{"gene":"CASP2","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1994,"finding":"CASP2 (ICH-1/Nedd2) encodes a cysteine protease that induces programmed cell death when overexpressed (ICH-1L isoform), while the alternatively spliced short isoform (ICH-1S/312 aa) suppresses serum deprivation-induced cell death, demonstrating that alternative splicing produces both positive and negative regulators of apoptosis from the same locus.","method":"Overexpression of alternatively spliced isoforms in mammalian cells; cell death assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function and suppression experiments with two isoforms, replicated conceptually by multiple subsequent labs","pmids":["8087842"],"is_preprint":false},{"year":1994,"finding":"Overexpression of Nedd2 (CASP2) in cultured fibroblast and neuroblastoma cells induces apoptosis, and this apoptosis is suppressed by co-expression of human BCL-2, placing CASP2 downstream of or in parallel with BCL-2 in the apoptotic pathway.","method":"Overexpression in cultured cells; BCL-2 rescue experiment","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis established by BCL-2 rescue, replicated across cell types and confirmed by independent labs","pmids":["7958843"],"is_preprint":false},{"year":1995,"finding":"CASP2 (Nedd2) is required for apoptosis: antisense suppression of Nedd2 in factor-dependent FDC-P1 cells significantly inhibits cell death upon cytokine withdrawal, demonstrating a direct pro-apoptotic role.","method":"Antisense expression; cell death assay upon cytokine withdrawal","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function antisense with defined phenotypic readout, single lab, single method","pmids":["7615091"],"is_preprint":false},{"year":1995,"finding":"CASP2 (Nedd2) can cleave poly(ADP-ribose) polymerase (PARP) in a manner identical to that observed in apoptotic cells, both in a co-transfection assay and in vitro with purified recombinant enzyme, establishing PARP as a substrate of CASP2.","method":"COS cell co-transfection assay; in vitro cleavage with purified recombinant enzyme","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical cleavage assay with purified recombinant enzyme plus cellular co-expression, two orthogonal methods in one study","pmids":["7642516"],"is_preprint":false},{"year":1996,"finding":"The p51 Nedd2 precursor (pro-CASP2) is processed in vitro by active CPP32 (caspase-3) and ICE (caspase-1), and to a lesser extent by Mch2 and Nedd2 itself, into p19+p12 subunits; granzyme B also cleaves pro-Nedd2, placing CASP2 as a downstream effector in cytotoxic T lymphocyte-mediated killing.","method":"In vitro cleavage assay using cell extracts and purified proteases; inhibitor studies","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of processing with multiple defined proteases, inhibitor controls, single lab with multiple orthogonal approaches","pmids":["9078393"],"is_preprint":false},{"year":1997,"finding":"CASP2 (Nedd2) is required for apoptosis induced by trophic factor (NGF/serum) deprivation in PC12 cells and sympathetic neurons; antisense oligonucleotide-mediated knockdown of Nedd2 rescues these cells from death. Nedd2 is not required for apoptosis induced by SOD1 downregulation, demonstrating stimulus-specific roles for distinct caspases.","method":"Antisense oligonucleotide knockdown; Western immunoblotting; immunohistochemistry; cell death assays","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with antisense, multiple cell types, two distinct apoptotic stimuli compared, replicated by independent lab (Stefanis et al. 1998)","pmids":["9045720"],"is_preprint":false},{"year":1997,"finding":"CASP2 (Nedd2) is activated early during apoptosis induced by multiple stimuli, prior to activation of caspase-3 (CPP32), suggesting CASP2 acts upstream of effector caspases.","method":"Western blot detection of processed subunits; comparison of activation kinetics across multiple apoptotic stimuli and resistant cell lines","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — temporal ordering of caspase activation by biochemical detection, single lab, multiple stimuli but no direct epistasis experiment","pmids":["9148927"],"is_preprint":false},{"year":1998,"finding":"Dimerization of the Nedd2/CASP2 precursor requires both the prodomain and the carboxyl-terminal residues; dimerization precedes processing; in vitro processing by recombinant active Nedd2 defined aspartate residues critical for processing, and self-processing correlates with induction of cell death.","method":"Yeast two-hybrid dimerization assay; site-directed mutagenesis of aspartate residues; in vitro processing with recombinant enzyme; cell death assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution, mutagenesis of active-site and processing sites, in vivo yeast dimerization assay, multiple orthogonal methods in one study","pmids":["9506977"],"is_preprint":false},{"year":1998,"finding":"The prodomain of CASP2 (Nedd2) is required for nuclear localization of the precursor; both precursor and processed caspase-2 localize to cytoplasmic and nuclear compartments. The prodomain fused to caspase-3 (normally cytoplasmic) is sufficient to transport caspase-3 to the nucleus, demonstrating a novel nuclear transport function for the CASP2 prodomain.","method":"GFP fusion constructs; live-cell fluorescence microscopy; domain-swap experiments with caspase-3","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization by GFP imaging, domain deletion and swap experiments providing functional validation, two orthogonal approaches","pmids":["9733748"],"is_preprint":false},{"year":1998,"finding":"CASP2 processing at D333 (forming a 37 kDa N-terminal product) and cell death in trophic factor-deprived PC12 cells and sympathetic neurons occur independently of caspase-3-like activity; caspase-3-like activity is neither necessary nor sufficient for death in this paradigm, and CASP2 is not upstream of caspase-3-like activity.","method":"Selective caspase inhibitors (DEVD-FMK vs. BAF/zVAD); antisense oligonucleotides; Western blot detection of processing; cell death assays","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — pharmacological and genetic dissection with multiple inhibitors, antisense, biochemical readouts; replicated from prior work by same group","pmids":["9801360"],"is_preprint":false},{"year":2014,"finding":"CASP2 is an endogenous repressor of autophagy; knockout or knockdown of CASP2 upregulates autophagy in multiple cell types and tissues via the canonical AMP-activated protein kinase/mTOR/MAPK pathway, and re-insertion of Casp2 in casp2−/− MEFs suppresses autophagy. Enhanced ROS production following CASP2 loss acts as an upstream signal for autophagy induction.","method":"Casp2 knockout MEFs; knockdown; Casp2 re-insertion rescue; autophagy pathway markers (AMPK, mTOR, MAPK, ATG proteins); ROS measurement","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO + rescue + knockdown across multiple cell types, pathway markers, single lab","pmids":["24879153"],"is_preprint":false},{"year":2023,"finding":"Biallelic truncating variants in CASP2 cause a neurodevelopmental disorder with lissencephaly and pachygyria, phenotypically similar to CRADD- and PIDD1-related disorders, demonstrating that CASP2 function as a component of the PIDDosome complex is required for normal human cortical development.","method":"Exome sequencing; RNA splice analysis (cryptic splice sites); family-based segregation analysis; clinical neuroimaging","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — human genetic loss-of-function with RNA functional validation, single study, no in vitro reconstitution of PIDDosome function","pmids":["37880421"],"is_preprint":false},{"year":2024,"finding":"CCN1 upregulates CASP2 mRNA transcription via E2F1 (through RB1 phosphorylation mediated by downregulation of p16/p21), but simultaneously upregulates HuR which binds CASP2 mRNA and blocks its protein translation, resulting in no CASP2 protein contribution to CCN1-induced apoptosis in esophageal adenocarcinoma cells.","method":"Reporter assays; Western blot; knockdown/overexpression; mRNA-protein level dissection","journal":"Journal of cell communication and signaling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single study, mechanistic pathway proposed with supporting knockdown/overexpression but limited orthogonal validation","pmids":["39524140"],"is_preprint":false}],"current_model":"CASP2 (ICH-1/Nedd2) is a cysteine protease that exists as a precursor requiring dimerization (dependent on both its prodomain and C-terminus) and proteolytic processing at defined aspartate residues to generate active p19+p12 subunits; it is activated early in apoptosis upstream of effector caspases (with its prodomain also directing nuclear localization), cleaves substrates including PARP, is itself processed by caspase-1, caspase-3, and granzyme B, acts as a required mediator of trophic factor deprivation-induced neuronal apoptosis (but not all apoptotic stimuli), and additionally functions as an endogenous repressor of autophagy through the AMPK/mTOR/MAPK pathway; loss of CASP2 function in humans causes lissencephaly, implicating its PIDDosome complex activity in cortical development."},"narrative":{"mechanistic_narrative":"CASP2 (ICH-1/Nedd2) is a cysteine protease that functions as a pro-apoptotic regulator, with alternative splicing of the locus producing both a death-inducing long isoform and a death-suppressing short isoform [PMID:8087842]. The enzyme is synthesized as an inactive precursor that must dimerize—a step requiring both the prodomain and the carboxyl-terminal residues—before undergoing proteolytic processing at defined aspartate residues to generate active p19+p12 subunits, with dimerization preceding processing and self-processing correlating with death induction [PMID:9506977]. The prodomain additionally serves as a nuclear localization signal, sufficient to redirect normally cytoplasmic caspase-3 to the nucleus [PMID:9733748]. CASP2 is activated early in apoptosis, ahead of effector caspases [PMID:9148927], and cleaves PARP in a manner identical to that seen in apoptotic cells [PMID:7642516]; its own precursor is processed by caspase-1, caspase-3, and granzyme B, integrating it into both intrinsic apoptotic and cytotoxic lymphocyte killing pathways [PMID:9078393]. Genetic loss-of-function studies establish CASP2 as a required mediator of trophic factor (NGF/serum) deprivation-induced death in neurons, but not of all apoptotic stimuli, and in this paradigm it acts independently of caspase-3-like activity [PMID:9045720, PMID:9801360]. Beyond apoptosis, CASP2 acts as an endogenous repressor of autophagy through the AMPK/mTOR/MAPK pathway, with its loss elevating ROS as an upstream autophagy-inducing signal [PMID:24879153]. Biallelic truncating CASP2 variants cause a neurodevelopmental disorder with lissencephaly and pachygyria, implicating its PIDDosome activity in human cortical development [PMID:37880421].","teleology":[{"year":1994,"claim":"Established that a single caspase locus can encode opposing regulators of cell death, defining CASP2's dual potential through alternative splicing.","evidence":"Overexpression of ICH-1L vs ICH-1S isoforms in mammalian cells with death assays","pmids":["8087842"],"confidence":"High","gaps":["Physiological balance of the two isoforms in vivo not established","Substrates and catalytic mechanism not yet defined"]},{"year":1994,"claim":"Positioned CASP2 within the apoptotic hierarchy by showing BCL-2 suppresses CASP2-induced death.","evidence":"Overexpression in fibroblast and neuroblastoma cells with BCL-2 rescue","pmids":["7958843"],"confidence":"High","gaps":["Whether BCL-2 acts directly on CASP2 or upstream not resolved","Endogenous requirement not tested by this gain-of-function approach"]},{"year":1995,"claim":"Demonstrated an endogenous pro-apoptotic requirement for CASP2 beyond overexpression, and identified PARP as a substrate.","evidence":"Antisense suppression in FDC-P1 cells; COS co-transfection and in vitro cleavage of PARP with recombinant enzyme","pmids":["7615091","7642516"],"confidence":"Medium","gaps":["Antisense specificity from a single lab/method","Full substrate repertoire unknown"]},{"year":1996,"claim":"Defined how the CASP2 precursor is activated, placing it as a substrate of upstream proteases including granzyme B.","evidence":"In vitro cleavage of the p51 precursor by caspase-3, caspase-1, Mch2, Nedd2, and granzyme B with inhibitor controls","pmids":["9078393"],"confidence":"High","gaps":["Relative physiological contribution of each protease unknown","Order of CASP2 relative to these proteases in cells not resolved"]},{"year":1997,"claim":"Established a stimulus-specific, non-redundant role for CASP2 in neuronal apoptosis driven by trophic factor withdrawal.","evidence":"Antisense knockdown in PC12 cells and sympathetic neurons; comparison across distinct death stimuli","pmids":["9045720"],"confidence":"High","gaps":["Molecular trigger linking trophic deprivation to CASP2 activation unknown","Downstream effectors in neurons not mapped"]},{"year":1997,"claim":"Provided temporal evidence that CASP2 activation precedes effector caspase activation, implying an apical position.","evidence":"Western detection of processed subunits across multiple stimuli and resistant cell lines","pmids":["9148927"],"confidence":"Medium","gaps":["No direct epistasis experiment","Activation timing differs by stimulus"]},{"year":1998,"claim":"Resolved the activation mechanism—dimerization requiring prodomain and C-terminus precedes aspartate processing—and uncovered prodomain-directed nuclear targeting.","evidence":"Yeast two-hybrid dimerization, aspartate mutagenesis, in vitro processing; GFP fusions and caspase-3 domain swaps","pmids":["9506977","9733748"],"confidence":"High","gaps":["Physiological dimerization platform (e.g. activating complex) not identified here","Functional consequence of nuclear localization for specific substrates unclear"]},{"year":1998,"claim":"Showed CASP2-dependent neuronal death and D333 processing proceed independently of caspase-3-like activity, refining the apical-vs-effector question.","evidence":"Selective caspase inhibitors and antisense in trophic-deprived PC12 cells and sympathetic neurons","pmids":["9801360"],"confidence":"High","gaps":["Identity of the executioner downstream of CASP2 in neurons unresolved","Apparent conflict with general upstream-of-caspase-3 model not reconciled across paradigms"]},{"year":2014,"claim":"Identified a non-apoptotic function: CASP2 represses autophagy via AMPK/mTOR/MAPK signaling, with ROS as an upstream cue.","evidence":"Casp2 knockout/knockdown/re-insertion in MEFs and tissues; autophagy and ROS markers","pmids":["24879153"],"confidence":"Medium","gaps":["Direct substrate or protein target linking CASP2 to the pathway not identified","Single-lab finding"]},{"year":2023,"claim":"Linked CASP2 loss-of-function to human disease, implicating its PIDDosome role in cortical development.","evidence":"Exome sequencing, RNA splice analysis, and family segregation in lissencephaly/pachygyria patients","pmids":["37880421"],"confidence":"Medium","gaps":["No in vitro reconstitution of PIDDosome dysfunction","Mechanism connecting CASP2 to neuronal migration not established"]},{"year":2024,"claim":"Described dual transcriptional/post-transcriptional control of CASP2 in cancer cells uncoupling its mRNA induction from protein output.","evidence":"Reporter assays, knockdown/overexpression of E2F1 and HuR in esophageal adenocarcinoma cells","pmids":["39524140"],"confidence":"Low","gaps":["Single study with limited orthogonal validation","Generality beyond esophageal adenocarcinoma unknown"]},{"year":null,"claim":"The molecular composition and activating platform of the human CASP2/PIDDosome and how it connects to both cortical development and autophagy repression remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No reconstituted human PIDDosome in the corpus","Direct CASP2 substrate(s) in autophagy and neurodevelopment not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,4,7]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[3,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1,5]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10]}],"complexes":["PIDDosome"],"partners":["BCL2","CASP3","CASP1","GZMB","PARP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P42575","full_name":"Caspase-2","aliases":["Neural precursor cell expressed developmentally down-regulated protein 2","NEDD-2","Protease ICH-1"],"length_aa":452,"mass_kda":50.7,"function":"Is a regulator of the cascade of caspases responsible for apoptosis execution (PubMed:11156409, PubMed:15073321, PubMed:8087842). Might function by either activating some proteins required for cell death or inactivating proteins necessary for cell survival (PubMed:15073321). Associates with PIDD1 and CRADD to form the PIDDosome, a complex that activates CASP2 and triggers apoptosis in response to genotoxic stress (PubMed:15073321) Acts as a positive regulator of apoptosis Acts as a negative regulator of apoptosis May function as an endogenous apoptosis inhibitor that antagonizes caspase activation and cell death","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P42575/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CASP2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000106144","cell_line_id":"CID001705","localizations":[{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"PDS5B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001705","total_profiled":1310},"omim":[{"mim_id":"620653","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 80, WITH VARIANT LISSENCEPHALY; MRT80","url":"https://www.omim.org/entry/620653"},{"mim_id":"619827","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 75, WITH NEUROPSYCHIATRIC FEATURES AND VARIANT LISSENCEPHALY; MRT75","url":"https://www.omim.org/entry/619827"},{"mim_id":"616466","title":"UNC5 NETRIN RECEPTOR D; UNC5D","url":"https://www.omim.org/entry/616466"},{"mim_id":"614499","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 34, WITH VARIANT LISSENCEPHALY; MRT34","url":"https://www.omim.org/entry/614499"},{"mim_id":"610934","title":"NOBOX OOGENESIS HOMEOBOX; NOBOX","url":"https://www.omim.org/entry/610934"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CASP2"},"hgnc":{"alias_symbol":["ICH1","PPP1R57","MGC2181"],"prev_symbol":["NEDD2"]},"alphafold":{"accession":"P42575","domains":[{"cath_id":"1.10.533.10","chopping":"33-125","consensus_level":"high","plddt":88.3939,"start":33,"end":125},{"cath_id":"3.40.50.1460","chopping":"180-325_359-437","consensus_level":"high","plddt":93.3777,"start":180,"end":437}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P42575","model_url":"https://alphafold.ebi.ac.uk/files/AF-P42575-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P42575-F1-predicted_aligned_error_v6.png","plddt_mean":78.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CASP2","jax_strain_url":"https://www.jax.org/strain/search?query=CASP2"},"sequence":{"accession":"P42575","fasta_url":"https://rest.uniprot.org/uniprotkb/P42575.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P42575/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P42575"}},"corpus_meta":[{"pmid":"8087842","id":"PMC_8087842","title":"Ich-1, an Ice/ced-3-related gene, encodes both positive and negative regulators of programmed cell death.","date":"1994","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/8087842","citation_count":824,"is_preprint":false},{"pmid":"7958843","id":"PMC_7958843","title":"Induction of apoptosis by the mouse Nedd2 gene, which encodes a protein similar to the product of the Caenorhabditis elegans cell death gene ced-3 and the mammalian IL-1 beta-converting enzyme.","date":"1994","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/7958843","citation_count":601,"is_preprint":false},{"pmid":"9507158","id":"PMC_9507158","title":"Alteration of proteins regulating apoptosis, Bcl-2, Bcl-x, Bax, Bak, Bad, ICH-1 and CPP32, in Alzheimer's disease.","date":"1998","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/9507158","citation_count":226,"is_preprint":false},{"pmid":"7642516","id":"PMC_7642516","title":"Cleavage of poly(ADP-ribose) polymerase by interleukin-1 beta converting enzyme and its homologs TX and Nedd-2.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7642516","citation_count":161,"is_preprint":false},{"pmid":"9045720","id":"PMC_9045720","title":"Nedd2 is required for apoptosis after trophic factor withdrawal, but not superoxide dismutase (SOD1) downregulation, in sympathetic neurons and PC12 cells.","date":"1997","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/9045720","citation_count":145,"is_preprint":false},{"pmid":"9733748","id":"PMC_9733748","title":"Prodomain-dependent nuclear localization of the caspase-2 (Nedd2) precursor. A novel function for a caspase prodomain.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9733748","citation_count":139,"is_preprint":false},{"pmid":"9148927","id":"PMC_9148927","title":"Functional activation of Nedd2/ICH-1 (caspase-2) is an early process in apoptosis.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9148927","citation_count":130,"is_preprint":false},{"pmid":"16166278","id":"PMC_16166278","title":"T25 repeat in the 3' untranslated region of the CASP2 gene: a sensitive and specific marker for microsatellite instability in colorectal cancer.","date":"2005","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16166278","citation_count":123,"is_preprint":false},{"pmid":"9506977","id":"PMC_9506977","title":"Dimerization and autoprocessing of the Nedd2 (caspase-2) precursor requires both the prodomain and the carboxyl-terminal regions.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9506977","citation_count":100,"is_preprint":false},{"pmid":"9801360","id":"PMC_9801360","title":"Caspase-2 (Nedd-2) processing and death of trophic factor-deprived PC12 cells and sympathetic neurons occur independently of caspase-3 (CPP32)-like activity.","date":"1998","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/9801360","citation_count":95,"is_preprint":false},{"pmid":"9485512","id":"PMC_9485512","title":"Evaluation of the CASP2 docking section.","date":"1997","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/9485512","citation_count":62,"is_preprint":false},{"pmid":"24879153","id":"PMC_24879153","title":"A nonapoptotic role for CASP2/caspase 2: modulation of autophagy.","date":"2014","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/24879153","citation_count":61,"is_preprint":false},{"pmid":"9078393","id":"PMC_9078393","title":"Processing of the Nedd2 precursor by ICE-like proteases and granzyme B.","date":"1996","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/9078393","citation_count":57,"is_preprint":false},{"pmid":"24727569","id":"PMC_24727569","title":"Combined suppression of CASP2 and CASP6 protects retinal ganglion cells from apoptosis and promotes axon regeneration through CNTF-mediated JAK/STAT signalling.","date":"2014","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24727569","citation_count":57,"is_preprint":false},{"pmid":"9326271","id":"PMC_9326271","title":"Inhibitors of trypsin-like serine proteases inhibit processing of the caspase Nedd-2 and protect PC12 cells and sympathetic neurons from death evoked by withdrawal of trophic support.","date":"1997","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9326271","citation_count":56,"is_preprint":false},{"pmid":"7615091","id":"PMC_7615091","title":"Inhibition of apoptosis by the expression of antisense Nedd2.","date":"1995","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/7615091","citation_count":55,"is_preprint":false},{"pmid":"9183288","id":"PMC_9183288","title":"Up-regulation of the Nedd2 gene encoding an ICE/Ced-3-like cysteine protease in the gerbil brain after transient global ischemia.","date":"1997","source":"Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/9183288","citation_count":55,"is_preprint":false},{"pmid":"28129024","id":"PMC_28129024","title":"BECN1-dependent CASP2 incomplete autophagy induction by binding to rabies virus phosphoprotein.","date":"2017","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/28129024","citation_count":55,"is_preprint":false},{"pmid":"10964483","id":"PMC_10964483","title":"Tumor necrosis factor-alpha-induced apoptosis in olfactory epithelium in vitro: possible roles of caspase 1 (ICE), caspase 2 (ICH-1), and caspase 3 (CPP32).","date":"2000","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/10964483","citation_count":55,"is_preprint":false},{"pmid":"35436510","id":"PMC_35436510","title":"miR-150-3p enhances neuroprotective effects of neural stem cell exosomes after hypoxic-ischemic brain injury by targeting CASP2.","date":"2022","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/35436510","citation_count":52,"is_preprint":false},{"pmid":"9671586","id":"PMC_9671586","title":"The ich1 gene of the mushroom Coprinus cinereus is essential for pileus formation in fruiting.","date":"1998","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9671586","citation_count":46,"is_preprint":false},{"pmid":"9135979","id":"PMC_9135979","title":"Meeting review: the Second meeting on the Critical Assessment of Techniques for Protein Structure Prediction (CASP2), Asilomar, California, December 13-16, 1996.","date":"1997","source":"Folding & design","url":"https://pubmed.ncbi.nlm.nih.gov/9135979","citation_count":43,"is_preprint":false},{"pmid":"9485507","id":"PMC_9485507","title":"CASP2: report on ab initio predictions.","date":"1997","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/9485507","citation_count":40,"is_preprint":false},{"pmid":"7789948","id":"PMC_7789948","title":"Apoptosis regulatory gene NEDD2 maps to human chromosome segment 7q34-35, a region frequently affected in haematological neoplasms.","date":"1995","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7789948","citation_count":38,"is_preprint":false},{"pmid":"9485516","id":"PMC_9485516","title":"CASP2 experiences with docking flexible ligands using FlexX.","date":"1997","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/9485516","citation_count":37,"is_preprint":false},{"pmid":"28783714","id":"PMC_28783714","title":"Aging and calorie restriction regulate the expression of miR-125a-5p and its target genes Stat3, Casp2 and Stard13.","date":"2017","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/28783714","citation_count":31,"is_preprint":false},{"pmid":"30816202","id":"PMC_30816202","title":"MiR-494 acts as a tumor promoter by targeting CASP2 in non-small cell lung cancer.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30816202","citation_count":31,"is_preprint":false},{"pmid":"8780721","id":"PMC_8780721","title":"Chromosomal localization of the human genes, CPP32, Mch2, Mch3, and Ich-1, involved in cellular apoptosis.","date":"1996","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/8780721","citation_count":22,"is_preprint":false},{"pmid":"9485499","id":"PMC_9485499","title":"A retrospective analysis of CASP2 threading predictions.","date":"1997","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/9485499","citation_count":19,"is_preprint":false},{"pmid":"11835484","id":"PMC_11835484","title":"CASP2 knowledge-based approach to distant homology recognition and fold prediction in CASP4.","date":"2001","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/11835484","citation_count":18,"is_preprint":false},{"pmid":"9224894","id":"PMC_9224894","title":"Characterization of the avian Ich-1 cDNA and expression of Ich-1L mRNA in the hen ovary.","date":"1997","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/9224894","citation_count":17,"is_preprint":false},{"pmid":"9269827","id":"PMC_9269827","title":"Cysteine protease CPP32, but not Ich1-L, is expressed in germinal center B cells and their neoplastic counterparts.","date":"1997","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/9269827","citation_count":16,"is_preprint":false},{"pmid":"11073159","id":"PMC_11073159","title":"Reactivation of Nedd-2, a developmentally down-regulated apoptotic gene, in apoptosis induced by a street strain of rabies virus.","date":"2000","source":"Journal of medical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/11073159","citation_count":16,"is_preprint":false},{"pmid":"9485514","id":"PMC_9485514","title":"CASP2 molecular docking predictions with the LIGIN software.","date":"1997","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/9485514","citation_count":15,"is_preprint":false},{"pmid":"9485508","id":"PMC_9485508","title":"Blind predictions of local protein structure in CASP2 targets using the I-sites library.","date":"1997","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/9485508","citation_count":15,"is_preprint":false},{"pmid":"9485502","id":"PMC_9485502","title":"Fold assignments for amino acid sequences of the CASP2 experiment.","date":"1997","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/9485502","citation_count":14,"is_preprint":false},{"pmid":"9809666","id":"PMC_9809666","title":"Expression of Nedd2/ICH-1 (caspase-2) in the developing rat retina.","date":"1998","source":"Neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/9809666","citation_count":12,"is_preprint":false},{"pmid":"37880421","id":"PMC_37880421","title":"Bi-allelic truncating variants in CASP2 underlie a neurodevelopmental disorder with lissencephaly.","date":"2023","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/37880421","citation_count":12,"is_preprint":false},{"pmid":"9209399","id":"PMC_9209399","title":"Characterization of a mammalian cell death gene Nedd2.","date":"1997","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/9209399","citation_count":11,"is_preprint":false},{"pmid":"35085690","id":"PMC_35085690","title":"MiR-17-5p protects neonatal mice from hypoxic-ischemic brain damage by targeting Casp2.","date":"2022","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/35085690","citation_count":9,"is_preprint":false},{"pmid":"38509889","id":"PMC_38509889","title":"PANoptosis-related molecule CASP2 affects the immune microenvironment and immunotherapy response of hepatocellular carcinoma.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38509889","citation_count":6,"is_preprint":false},{"pmid":"39524140","id":"PMC_39524140","title":"Cellular communication network 1 promotes CASP2 mRNA expression but suppresses its protein translation in esophageal adenocarcinoma.","date":"2024","source":"Journal of cell communication and signaling","url":"https://pubmed.ncbi.nlm.nih.gov/39524140","citation_count":1,"is_preprint":false},{"pmid":"12297434","id":"PMC_12297434","title":"[Relationship between hepatitis C virus infection and expression of apoptosis-related gene bcl-2, bax and ICH-1 in hepatocellular carcinoma tissues].","date":"2002","source":"Di 1 jun yi da xue xue bao = Academic journal of the first medical college of PLA","url":"https://pubmed.ncbi.nlm.nih.gov/12297434","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19531,"output_tokens":3253,"usd":0.053694,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10655,"output_tokens":3288,"usd":0.067738,"stage2_stop_reason":"end_turn"},"total_usd":0.121432,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"CASP2 (ICH-1/Nedd2) encodes a cysteine protease that induces programmed cell death when overexpressed (ICH-1L isoform), while the alternatively spliced short isoform (ICH-1S/312 aa) suppresses serum deprivation-induced cell death, demonstrating that alternative splicing produces both positive and negative regulators of apoptosis from the same locus.\",\n      \"method\": \"Overexpression of alternatively spliced isoforms in mammalian cells; cell death assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function and suppression experiments with two isoforms, replicated conceptually by multiple subsequent labs\",\n      \"pmids\": [\"8087842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Overexpression of Nedd2 (CASP2) in cultured fibroblast and neuroblastoma cells induces apoptosis, and this apoptosis is suppressed by co-expression of human BCL-2, placing CASP2 downstream of or in parallel with BCL-2 in the apoptotic pathway.\",\n      \"method\": \"Overexpression in cultured cells; BCL-2 rescue experiment\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis established by BCL-2 rescue, replicated across cell types and confirmed by independent labs\",\n      \"pmids\": [\"7958843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CASP2 (Nedd2) is required for apoptosis: antisense suppression of Nedd2 in factor-dependent FDC-P1 cells significantly inhibits cell death upon cytokine withdrawal, demonstrating a direct pro-apoptotic role.\",\n      \"method\": \"Antisense expression; cell death assay upon cytokine withdrawal\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function antisense with defined phenotypic readout, single lab, single method\",\n      \"pmids\": [\"7615091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CASP2 (Nedd2) can cleave poly(ADP-ribose) polymerase (PARP) in a manner identical to that observed in apoptotic cells, both in a co-transfection assay and in vitro with purified recombinant enzyme, establishing PARP as a substrate of CASP2.\",\n      \"method\": \"COS cell co-transfection assay; in vitro cleavage with purified recombinant enzyme\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical cleavage assay with purified recombinant enzyme plus cellular co-expression, two orthogonal methods in one study\",\n      \"pmids\": [\"7642516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The p51 Nedd2 precursor (pro-CASP2) is processed in vitro by active CPP32 (caspase-3) and ICE (caspase-1), and to a lesser extent by Mch2 and Nedd2 itself, into p19+p12 subunits; granzyme B also cleaves pro-Nedd2, placing CASP2 as a downstream effector in cytotoxic T lymphocyte-mediated killing.\",\n      \"method\": \"In vitro cleavage assay using cell extracts and purified proteases; inhibitor studies\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of processing with multiple defined proteases, inhibitor controls, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"9078393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CASP2 (Nedd2) is required for apoptosis induced by trophic factor (NGF/serum) deprivation in PC12 cells and sympathetic neurons; antisense oligonucleotide-mediated knockdown of Nedd2 rescues these cells from death. Nedd2 is not required for apoptosis induced by SOD1 downregulation, demonstrating stimulus-specific roles for distinct caspases.\",\n      \"method\": \"Antisense oligonucleotide knockdown; Western immunoblotting; immunohistochemistry; cell death assays\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with antisense, multiple cell types, two distinct apoptotic stimuli compared, replicated by independent lab (Stefanis et al. 1998)\",\n      \"pmids\": [\"9045720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CASP2 (Nedd2) is activated early during apoptosis induced by multiple stimuli, prior to activation of caspase-3 (CPP32), suggesting CASP2 acts upstream of effector caspases.\",\n      \"method\": \"Western blot detection of processed subunits; comparison of activation kinetics across multiple apoptotic stimuli and resistant cell lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — temporal ordering of caspase activation by biochemical detection, single lab, multiple stimuli but no direct epistasis experiment\",\n      \"pmids\": [\"9148927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Dimerization of the Nedd2/CASP2 precursor requires both the prodomain and the carboxyl-terminal residues; dimerization precedes processing; in vitro processing by recombinant active Nedd2 defined aspartate residues critical for processing, and self-processing correlates with induction of cell death.\",\n      \"method\": \"Yeast two-hybrid dimerization assay; site-directed mutagenesis of aspartate residues; in vitro processing with recombinant enzyme; cell death assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution, mutagenesis of active-site and processing sites, in vivo yeast dimerization assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"9506977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The prodomain of CASP2 (Nedd2) is required for nuclear localization of the precursor; both precursor and processed caspase-2 localize to cytoplasmic and nuclear compartments. The prodomain fused to caspase-3 (normally cytoplasmic) is sufficient to transport caspase-3 to the nucleus, demonstrating a novel nuclear transport function for the CASP2 prodomain.\",\n      \"method\": \"GFP fusion constructs; live-cell fluorescence microscopy; domain-swap experiments with caspase-3\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by GFP imaging, domain deletion and swap experiments providing functional validation, two orthogonal approaches\",\n      \"pmids\": [\"9733748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CASP2 processing at D333 (forming a 37 kDa N-terminal product) and cell death in trophic factor-deprived PC12 cells and sympathetic neurons occur independently of caspase-3-like activity; caspase-3-like activity is neither necessary nor sufficient for death in this paradigm, and CASP2 is not upstream of caspase-3-like activity.\",\n      \"method\": \"Selective caspase inhibitors (DEVD-FMK vs. BAF/zVAD); antisense oligonucleotides; Western blot detection of processing; cell death assays\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pharmacological and genetic dissection with multiple inhibitors, antisense, biochemical readouts; replicated from prior work by same group\",\n      \"pmids\": [\"9801360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CASP2 is an endogenous repressor of autophagy; knockout or knockdown of CASP2 upregulates autophagy in multiple cell types and tissues via the canonical AMP-activated protein kinase/mTOR/MAPK pathway, and re-insertion of Casp2 in casp2−/− MEFs suppresses autophagy. Enhanced ROS production following CASP2 loss acts as an upstream signal for autophagy induction.\",\n      \"method\": \"Casp2 knockout MEFs; knockdown; Casp2 re-insertion rescue; autophagy pathway markers (AMPK, mTOR, MAPK, ATG proteins); ROS measurement\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO + rescue + knockdown across multiple cell types, pathway markers, single lab\",\n      \"pmids\": [\"24879153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Biallelic truncating variants in CASP2 cause a neurodevelopmental disorder with lissencephaly and pachygyria, phenotypically similar to CRADD- and PIDD1-related disorders, demonstrating that CASP2 function as a component of the PIDDosome complex is required for normal human cortical development.\",\n      \"method\": \"Exome sequencing; RNA splice analysis (cryptic splice sites); family-based segregation analysis; clinical neuroimaging\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — human genetic loss-of-function with RNA functional validation, single study, no in vitro reconstitution of PIDDosome function\",\n      \"pmids\": [\"37880421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCN1 upregulates CASP2 mRNA transcription via E2F1 (through RB1 phosphorylation mediated by downregulation of p16/p21), but simultaneously upregulates HuR which binds CASP2 mRNA and blocks its protein translation, resulting in no CASP2 protein contribution to CCN1-induced apoptosis in esophageal adenocarcinoma cells.\",\n      \"method\": \"Reporter assays; Western blot; knockdown/overexpression; mRNA-protein level dissection\",\n      \"journal\": \"Journal of cell communication and signaling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single study, mechanistic pathway proposed with supporting knockdown/overexpression but limited orthogonal validation\",\n      \"pmids\": [\"39524140\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CASP2 (ICH-1/Nedd2) is a cysteine protease that exists as a precursor requiring dimerization (dependent on both its prodomain and C-terminus) and proteolytic processing at defined aspartate residues to generate active p19+p12 subunits; it is activated early in apoptosis upstream of effector caspases (with its prodomain also directing nuclear localization), cleaves substrates including PARP, is itself processed by caspase-1, caspase-3, and granzyme B, acts as a required mediator of trophic factor deprivation-induced neuronal apoptosis (but not all apoptotic stimuli), and additionally functions as an endogenous repressor of autophagy through the AMPK/mTOR/MAPK pathway; loss of CASP2 function in humans causes lissencephaly, implicating its PIDDosome complex activity in cortical development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CASP2 (ICH-1/Nedd2) is a cysteine protease that functions as a pro-apoptotic regulator, with alternative splicing of the locus producing both a death-inducing long isoform and a death-suppressing short isoform [#0]. The enzyme is synthesized as an inactive precursor that must dimerize—a step requiring both the prodomain and the carboxyl-terminal residues—before undergoing proteolytic processing at defined aspartate residues to generate active p19+p12 subunits, with dimerization preceding processing and self-processing correlating with death induction [#7]. The prodomain additionally serves as a nuclear localization signal, sufficient to redirect normally cytoplasmic caspase-3 to the nucleus [#8]. CASP2 is activated early in apoptosis, ahead of effector caspases [#6], and cleaves PARP in a manner identical to that seen in apoptotic cells [#3]; its own precursor is processed by caspase-1, caspase-3, and granzyme B, integrating it into both intrinsic apoptotic and cytotoxic lymphocyte killing pathways [#4]. Genetic loss-of-function studies establish CASP2 as a required mediator of trophic factor (NGF/serum) deprivation-induced death in neurons, but not of all apoptotic stimuli, and in this paradigm it acts independently of caspase-3-like activity [#5, #9]. Beyond apoptosis, CASP2 acts as an endogenous repressor of autophagy through the AMPK/mTOR/MAPK pathway, with its loss elevating ROS as an upstream autophagy-inducing signal [#10]. Biallelic truncating CASP2 variants cause a neurodevelopmental disorder with lissencephaly and pachygyria, implicating its PIDDosome activity in human cortical development [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established that a single caspase locus can encode opposing regulators of cell death, defining CASP2's dual potential through alternative splicing.\",\n      \"evidence\": \"Overexpression of ICH-1L vs ICH-1S isoforms in mammalian cells with death assays\",\n      \"pmids\": [\"8087842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological balance of the two isoforms in vivo not established\", \"Substrates and catalytic mechanism not yet defined\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Positioned CASP2 within the apoptotic hierarchy by showing BCL-2 suppresses CASP2-induced death.\",\n      \"evidence\": \"Overexpression in fibroblast and neuroblastoma cells with BCL-2 rescue\",\n      \"pmids\": [\"7958843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BCL-2 acts directly on CASP2 or upstream not resolved\", \"Endogenous requirement not tested by this gain-of-function approach\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Demonstrated an endogenous pro-apoptotic requirement for CASP2 beyond overexpression, and identified PARP as a substrate.\",\n      \"evidence\": \"Antisense suppression in FDC-P1 cells; COS co-transfection and in vitro cleavage of PARP with recombinant enzyme\",\n      \"pmids\": [\"7615091\", \"7642516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Antisense specificity from a single lab/method\", \"Full substrate repertoire unknown\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Defined how the CASP2 precursor is activated, placing it as a substrate of upstream proteases including granzyme B.\",\n      \"evidence\": \"In vitro cleavage of the p51 precursor by caspase-3, caspase-1, Mch2, Nedd2, and granzyme B with inhibitor controls\",\n      \"pmids\": [\"9078393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative physiological contribution of each protease unknown\", \"Order of CASP2 relative to these proteases in cells not resolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Established a stimulus-specific, non-redundant role for CASP2 in neuronal apoptosis driven by trophic factor withdrawal.\",\n      \"evidence\": \"Antisense knockdown in PC12 cells and sympathetic neurons; comparison across distinct death stimuli\",\n      \"pmids\": [\"9045720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger linking trophic deprivation to CASP2 activation unknown\", \"Downstream effectors in neurons not mapped\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Provided temporal evidence that CASP2 activation precedes effector caspase activation, implying an apical position.\",\n      \"evidence\": \"Western detection of processed subunits across multiple stimuli and resistant cell lines\",\n      \"pmids\": [\"9148927\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct epistasis experiment\", \"Activation timing differs by stimulus\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Resolved the activation mechanism—dimerization requiring prodomain and C-terminus precedes aspartate processing—and uncovered prodomain-directed nuclear targeting.\",\n      \"evidence\": \"Yeast two-hybrid dimerization, aspartate mutagenesis, in vitro processing; GFP fusions and caspase-3 domain swaps\",\n      \"pmids\": [\"9506977\", \"9733748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological dimerization platform (e.g. activating complex) not identified here\", \"Functional consequence of nuclear localization for specific substrates unclear\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed CASP2-dependent neuronal death and D333 processing proceed independently of caspase-3-like activity, refining the apical-vs-effector question.\",\n      \"evidence\": \"Selective caspase inhibitors and antisense in trophic-deprived PC12 cells and sympathetic neurons\",\n      \"pmids\": [\"9801360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the executioner downstream of CASP2 in neurons unresolved\", \"Apparent conflict with general upstream-of-caspase-3 model not reconciled across paradigms\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified a non-apoptotic function: CASP2 represses autophagy via AMPK/mTOR/MAPK signaling, with ROS as an upstream cue.\",\n      \"evidence\": \"Casp2 knockout/knockdown/re-insertion in MEFs and tissues; autophagy and ROS markers\",\n      \"pmids\": [\"24879153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate or protein target linking CASP2 to the pathway not identified\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked CASP2 loss-of-function to human disease, implicating its PIDDosome role in cortical development.\",\n      \"evidence\": \"Exome sequencing, RNA splice analysis, and family segregation in lissencephaly/pachygyria patients\",\n      \"pmids\": [\"37880421\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of PIDDosome dysfunction\", \"Mechanism connecting CASP2 to neuronal migration not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Described dual transcriptional/post-transcriptional control of CASP2 in cancer cells uncoupling its mRNA induction from protein output.\",\n      \"evidence\": \"Reporter assays, knockdown/overexpression of E2F1 and HuR in esophageal adenocarcinoma cells\",\n      \"pmids\": [\"39524140\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single study with limited orthogonal validation\", \"Generality beyond esophageal adenocarcinoma unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular composition and activating platform of the human CASP2/PIDDosome and how it connects to both cortical development and autophagy repression remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstituted human PIDDosome in the corpus\", \"Direct CASP2 substrate(s) in autophagy and neurodevelopment not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 4, 7]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\"PIDDosome\"],\n    \"partners\": [\"BCL2\", \"CASP3\", \"CASP1\", \"GZMB\", \"PARP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}