary: axonal fasciculation: the precise claim remains unresolved for a specified source-level reason. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. The rat source PMID:25898930 examines PrP106-126-induced spinal-neuron axonal degeneration, DR6 knockdown and caspase-6 inhibition/siRNA. Its accessible abstract localizes cleaved caspase-3 to somata and reports axonal protection from caspase-6 manipulation. GO:0007413 specifically denotes collecting axons into bundles, not any axonal injury phenotype. The normal force-fetch remained abstract-only; it cannot establish whether a separate caspase-3-dependent bundling assay appears in the full text. Retain uncertainty about this exact transfer, not a claim that CASP3 lacks any neuronal function or that the curator confused paralogs. Supporting Evidence: PMID:25898930 cleaved caspase-3 is only enriched in cell bodies, but cleaved caspase-6 is expressed in both cell bodies and axons. |
| 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. Independent source audit: Native mouse Alzheimer-model synaptic/memory phenotype; not evidence of an obligatory role in all learning. When the cited work is in mouse or rat, it supports conserved contextual inference rather than a direct human experiment. Supporting Evidence: PMID:21151119 pharmacological inhibition of caspase-3 activity in Tg2576 mice rescued |
| GO:0008233 peptidase activity | IEA GO_REF:0000107 | MODIFY | Summary: CASP3 cleaves internal peptide bonds using a catalytic cysteine. Reason: CASP3 cleaves internal peptide bonds using a catalytic cysteine. Asp at the substrate cleavage site specifies recognition, not an aspartic catalytic mechanism. The supported specific activity is cysteine-type endopeptidase activity. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Belongs to the peptidase C14A family. file:human/CASP3/CASP3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| 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. Independent source audit: Native mouse hypertonic medullary apoptosis supports a contextual execution response; the initiating perturbation concerns COX-2/Bad. When the cited work is in mouse or rat, it supports conserved contextual inference rather than a direct human experiment. Supporting Evidence: PMID:21716255 The abundance of cleaved caspase-3, a marker of apoptosis, was significantly higher in papillary homogenates |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: response to xenobiotic stimulus: retain with the primary study's context and species limits. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. The full rat donor study measures myocardial caspase-3 protein expression during baicalin/octreotide treatment of severe acute pancreatitis. GO:0009410 includes changes in enzyme production and gene expression after a xenobiotic; it does not require that CASP3 be the drug receptor or upstream sensor. Retain the broad contextual response inference, not the authors' cardioprotection mechanism as a CASP3-specific function. Protein abundance is not itself proof of catalytic activation or apoptotic myocardial death; the paper reports very little myocardial apoptosis. Supporting Evidence: PMID:18274634 The levels of myocardial tissue Caspase-3 protein expression in the Baicalin-treated group at the points of 6 hours and 12 hours were significantly greater than those of the sham operation group |
| GO:0009749 response to glucose | IEA GO_REF:0000107 | UNDECIDED | Summary: response to glucose: the precise claim remains unresolved for a specified source-level reason. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. The traced rat donor reference concerns HO-1/carbon monoxide/adiponectin treatment in streptozotocin diabetes. Its cached abstract explicitly describes TNF-alpha-induced endothelial caspase-3 activity, not a defined glucose-exposure assay. GO:0009749 requires a glucose stimulus; diabetes alone does not identify that stimulus. The full experimental article remains unavailable in the inspected cache, so a glucose-specific experiment cannot be confirmed or excluded. Retain UNDECIDED rather than treat a diabetic-model context as direct glucose-response evidence or assert that the annotation is false. Supporting Evidence: PMID:19356108 Increased adiponectin levels were associated with a decrease in TNF-alpha-induced ICAM-1 and VCAM-1 and caspase 3 activity in endothelial cells |
| GO:0010038 response to metal ion | IEA GO_REF:0000107 | MODIFY | Summary: response to metal ion: refine to the independently supported cobalt response. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. The traced source PMID:18483861 treats cultured rat cardiomyocytes with the platinum drug carboplatin; it does not by itself isolate a free-metal-ion stimulus. Independent PMID:18598848 directly tests cobalt chloride in rat PC12 cells and measures the caspase cascade. Thus the broad metal-response claim is supported at least for cobalt, and is refined to the already-present response-to-cobalt-ion term, rather than removed. This neither attributes metal binding to CASP3 nor equates carboplatin exposure with isolated platinum-ion sensing. Proposed replacements: response to cobalt ion Supporting Evidence: PMID:18598848 limited the activities of the caspase cascades, such as caspase-8, -9 and -3. |
| GO:0010165 response to X-ray | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: response to X-ray: retain with the primary study's context and species limits. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. The rat source compares locally X-irradiated nephritic kidneys with nonirradiated nephritic controls and measures increased active caspase-3/7 together with tissue apoptosis. Retain a conserved executioner response to irradiation as non-core. This is not DNA-repair activity, a direct human kidney experiment, or proof that CASP3 alone mediates the therapeutic effect. Supporting Evidence: PMID:18239382 Western blot analysis showed marked increase in active caspase 3 and active caspase 7 expression in irradiated kidneys compared with NTS injection only. |
| GO:0014069 postsynaptic density | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: postsynaptic density: retain with the primary study's context and species limits. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P70677|ensembl:ENSMUSP00000147767. This cellular-component transfer traces to mouse Casp3 and PMID:21151119, not to the rat stimulus-response papers. The donor study detects local caspase-3 activity in hippocampal spines and connects it to calcineurin-dependent loss of postsynaptic GluR1. Retain the experimentally curated postsynaptic compartment as a comparative non-core localization. The available abstract supports the local synaptic pool but does not reproduce the full postsynaptic-density fractionation/imaging methods; no direct human localization assay is claimed. Supporting Evidence: PMID:21151119 non-apoptotic baseline caspase-3 activity in hippocampal dendritic spines |
| GO:0016005 phospholipase A2 activator activity | IEA GO_REF:0000107 | REMOVE | Summary: Phospholipase activation downstream of caspase cleavage does not establish the noncovalent molecular-function-regulator activity represented by this enzyme-activator descendant. Reason: Phospholipase activation downstream of caspase cleavage does not establish the noncovalent molecular-function-regulator activity represented by this enzyme-activator descendant. This does not deny proteolytic activation of phospholipase pathways; the protease activity is retained separately. 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 | UNDECIDED | Summary: hippocampus development: the precise claim remains unresolved for a specified source-level reason. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. The rat donor study measures active/precursor caspase-3 distribution, nuclear morphology and developmental age in CA1, CA3 and dentate gyrus. This is genuine region-specific expression evidence, but the available abstract does not establish the precise contribution of CASP3 to hippocampal anatomical development, as distinct from expression in developing tissue or removal of individual cells. The full article has not been available in the inspected cache. Preserve this contextual process claim as unresolved without rejecting the measured expression or inferring target-specific loss. Supporting Evidence: PMID:18459132 there were specific spatio-temporal patterns of expression of active and precursor caspase-3 in the postnatally developing rat hippocampal subregions |
| GO:0030163 protein catabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: CASP3 directly cleaves and dismantles many protein substrates during apoptotic execution. Reason: CASP3 directly cleaves and dismantles many protein substrates during apoptotic execution. This supports protein catabolic participation, while regulatory cleavage of individual substrates need not imply their complete degradation. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins |
| GO:0030182 neuron differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: neuron differentiation: retain with the primary study's context and species limits. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. The rat donor publication PMID:15248196 distinguishes active-caspase-3-positive proliferating/differentiating cerebellar cells from apoptotic cells. Independent PMID:16103108 goes beyond colocalization: caspase activity rises in nonapoptotic differentiating neuronal populations and peptide inhibition impairs neurosphere differentiation. The inhibitor experiment is not a caspase-3-specific genetic knockout, but together with the PAINT/conserved caspase context it supports a non-core neuronal differentiation role, not universal dependence of all neurons. The abstract does not specify the neurosphere species, so no direct human or mouse assay is invented. Supporting Evidence: PMID:16103108 peptide inhibition of protease activity effectively inhibits the differentiation process in a cultured neurosphere model. PMID:15248196 Proliferative (Ki67-positive) and differentiated (TUJ1-positive) cells within the EGL exhibited a cytosolic expression of caspase-3 |
| GO:0031264 death-inducing signaling complex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The PAINT-supported death-inducing signaling complex association need not imply an initiator-caspase role. Reason: The PAINT-supported death-inducing signaling complex association need not imply an initiator-caspase role. PMID:17518537 reports a Fas/FADD/caspase-8/c-FLIP/caspase-3 complex in rat spinal injury; retain the conserved contextual association without asserting direct binary death-receptor binding. Supporting Evidence: |
| GO:0031647 regulation of protein stability | IEA GO_REF:0000107 | 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:0032025 response to cobalt ion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: response to cobalt ion: retain with the primary study's context and species limits. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. The rat PC12 donor experiment directly applies CoCl2 and measures apoptotic caspase activities, DNA fragmentation and their attenuation by estradiol. Retain the conserved stress-execution response to cobalt as non-core. The evidence concerns chemically induced hypoxic stress, not a cobalt cofactor requirement, direct metal receptor, or a native human tissue assay. Supporting Evidence: PMID:18598848 limited the activities of the caspase cascades, such as caspase-8, -9 and -3. |
| GO:0032355 response to estradiol | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: response to estradiol: retain with the primary study's context and species limits. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. The same traced PC12 study tests estradiol pretreatment and measures decreased caspase-cascade activity under cobalt stress. A response term can include reduced activity; it does not imply that estradiol activates CASP3. Retain this conserved, context-dependent modulation as non-core, without assigning estrogen-receptor activity or claiming an unchallenged human neuronal response. Supporting Evidence: PMID:18598848 Pre-incubation of estradiol prior to CoCl(2) treatment attenuated CoCl(2)-mediated the reactive oxygen species (ROS) production and limited the activities of the caspase cascades |
| GO:0032496 response to lipopolysaccharide | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: response to lipopolysaccharide: retain with the primary study's context and species limits. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. The rat donor study injects LPS into pregnant animals and measures a time-ordered caspase cascade and cleaved caspase-3 in fetal brain. Retain execution downstream of this inflammatory stimulus as a non-core comparative response. Maternal/fetal injury is not direct LPS recognition by CASP3, and the result must not be generalized to all tissues or treated as an innate immune receptor mechanism. Normal refresh still lacks complete full text; the specific activation time course is explicit in the abstract. Supporting Evidence: PMID:18289516 Caspase activity assays demonstrated rapid increases in (i) caspases-9 and -10 within 1 h, (ii) caspase-8 at 2 h and (iii) caspase-3 at 4 h. |
| 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. Independent source audit: Native mouse spinal injury provides glial-apoptosis context; the principal genetic perturbation in this paper is Bax. When the cited work is in mouse or rat, it supports conserved contextual inference rather than a direct human experiment. Supporting Evidence: PMID:14507967 anti-activated caspase-3 characterized the ongoing oligodendrocyte death |
| GO:0035094 response to nicotine | IEA GO_REF:0000107 | UNDECIDED | Summary: response to nicotine: the precise claim remains unresolved for a specified source-level reason. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. The rat PC12 source tests nicotine during tunicamycin versus thapsigargin ER stress. Its accessible abstract reports GRP78, caspase-12, XBP1 and ATF6 changes, but does not expose a caspase-3-specific result. This is not a wrong-paralog verdict: CASP3 could have been assayed in the full text, which was not available in the inspected cache. The exact CASP3 nicotine-response transfer therefore remains unresolved, with a source and specific missing assay identified. Supporting Evidence: PMID:18477628 nicotine reduced the activation of caspase-12 in Tm-treated cells, but not in Tg-treated cells. |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000107 | MODIFY | Summary: CASP3 directly participates in proteolytic apoptotic signaling. Reason: CASP3 directly participates in proteolytic apoptotic signaling. Refine the broad intracellular signaling annotation to the supported apoptotic signaling pathway; being downstream does not mean it performs no signaling step. Proposed replacements: apoptotic signaling pathway Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins |
| GO:0036269 swimming behavior | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: swimming behavior: the transferred behavioral claim exceeds the donor experiment. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. The complete rat source measures Morris-water-maze performance after splenectomy and IGF1 treatment while measuring hippocampal caspase-3 as an expression marker. It does not manipulate CASP3 to establish a locomotor swimming role; moreover, the assay is interpreted as cognitive performance, not a CASP3-dependent swimming motor program. GO:0036269 specifically denotes the locomotory response of swimming. Transferring this assay-associated marker into a human swimming-behavior function overstates the source context. This does not assert that caspase-3 cannot influence neurons, cognition or behavior in other experiments. Supporting Evidence: PMID:33574912 The current study assessed the therapeutic effects of insulin-like growth factor-1 (IGF-1) on POCD in aged rats and explored the underlying mechanisms. |
| GO:0042542 response to hydrogen peroxide | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: response to hydrogen peroxide: retain with the primary study's context and species limits. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. The donor experiment uses rat H9c2 cardiomyocytes and directly measures peroxide-induced caspase-3 cleavage/activity and protection after short leptin pretreatment. Retain the conserved oxidative-stress execution response as non-core, not peroxide detoxification or sensing. The 1-hour versus 24-hour pretreatment difference is a source-specific limitation, not a universal leptin/CASP3 relationship. Supporting Evidence: PMID:18479463 leptin prevented H(2)O(2)-induced increases in caspase-3 cleavage and activity |
| GO:0043025 neuronal cell body | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: neuronal cell body: retain with the primary study's context and species limits. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. Unlike the axon-bundling process claim transferred from the same paper, this cellular-component assertion has direct support in the rat source abstract: cleaved caspase-3 is enriched in neuronal cell bodies during prion-peptide injury. Retain the conserved somatic neuronal pool as a non-core localization. The experimental condition does not establish exclusive somatic localization in every neuron or direct localization in the target species. Supporting Evidence: PMID:25898930 cleaved caspase-3 is only enriched in cell bodies |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000120 | ACCEPT | Summary: CASP3 supplies both apoptotic execution and proteolytic amplification. Reason: Human CASP3 cleaves downstream substrates and other caspases, supporting a direct positive contribution to apoptosis. Native mouse PMID:16469926 provides comparative feedback evidence for the Casp3/Casp7 axis promoting early cytochrome-c release; it is not presented as a human knockout. Retain the regulatory claim independently of the execution-phase claim: GO:0097194 is not an is_a/part_of descendant of GO:0043065, and broad positive regulation is not peripheral merely because execution is a more specific stage. Full PMID:18723680 independently compares recombinant human and murine enzymes and resolves CASP3-driven propagation of the caspase activation cascade, strengthening the amplification interpretation beyond a family annotation. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Cleaves and activates caspase-6, -7 and -9 PMID:16469926 This suggests a pathway from caspase 9 through caspases 3 and 7 that promotes cytochrome c release at early time points. PMID:18723680 These data suggest that caspase-3 is a more efficient enzyme than caspase-7 in terms of its ability to propagate the caspase activation cascade. |
| GO:0043200 response to amino acid | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: response to amino acid: retain with the primary study's context and species limits. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. The full rat spinal-cord study applies glutamate and measures activated caspase-3 after excitotoxic exposure. Retain the amino-acid-stimulus response in this injury context, not amino-acid biosynthesis or nutrient sensing. The paper explicitly notes persistent staining when little further cell loss occurs, so caspase-3 staining is not equated with inevitable rapid apoptosis or a universal human spinal injury mechanism. Supporting Evidence: PMID:18423997 The nuclei of many cells strongly and specifically stained for activated caspase-3, an indicator of apoptosis, in response to exposure to glutamate. |
| 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. Independent source audit: Native mouse developmental neuronal regulation. When the cited work is in mouse or rat, it supports conserved contextual inference rather than a direct human experiment. Supporting Evidence: PMID:10618441 it independently regulates apoptosis of neuronal founder cells |
| 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). Independent source audit: Native mouse developmental neuronal apoptosis; necessity varies among neuronal populations. When the cited work is in mouse or rat, it supports conserved contextual inference rather than a direct human experiment. Supporting Evidence: PMID:10618441 caspase-3 deficiency abrogated the |
| GO:0044877 protein-containing complex binding | IEA GO_REF:0000107 | UNDECIDED | Summary: The specific protein-containing complex binding interaction is unresolved beyond the rat DISC association. Reason: Provenance: GO_REF:0000107 from UniProtKB:P55213, traced to PMID:17518537 in adult female Fischer rat spinal cord after injury. The rat donor evidence describes recruitment into a Fas-associated DISC. Its abstract does not resolve whether the measured event establishes binding of caspase-3 to the assembled macromolecular complex, versus membership or co-recruitment inferred from its component associations. Normal force retrieval remains abstract-only. The exact experimental distinction cannot be settled from that abstract, and no binding absence, wrong-protein error, or target-species loss is inferred. The source association is genuine; this uncertainty is about the molecular claim and its transfer, not the general apoptotic role of CASP3. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P55213 UNRESOLVED The rat donor evidence describes recruitment into a Fas-associated DISC. Its abstract does not resolve whether the measured event establishes binding of caspase-3 to the assembled macromolecular complex, versus membership or co-recruitment inferred from its component associations. Full assay details remain inaccessible in the normally fetched source. Supporting Evidence: PMID:17518537 SCI resulted in FasL and Fas translocation into membrane raft microdomains where Fas associates with the adaptor proteins Fas-associated death domain (FADD), caspase-8, cellular FLIP long form (cFLIPL ), and caspase-3, forming a death-inducing signaling complex (DISC). |
| GO:0045471 response to ethanol | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: response to ethanol: retain with the primary study's context and species limits. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. The full rat hippocampal study detects increased total caspase-3 after repeated ethanol exposure but no detectable cleaved caspase-3. The second donor PMID:30926569 reports ethanol-modulated caspase-3 expression in rat kidney/liver. A response term includes enzyme-production/expression changes, so retain the contextual response without claiming activation in the hippocampal experiment. Do not relabel the first study as evidence that CASP3 executes the observed neurodegeneration; the authors instead discuss nonapoptotic pathways. Supporting Evidence: PMID:23102656 caspase-3 levels were 2-fold greater PMID:23102656 cleaved caspase-3 was undetectable in the HC of either ethanol-intoxicated or control rats. |
| 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. Independent source audit: Myogenic context supports a differentiated nonapoptotic role; the abstract alone does not establish universality. When the cited work is in mouse or rat, it supports conserved contextual inference rather than a direct human experiment. Supporting Evidence: PMID:23727203 caspase-3 activity, an important factor for myogenic differentiation, was enhanced by Nek5 cleavage |
| GO:0051384 response to glucocorticoid | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: response to glucocorticoid: retain with the primary study's context and species limits. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. The full donor study measures thymic caspase-3 immunostaining and apoptotic index after dexamethasone treatment in rats with severe pancreatitis. Retain this contextual glucocorticoid response as a comparative non-core claim. Its caspase-3 measurement is protein abundance rather than a purified activity or CASP3-specific perturbation assay, and it does not establish direct glucocorticoid-receptor binding or universal steroid responses. Supporting Evidence: PMID:18288275 The treated group in Caspase-3 protein expression of thymus significantly exceeded the model group at 12 hours. |
| GO:0071887 leukocyte apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: leukocyte apoptotic process: retain with the primary study's context and species limits. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. The traced donor study uses the rat LT12 acute myeloid leukemia line and photodynamic therapy, with apoptosis measurements and sequential cleavage of effector caspases/PARP. The activated executioner contributes directly to leukocyte-lineage cell apoptosis; retain that conserved contextual process as non-core. This does not prove the same photosensitizer response in every primary leukocyte or a universal requirement for CASP3 rather than CASP7. Supporting Evidence: PMID:26861981 cleaved caspase-3 delayed to 6-12 h PMID:26861981 rat acute myeloid leukemia cell line LT12 |
| GO:0072347 response to anesthetic | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: response to anesthetic: retain with the primary study's context and species limits. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. The neonatal-rat source exposes pups to sevoflurane and measures cleaved caspase-3 immunohistochemically alongside neuronal apoptosis, with CAPE as the intervention. Retain the comparative stress-execution response to this anesthetic as non-core. The result is not anesthetic sensing, a claim that all anesthetics are neurotoxic, or direct evidence in human infants. Supporting Evidence: PMID:27498600 CAPE significantly reduced sevofluraneβinduced apoptosis, downregulated the expression levels of caspases |
| GO:0098693 regulation of synaptic vesicle cycle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: regulation of synaptic vesicle cycle: retain with the primary study's context and species limits. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P70677|ensembl:ENSMUSP00000147767. This transfer traces to native mouse hippocampal experiments in PMID:33303681. Full text tests caspase inhibition/activation, autophagic flux and activity-induced vesicle-pool depletion/recovery. Retain the conserved nonapoptotic modulation as non-core, without making CASP3 a structural vesicle protein or assuming that every synapse uses this regulatory route. Pharmacological pathway measurements do not establish an exclusive CASP3 substrate mechanism in human terminals. Supporting Evidence: PMID:33303681 the BAD-BAX-caspase-3 pathway regulates autophagy, which in turn limits the size of synaptic vesicle pools |
| 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. Independent source audit: Native mouse/neuron data support local nonlethal synaptic remodeling. When the cited work is in mouse or rat, it supports conserved contextual inference rather than a direct human experiment. Supporting Evidence: PMID:24478350 local elimination of dendritic spines and dendrite retraction occurred |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: glutamatergic synapse: retain with the primary study's context and species limits. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P70677|ensembl:ENSMUSP00000147767. This cellular-component transfer traces to mouse hippocampal spines in PMID:21151119, where local caspase-3 activity, calcineurin and AMPA-receptor changes accompany altered glutamatergic transmission. Retain a comparative non-core synaptic pool, not a claim that all CASP3 resides at glutamatergic synapses or that it is a neurotransmitter receptor. The source is a mouse model, not a direct human localization assay. Supporting Evidence: PMID:21151119 removal of the GluR1 subunit of AMPA-type receptor from postsynaptic sites. |
| GO:1902004 positive regulation of amyloid-beta formation | IEA GO_REF:0000107 | 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:1990418 response to insulin-like growth factor stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: response to insulin-like growth factor stimulus: retain with the primary study's context and species limits. Reason: Provenance trace: GO_REF:0000107 via UniProtKB:P55213|ensembl:ENSRNOP00000014096. The full donor study administers IGF-1 to aged splenectomized rats and detects hippocampal caspase-3 expression changes. Response-to-stimulus terms include changes in enzyme production/gene expression, so retain this contextual expression response as non-core. It does not demonstrate that CASP3 is an IGF receptor, directly transduces IGF1 signaling, or mediates the observed behavioral rescue. Supporting Evidence: PMID:33574912 IGF-1 downregulated caspase-3 and Bax, and upregulated Bcl2 following splenectomy |
| GO:0032880 regulation of protein localization | IMP PMID:17559062 The most widespread desmosomal cadherin, desmoglein 2, is a ... | KEEP AS NON CORE | Summary: Apoptotic DSG2 cleavage redistributes its cytoplasmic fragment and disrupts junctional association. Reason: PMID:17559062 explicitly reports DSG2 cleavage, cytosolic appearance of a 70-kDa fragment, loss of cell-surface staining, and plakoglobin cleavage/detachment in staurosporine-treated human HaCaT and HT-29 cells. z-DEVD-fmk preserves the surface labeling. This supports a specific proteolysis-dependent localization outcome, not a general protein-transport activity. The abstract supplies those results; unavailable full methods are not invented. Supporting Evidence: PMID:17559062 The proteolytic processing of full-length Dsg2 resulted in the appearance of a 70-kDa fragment which was released into the cytosol. |
| 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). Independent source audit: Native mouse/neuron data support local nonlethal synaptic remodeling. When the cited work is in mouse or rat, it supports conserved contextual inference rather than a direct human experiment. Supporting Evidence: PMID:24478350 local elimination of dendritic spines and dendrite retraction occurred |
| 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 ... | MODIFY | Summary: CASP3 acts in a soluble cytosolic pool during proteolytic signaling. Reason: CASP3 acts in a soluble cytosolic pool during proteolytic signaling. Refine the broad cytoplasm annotation to the supported cytosol compartment; nuclear or extracellular pools are represented separately. Proposed replacements: cytosol Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Cytoplasm |
| 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: CASP3 proteolysis directly suppresses NF-kappaB-dependent cytokine production. Reason: Full PMID:36002459 combines human CASP3 knockdown/knockout, purified human enzyme cleavage of p65/RelA, RelB and c-Rel, and cleavage-resistant substrate mutants that resist cytokine suppression. The native mouse macrophage and knockout-mouse results corroborate the function across species, but the construct assays retain their identity. This is direct proteolytic regulation, not merely fewer living cytokine-producing cells. Supporting Evidence: PMID:36002459 These recombinant proteins were then incubated with purified active human recombinant caspase-3. PMID:36002459 the cytokine production induced by RelBD205A was resistant to caspase-3-mediated repression |
| 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-ΞΊBs in both Mammals and Flies. |
| GO:0006915 apoptotic process | IDA PMID:34480022 Endotoxin stabilizes protein arginine methyltransferase 4 (P... | MODIFY | Summary: CASP3 directly performs proteolytic steps of apoptotic execution. Reason: The target effector protease directly performs the controlled substrate breakdown of apoptotic execution. Refine apoptotic process to the already represented GO:0097194 execution phase, supported by target-specific substrate/nuclear-change evidence rather than C14A membership, which also includes initiator and inflammatory caspases. Human-enzyme PMID:18723680 directly compares substrate cleavage by executioner caspases. The original full source measures activated CASP3 after PRMT4/LPS manipulation in human and mouse epithelia; independent execution biochemistry supports the refinement beyond the activation marker. Proposed replacements: execution phase of apoptosis Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins 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:0070269 pyroptotic inflammatory response | IDA PMID:36426955 TRIM21 Regulates Virus-Induced Cell Pyroptosis through Polyu... | KEEP AS NON CORE | Summary: Virus-triggered CASP3/GSDME activity can produce a pyroptotic inflammatory response. Reason: The original PMID:36426955 abstract explicitly connects TRIM21/ISG12a-driven caspase-3 activation to GSDME cleavage and membrane perforation during viral infection. Independent full 33852854 demonstrates that GSDME can permit IL-1beta release in sublytic as well as overtly lytic phases. Retain the broader inflammatory-response outcome as conditional non-core context, while the direct GSDME-activating proteolysis is separately a supported core activity. Neither cell lysis alone nor every apoptotic CASP3 activation implies an identical cytokine response. Supporting Evidence: PMID:36426955 Gasdermin E (GSDME) is specifically cleaved by caspase 3 upon viral infection PMID:33852854 Endogenous GSDME activation permitted sublytic, continuous interleukin-1Ξ² (IL-1Ξ²) release and membrane leakage |
| 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: CASP3-mediated GSDME cleavage can promote IL-1beta release before or during lysis. Reason: Full PMID:33852854 distinguishes endogenous GSDME-dependent sublytic IL-1beta release from overt pyroptosis at higher GSDME abundance. Human THP-1 knockout/rescue and cleavage-resistant GSDME establish the route; the cross-species iBMM rescue uses human GSDME, not native mouse GSDME. Accept the positive-regulatory mechanism with those expression and assay boundaries rather than equating all inflammatory secretion with cell lysis. Supporting Evidence: PMID:33852854 Endogenous GSDME activation permitted sublytic, continuous interleukin-1Ξ² (IL-1Ξ²) release and membrane leakage |
| GO:0140639 positive regulation of pyroptotic inflammatory response | IDA PMID:35594856 Human NLRP1 is a sensor of pathogenic coronavirus 3CL protea... | ACCEPT | Summary: CASP3/GSDME supplies an alternative inflammatory-death route in infected human epithelia. Reason: Full PMID:35594856 detects caspase activation and GSDME processing in SARS-CoV-2-infected human epithelial models and shows reduced LDH release after CASP3 or GSDME genetic removal in engineered A549 cells. The route compensates for inefficient GSDMD activation and depends on epithelial context; it does not make CASP3 the universal NLRP1 sensor or every inflammasome executor. Supporting Evidence: PMID:35594856 both genetic removal caspase-3 and GSDME improved cell survival upon SARS-CoV-2 infection |
| 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... | MODIFY | Summary: CASP3 acts in a soluble cytosolic pool during proteolytic signaling. Reason: CASP3 acts in a soluble cytosolic pool during proteolytic signaling. Refine the broad cytoplasm annotation to the supported cytosol compartment; nuclear or extracellular pools are represented separately. Proposed replacements: cytosol Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Cytoplasm |
| GO:0097193 intrinsic apoptotic signaling pathway | IMP PMID:15565177 A novel mitochondrial protein DIP mediates E2F1-induced apop... | ACCEPT | Summary: CASP3 participates in intrinsic-apoptosis signaling and its amplification. Reason: PMID:15565177 reports mitochondrial DIP/E2F1-induced apoptosis with caspase-3 activation and PARP cleavage; its accessible abstract primarily perturbs DIP rather than CASP3. The conserved feedback contribution is independently supported by native mouse Casp3/Casp7 experiments in full 16469926, which delay early mitochondrial events when both effectors are absent. This supports the existing signaling claim with an explicit comparative boundary; it is not justified simply by equating downstream execution with the GO pathway that ends at execution onset. Supporting Evidence: PMID:15565177 typical apoptotic features such as caspase-3 activation and cleavage of poly(ADP-ribose)-polymerase PMID:16469926 This suggests a pathway from caspase 9 through caspases 3 and 7 that promotes cytochrome c release at early time points. |
| 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... | ACCEPT | Summary: CASP3 has a supported nuclear pool and cleaves nuclear substrates. Reason: CASP3 has a supported nuclear pool and cleaves nuclear substrates. Retain nucleus because the available localization evidence is not uniformly resolved to a single nuclear subcompartment. Supporting Evidence: PMID:22253444 caspase-3 active fragments can also be evidenced in the nuclear fractions after STP treatment |
| GO:0030163 protein catabolic process | IDA PMID:16374543 Nuclear caspase-3 and caspase-7 activation, and poly(ADP-rib... | ACCEPT | Summary: CASP3 directly cleaves and dismantles many protein substrates during apoptotic execution. Reason: CASP3 directly cleaves and dismantles many protein substrates during apoptotic execution. This supports protein catabolic participation, while regulatory cleavage of individual substrates need not imply their complete degradation. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins |
| 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... | MODIFY | Summary: CASP3 cleaves internal peptide bonds using a catalytic cysteine. Reason: CASP3 cleaves internal peptide bonds using a catalytic cysteine. Asp at the substrate cleavage site specifies recognition, not an aspartic catalytic mechanism. The supported specific activity is cysteine-type endopeptidase activity. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Belongs to the peptidase C14A family. file:human/CASP3/CASP3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0005515 protein binding | IPI PMID:15246877 S-nitrosation of thioredoxin in the nitrogen monoxide/supero... | UNDECIDED | Summary: The original CASP3-thioredoxin interaction assay remains inaccessible. Reason: Normal force retrieval of PMID:15246877 remains abstract-only. It describes S-nitrosation of thioredoxin and dissociation/activation of ASK1 in the NO/superoxide system, but does not expose the CASP3 interaction experiment underlying this IPI row. The original full text may contain that experiment; its absence from the abstract is not evidence of wrong-gene attribution. Preserve uncertainty rather than remove a binding assertion whose precise evidence cannot be adjudicated. Supporting Evidence: PMID:15246877 N2O3-dependent S-nitrosation of Trx at approximately 2-fold of NO excess compared to the superoxide amount resulted in dissociation and activation of apoptosis signal regulating kinase 1 (ASK1). |
| GO:0006508 proteolysis | IDA PMID:17553422 Depletion of GGA3 stabilizes BACE and enhances beta-secretas... | ACCEPT | Summary: CASP3 directly catalyzes proteolysis of diverse substrates. Reason: CASP3 directly catalyzes proteolysis of diverse substrates. This process is core and spans destructive and regulatory cleavage, so no single narrower protein-processing process replaces its full scope. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Belongs to the peptidase C14A family. file:human/CASP3/CASP3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| 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... | MODIFY | Summary: CASP3 directly performs proteolytic steps of apoptotic execution. Reason: The target effector protease directly performs the controlled substrate breakdown of apoptotic execution. Refine apoptotic process to the already represented GO:0097194 execution phase, supported by target-specific substrate/nuclear-change evidence rather than C14A membership, which also includes initiator and inflammatory caspases. Human-enzyme PMID:18723680 directly compares substrate cleavage by executioner caspases. The original DIP/E2F1 source reports CASP3 activation and PARP cleavage; DIP is the directly perturbed factor in the accessible abstract. Proposed replacements: execution phase of apoptosis Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins 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: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... | MODIFY | Summary: CASP3 cleaves internal peptide bonds using a catalytic cysteine. Reason: CASP3 cleaves internal peptide bonds using a catalytic cysteine. Asp at the substrate cleavage site specifies recognition, not an aspartic catalytic mechanism. The supported specific activity is cysteine-type endopeptidase activity. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Belongs to the peptidase C14A family. file:human/CASP3/CASP3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| 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 ... | UNDECIDED | Summary: The CASP3 step within NT-3/TrkC receptor signaling remains unresolved. Reason: PMID:23954828 separates mouse DRG expression/colocalization from HEK293T experiments in which TrkC induces apoptosis, NT-3 protects, and Dok5 knockdown changes caspase-3 activity. The normal force retrieval remains abstract-only. Those results establish a caspase readout downstream of the survival/death manipulation, but do not expose the experiment distinguishing a CASP3-performed receptor-signaling step from downstream apoptotic execution. No absence of CASP3 function or false curator assignment is inferred; the precise pathway participation and target-species transfer remain unresolved. Supporting Evidence: PMID:23954828 siRNA knockdown of Dok5 expression partially prevented the protection of NT-3 against TrkC-induced apoptosis by regulating the activity of caspase-3. |
| 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 | ACCEPT | Summary: CASP3 acts on nuclear substrates in the nucleoplasm during apoptosis. Reason: CASP3 acts on nuclear substrates in the nucleoplasm during apoptosis. This is a site of its core proteolytic function, not merely an incidental location. Supporting Evidence: PMID:22253444 caspase-3 active fragments can also be evidenced in the nuclear fractions after STP treatment |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-211190 | ACCEPT | Summary: CASP3 acts on nuclear substrates in the nucleoplasm during apoptosis. Reason: CASP3 acts on nuclear substrates in the nucleoplasm during apoptosis. This is a site of its core proteolytic function, not merely an incidental location. Supporting Evidence: PMID:22253444 caspase-3 active fragments can also be evidenced in the nuclear fractions after STP treatment |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-211219 | ACCEPT | Summary: CASP3 acts on nuclear substrates in the nucleoplasm during apoptosis. Reason: CASP3 acts on nuclear substrates in the nucleoplasm during apoptosis. This is a site of its core proteolytic function, not merely an incidental location. Supporting Evidence: PMID:22253444 caspase-3 active fragments can also be evidenced in the nuclear fractions after STP treatment |
| 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. | REMOVE | Summary: Casper is reported to interact with caspase-3 along with several FADD/death-effector-pathway proteins. Reason: The cached abstract supports only a Casper-CASP3 physical interaction and Casper's apoptotic effect when overexpressed. It does not define a more informative CASP3 molecular function, so the unqualified protein binding row should be removed. Supporting Evidence: PMID:9208847 Casper interacts with FADD, caspase-8, caspase-3, TRAF1, and TRAF2 through distinct domains. |
| GO:0005634 nucleus | IDA PMID:17167422 Hsp70 regulates erythropoiesis by preventing caspase-3-media... | ACCEPT | Summary: CASP3 has a supported nuclear pool and cleaves nuclear substrates. Reason: CASP3 has a supported nuclear pool and cleaves nuclear substrates. Retain nucleus because the available localization evidence is not uniformly resolved to a single nuclear subcompartment. Supporting Evidence: PMID:22253444 caspase-3 active fragments can also be evidenced in the nuclear fractions after STP treatment |
| 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... | MODIFY | Summary: CASP3 cleaves internal peptide bonds using a catalytic cysteine. Reason: CASP3 cleaves internal peptide bonds using a catalytic cysteine. Asp at the substrate cleavage site specifies recognition, not an aspartic catalytic mechanism. The supported specific activity is cysteine-type endopeptidase activity. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Belongs to the peptidase C14A family. file:human/CASP3/CASP3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0005515 protein binding | IPI PMID:17823127 Cytosolic accumulation of HSP60 during apoptosis with or wit... | REMOVE | Summary: Cytosolic HSP60 differentially associates with active caspase-3 in apoptotic systems and modulates caspase-3 activation. Reason: The HSP60 row captures regulation of caspase-3 by a chaperonin and not an additional CASP3 molecular activity. The same paper's direct protease evidence is already captured by a separate cysteine-type endopeptidase activity row. 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: CASP3 directly catalyzes proteolysis of diverse substrates. Reason: CASP3 directly catalyzes proteolysis of diverse substrates. This process is core and spans destructive and regulatory cleavage, so no single narrower protein-processing process replaces its full scope. Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt Belongs to the peptidase C14A family. file:human/CASP3/CASP3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0005515 protein binding | IPI PMID:9736630 Tau cleavage and dephosphorylation in cerebellar granule neu... | MODIFY | Summary: Recombinant human caspase-3 cleaves tau in vitro, supporting tau as a CASP3 substrate. Reason: The CASP3-tau interaction is a substrate-cleavage context and is more informatively represented by cysteine-type endopeptidase activity than by a bare protein binding row. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: PMID:9736630 The treatment of in vitro translated tau by caspase-3 (Fig. 9 C ) clearly reveals that tau can act as an in vitro substrate for this protease |
| 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... | MODIFY | Summary: CASP3 directly performs proteolytic steps of apoptotic execution. Reason: The target effector protease directly performs the controlled substrate breakdown of apoptotic execution. Refine apoptotic process to the already represented GO:0097194 execution phase, supported by target-specific substrate/nuclear-change evidence rather than C14A membership, which also includes initiator and inflammatory caspases. Human-enzyme PMID:18723680 directly compares substrate cleavage by executioner caspases. The original human CPP32 study uses expression in Sf9 insect cells, including coexpressed processed chains; the heterologous host is not a native human-cell experiment. Proposed replacements: execution phase of apoptosis Supporting Evidence: file:human/CASP3/CASP3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins 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. |
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Download this section (compressed HTML)Q: 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?
Suggested experts: Salvesen GS, Martin SJ
Q: 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?
Suggested experts: Thornberry NA
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
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