Mouse Casp3 encodes caspase-3, a cysteine-aspartate effector protease that is activated by initiator caspases and executes apoptosis by cleaving many cellular substrates, including PARP1 and other proteins that drive apoptotic morphology and DNA fragmentation. Its core biology is cytoplasmic/cytosolic proteolysis during the execution phase of apoptosis, with additional context-specific roles in neuronal remodeling, inflammation, and development. Neural abnormalities and survival after Casp3 deletion depend strongly on genetic background. Mouse Casp7 can compensate for ICAD cleavage in some contexts, so loss of Casp3 does not establish a universal block of apoptosis or DNA fragmentation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| 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. Native mouse PMID:16469926 resolves PARP cleavage and DNA/nuclear changes. 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:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins PMID:16469926 Caspase 3 controls DNA fragmentation and morphologic changes of apoptosis, whereas caspase 7 plays little role in these processes. |
| GO:0004197 cysteine-type endopeptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: cysteine-type endopeptidase activity is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. file:mouse/Casp3/Casp3-deep-research-falcon.md Caspase-3 is a cysteine-aspartate protease with a strict requirement for **Asp at P1** and preference for **DEVD-like** motifs. |
| 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:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/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: DISC membership traces to an experimental annotation on the rat ortholog, so it is retained as a context-specific, non-core localization. Reason: The sole IBD seed at PANTHER node PTN002573018 is RGD:2275, the rat caspase-3 record (P55213, corroborated through its UniProt cross-reference), which carries its own IDA to this term from PMID:17518537. That cached publication states that after spinal cord injury Fas associates with FADD, caspase-8, cFLIP-long and caspase-3 to form a DISC, so the source is an experimental annotation on the direct ortholog rather than a paralog or family overreach, and there is no mouse evidence of loss. Removing it would overrule a curated experimental annotation on the orthologous gene on textbook grounds alone. Retained as non-core: the association is injury- and context-specific and is not part of the core effector-protease function. Independent source audit: Rat SCI complex association supplies comparative support, not direct binary Fas binding. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: RGD:2275 Β· rat Casp3 SUPPORTS TRANSFER Sole IBD seed for this term at the node; corroborated through the UniProt cross-reference for this RGD id (P55213, rat caspase-3). Its own GOA carries an IDA to GO:0031264 from PMID:17518537, whose abstract places caspase-3 in the Fas/FADD/caspase-8 DISC after spinal cord injury. A single well-characterised ortholog seed is not weak support. PANTHER:PTN002573018 SUPPORTS TRANSFER Euteleostomi-level node in PTHR10454 (taxon:117571 in the local PAINT cache); mouse Casp3 is an orthologous descendant, so the node placement supports the transfer. The term is contextual rather than core, which is a matter for the action, not for the propagation. Supporting Evidence: PMID:17518537 caspase-3, forming a death-inducing signaling |
| GO:0097194 execution phase of apoptosis | IBA GO_REF:0000033 | ACCEPT | Summary: execution phase of apoptosis is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage |
| 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 The issue is the enzymatic role represented by the GO term, not demonstrated loss of an ancestral caspase function. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/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: positive regulation of neuron apoptotic process reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Native mouse developmental neuronal apoptosis; necessity varies among neuronal populations. Supporting Evidence: PMID:10618441 caspase-3 deficiency abrogated the |
| 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: keratinocyte differentiation reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Native mouse keratinocyte perturbation supports the contextual nonapoptotic role. Supporting Evidence: PMID:15068794 lack of caspase 3 results in increased proliferation and decreased differentiation |
| GO:0030218 erythrocyte differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: erythrocyte differentiation reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Human erythroid evidence is retained as contextual support; mouse use is comparative, not a native mouse assay. Supporting Evidence: PMID:17167422 Caspase-3 is activated during both terminal differentiation and |
| 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:mouse/Casp3/Casp3-uniprot.txt Cytoplasm |
| 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:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0005515 protein binding | IPI PMID:17124493 Huntingtin inhibits caspase-3 activation. | REMOVE | Summary: protein binding is not a supported direct annotation for Casp3 in this review. Reason: The term conflicts with, or is too far removed from, the direct effector-caspase role. Generic protein-binding/signaling terms and incorrect molecular functions should not be retained for Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis. |
| GO:0005515 protein binding | IPI PMID:18585351 Ronin is essential for embryogenesis and the pluripotency of... | REMOVE | Summary: protein binding is not a supported direct annotation for Casp3 in this review. Reason: The term conflicts with, or is too far removed from, the direct effector-caspase role. Generic protein-binding/signaling terms and incorrect molecular functions should not be retained for Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis. |
| GO:0005515 protein binding | IPI PMID:19759058 Proteome-wide substrate analysis indicates substrate exclusi... | REMOVE | Summary: protein binding is not a supported direct annotation for Casp3 in this review. Reason: The term conflicts with, or is too far removed from, the direct effector-caspase role. Generic protein-binding/signaling terms and incorrect molecular functions should not be retained for Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of 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 mice, 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 mouse 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:0001818 negative regulation of cytokine production | IEA GO_REF:0000107 | ACCEPT | Summary: Casp3 directly suppresses cytokine signaling, supported by native mouse perturbations. Reason: Full PMID:36002459 shows increased poly(I:C)-induced cytokine expression after Casp3 siRNA in primary mouse peritoneal macrophages and increased serum IFNbeta, IL-6 and TNFalpha in Casp3-deficient mice. Purified human CASP3 cleavage of NF-kappaB subunits and cleavage-resistant mutants establish the biochemical mechanism in the same paper; these are not mislabeled as purified mouse-protein assays. PMID:30878284 independently supports antiviral suppression and explicitly distinguishes human CASP3 from additional murine Casp7 participation in cGAS inactivation. Retain this direct immunoregulatory protease role as core, not as an unexplained peripheral phenotype or a universal anti-inflammatory effect. Supporting Evidence: PMID:36002459 the deficiency of caspase-3 significantly increased the levels of IFNΞ², IL-6, and TNFΞ± in sera PMID:30878284 Caspase-3 was exclusively required in human cells, whereas caspase-7 was involved only in murine cells to inactivate cGAS |
| 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: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. Human nuclear-fraction experiments provide comparative support; the original native mouse annotation is preserved without claiming that this paper tested mouse CASP3. Supporting Evidence: PMID:22253444 caspase-3 active fragments can also be evidenced in the nuclear fractions after STP treatment |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: cytosol is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Cytoplasm |
| GO:0006915 apoptotic process | IEA GO_REF:0000107 | 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. Native mouse PMID:16469926 resolves PARP cleavage and DNA/nuclear changes. Proposed replacements: execution phase of apoptosis Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins PMID:16469926 Caspase 3 controls DNA fragmentation and morphologic changes of apoptosis, whereas caspase 7 plays little role in these processes. |
| 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: learning or memory reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Native mouse Alzheimer-model synaptic/memory phenotype; not evidence of an obligatory role in all learning. Supporting Evidence: PMID:21151119 pharmacological inhibition of caspase-3 activity in Tg2576 mice rescued |
| 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 mouse 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: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: PMID:12492473 experiments with Ac-DEVD-CMK (caspase-3 specific inhibitor) have led us to conclude that caspase-3 is downstream of ceramide in activating the brain plasmalogen-selective phospholipase A2. file:mouse/Casp3/Casp3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis. |
| GO:0016485 protein processing | IEA GO_REF:0000107 | ACCEPT | Summary: Casp3 directly processes protein substrates, including activation or inactivation by limited cleavage. Reason: Casp3 directly processes protein substrates, including activation or inactivation by limited cleavage. This is part of its core proteolytic function, separate from mere processing of Casp3 itself. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins |
| 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:0000120 | 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:mouse/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:0030218 erythrocyte differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: erythrocyte differentiation reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Human erythroid evidence is retained as contextual support; mouse use is comparative, not a native mouse assay. Supporting Evidence: PMID:17167422 Caspase-3 is activated during both terminal differentiation and |
| GO:0031264 death-inducing signaling complex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retained as non-core on the same grounds as the IBA GO_REF:0000033 row on this term, which this review kept because the transfer's donor carries its own experimental annotation. Caspase-3's DISC association is contextual rather than absent. Reason: Downgraded from REMOVE for consistency with the IBA row on this same term. All three GO:0031264 rows trace to one donor: this row's WITH/FROM is UniProtKB:P55213|ensembl:ENSRNOP00000014096, and rat Casp3 carries part_of GO:0031264 with ECO:0000314 IDA from PMID:17518537 (P55213 = Caspase-3, Rattus norvegicus, in PTHR10454-entries.csv). So the ground for keeping the IBA row - that removing would overrule a curated ortholog annotation - applies verbatim here. The previous shared reason offered a disjunction, "conflicts with, or is too far removed from, the direct effector-caspase role"; the disjunct that fits is the second, and being too far removed from the core role is what KEEP_AS_NON_CORE encodes rather than an argument for removal. Casp3 is an effector caspase acting downstream of DISC assembly, so the term is a genuine but peripheral location for it, reached here by an electronic ortholog mapping. Independent source audit: Rat SCI complex association supplies comparative support, not direct binary Fas binding. Supporting Evidence: PMID:17518537 caspase-3, forming a death-inducing signaling |
| GO:0031647 regulation of protein stability | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Proteolytic regulation of GGA3 links caspase-3 to BACE stability and amyloid-beta production (PMID:17553422). Reason: Proteolytic regulation of GGA3 links caspase-3 to BACE stability and amyloid-beta production (PMID:17553422). Retain this contextual regulatory role as conserved support rather than reject it simply because it is downstream of apoptosis; this is not amyloid-beta-cleaving enzyme activity. Supporting Evidence: |
| 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 mouse 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 mouse 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:0032880 regulation of protein localization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Conserved junctional-substrate cleavage changes protein localization during apoptosis. Reason: The original human donor source PMID:17559062 studies staurosporine-treated HaCaT and HT-29 cells: DSG2 cleavage releases a 70-kDa cytosolic fragment, surface DSG2 labeling disappears, and plakoglobin/JUP is cleaved and detaches. z-DEVD-fmk preserves DSG2 surface labeling. Retain the mouse transfer as a substrate-dependent localization outcome, corroborated by curated orthology, without relabeling human epithelial assays as native mouse evidence or claiming that Casp3 is a transport carrier. The accessible abstract gives explicit results but full methods remain unavailable. 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. file:mouse/Casp3/Casp3-uniprot.txt Cleaves DSG2 in response to apoptosis resulting in a loss of full length DSG2 at desmosome cell junctions and subsequent loss of cell-cell adhesion |
| GO:0034349 glial cell apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: glial cell apoptotic process reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Native mouse spinal injury provides glial-apoptosis context; the principal genetic perturbation in this paper is Bax. 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:mouse/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 mouse 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:0000107 | ACCEPT | Summary: Casp3 directly executes and amplifies apoptotic signaling. Reason: Casp3 performs apoptotic substrate cleavage and can amplify the death pathway. Full native mouse PMID:16469926 demonstrates Casp3-dependent PARP cleavage and nuclear fragmentation, with combined Casp3/Casp7 loss delaying Bax translocation and cytochrome-c release. The latter is a feedback contribution, not a claim that Casp3 alone is obligatory for every mitochondrial event. Retain positive apoptotic regulation as core rather than calling the direct effector/amplifier role peripheral. GO:0097194 execution phase is not an is_a/part_of descendant of GO:0043065 positive regulation, so replacing this claim solely as an entailed ancestor would conflate execution with regulation. 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: PMID:16469926 This suggests a pathway from caspase 9 through caspases 3 and 7 that promotes cytochrome c release at early time points. file:mouse/Casp3/Casp3-uniprot.txt Cleaves and activates caspase-6, -7 and -9 (CASP6, CASP7 and CASP9, respectively). 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 mouse 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: regulation of neuron apoptotic process reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Native mouse developmental neuronal regulation. 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: positive regulation of neuron apoptotic process reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Native mouse developmental neuronal apoptosis; necessity varies among neuronal populations. 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: striated muscle cell differentiation reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Myogenic context supports a differentiated nonapoptotic role; the abstract alone does not establish universality. 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:0070269 pyroptotic inflammatory response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: GSDME-dependent inflammatory output is a conditional Casp3 context. Reason: Caspase-3 cleaves GSDME to release its pore-forming amino-terminal fragment, supporting a conditional lytic/inflammatory route. PMID:28459430 directly describes human primary-cell GSDME-dependent pyroptosis and Gsdme-null mouse protection after chemotherapy. Full 33852854 separates sublytic IL-1beta release from overt lysis and shows that low-GSDME murine iBMMs behave differently; its rescue uses human GSDME in a mouse host. Thus the human-to-mouse transfer supports conserved conditional proteolytic activation, not a native mouse assay for every construct or an invariant inflammatory outcome whenever Casp3 is active. Retain the broader inflammatory-response attribution as non-core context, consistently with the human review; expression, stimulus and cellular release machinery determine the full response. 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. PMID:33852854 Gsdmdβ/β murine iBMMs lacked both GSDME and delayed cell death |
| 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 mouse infants. Supporting Evidence: PMID:27498600 CAPE significantly reduced sevofluraneβinduced apoptosis, downregulated the expression levels of caspases |
| GO:0072734 cellular response to staurosporine | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Casp3 participates in cellular responses to staurosporine. Reason: The human donor P42574 has direct PMID:22253444 evidence in SK-N-AS and SH-SY5Y neuroblastoma cells: staurosporine induces caspase-3 processing and ICAD/CAD-pathway effects. This is a response, not direct drug binding. Independently, full PMID:16469926 assays staurosporine and UV responses in mouse Casp3/Casp7-deficient MEFs. Retain the conserved stimulus-response context as non-core without requiring caspase-3 alone to be indispensable for all cell death or attributing the human cell-line experiment to mouse. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P42574 SUPPORTS TRANSFER Human PMID:22253444 directly supports the staurosporine response; native mouse MEF perturbations in PMID:16469926 independently corroborate this response context. 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 PMID:16469926 the sensitivity of MEFs to two inducers of mitochondrially mediated apoptosisβultraviolet (UV) irradiation and staurosporine |
| GO:0097193 intrinsic apoptotic signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Casp3 contributes to mitochondrial apoptotic signaling through an executioner feedback loop. Reason: Full PMID:16469926 establishes native mouse Casp3/Casp7 involvement in mitochondrial apoptosis and, specifically, feedback that accelerates Bax translocation and cytochrome-c release. The GO intrinsic-signaling definition ends when execution is triggered, so execution alone would not establish participation in this upstream signaling phase; the feedback evidence supplies the additional mechanistic rationale. Preserve the human-ortholog transfer, corroborated independently in mouse, without assigning all double-knockout phenotypes uniquely to Casp3 or making Casp3 universally necessary. Supporting Evidence: PMID:16469926 This suggests a pathway from caspase 9 through caspases 3 and 7 that promotes cytochrome c release at early time points. |
| GO:0140639 positive regulation of pyroptotic inflammatory response | IEA GO_REF:0000107 | ACCEPT | Summary: Proteolytic activation of GSDME is a supported conditional Casp3 activity. Reason: Caspase-3 cleaves GSDME to release its pore-forming amino-terminal fragment, supporting a conditional lytic/inflammatory route. PMID:28459430 directly describes human primary-cell GSDME-dependent pyroptosis and Gsdme-null mouse protection after chemotherapy. Full 33852854 separates sublytic IL-1beta release from overt lysis and shows that low-GSDME murine iBMMs behave differently; its rescue uses human GSDME in a mouse host. Thus the human-to-mouse transfer supports conserved conditional proteolytic activation, not a native mouse assay for every construct or an invariant inflammatory outcome whenever Casp3 is active. The specific positive-regulatory role is accepted because the protease performs the activating cleavage itself; this is mechanistic participation rather than necessity as a substrate. Its core description is explicitly conditional, matching human CASP3 without claiming identical cellular outcomes. 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. PMID:33852854 increasing the amount of GSDME in cells is sufficient to transform sublytic activation to bona fide lysis |
| GO:1902004 positive regulation of amyloid-beta formation | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Proteolytic regulation of GGA3 links caspase-3 to BACE stability and amyloid-beta production (PMID:17553422). Reason: Proteolytic regulation of GGA3 links caspase-3 to BACE stability and amyloid-beta production (PMID:17553422). Retain this contextual regulatory role as conserved support rather than reject it simply because it is downstream of apoptosis; this is not amyloid-beta-cleaving enzyme activity. Supporting Evidence: |
| 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:0031264 death-inducing signaling complex | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Retained as non-core on the same grounds as the IBA GO_REF:0000033 row on this term, which this review kept because the transfer's donor carries its own experimental annotation. Caspase-3's DISC association is contextual rather than absent. Reason: Downgraded from REMOVE for consistency with the IBA row on this same term. All three GO:0031264 rows trace to one donor: this row's WITH/FROM is RGD:2275, the rat caspase-3 record itself, and rat Casp3 carries part_of GO:0031264 with ECO:0000314 IDA from PMID:17518537 (P55213 = Caspase-3, Rattus norvegicus, in PTHR10454-entries.csv). So the ground for keeping the IBA row - that removing would overrule a curated ortholog annotation - applies verbatim here. The previous shared reason offered a disjunction, "conflicts with, or is too far removed from, the direct effector-caspase role"; the disjunct that fits is the second, and being too far removed from the core role is what KEEP_AS_NON_CORE encodes rather than an argument for removal. Casp3 is an effector caspase acting downstream of DISC assembly, so the term is a genuine but peripheral location for it, reached here by pairwise ortholog transfer. Independent source audit: Rat SCI complex association supplies comparative support, not direct binary Fas binding. Supporting Evidence: PMID:17518537 caspase-3, forming a death-inducing signaling |
| GO:0008303 caspase complex | ISO GO_REF:0000119 | ACCEPT | Summary: caspase complex is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Heterotetramer that consists of two anti-parallel arranged |
| GO:0043065 positive regulation of apoptotic process | ISO GO_REF:0000119 | ACCEPT | Summary: Casp3 directly executes and amplifies apoptotic signaling. Reason: Casp3 performs apoptotic substrate cleavage and can amplify the death pathway. Full native mouse PMID:16469926 demonstrates Casp3-dependent PARP cleavage and nuclear fragmentation, with combined Casp3/Casp7 loss delaying Bax translocation and cytochrome-c release. The latter is a feedback contribution, not a claim that Casp3 alone is obligatory for every mitochondrial event. Retain positive apoptotic regulation as core rather than calling the direct effector/amplifier role peripheral. GO:0097194 execution phase is not an is_a/part_of descendant of GO:0043065 positive regulation, so replacing this claim solely as an entailed ancestor would conflate execution with regulation. 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: PMID:16469926 This suggests a pathway from caspase 9 through caspases 3 and 7 that promotes cytochrome c release at early time points. file:mouse/Casp3/Casp3-uniprot.txt Cleaves and activates caspase-6, -7 and -9 (CASP6, CASP7 and CASP9, respectively). 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:1902512 positive regulation of apoptotic DNA fragmentation | ISO GO_REF:0000119 | ACCEPT | Summary: positive regulation of apoptotic DNA fragmentation is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Direct ICAD processing provides the mechanistic link to CAD-dependent DNA fragmentation; mouse CASP7 overlap is strain-dependent. Supporting Evidence: |
| GO:0098883 synapse pruning | IMP PMID:24478350 Local pruning of dendrites and spines by caspase-3-dependent... | KEEP AS NON CORE | Summary: synapse pruning reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Native mouse/neuron data support local nonlethal synaptic remodeling. Supporting Evidence: PMID:24478350 local elimination of dendritic spines and dendrite retraction occurred |
| GO:0005829 cytosol | ISO GO_REF:0000119 | ACCEPT | Summary: cytosol is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Cytoplasm |
| GO:0001818 negative regulation of cytokine production | ISO GO_REF:0000119 | ACCEPT | Summary: Casp3 directly suppresses cytokine signaling, supported by native mouse perturbations. Reason: Full PMID:36002459 shows increased poly(I:C)-induced cytokine expression after Casp3 siRNA in primary mouse peritoneal macrophages and increased serum IFNbeta, IL-6 and TNFalpha in Casp3-deficient mice. Purified human CASP3 cleavage of NF-kappaB subunits and cleavage-resistant mutants establish the biochemical mechanism in the same paper; these are not mislabeled as purified mouse-protein assays. PMID:30878284 independently supports antiviral suppression and explicitly distinguishes human CASP3 from additional murine Casp7 participation in cGAS inactivation. Retain this direct immunoregulatory protease role as core, not as an unexplained peripheral phenotype or a universal anti-inflammatory effect. Supporting Evidence: PMID:36002459 the deficiency of caspase-3 significantly increased the levels of IFNΞ², IL-6, and TNFΞ± in sera PMID:30878284 Caspase-3 was exclusively required in human cells, whereas caspase-7 was involved only in murine cells to inactivate cGAS |
| GO:0002020 protease binding | ISO GO_REF:0000096 | UNDECIDED | Summary: The specific protease binding interaction is unresolved beyond the rat DISC association. Reason: Provenance: GO_REF:0000096 from RGD:2275, 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: RGD:2275 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:0004197 cysteine-type endopeptidase activity | ISO GO_REF:0000119 | ACCEPT | Summary: cysteine-type endopeptidase activity is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0005123 death receptor binding | ISO GO_REF:0000096 | UNDECIDED | Summary: The specific death receptor binding interaction is unresolved beyond the rat DISC association. Reason: Provenance: GO_REF:0000096 from RGD:2275, 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: RGD:2275 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 | ISO GO_REF:0000119 | 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. Human nuclear-fraction experiments provide comparative support; the original native mouse annotation is preserved without claiming that this paper tested mouse CASP3. Supporting Evidence: PMID:22253444 caspase-3 active fragments can also be evidenced in the nuclear fractions after STP treatment |
| GO:0005737 cytoplasm | ISO GO_REF:0000119 | 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: UniProtKB:P42574 SUPPORTS TRANSFER The conserved original claim is defensible; the target evidence supports the stated refinement. This assessment does not relocate the PAINT ancestral assertion. Proposed replacements: cytosol Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Cytoplasm |
| GO:0005737 cytoplasm | ISO GO_REF:0000096 | 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: RGD:2275 SUPPORTS TRANSFER The conserved original claim is defensible; the target evidence supports the stated refinement. This assessment does not relocate the PAINT ancestral assertion. Proposed replacements: cytosol Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Cytoplasm |
| GO:0006508 proteolysis | ISO GO_REF:0000096 | 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:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0006508 proteolysis | ISO GO_REF:0000119 | 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:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0006915 apoptotic process | ISO GO_REF:0000119 | 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. Native mouse PMID:16469926 resolves PARP cleavage and DNA/nuclear changes. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P42574 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:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins PMID:16469926 Caspase 3 controls DNA fragmentation and morphologic changes of apoptosis, whereas caspase 7 plays little role in these processes. |
| GO:0007413 axonal fasciculation | ISO GO_REF:0000096 | UNDECIDED | Summary: axonal fasciculation: the precise claim remains unresolved for a specified source-level reason. Reason: Provenance trace: GO_REF:0000096 via RGD:2275. 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. Propagation Review Root cause: UNRESOLVED Sources checked: RGD:2275 UNRESOLVED Rat Casp3 donor traced to PMID:25898930. The accessible abstract supports somatic localization and caspase-6-dependent axonal degeneration, but not a specific CASP3 axon-bundling assay. The normal force-fetch remains abstract-only; no wrong-paralog attribution or target-specific functional loss is asserted. 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 | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: learning or memory reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Native mouse Alzheimer-model synaptic/memory phenotype; not evidence of an obligatory role in all learning. Supporting Evidence: PMID:21151119 pharmacological inhibition of caspase-3 activity in Tg2576 mice rescued |
| GO:0008233 peptidase activity | ISO GO_REF:0000119 | 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. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P42574 SUPPORTS TRANSFER The conserved original claim is defensible; the target evidence supports the stated refinement. This assessment does not relocate the PAINT ancestral assertion. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0008234 cysteine-type peptidase activity | ISO GO_REF:0000096 | 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. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: RGD:2275 SUPPORTS TRANSFER The conserved original claim is defensible; the target evidence supports the stated refinement. This assessment does not relocate the PAINT ancestral assertion. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0009749 response to glucose | ISO GO_REF:0000096 | UNDECIDED | Summary: response to glucose: the precise claim remains unresolved for a specified source-level reason. Reason: Provenance trace: GO_REF:0000096 via RGD:2275 (rat Casp3, the same protein as UniProtKB:P55213). 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. Propagation Review Root cause: UNRESOLVED Sources checked: RGD:2275 UNRESOLVED Rat donor PMID:19356108 does not expose a defined glucose-stimulus assay in its available abstract; TNF-alpha activity in a diabetic model does not settle that exact claim. 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:0016005 phospholipase A2 activator activity | ISO GO_REF:0000096 | 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. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: RGD:2275 SUPPORTS TRANSFER The conserved original claim is defensible; the target evidence supports the stated refinement. This assessment does not relocate the PAINT ancestral assertion. Supporting Evidence: PMID:12492473 experiments with Ac-DEVD-CMK (caspase-3 specific inhibitor) have led us to conclude that caspase-3 is downstream of ceramide in activating the brain plasmalogen-selective phospholipase A2. file:mouse/Casp3/Casp3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis. |
| GO:0016485 protein processing | ISO GO_REF:0000119 | ACCEPT | Summary: Casp3 directly processes protein substrates, including activation or inactivation by limited cleavage. Reason: Casp3 directly processes protein substrates, including activation or inactivation by limited cleavage. This is part of its core proteolytic function, separate from mere processing of Casp3 itself. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins |
| GO:0030163 protein catabolic process | ISO GO_REF:0000096 | 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:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins |
| GO:0030163 protein catabolic process | ISO GO_REF:0000119 | 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:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins |
| GO:0030218 erythrocyte differentiation | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: erythrocyte differentiation reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Human erythroid evidence is retained as contextual support; mouse use is comparative, not a native mouse assay. Supporting Evidence: PMID:17167422 Caspase-3 is activated during both terminal differentiation and |
| GO:0031647 regulation of protein stability | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Proteolytic regulation of GGA3 links caspase-3 to BACE stability and amyloid-beta production (PMID:17553422). Reason: Proteolytic regulation of GGA3 links caspase-3 to BACE stability and amyloid-beta production (PMID:17553422). Retain this contextual regulatory role as conserved support rather than reject it simply because it is downstream of apoptosis; this is not amyloid-beta-cleaving enzyme activity. Supporting Evidence: |
| GO:0031647 regulation of protein stability | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Proteolytic regulation of GGA3 links caspase-3 to BACE stability and amyloid-beta production (PMID:17553422). Reason: Proteolytic regulation of GGA3 links caspase-3 to BACE stability and amyloid-beta production (PMID:17553422). Retain this contextual regulatory role as conserved support rather than reject it simply because it is downstream of apoptosis; this is not amyloid-beta-cleaving enzyme activity. Supporting Evidence: |
| GO:0035556 intracellular signal transduction | ISO GO_REF:0000096 | 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. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: RGD:2275 SUPPORTS TRANSFER The conserved original claim is defensible; the target evidence supports the stated refinement. This assessment does not relocate the PAINT ancestral assertion. Proposed replacements: apoptotic signaling pathway Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins |
| GO:0035655 interleukin-18-mediated signaling pathway | ISO GO_REF:0000119 | UNDECIDED | Summary: Human IL-18 proteolytic inactivation does not settle a receptor-signaling claim. Reason: The ISO points to human P42574, but the live exact-term donor search did not recover a current GO:0035655 assertion. Independent primary PMID:9334240 in human THP.1 cells establishes CASP3 cleavage of precursor and mature IL-18 into inactive products. GO:0035655 denotes signals initiated by IL-18 binding its receptor and propagating to a downstream process; cytokine processing alone does not identify a step in that receptor pathway. The historic donor assay connecting CASP3 specifically to receptor-initiated signaling could not be recovered. Retain precise uncertainty without denying IL-18 cleavage, asserting a mouse receptor assay, or treating the absence from current annotation state as biological counterevidence. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P42574 SOURCE STALE OR MISSING The current exact-term donor search did not recover GO:0035655. Human primary PMID:9334240 supports cytokine inactivation, not an identified receptor-signaling step; the historic source chain remains unresolved. Supporting Evidence: PMID:9334240 caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products. |
| GO:0042542 response to hydrogen peroxide | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: response to hydrogen peroxide: retain with the primary study's context and species limits. Reason: Provenance trace: GO_REF:0000096 via RGD:2275 (rat Casp3, the same protein as UniProtKB:P55213). 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. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: RGD:2275 SUPPORTS TRANSFER Rat donor PMID:18479463 directly measures H2O2-induced caspase-3 activation in H9c2 cardiomyocytes; retain the conserved stress-response role without a direct mouse cardiomyocyte assay claim. Supporting Evidence: PMID:18479463 leptin prevented H(2)O(2)-induced increases in caspase-3 cleavage and activity |
| GO:0043025 neuronal cell body | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: neuronal cell body: retain with the primary study's context and species limits. Reason: Provenance trace: GO_REF:0000096 via RGD:2275. 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 | ISO GO_REF:0000096 | ACCEPT | Summary: Casp3 directly executes and amplifies apoptotic signaling. Reason: Casp3 performs apoptotic substrate cleavage and can amplify the death pathway. Full native mouse PMID:16469926 demonstrates Casp3-dependent PARP cleavage and nuclear fragmentation, with combined Casp3/Casp7 loss delaying Bax translocation and cytochrome-c release. The latter is a feedback contribution, not a claim that Casp3 alone is obligatory for every mitochondrial event. Retain positive apoptotic regulation as core rather than calling the direct effector/amplifier role peripheral. GO:0097194 execution phase is not an is_a/part_of descendant of GO:0043065 positive regulation, so replacing this claim solely as an entailed ancestor would conflate execution with regulation. 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: PMID:16469926 This suggests a pathway from caspase 9 through caspases 3 and 7 that promotes cytochrome c release at early time points. file:mouse/Casp3/Casp3-uniprot.txt Cleaves and activates caspase-6, -7 and -9 (CASP6, CASP7 and CASP9, respectively). 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:0043525 positive regulation of neuron apoptotic process | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: positive regulation of neuron apoptotic process reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Native mouse developmental neuronal apoptosis; necessity varies among neuronal populations. Supporting Evidence: PMID:10618441 caspase-3 deficiency abrogated the |
| GO:0044877 protein-containing complex binding | ISO GO_REF:0000096 | UNDECIDED | Summary: The specific protein-containing complex binding interaction is unresolved beyond the rat DISC association. Reason: Provenance: GO_REF:0000096 from RGD:2275, 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: RGD:2275 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:0051604 protein maturation | ISO GO_REF:0000119 | ACCEPT | Summary: Casp3 directly processes protein substrates, including activation or inactivation by limited cleavage. Reason: Casp3 directly processes protein substrates, including activation or inactivation by limited cleavage. This is part of its core proteolytic function, separate from mere processing of Casp3 itself. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins |
| GO:0070212 protein poly-ADP-ribosylation | ISO GO_REF:0000119 | REMOVE | Summary: protein poly-ADP-ribosylation is not a supported direct annotation for Casp3 in this review. Reason: The term conflicts with, or is too far removed from, the direct effector-caspase role. Generic protein-binding/signaling terms and incorrect molecular functions should not be retained for Casp3. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P42574 SUPPORTS SOURCE BUT NOT TARGET The ortholog source supports related executioner-caspase biology, but does not support this direct binding, signaling, or negative-regulatory assertion for mouse Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis. |
| GO:0070269 pyroptotic inflammatory response | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: GSDME-dependent inflammatory output is a conditional Casp3 context. Reason: Caspase-3 cleaves GSDME to release its pore-forming amino-terminal fragment, supporting a conditional lytic/inflammatory route. PMID:28459430 directly describes human primary-cell GSDME-dependent pyroptosis and Gsdme-null mouse protection after chemotherapy. Full 33852854 separates sublytic IL-1beta release from overt lysis and shows that low-GSDME murine iBMMs behave differently; its rescue uses human GSDME in a mouse host. Thus the human-to-mouse transfer supports conserved conditional proteolytic activation, not a native mouse assay for every construct or an invariant inflammatory outcome whenever Casp3 is active. Retain the broader inflammatory-response attribution as non-core context, consistently with the human review; expression, stimulus and cellular release machinery determine the full response. 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. PMID:33852854 Gsdmdβ/β murine iBMMs lacked both GSDME and delayed cell death |
| GO:0072734 cellular response to staurosporine | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Casp3 participates in cellular responses to staurosporine. Reason: The human donor P42574 has direct PMID:22253444 evidence in SK-N-AS and SH-SY5Y neuroblastoma cells: staurosporine induces caspase-3 processing and ICAD/CAD-pathway effects. This is a response, not direct drug binding. Independently, full PMID:16469926 assays staurosporine and UV responses in mouse Casp3/Casp7-deficient MEFs. Retain the conserved stimulus-response context as non-core without requiring caspase-3 alone to be indispensable for all cell death or attributing the human cell-line experiment to mouse. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P42574 SUPPORTS TRANSFER Human PMID:22253444 directly supports the staurosporine response; native mouse MEF perturbations in PMID:16469926 independently corroborate this response context. 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 PMID:16469926 the sensitivity of MEFs to two inducers of mitochondrially mediated apoptosisβultraviolet (UV) irradiation and staurosporine |
| GO:0097193 intrinsic apoptotic signaling pathway | ISO GO_REF:0000119 | ACCEPT | Summary: Casp3 contributes to mitochondrial apoptotic signaling through an executioner feedback loop. Reason: Full PMID:16469926 establishes native mouse Casp3/Casp7 involvement in mitochondrial apoptosis and, specifically, feedback that accelerates Bax translocation and cytochrome-c release. The GO intrinsic-signaling definition ends when execution is triggered, so execution alone would not establish participation in this upstream signaling phase; the feedback evidence supplies the additional mechanistic rationale. Preserve the human-ortholog transfer, corroborated independently in mouse, without assigning all double-knockout phenotypes uniquely to Casp3 or making Casp3 universally necessary. Supporting Evidence: PMID:16469926 This suggests a pathway from caspase 9 through caspases 3 and 7 that promotes cytochrome c release at early time points. |
| GO:0097194 execution phase of apoptosis | ISO GO_REF:0000119 | ACCEPT | Summary: execution phase of apoptosis is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage |
| GO:0140639 positive regulation of pyroptotic inflammatory response | ISO GO_REF:0000119 | ACCEPT | Summary: Proteolytic activation of GSDME is a supported conditional Casp3 activity. Reason: Caspase-3 cleaves GSDME to release its pore-forming amino-terminal fragment, supporting a conditional lytic/inflammatory route. PMID:28459430 directly describes human primary-cell GSDME-dependent pyroptosis and Gsdme-null mouse protection after chemotherapy. Full 33852854 separates sublytic IL-1beta release from overt lysis and shows that low-GSDME murine iBMMs behave differently; its rescue uses human GSDME in a mouse host. Thus the human-to-mouse transfer supports conserved conditional proteolytic activation, not a native mouse assay for every construct or an invariant inflammatory outcome whenever Casp3 is active. The specific positive-regulatory role is accepted because the protease performs the activating cleavage itself; this is mechanistic participation rather than necessity as a substrate. Its core description is explicitly conditional, matching human CASP3 without claiming identical cellular outcomes. 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. PMID:33852854 increasing the amount of GSDME in cells is sufficient to transform sublytic activation to bona fide lysis |
| GO:1902004 positive regulation of amyloid-beta formation | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Proteolytic regulation of GGA3 links caspase-3 to BACE stability and amyloid-beta production (PMID:17553422). Reason: Proteolytic regulation of GGA3 links caspase-3 to BACE stability and amyloid-beta production (PMID:17553422). Retain this contextual regulatory role as conserved support rather than reject it simply because it is downstream of apoptosis; this is not amyloid-beta-cleaving enzyme activity. Supporting Evidence: |
| GO:1902004 positive regulation of amyloid-beta formation | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Proteolytic regulation of GGA3 links caspase-3 to BACE stability and amyloid-beta production (PMID:17553422). Reason: Proteolytic regulation of GGA3 links caspase-3 to BACE stability and amyloid-beta production (PMID:17553422). Retain this contextual regulatory role as conserved support rather than reject it simply because it is downstream of apoptosis; this is not amyloid-beta-cleaving enzyme activity. Supporting Evidence: |
| GO:0014069 postsynaptic density | IEP PMID:21151119 Caspase-3 triggers early synaptic dysfunction in a mouse mod... | KEEP AS NON CORE | Summary: postsynaptic density is supported as a specialized non-apoptotic neuronal context for Casp3, not as its core molecular function. Reason: Primary neuronal studies support local synaptic/spine or vesicle-pool roles for caspase-3, but the core function remains executioner caspase protease activity. Supporting Evidence: PMID:21151119 non-apoptotic baseline caspase-3 activity in hippocampal dendritic spines PMID:21151119 removal of the GluR1 subunit of AMPA-type receptor from postsynaptic sites |
| GO:0014069 postsynaptic density | IDA PMID:21151119 Caspase-3 triggers early synaptic dysfunction in a mouse mod... | KEEP AS NON CORE | Summary: postsynaptic density is supported as a specialized non-apoptotic neuronal context for Casp3, not as its core molecular function. Reason: Primary neuronal studies support local synaptic/spine or vesicle-pool roles for caspase-3, but the core function remains executioner caspase protease activity. Supporting Evidence: PMID:21151119 non-apoptotic baseline caspase-3 activity in hippocampal dendritic spines PMID:21151119 removal of the GluR1 subunit of AMPA-type receptor from postsynaptic sites |
| GO:0098693 regulation of synaptic vesicle cycle | IMP PMID:33303681 The BAD-BAX-Caspase-3 Cascade Modulates Synaptic Vesicle Poo... | KEEP AS NON CORE | Summary: regulation of synaptic vesicle cycle is supported as a specialized non-apoptotic neuronal context for Casp3, not as its core molecular function. Reason: Primary neuronal studies support local synaptic/spine or vesicle-pool roles for caspase-3, but the core function remains executioner caspase protease activity. Supporting Evidence: PMID:33303681 the BAD-BAX-caspase-3 pathway regulates autophagy, which in turn limits the size of synaptic vesicle pools PMID:33303681 nonapoptotic function of the BAD-BAX-caspase-3 pathway in presynaptic terminals |
| GO:0098693 regulation of synaptic vesicle cycle | IDA PMID:33303681 The BAD-BAX-Caspase-3 Cascade Modulates Synaptic Vesicle Poo... | KEEP AS NON CORE | Summary: regulation of synaptic vesicle cycle is supported as a specialized non-apoptotic neuronal context for Casp3, not as its core molecular function. Reason: Primary neuronal studies support local synaptic/spine or vesicle-pool roles for caspase-3, but the core function remains executioner caspase protease activity. Supporting Evidence: PMID:33303681 the BAD-BAX-caspase-3 pathway regulates autophagy, which in turn limits the size of synaptic vesicle pools PMID:33303681 nonapoptotic function of the BAD-BAX-caspase-3 pathway in presynaptic terminals |
| GO:0098978 glutamatergic synapse | IEP PMID:21151119 Caspase-3 triggers early synaptic dysfunction in a mouse mod... | KEEP AS NON CORE | Summary: glutamatergic synapse is supported as a specialized non-apoptotic neuronal context for Casp3, not as its core molecular function. Reason: Primary neuronal studies support local synaptic/spine or vesicle-pool roles for caspase-3, but the core function remains executioner caspase protease activity. Supporting Evidence: PMID:21151119 glutamatergic synaptic transmission and plasticity PMID:21151119 caspase-3-dependent mechanism that drives synaptic failure |
| GO:0098978 glutamatergic synapse | IDA PMID:21151119 Caspase-3 triggers early synaptic dysfunction in a mouse mod... | KEEP AS NON CORE | Summary: glutamatergic synapse is supported as a specialized non-apoptotic neuronal context for Casp3, not as its core molecular function. Reason: Primary neuronal studies support local synaptic/spine or vesicle-pool roles for caspase-3, but the core function remains executioner caspase protease activity. Supporting Evidence: PMID:21151119 glutamatergic synaptic transmission and plasticity PMID:21151119 caspase-3-dependent mechanism that drives synaptic failure |
| GO:0004197 cysteine-type endopeptidase activity | IDA PMID:37327784 Gasdermin D licenses MHCII induction to maintain food tolera... | ACCEPT | Summary: cysteine-type endopeptidase activity is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0097194 execution phase of apoptosis | IMP PMID:8934524 Decreased apoptosis in the brain and premature lethality in ... | ACCEPT | Summary: execution phase of apoptosis is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage |
| GO:0004197 cysteine-type endopeptidase activity | IDA PMID:25231987 Exposure of phosphatidylserine by Xk-related protein family ... | ACCEPT | Summary: cysteine-type endopeptidase activity is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0051402 neuron apoptotic process | IDA PMID:15231831 BAD is a pro-survival factor prior to activation of its pro-... | KEEP AS NON CORE | Summary: Neuron apoptotic process is a valid developmental or neuronal context for Casp3, but not its core molecular function. Reason: Casp3 core function is cysteine-type endopeptidase executioner caspase activity; neuron apoptosis is a context-specific process output. Independent source audit: The native mouse PNS result does not extend universal necessity to CNS neurons. Supporting Evidence: PMID:11549719 PNS neurons are dependent on caspase 3 |
| GO:0004175 endopeptidase activity | IDA PMID:12124386 The role of Asp-462 in regulating Akt activity. | 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:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0031647 regulation of protein stability | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Proteolytic regulation of GGA3 links caspase-3 to BACE stability and amyloid-beta production (PMID:17553422). Reason: Proteolytic regulation of GGA3 links caspase-3 to BACE stability and amyloid-beta production (PMID:17553422). Retain this contextual regulatory role as conserved support rather than reject it simply because it is downstream of apoptosis; this is not amyloid-beta-cleaving enzyme activity. Supporting Evidence: |
| GO:1902004 positive regulation of amyloid-beta formation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Proteolytic regulation of GGA3 links caspase-3 to BACE stability and amyloid-beta production (PMID:17553422). Reason: Proteolytic regulation of GGA3 links caspase-3 to BACE stability and amyloid-beta production (PMID:17553422). Retain this contextual regulatory role as conserved support rather than reject it simply because it is downstream of apoptosis; this is not amyloid-beta-cleaving enzyme activity. Supporting Evidence: |
| GO:0061713 anterior neural tube closure | IMP PMID:21515572 Focusing forward genetics: a tripartite ENU screen for neuro... | UNDECIDED | Summary: anterior neural tube closure: the precise claim remains unresolved for a specified source-level reason. Reason: Provenance trace: PMID:21515572 via MGI:MGI:5056374. The full original mouse study identifies hith2 as a Casp3 splice-disrupting allele with little/no protein, encephaloceles and incompletely penetrant cleft palate. It separately describes anterior-posterior open neural tube phenotypes for the Scrib crn2 allele. GO:0061713 specifically denotes bringing together and fusing anterior neural folds; encephaloceles alone do not distinguish failed neural-fold fusion from another cranial defect. The target-specific hith2 phenotype is real, but the exact anterior-neural-fold-closure interpretation remains unresolved. No wrong-gene accusation or rejection of the curator's developmental evidence is made. Supporting Evidence: PMID:21515572 Hith2 mutants have significant encephaloceles PMID:21515572 immunohistochemical analysis demonstrated that little or no CASPASE-3 is produced in hith2 mutants |
| GO:0004197 cysteine-type endopeptidase activity | ISS GO_REF:0000024 | ACCEPT | Summary: cysteine-type endopeptidase activity is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0005737 cytoplasm | IDA PMID:21716255 Cyclooxygenase-2-dependent phosphorylation of the pro-apopto... | 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:mouse/Casp3/Casp3-uniprot.txt Cytoplasm |
| GO:0008627 intrinsic apoptotic signaling pathway in response to osmotic stress | IDA PMID:21716255 Cyclooxygenase-2-dependent phosphorylation of the pro-apopto... | KEEP AS NON CORE | Summary: intrinsic apoptotic signaling pathway in response to osmotic stress reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Native mouse hypertonic medullary apoptosis supports a contextual execution response; the initiating perturbation concerns COX-2/Bad. Supporting Evidence: PMID:21716255 The abundance of cleaved caspase-3, a marker of apoptosis, was significantly higher in papillary homogenates |
| GO:0043065 positive regulation of apoptotic process | IDA PMID:21716255 Cyclooxygenase-2-dependent phosphorylation of the pro-apopto... | ACCEPT | Summary: Retain the established pro-apoptotic role while distinguishing the original renal marker assay. Reason: Casp3 performs apoptotic substrate cleavage and can amplify the death pathway. Full native mouse PMID:16469926 demonstrates Casp3-dependent PARP cleavage and nuclear fragmentation, with combined Casp3/Casp7 loss delaying Bax translocation and cytochrome-c release. The latter is a feedback contribution, not a claim that Casp3 alone is obligatory for every mitochondrial event. Retain positive apoptotic regulation as core rather than calling the direct effector/amplifier role peripheral. GO:0097194 execution phase is not an is_a/part_of descendant of GO:0043065 positive regulation, so replacing this claim solely as an entailed ancestor would conflate execution with regulation. The original PMID:21716255 abstract reports increased cleaved Casp3 in COX-2-deficient mouse renal papillae and Bad knockdown in canine MDCK cells; Casp3 cleavage is an apoptosis readout, not a Casp3 knockout/rescue experiment. Normal force retrieval remained abstract-only and publisher full-text/PDF retrieval returned 403. The core claim is independently supported by 16469926, not by inventing a direct causal Casp3 perturbation in 21716255. 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: PMID:21716255 The abundance of cleaved caspase-3, a marker of apoptosis, was significantly higher in papillary homogenates 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:0005737 cytoplasm | IDA PMID:25139234 Mammalian target of rapamycin is essential for cardiomyocyte... | 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:mouse/Casp3/Casp3-uniprot.txt Cytoplasm |
| GO:0048011 neurotrophin TRK receptor signaling pathway | ISO 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. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P42574 UNRESOLVED The source primary assays caspase-3 activity in HEK293T cells but does not expose the exact CASP3 receptor-signaling step in its accessible abstract; mouse DRG coexpression concerns Dok5/TrkC, not a direct mouse Casp3 signaling assay. 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:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress | NAS PMID:12097332 An endoplasmic reticulum stress-specific caspase cascade in ... | KEEP AS NON CORE | Summary: intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Murine ER-stress cascade context; this does not establish a universal CASP12 route in mammals. Supporting Evidence: PMID:12097332 caspase-9 as well as caspase-12 and -3 are activated in cytochrome c-free cytosols in murine myoblast cells under ER stress |
| GO:0006915 apoptotic process | IMP PMID:12970760 Caspase-3 regulates cell cycle in B cells: a consequence of ... | 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. Native mouse PMID:16469926 resolves PARP cleavage and DNA/nuclear changes. The original abstract describes Casp3-deficient B-cell hyperproliferation with normal apoptosis in that setting, so it is not presented as direct proof of universal apoptotic dependence; independent target execution evidence supplies this refinement. Proposed replacements: execution phase of apoptosis Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins PMID:16469926 Caspase 3 controls DNA fragmentation and morphologic changes of apoptosis, whereas caspase 7 plays little role in these processes. |
| GO:0006915 apoptotic process | IMP PMID:16469926 Caspases 3 and 7: key mediators of mitochondrial events of a... | 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. Native mouse PMID:16469926 resolves PARP cleavage and DNA/nuclear changes. The original full study separates Casp3-dependent nuclear fragmentation/PARP cleavage from partially redundant Casp3/Casp7 viability effects. Proposed replacements: execution phase of apoptosis Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins PMID:16469926 Caspase 3 controls DNA fragmentation and morphologic changes of apoptosis, whereas caspase 7 plays little role in these processes. |
| GO:0006915 apoptotic process | IMP PMID:9512515 Essential contribution of caspase 3/CPP32 to apoptosis and i... | 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. Native mouse PMID:16469926 resolves PARP cleavage and DNA/nuclear changes. The original mouse knockout study explicitly reports stimulus- and cell-type-dependent failure of apoptotic nuclear changes; refinement does not mean universal necessity. Proposed replacements: execution phase of apoptosis Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins PMID:16469926 Caspase 3 controls DNA fragmentation and morphologic changes of apoptosis, whereas caspase 7 plays little role in these processes. |
| GO:0097194 execution phase of apoptosis | IDA PMID:12954857 Ischemic preconditioning by caspase cleavage of poly(ADP-rib... | ACCEPT | Summary: execution phase of apoptosis is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage |
| GO:0005634 nucleus | IDA PMID:22358842 Maintenance of muscle stem-cell quiescence by microRNA-489. | 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. Human nuclear-fraction experiments provide comparative support; the original native mouse annotation is preserved without claiming that this paper tested mouse CASP3. Supporting Evidence: PMID:22253444 caspase-3 active fragments can also be evidenced in the nuclear fractions after STP treatment |
| GO:0004197 cysteine-type endopeptidase activity | IDA PMID:24378336 BDNF and NT4 play interchangeable roles in gustatory develop... | ACCEPT | Summary: cysteine-type endopeptidase activity is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0005737 cytoplasm | IDA PMID:23861879 Loss of Usp9x disrupts cortical architecture, hippocampal de... | 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:mouse/Casp3/Casp3-uniprot.txt Cytoplasm |
| GO:0004190 aspartic-type endopeptidase activity | IDA PMID:23727203 Nek5, a novel substrate for caspase-3, promotes skeletal mus... | 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:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0097194 execution phase of apoptosis | IGI PMID:16469926 Caspases 3 and 7: key mediators of mitochondrial events of a... | ACCEPT | Summary: execution phase of apoptosis is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage |
| GO:0004197 cysteine-type endopeptidase activity | IDA PMID:16183742 Apoptosis caused by p53-induced protein with death domain (P... | ACCEPT | Summary: cysteine-type endopeptidase activity is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0004197 cysteine-type endopeptidase activity | IDA PMID:15456877 Vhlh gene deletion induces Hif-1-mediated cell death in thym... | ACCEPT | Summary: cysteine-type endopeptidase activity is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0097194 execution phase of apoptosis | IDA PMID:15456877 Vhlh gene deletion induces Hif-1-mediated cell death in thym... | ACCEPT | Summary: execution phase of apoptosis is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage |
| GO:0004197 cysteine-type endopeptidase activity | IDA PMID:14657025 Transcriptional activation of known and novel apoptotic path... | ACCEPT | Summary: cysteine-type endopeptidase activity is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0034349 glial cell apoptotic process | IMP PMID:11549719 Caspase 3 deficiency rescues peripheral nervous system defec... | KEEP AS NON CORE | Summary: glial cell apoptotic process reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Native mouse spinal injury provides glial-apoptosis context; the principal genetic perturbation in this paper is Bax. Supporting Evidence: PMID:14507967 anti-activated caspase-3 characterized the ongoing oligodendrocyte death |
| GO:0051402 neuron apoptotic process | IMP PMID:11549719 Caspase 3 deficiency rescues peripheral nervous system defec... | KEEP AS NON CORE | Summary: Neuron apoptotic process is a valid developmental or neuronal context for Casp3, but not its core molecular function. Reason: Casp3 core function is cysteine-type endopeptidase executioner caspase activity; neuron apoptosis is a context-specific process output. Independent source audit: The native mouse PNS result does not extend universal necessity to CNS neurons. Supporting Evidence: PMID:11549719 PNS neurons are dependent on caspase 3 |
| GO:0097194 execution phase of apoptosis | IMP PMID:11549719 Caspase 3 deficiency rescues peripheral nervous system defec... | ACCEPT | Summary: execution phase of apoptosis is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage |
| GO:0004197 cysteine-type endopeptidase activity | IDA PMID:12124386 The role of Asp-462 in regulating Akt activity. | ACCEPT | Summary: cysteine-type endopeptidase activity is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0051402 neuron apoptotic process | IMP PMID:10618441 Epistatic and independent functions of caspase-3 and Bcl-X(L... | KEEP AS NON CORE | Summary: Neuron apoptotic process is a valid developmental or neuronal context for Casp3, but not its core molecular function. Reason: Casp3 core function is cysteine-type endopeptidase executioner caspase activity; neuron apoptosis is a context-specific process output. Independent source audit: The native mouse PNS result does not extend universal necessity to CNS neurons. Supporting Evidence: PMID:11549719 PNS neurons are dependent on caspase 3 |
| GO:0051402 neuron apoptotic process | IGI PMID:10618441 Epistatic and independent functions of caspase-3 and Bcl-X(L... | KEEP AS NON CORE | Summary: Neuron apoptotic process is a valid developmental or neuronal context for Casp3, but not its core molecular function. Reason: Casp3 core function is cysteine-type endopeptidase executioner caspase activity; neuron apoptosis is a context-specific process output. Independent source audit: The native mouse PNS result does not extend universal necessity to CNS neurons. Supporting Evidence: PMID:11549719 PNS neurons are dependent on caspase 3 |
| GO:0097194 execution phase of apoptosis | IDA PMID:12124386 The role of Asp-462 in regulating Akt activity. | ACCEPT | Summary: execution phase of apoptosis is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage |
| GO:0051402 neuron apoptotic process | IMP PMID:10479688 Bax-dependent caspase-3 activation is a key determinant in p... | KEEP AS NON CORE | Summary: Neuron apoptotic process is a valid developmental or neuronal context for Casp3, but not its core molecular function. Reason: Casp3 core function is cysteine-type endopeptidase executioner caspase activity; neuron apoptosis is a context-specific process output. Independent source audit: The native mouse PNS result does not extend universal necessity to CNS neurons. Supporting Evidence: PMID:11549719 PNS neurons are dependent on caspase 3 |
| GO:0005829 cytosol | TAS Reactome:R-MMU-418855 | ACCEPT | Summary: cytosol is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-NUL-2534247 | ACCEPT | Summary: cytosol is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Cytoplasm |
| GO:0004197 cysteine-type endopeptidase activity | IDA PMID:19759058 Proteome-wide substrate analysis indicates substrate exclusi... | ACCEPT | Summary: cysteine-type endopeptidase activity is consistent with Casp3 as an executioner caspase that cleaves protein substrates during apoptotic execution. Reason: This term captures the core cysteine protease activity, apoptotic execution role, caspase complex context, or well-supported cytoplasmic/cytosolic localization of Casp3. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0009611 response to wounding | IDA PMID:14507967 Enhanced oligodendrocyte survival after spinal cord injury i... | KEEP AS NON CORE | Summary: response to wounding reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Retain execution within the native mouse injury response; do not claim a specific caspase-3-dependent wound-sensing mechanism. Supporting Evidence: PMID:14507967 anti-activated caspase-3 characterized the ongoing oligodendrocyte death |
| GO:0004190 aspartic-type endopeptidase activity | IDA PMID:15231831 BAD is a pro-survival factor prior to activation of its pro-... | 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:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0016485 protein processing | IDA PMID:15231831 BAD is a pro-survival factor prior to activation of its pro-... | ACCEPT | Summary: Casp3 directly processes protein substrates, including activation or inactivation by limited cleavage. Reason: Casp3 directly processes protein substrates, including activation or inactivation by limited cleavage. This is part of its core proteolytic function, separate from mere processing of Casp3 itself. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins |
| GO:0006915 apoptotic process | IDA PMID:17901126 Estrogen suppresses uterine epithelial apoptosis by inducing... | 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. Native mouse PMID:16469926 resolves PARP cleavage and DNA/nuclear changes. The original PMID:17901126 abstract establishes estrogen/Birc1-dependent suppression of apoptosis in mouse uterine epithelium, but normal recovery did not expose its full Casp3 assay. It is retained as the original citation, while independent native Casp3 substrate/nuclear-change evidence supports the gene-level execution refinement; no wrong-gene or absence conclusion is inferred from the incomplete source. Proposed replacements: execution phase of apoptosis Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins PMID:16469926 Caspase 3 controls DNA fragmentation and morphologic changes of apoptosis, whereas caspase 7 plays little role in these processes. |
| GO:0006915 apoptotic process | IDA PMID:12847083 Bax and Bak can localize to the endoplasmic reticulum to ini... | 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. Native mouse PMID:16469926 resolves PARP cleavage and DNA/nuclear changes. The original full study tests ectopic caspase-3 expression in wild-type and Bax/Bak-deficient MEFs; it is a downstream-effector reconstitution, not proof of an upstream mitochondrial requirement. Proposed replacements: execution phase of apoptosis Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins PMID:16469926 Caspase 3 controls DNA fragmentation and morphologic changes of apoptosis, whereas caspase 7 plays little role in these processes. |
| GO:0008234 cysteine-type peptidase activity | IDA PMID:17544522 Targeted disruption of the murine large nuclear KIAA1440/Int... | 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:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0008233 peptidase activity | ISO GO_REF:0000008 | 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. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P42574 SUPPORTS TRANSFER The conserved original claim is defensible; the target evidence supports the stated refinement. This assessment does not relocate the PAINT ancestral assertion. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0008233 peptidase activity | IDA PMID:12427836 p73 is required for survival and maintenance of CNS neurons. | 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:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0008233 peptidase activity | RCA PMID:12819136 Comparative analysis of apoptosis and inflammation genes of ... | 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:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0008233 peptidase activity | IDA PMID:13679151 Roles of MGMT and MLH1 proteins in alkylation-induced apopto... | 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:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0008233 peptidase activity | IDA PMID:14561754 Molecular components of a cell death pathway activated by en... | 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:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0008233 peptidase activity | IMP PMID:16469926 Caspases 3 and 7: key mediators of mitochondrial events of a... | 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:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0006974 DNA damage response | IDA PMID:11092819 DNA damage-induced neural precursor cell apoptosis requires ... | KEEP AS NON CORE | Summary: Casp3 has supported genotoxic/UV response functions with cell-type-dependent redundancy. Reason: The original PMID:11092819 abstract concerns drug/gamma-irradiation injury in neural precursors and shows that death does not require Casp3; it does not demonstrate absence of Casp3 activation/participation or settle every tissue. Its full text remains unavailable. Full PMID:16469926 directly tests UV-irradiated mouse Casp3/Casp7-deficient MEFs: Casp3 loss impairs nuclear morphology and DNA fragmentation, with overlapping survival roles for Casp7. Independent native-mouse PMID:22949508 additionally demonstrates a protective Casp3/RasGAP response to UV-B skin injury. These direct target-species data support the existing response claim without asserting universal Casp3 necessity, direct UV sensing, or DNA-repair enzyme activity. Supporting Evidence: PMID:16469926 the sensitivity of MEFs to two inducers of mitochondrially mediated apoptosisβultraviolet (UV) irradiation and staurosporine PMID:16469926 Caspase 3 controls DNA fragmentation and morphologic changes of apoptosis, whereas caspase 7 plays little role in these processes. PMID:22949508 Mice homozygous for a mutation in RasGAP that prevents its cleavage by caspase-3 exhibited a similar defect in Akt activation, leading to increased apoptosis in stressed organs |
| GO:0009411 response to UV | IDA PMID:11092819 DNA damage-induced neural precursor cell apoptosis requires ... | KEEP AS NON CORE | Summary: Casp3 has supported genotoxic/UV response functions with cell-type-dependent redundancy. Reason: The original PMID:11092819 abstract concerns drug/gamma-irradiation injury in neural precursors and shows that death does not require Casp3; it does not demonstrate absence of Casp3 activation/participation or settle every tissue. Its full text remains unavailable. Full PMID:16469926 directly tests UV-irradiated mouse Casp3/Casp7-deficient MEFs: Casp3 loss impairs nuclear morphology and DNA fragmentation, with overlapping survival roles for Casp7. Independent native-mouse PMID:22949508 additionally demonstrates a protective Casp3/RasGAP response to UV-B skin injury. These direct target-species data support the existing response claim without asserting universal Casp3 necessity, direct UV sensing, or DNA-repair enzyme activity. Supporting Evidence: PMID:16469926 the sensitivity of MEFs to two inducers of mitochondrially mediated apoptosisβultraviolet (UV) irradiation and staurosporine PMID:16469926 Caspase 3 controls DNA fragmentation and morphologic changes of apoptosis, whereas caspase 7 plays little role in these processes. PMID:22949508 Mice homozygous for a mutation in RasGAP that prevents its cleavage by caspase-3 exhibited a similar defect in Akt activation, leading to increased apoptosis in stressed organs |
| GO:0043066 negative regulation of apoptotic process | ISO GO_REF:0000008 | KEEP AS NON CORE | Summary: Casp3 can limit apoptosis through RasGAP-dependent survival feedback under mild stress. Reason: The historical human-donor exact-term assertion is not currently recovered, but native mouse primary PMID:22949508 independently resolves the biological claim. Casp3-knockout mice fail to activate protective Akt signaling under several stresses, and a cleavage-resistant RasGAP knock-in phenocopies the defect with increased tissue apoptosis. Casp3 performs the proteolytic step generating the protective response; this is participation, not mere necessity. Retain a context-dependent anti-apoptotic role as non-core, alongside its principal executioner function, without claiming that high caspase-3 activity universally protects cells. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P42574 SOURCE STALE OR MISSING The historic human transfer source is not reproduced by the current exact-term query. Native mouse Casp3 knockout and RasGAP cleavage-resistant knock-in experiments in PMID:22949508 independently support the accepted non-core protective function. Supporting Evidence: PMID:22949508 Mice homozygous for a mutation in RasGAP that prevents its cleavage by caspase-3 exhibited a similar defect in Akt activation, leading to increased apoptosis in stressed organs PMID:22949508 Defective Akt activation in caspase-3-knockout mice was accompanied by increased cell death and impaired survival in some cases. |
| GO:0051402 neuron apoptotic process | IDA PMID:12427836 p73 is required for survival and maintenance of CNS neurons. | KEEP AS NON CORE | Summary: Neuron apoptotic process is a valid developmental or neuronal context for Casp3, but not its core molecular function. Reason: Casp3 core function is cysteine-type endopeptidase executioner caspase activity; neuron apoptosis is a context-specific process output. Independent source audit: The native mouse PNS result does not extend universal necessity to CNS neurons. Supporting Evidence: PMID:11549719 PNS neurons are dependent on caspase 3 |
| GO:0007605 sensory perception of sound | IMP PMID:11374883 Deafness due to degeneration of cochlear neurons in caspase-... | KEEP AS NON CORE | Summary: sensory perception of sound reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Native mouse hearing phenotype supports a contextual maintenance contribution, not auditory receptor activity. Supporting Evidence: PMID:11374883 Spiral ganglion neurons and cochlear hair cells thus appear to require caspase-3 for survival |
| GO:0007507 heart development | IGI PMID:16469926 Caspases 3 and 7: key mediators of mitochondrial events of a... | KEEP AS NON CORE | Summary: heart development reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Native mouse double-knockout phenotype establishes combined CASP3/CASP7 developmental involvement. Supporting Evidence: PMID:16469926 died immediately after birth with defects in cardiac development |
| GO:0009411 response to UV | IGI PMID:16469926 Caspases 3 and 7: key mediators of mitochondrial events of a... | KEEP AS NON CORE | Summary: Casp3 has supported genotoxic/UV response functions with cell-type-dependent redundancy. Reason: The previous reason cited a different neural-precursor paper instead of the row's own PMID:16469926. Normal retrieval now provides the actual full primary source. Full PMID:16469926 directly tests UV-irradiated mouse Casp3/Casp7-deficient MEFs: Casp3 loss impairs nuclear morphology and DNA fragmentation, with overlapping survival roles for Casp7. Independent native-mouse PMID:22949508 additionally demonstrates a protective Casp3/RasGAP response to UV-B skin injury. These direct target-species data support the existing response claim without asserting universal Casp3 necessity, direct UV sensing, or DNA-repair enzyme activity. Supporting Evidence: PMID:16469926 the sensitivity of MEFs to two inducers of mitochondrially mediated apoptosisβultraviolet (UV) irradiation and staurosporine PMID:16469926 Caspase 3 controls DNA fragmentation and morphologic changes of apoptosis, whereas caspase 7 plays little role in these processes. PMID:22949508 Mice homozygous for a mutation in RasGAP that prevents its cleavage by caspase-3 exhibited a similar defect in Akt activation, leading to increased apoptosis in stressed organs |
| GO:0008233 peptidase activity | IMP PMID:11549719 Caspase 3 deficiency rescues peripheral nervous system defec... | 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:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0006508 proteolysis | RCA PMID:12819136 Comparative analysis of apoptosis and inflammation genes of ... | 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:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0030216 keratinocyte differentiation | IMP PMID:15068794 High commitment of embryonic keratinocytes to terminal diffe... | KEEP AS NON CORE | Summary: keratinocyte differentiation reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Native mouse keratinocyte perturbation supports the contextual nonapoptotic role. Supporting Evidence: PMID:15068794 lack of caspase 3 results in increased proliferation and decreased differentiation |
| GO:0045165 cell fate commitment | IMP PMID:15068794 High commitment of embryonic keratinocytes to terminal diffe... | KEEP AS NON CORE | Summary: cell fate commitment reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Native embryonic keratinocyte commitment, not a universal differentiation mechanism. Supporting Evidence: PMID:15068794 a Notch1-caspase 3 regulatory mechanism |
| GO:0001782 B cell homeostasis | IMP PMID:12970760 Caspase-3 regulates cell cycle in B cells: a consequence of ... | KEEP AS NON CORE | Summary: B cell homeostasis reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Native mouse B-cell genetic and biochemical evidence. Supporting Evidence: PMID:12970760 caspase-3 is essential in the regulation of B cell homeostasis |
| GO:0004861 cyclin-dependent protein serine/threonine kinase inhibitor activity | IMP PMID:12970760 Caspase-3 regulates cell cycle in B cells: a consequence of ... | REMOVE | Summary: cyclin-dependent protein serine/threonine kinase inhibitor activity is not a supported direct annotation for Casp3 in this review. Reason: GO:0004861 is cyclin-dependent protein serine/threonine kinase inhibitor activity, an enables molecular-function term. Casp3 is a cysteine-type endopeptidase: cleaving a CDK inhibitor is not the same as being one, so the term assigns the substrate's activity to the protease. That is a molecular-identity argument about Casp3 itself, needing no access to the cited full text, which is why this row stays REMOVE while the abstract-only class elsewhere in this file is UNDECIDED. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis. |
| GO:0008233 peptidase activity | IMP PMID:12970760 Caspase-3 regulates cell cycle in B cells: a consequence of ... | 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:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0030889 negative regulation of B cell proliferation | IMP PMID:12970760 Caspase-3 regulates cell cycle in B cells: a consequence of ... | KEEP AS NON CORE | Summary: negative regulation of B cell proliferation reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Native mouse B-cell cycling phenotype. Supporting Evidence: PMID:12970760 caspase-3 is a negative regulator of B cell cycling |
| GO:0043029 T cell homeostasis | IMP PMID:12970760 Caspase-3 regulates cell cycle in B cells: a consequence of ... | UNDECIDED | Summary: T cell homeostasis: the precise claim remains unresolved for a specified source-level reason. Reason: Provenance trace: PMID:12970760 via MGI:MGI:2178778. The original mouse paper remains abstract-only after normal force-fetch. Its abstract establishes B-cell cycling/homeostasis; that is not evidence that T cells were absent from the full experiments. Independent full PMID:18701083 establishes CASP3-dependent anergy and TCR-signal cleavage, but GO:0043029 specifically requires maintaining stable T-cell numbers in the absence of an outside stimulus. Neither the accessible original abstract nor the inspected anergy experiments settles that exact steady-state population claim. Retain uncertainty with this specific source-access and physiological distinction, not a B-versus-T misattribution verdict. Supporting Evidence: PMID:12970760 caspase-3 is essential in the regulation of B cell homeostasis. |
| GO:0045736 negative regulation of cyclin-dependent protein serine/threonine kinase activity | IMP PMID:12970760 Caspase-3 regulates cell cycle in B cells: a consequence of ... | KEEP AS NON CORE | Summary: negative regulation of cyclin-dependent protein serine/threonine kinase activity reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Regulation in the B-cell genetic context does not confer noncovalent CDK inhibitor molecular activity. Supporting Evidence: PMID:12970760 CDK activities and proliferating cell nuclear antigen (PCNA) were increased in Casp3-/- B cells |
| GO:0045786 negative regulation of cell cycle | IMP PMID:12970760 Caspase-3 regulates cell cycle in B cells: a consequence of ... | KEEP AS NON CORE | Summary: negative regulation of cell cycle reflects a context-specific phenotype, cell type, stimulus response, localization, or specialized non-apoptotic role rather than the core Casp3 molecular function. Reason: Casp3 can be required in many developmental, neuronal, inflammatory, and stress contexts, but these annotations are downstream of or peripheral to its core protease activity in apoptotic execution. Independent source audit: Native mouse cell-cycle regulation in B cells. Supporting Evidence: PMID:12970760 caspase-3 is a negative regulator of B cell cycling |
| GO:0046007 negative regulation of activated T cell proliferation | IMP PMID:12970760 Caspase-3 regulates cell cycle in B cells: a consequence of ... | KEEP AS NON CORE | Summary: negative regulation of activated T cell proliferation: retain with the primary study's context and species limits. Reason: Provenance trace: PMID:12970760 via MGI:MGI:2178778. The original PMID:12970760 abstract foregrounds B cells and does not expose its T-cell data, so it is not used to invent a T-cell experiment. Independent full PMID:18701083 uses primary mouse T cells, proliferation assays, Casp3-deficient cells/siRNA, and caspase-resistant GADS/Vav1 to establish nonapoptotic proteolytic restraint of TCR responses during anergy. This supports inhibition of activated T-cell proliferation in a defined tolerance context. Retain as non-core, not universal inhibition of all stimulated T cells or steady-state T-cell-number homeostasis. Supporting Evidence: PMID:18701083 Blocking caspase 3 expression with siRNA or using T cells from caspase 3-deficient mice leads to defective anergy induction PMID:18701083 Induction of anergy was confirmed by decreased proliferation and IL-2 production |
| GO:0008233 peptidase activity | IDA PMID:12954857 Ischemic preconditioning by caspase cleavage of poly(ADP-rib... | 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:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0005737 cytoplasm | IDA PMID:12477715 Role of prodomain in importin-mediated nuclear localization ... | 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:mouse/Casp3/Casp3-uniprot.txt Cytoplasm |
| GO:0005515 protein binding | IPI PMID:19759058 Proteome-wide substrate analysis indicates substrate exclusi... | REMOVE | Summary: Generic protein binding is uninformative despite the substrate-screen evidence. Reason: PMID:19759058 is a caspase-3/caspase-7 substrate-specificity screen in mouse macrophage lysate. Retain Casp3 cysteine endopeptidase activity from the same paper, but remove this generic IntAct protein-binding assertion rather than representing a candidate substrate interaction as a molecular function. |
| GO:0005634 nucleus | ISO GO_REF:0000119 | 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. Human nuclear-fraction experiments provide comparative support; the original native mouse annotation is preserved without claiming that this paper tested mouse CASP3. Supporting Evidence: PMID:22253444 caspase-3 active fragments can also be evidenced in the nuclear fractions after STP treatment |
| GO:0005829 cytosol | ISO GO_REF:0000119 | ACCEPT | Summary: cytosol is consistent with Casp3 as an executioner caspase that cleaves substrates during apoptotic execution. Reason: This term captures the established cytosolic pool of the effector caspase and is consistent with prior accepted Ensembl, Reactome, and human-ortholog cytosol rows. |
| GO:0070269 pyroptotic inflammatory response | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: GSDME-dependent inflammatory output is a conditional Casp3 context. Reason: Caspase-3 cleaves GSDME to release its pore-forming amino-terminal fragment, supporting a conditional lytic/inflammatory route. PMID:28459430 directly describes human primary-cell GSDME-dependent pyroptosis and Gsdme-null mouse protection after chemotherapy. Full 33852854 separates sublytic IL-1beta release from overt lysis and shows that low-GSDME murine iBMMs behave differently; its rescue uses human GSDME in a mouse host. Thus the human-to-mouse transfer supports conserved conditional proteolytic activation, not a native mouse assay for every construct or an invariant inflammatory outcome whenever Casp3 is active. Retain the broader inflammatory-response attribution as non-core context, consistently with the human review; expression, stimulus and cellular release machinery determine the full response. 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. PMID:33852854 Gsdmdβ/β murine iBMMs lacked both GSDME and delayed cell death |
| GO:0004197 cysteine-type endopeptidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: cysteine-type endopeptidase activity is the core Casp3 molecular function. Reason: The InterPro/ortholog-based UniProt IEA repeats the established cysteine effector-caspase activity represented by direct mouse IDA, ISO, ISS, and PAINT rows. |
| 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 The conserved original claim is defensible; the target evidence supports the stated refinement. This assessment does not relocate the PAINT ancestral assertion. Proposed replacements: cytosol Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Cytoplasm |
| GO:0005737 cytoplasm | ISO GO_REF:0000119 | 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: UniProtKB:P42574 SUPPORTS TRANSFER The conserved original claim is defensible; the target evidence supports the stated refinement. This assessment does not relocate the PAINT ancestral assertion. Proposed replacements: cytosol Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt Cytoplasm |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | 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: UniProtKB:P42574 SUPPORTS TRANSFER The conserved original claim is defensible; the target evidence supports the stated refinement. This assessment does not relocate the PAINT ancestral assertion. Proposed replacements: cytosol Supporting Evidence: file:mouse/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:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0006915 apoptotic process | IDA PMID:24378336 BDNF and NT4 play interchangeable roles in gustatory develop... | 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. Native mouse PMID:16469926 resolves PARP cleavage and DNA/nuclear changes. The original full taste-development study counts active-Casp3-positive neurons after BDNF/NT4 manipulation; those manipulations and marker counts are distinguished from direct Casp3 genetic tests. Proposed replacements: execution phase of apoptosis Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins PMID:16469926 Caspase 3 controls DNA fragmentation and morphologic changes of apoptosis, whereas caspase 7 plays little role in these processes. |
| GO:0008233 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:mouse/Casp3/Casp3-uniprot.txt Belongs to the peptidase C14A family. file:mouse/Casp3/Casp3-uniprot.txt Strict requirement for an Asp residue at positions P1 and P4. |
| GO:0032880 regulation of protein localization | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Conserved junctional-substrate cleavage changes protein localization during apoptosis. Reason: The original human donor source PMID:17559062 studies staurosporine-treated HaCaT and HT-29 cells: DSG2 cleavage releases a 70-kDa cytosolic fragment, surface DSG2 labeling disappears, and plakoglobin/JUP is cleaved and detaches. z-DEVD-fmk preserves DSG2 surface labeling. Retain the mouse transfer as a substrate-dependent localization outcome, corroborated by curated orthology, without relabeling human epithelial assays as native mouse evidence or claiming that Casp3 is a transport carrier. The accessible abstract gives explicit results but full methods remain unavailable. 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. file:mouse/Casp3/Casp3-uniprot.txt Cleaves DSG2 in response to apoptosis resulting in a loss of full length DSG2 at desmosome cell junctions and subsequent loss of cell-cell adhesion |
| GO:0051604 protein maturation | IEA GO_REF:0000107 | ACCEPT | Summary: Casp3 directly processes protein substrates, including activation or inactivation by limited cleavage. Reason: Casp3 directly processes protein substrates, including activation or inactivation by limited cleavage. This is part of its core proteolytic function, separate from mere processing of Casp3 itself. Supporting Evidence: file:mouse/Casp3/Casp3-uniprot.txt mediates execution of apoptosis by catalyzing cleavage of many proteins |
| GO:0097190 apoptotic signaling pathway | IDA PMID:16183742 Apoptosis caused by p53-induced protein with death domain (P... | KEEP AS NON CORE | Summary: Casp3 is activated during PIDD-induced apoptotic signaling. Reason: PMID:16183742 reports RAIDD-dependent processing of procaspase-3 and -7 after PIDD expression in mouse embryonic fibroblasts. This supports Casp3 acting within that apoptotic signaling context, while the core function remains execution-phase proteolysis. |
| GO:0097194 execution phase of apoptosis | IEA GO_REF:0000107 | ACCEPT | Summary: execution phase of apoptosis is the core Casp3 biological process. Reason: The Ensembl transfer from human CASP3 repeats the most specific core apoptotic role for mouse Casp3 as an effector caspase that executes cell demolition downstream of initiator-caspase activation. |
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Download this section (compressed HTML)Q: Which mouse Casp3 inflammatory and pyroptotic annotations reflect direct Casp3 substrate cleavage versus downstream consequences of apoptosis or gasdermin-E activation?
Q: Which non-lethal neuronal remodeling functions of Casp3 are sufficiently direct and conserved to retain as non-core GO annotations?
Experiment: Use catalytically inactive Casp3 rescue alleles in apoptotic and non-apoptotic mouse cells to separate direct protease-dependent functions from downstream phenotypes.
Experiment: Perform substrate-trapping proteomics for active Casp3 in apoptotic cells, neurons, and inflammatory epithelial cells to identify context-specific direct substrates.
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