{"gene":"ADAMTS3","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2001,"finding":"ADAMTS-3 has procollagen II N-propeptidase activity: stable transfection of ADAMTS-3 into RCS-LTC cells (which fail to process procollagen II N-propeptide) partially rescued the processing defect, demonstrating that ADAMTS-3 can cleave the procollagen II N-propeptide. ADAMTS-3 mRNA is expressed 5-fold higher than ADAMTS-2 in human cartilage, suggesting it is the physiologically more relevant procollagen II N-propeptidase in cartilage.","method":"Stable transfection rescue assay in RCS-LTC cells; RT-PCR mRNA expression analysis in human tissues","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — functional rescue experiment in cells with defined processing defect, corroborated by tissue expression data","pmids":["11408482"],"is_preprint":false},{"year":2017,"finding":"ADAMTS-3 is the major enzyme that cleaves and inactivates Reelin in the cerebral cortex and hippocampus. Recombinant ADAMTS-3 cleaved Reelin at the N-t site (within Reelin repeat 3). N-t cleavage of Reelin was markedly decreased in the embryonic cerebral cortex of ADAMTS-3 knock-out mice. ADAMTS-3 KO mice showed decreased Dab1 levels and decreased Tau phosphorylation (indicative of increased Reelin signaling), and conditional KO of ADAMTS-3 in excitatory neurons increased dendritic branching and elongation in the postnatal cerebral cortex.","method":"Partial purification and identification of the Reelin-cleaving enzyme from cortical neuron supernatant; recombinant ADAMTS-3 in vitro cleavage assay; ADAMTS-3 knock-out mice with biochemical and morphological readouts; conditional KO in excitatory neurons","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods: in vitro cleavage, KO mice with biochemical phenotype, conditional KO with cellular phenotype","pmids":["28213441"],"is_preprint":false},{"year":2017,"finding":"Loss-of-function mutations in ADAMTS3 cause Hennekam lymphangiectasia-lymphedema syndrome 3 (HKLLS3). Bi-allelic missense mutations affecting conserved residues in the prodomain and peptidase domain of ADAMTS3 result in abnormal processing and intracellular sequestration of the mutant proteins, abolishing proteolytic activation of pro-VEGFC. This places ADAMTS3 as a key activator of the VEGFC/VEGFR3 lymphangiogenic signaling axis, functionally interacting with CCBE1.","method":"Whole-exome sequencing; in vitro expression and processing assays of mutant proteins; pro-VEGFC activation assay","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — patient mutations with in vitro functional validation demonstrating loss of pro-VEGFC processing","pmids":["28985353"],"is_preprint":false},{"year":2019,"finding":"Reducing ADAMTS-3 inhibits amyloid β (Aβ) deposition in AppNL-F knock-in mice (which produce human wild-type Aβ), consistent with ADAMTS-3-mediated Reelin inactivation promoting Aβ accumulation. No effect was observed in AppNL-G-F mice producing the Arctic mutant Aβ, suggesting the protective mechanism is specific to wild-type Aβ pathology.","method":"Drug-inducible conditional ADAMTS-3 knock-out mice crossed with next-generation AD model mice; Aβ deposition quantification","journal":"Biological & pharmaceutical bulletin","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo genetic model with defined readout, single lab, single method","pmids":["30828067"],"is_preprint":false},{"year":2022,"finding":"ADAMTS2 and ADAMTS14 can substitute for ADAMTS3 in processing pro-VEGFC into active VEGFC in adults. In vitro, both cleave pro-VEGFC as efficiently as ADAMTS3. In vivo, adult Adamts2-KO mice develop skin lymphedema due to reduced lymphatic vessel density/diameter, while Adamts14-KO had no phenotype alone but combined Adamts2/Adamts14 double-KO further reduced lymphangiogenesis in a corneal injury model.","method":"In vitro pro-VEGFC processing assays with recombinant proteins; Adamts2-KO, Adamts14-KO, and double-KO mice; lymphatic vessel imaging; corneal lymphangiogenesis model","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1–2 — reconstitution in vitro plus multiple KO mouse models with functional lymphatic readouts","pmids":["35316211"],"is_preprint":false},{"year":2019,"finding":"A missense variant (c.2786G>A) in ADAMTS3 is associated with Upper Airway Syndrome in Norwich Terriers and enriched in BOAS-susceptible French and English Bulldogs, suggesting that disruption of ADAMTS3 function causes airway oedema (consistent with its role in lymphatic development/function) that predisposes to respiratory obstruction.","method":"Genome-wide association analysis; whole genome resequencing; Sanger sequencing; genotyping in 401 dogs","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 3 — genetic association with functional inference based on known ADAMTS3 biology, no direct in vitro/in vivo mechanistic validation of the variant","pmids":["31095560"],"is_preprint":false},{"year":2023,"finding":"ADAMTS3 acts as a tumour suppressor in early breast cancer by mediating fibronectin degradation. Loss of myoepithelial ADAMTS3 enhances fibronectin levels in the microenvironment, promoting invasion through canonical integrin α5β1 activation. Degradomic analysis (TAILS) identified fibronectin as an ADAMTS3 substrate.","method":"Heterocellular spheroid invasion model; TAILS degradomics; functional invasion assays; integrin α5β1 blocking experiments","journal":"Matrix biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (degradomics + functional assays) in a single study","pmids":["37336268"],"is_preprint":false},{"year":2021,"finding":"USF1 transcription factor negatively regulates ADAMTS-3 expression: overexpression of USF1 in osteosarcoma cells decreased ADAMTS-3 mRNA and protein levels, suppressed ADAMTS-3 promoter activity in co-transfection studies, and USF1 binding to the ADAMTS-3 promoter region was confirmed by EMSA.","method":"Ectopic USF1 overexpression; co-transfection promoter-reporter assays; EMSA","journal":"Molekuliarnaia biologiia","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple methods (overexpression, reporter, EMSA) in a single lab","pmids":["34432781"],"is_preprint":false},{"year":2024,"finding":"A splice site variant in ADAMTS3 (single nucleotide deletion 3 bp downstream from a donor splice site in exon 14) is the likely causal variant for pulmonary hypoplasia with anasarca (hydrops fetalis) in Persian/Persian-cross sheep, introducing an early splice site and loss of 6 amino acids at the exon14/intron14-15 junction, segregating with disease in 209 animals.","method":"SNP genotyping (homozygosity mapping); whole genome sequencing; Sanger sequencing of cDNA; genotyping assay","journal":"Animals","confidence":"Medium","confidence_rationale":"Tier 3 — genetic segregation with cDNA-level splice validation, no in vitro functional assay of protein activity","pmids":["39409761"],"is_preprint":false},{"year":2001,"finding":"ADAMTS3 (then called ADAM-TS3/KIAA0366) was identified as a member of the ADAMTS family of zinc metalloproteinases, characterized by a preproregion, reprolysin-type catalytic domain, disintegrin-like domain, thrombospondin type-1 module, cysteine-rich domain, and spacer domain, with differential expression during mouse embryogenesis.","method":"cDNA cloning; domain architecture analysis; Northern blot/in situ expression profiling during embryogenesis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — initial molecular characterization by cloning and expression analysis","pmids":["10464288"],"is_preprint":false}],"current_model":"ADAMTS3 is a secreted zinc metalloproteinase that functions as a procollagen II N-propeptidase in cartilage, cleaves and inactivates the neuronal guidance protein Reelin (thereby modulating brain development and Aβ deposition), activates pro-VEGFC (a prerequisite for lymphangiogenesis and lymphatic homeostasis in cooperation with CCBE1), and degrades fibronectin to restrain cancer invasion — loss-of-function mutations in ADAMTS3 cause Hennekam lymphangiectasia-lymphedema syndrome 3 and related lymphatic dysplasias."},"narrative":{"teleology":[{"year":2001,"claim":"Molecular cloning established ADAMTS3 as a new member of the ADAMTS zinc metalloproteinase family with a characteristic multi-domain architecture, addressing the question of gene identity and domain organization.","evidence":"cDNA cloning, domain analysis, and Northern blot/in situ hybridization during mouse embryogenesis","pmids":["10464288"],"confidence":"Medium","gaps":["No enzymatic activity demonstrated at this stage","Physiological substrates unknown"]},{"year":2001,"claim":"A functional rescue experiment showed that ADAMTS3 possesses procollagen II N-propeptidase activity and is the likely dominant enzyme for this function in cartilage, answering whether ADAMTS family members beyond ADAMTS2 could process procollagen II.","evidence":"Stable transfection of ADAMTS3 into RCS-LTC cells rescued procollagen II N-propeptide processing; RT-PCR showed 5-fold higher ADAMTS3 than ADAMTS2 mRNA in human cartilage","pmids":["11408482"],"confidence":"High","gaps":["No in vivo knockout confirmation of cartilage phenotype","Relative contribution versus ADAMTS2 and ADAMTS14 not resolved"]},{"year":2017,"claim":"Identification of ADAMTS3 as the principal Reelin-cleaving enzyme in the cerebral cortex resolved a long-standing question about how Reelin signaling is terminated, revealing roles in dendritic morphogenesis and cortical development.","evidence":"Purification of Reelin-cleaving activity from cortical neuron supernatants; recombinant ADAMTS3 cleavage assay; global and conditional ADAMTS3 KO mice with biochemical (Dab1, Tau phosphorylation) and morphological (dendritic branching) readouts","pmids":["28213441"],"confidence":"High","gaps":["Whether other ADAMTS proteases contribute to Reelin cleavage in vivo","Mechanism of ADAMTS3 regulation in neurons not defined"]},{"year":2017,"claim":"Human genetic evidence demonstrated that ADAMTS3 is the essential activator of pro-VEGFC for lymphangiogenesis, placing it in the CCBE1–ADAMTS3–VEGFC–VEGFR3 signaling axis and establishing a Mendelian disease mechanism.","evidence":"Whole-exome sequencing identified bi-allelic ADAMTS3 mutations in Hennekam syndrome patients; in vitro expression showed mutant proteins were retained intracellularly and failed to activate pro-VEGFC","pmids":["28985353"],"confidence":"High","gaps":["Structural basis of CCBE1–ADAMTS3 cooperation unresolved","Whether residual pro-VEGFC activation occurs through ADAMTS2/14 in these patients"]},{"year":2019,"claim":"Linking ADAMTS3-mediated Reelin inactivation to amyloid-β pathology showed that reducing ADAMTS3 protects against Aβ deposition in a wild-type Aβ model, extending the enzyme's relevance to neurodegeneration.","evidence":"Drug-inducible conditional ADAMTS3 KO crossed with AppNL-F and AppNL-G-F knock-in mice; quantification of Aβ deposits","pmids":["30828067"],"confidence":"Medium","gaps":["Mechanism linking enhanced Reelin signaling to reduced Aβ deposition not dissected","Effect limited to wild-type Aβ; no benefit with Arctic mutant Aβ","Single study, not independently replicated"]},{"year":2022,"claim":"Demonstration that ADAMTS2 and ADAMTS14 can substitute for ADAMTS3 in pro-VEGFC activation in adults clarified redundancy within the ADAMTS procollagen N-propeptidase subclade for lymphangiogenesis.","evidence":"Recombinant in vitro cleavage assays; Adamts2-KO mice with skin lymphedema; Adamts2/Adamts14 double-KO corneal lymphangiogenesis model","pmids":["35316211"],"confidence":"High","gaps":["Relative contributions of ADAMTS3 versus ADAMTS2/14 during embryonic versus adult lymphangiogenesis not fully delineated","No triple-KO model"]},{"year":2023,"claim":"Identification of fibronectin as a novel ADAMTS3 substrate revealed a tumor-suppressive role in breast cancer, showing that myoepithelial ADAMTS3 limits invasion by preventing fibronectin-driven integrin α5β1 activation.","evidence":"TAILS degradomics; heterocellular spheroid invasion assays; integrin-blocking experiments","pmids":["37336268"],"confidence":"Medium","gaps":["In vivo validation of tumor-suppressive role lacking","Whether fibronectin degradation is relevant outside breast cancer not tested","Single study"]},{"year":null,"claim":"Major open questions include the structural basis of CCBE1-dependent ADAMTS3 activation of pro-VEGFC, whether ADAMTS3 has additional physiological substrates, the regulation of ADAMTS3 activity in the brain, and the in vivo significance of fibronectin cleavage in cancer.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure or cryo-EM model of ADAMTS3 or ADAMTS3–CCBE1 complex","Full substrate repertoire not systematically mapped","Transcriptional and post-translational regulation largely unexplored beyond USF1"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,4,6]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,6]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,2,6]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,6]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2]}],"complexes":[],"partners":["CCBE1","VEGFC","RELN","FN1"],"other_free_text":[]},"mechanistic_narrative":"ADAMTS3 is a secreted zinc metalloproteinase with multiple physiologically important substrates, functioning in collagen maturation, lymphangiogenesis, neuronal Reelin signaling, and extracellular matrix remodeling. It cleaves the N-propeptide of procollagen II and is the predominant procollagen II N-propeptidase in cartilage [PMID:11408482]; it proteolytically activates pro-VEGFC in cooperation with CCBE1, a step essential for VEGFC/VEGFR3-driven lymphangiogenesis, and bi-allelic loss-of-function mutations cause Hennekam lymphangiectasia-lymphedema syndrome 3 [PMID:28985353, PMID:35316211]. In the brain, ADAMTS3 is the principal protease that cleaves and inactivates Reelin at the N-t site, thereby modulating dendritic morphogenesis and amyloid-β deposition [PMID:28213441, PMID:30828067]. ADAMTS3 also degrades fibronectin in the breast tumor microenvironment, restraining integrin α5β1-mediated invasion [PMID:37336268]."},"prefetch_data":{"uniprot":{"accession":"O15072","full_name":"A disintegrin and metalloproteinase with thrombospondin motifs 3","aliases":["Procollagen II N-proteinase","PC II-NP","Procollagen II amino propeptide-processing enzyme"],"length_aa":1205,"mass_kda":135.6,"function":"Cleaves the propeptides of type II collagen prior to fibril assembly. Does not act on types I and III collagens","subcellular_location":"Secreted; Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/O15072/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADAMTS3","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADAMTS3","total_profiled":1310},"omim":[{"mim_id":"619504","title":"CHOPRA-AMIEL-GORDON SYNDROME; CAGS","url":"https://www.omim.org/entry/619504"},{"mim_id":"618154","title":"HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME 3; HKLLS3","url":"https://www.omim.org/entry/618154"},{"mim_id":"615929","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 17; ANKRD17","url":"https://www.omim.org/entry/615929"},{"mim_id":"607506","title":"A DISINTEGRIN-LIKE AND METALLOPROTEINASE WITH THROMBOSPONDIN TYPE 1 MOTIF, 14; ADAMTS14","url":"https://www.omim.org/entry/607506"},{"mim_id":"606255","title":"STATURE AS A QUANTITATIVE TRAIT","url":"https://www.omim.org/entry/606255"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Intermediate filaments","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"retina","ntpm":7.8}],"url":"https://www.proteinatlas.org/search/ADAMTS3"},"hgnc":{"alias_symbol":["KIAA0366","ADAMTS-4"],"prev_symbol":[]},"alphafold":{"accession":"O15072","domains":[{"cath_id":"3.40.1620.60","chopping":"473-543","consensus_level":"high","plddt":79.5827,"start":473,"end":543},{"cath_id":"2.20.100.10","chopping":"554-601","consensus_level":"medium","plddt":87.9846,"start":554,"end":601},{"cath_id":"2.60.120.830","chopping":"712-826","consensus_level":"medium","plddt":88.1435,"start":712,"end":826},{"cath_id":"-","chopping":"848-900","consensus_level":"medium","plddt":83.8285,"start":848,"end":900},{"cath_id":"-","chopping":"972-996_1006-1013","consensus_level":"medium","plddt":80.8567,"start":972,"end":1013},{"cath_id":"-","chopping":"1027-1054","consensus_level":"high","plddt":80.2439,"start":1027,"end":1054}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15072","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15072-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15072-F1-predicted_aligned_error_v6.png","plddt_mean":70.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADAMTS3","jax_strain_url":"https://www.jax.org/strain/search?query=ADAMTS3"},"sequence":{"accession":"O15072","fasta_url":"https://rest.uniprot.org/uniprotkb/O15072.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15072/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15072"}},"corpus_meta":[{"pmid":"11278559","id":"PMC_11278559","title":"Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11278559","citation_count":389,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17265492","id":"PMC_17265492","title":"Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5.","date":"2007","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/17265492","citation_count":333,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12568957","id":"PMC_12568957","title":"IL-1 beta induces COX2, MMP-1, -3 and -13, ADAMTS-4, IL-1 beta and IL-6 in human tendon cells.","date":"2003","source":"Journal of orthopaedic research : official publication of the Orthopaedic Research Society","url":"https://pubmed.ncbi.nlm.nih.gov/12568957","citation_count":300,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15334469","id":"PMC_15334469","title":"Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice.","date":"2004","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/15334469","citation_count":245,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17430884","id":"PMC_17430884","title":"Proteolytic activities of human ADAMTS-5: comparative studies with ADAMTS-4.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17430884","citation_count":219,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10751421","id":"PMC_10751421","title":"Sites of aggrecan cleavage by recombinant human aggrecanase-1 (ADAMTS-4).","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10751421","citation_count":197,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11408482","id":"PMC_11408482","title":"Procollagen II amino propeptide processing by ADAMTS-3. 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Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18937294","citation_count":88,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10094461","id":"PMC_10094461","title":"ADAMTS: a novel family of proteases with an ADAM protease domain and thrombospondin 1 repeats.","date":"1999","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/10094461","citation_count":68,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20574651","id":"PMC_20574651","title":"ADAMTS-2 functions as anti-angiogenic and anti-tumoral molecule independently of its catalytic activity.","date":"2010","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/20574651","citation_count":59,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22990015","id":"PMC_22990015","title":"A genome-wide association study identifies a gene network of ADAMTS genes in the predisposition to pediatric stroke.","date":"2012","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/22990015","citation_count":56,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18624398","id":"PMC_18624398","title":"Protein interaction data set highlighted with human Ras-MAPK/PI3K signaling pathways.","date":"2008","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/18624398","citation_count":39,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26765342","id":"PMC_26765342","title":"Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis type.","date":"2016","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26765342","citation_count":33,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24752352","id":"PMC_24752352","title":"IL-6 upregulates a disintegrin and metalloproteinase with thrombospondin motifs 2 (ADAMTS-2) in human osteosarcoma cells mediated by JNK pathway.","date":"2014","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24752352","citation_count":24,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31740729","id":"PMC_31740729","title":"Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics.","date":"2019","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/31740729","citation_count":23,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22205175","id":"PMC_22205175","title":"Expression of ADAMTS-2, -3, -13, and -14 in culprit coronary lesions in patients with acute myocardial infarction or stable angina.","date":"2012","source":"Journal of thrombosis and thrombolysis","url":"https://pubmed.ncbi.nlm.nih.gov/22205175","citation_count":22,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11788898","id":"PMC_11788898","title":"Human thrombospondin 2 inhibits proliferation of microvascular endothelial cells.","date":"2002","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/11788898","citation_count":18,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25674217","id":"PMC_25674217","title":"Gene expression profiling of craniofacial fibrous dysplasia reveals ADAMTS2 overexpression as a potential marker.","date":"2014","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/25674217","citation_count":16,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"7735500","id":"PMC_7735500","title":"The natural history of human dermatosparaxis (Ehlers-Danlos syndrome type VIIC).","date":"1995","source":"Clinical dysmorphology","url":"https://pubmed.ncbi.nlm.nih.gov/7735500","citation_count":16,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55172,"output_tokens":2634,"usd":0.102513},"stage2":{"model":"claude-opus-4-6","input_tokens":5965,"output_tokens":2028,"usd":0.120788},"total_usd":0.473316,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":67917,"output_tokens":2699,"usd":0.122118},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6303,"output_tokens":2150,"usd":0.127897}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"ADAMTS-3 has procollagen II N-propeptidase activity: stable transfection of RCS-LTC cells (which fail to process procollagen II N-propeptide) with human ADAMTS-3 partially rescued the processing defect, demonstrating ADAMTS-3 can cleave the procollagen II N-propeptide. ADAMTS-3 mRNA was 5-fold higher than ADAMTS-2 in human cartilage, suggesting it is the physiologically relevant procollagen II N-propeptidase in cartilage.\",\n      \"method\": \"Stable transfection rescue assay in RCS-LTC cells; mRNA quantification in human tissues\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional rescue experiment in cell line with defined processing defect, supported by tissue expression data\",\n      \"pmids\": [\"11408482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ADAMTS-3 cleaves and inactivates Reelin at the N-t site (within Reelin repeat 3). Recombinant ADAMTS-3 directly cleaved Reelin at this site in vitro. In ADAMTS-3 knockout mice, N-t cleavage of Reelin was markedly decreased in embryonic cerebral cortex, Dab1 levels and Tau phosphorylation were decreased, and conditional KO (excitatory neurons of forebrain) showed increased dendritic branching and elongation, establishing ADAMTS-3 as the major Reelin-inactivating enzyme in the cerebral cortex and hippocampus.\",\n      \"method\": \"Biochemical purification and identification of Reelin-cleaving enzyme; recombinant protein cleavage assay; germline and conditional knockout mice with multiple phenotypic readouts (Western blot for Dab1/phospho-Tau, immunohistochemistry, dendritic morphology)\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution with recombinant protein plus multiple in vivo genetic KO models with orthogonal functional readouts\",\n      \"pmids\": [\"28213441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss-of-function mutations in ADAMTS3 cause Hennekam lymphangiectasia-lymphedema syndrome type 3. Bi-allelic missense mutations affecting the prodomain and peptidase domain resulted in abnormal protein processing, intracellular sequestration of mutant proteins, and abolished proteolytic activation of pro-VEGFC in vitro, linking ADAMTS3 enzymatic activity to VEGFR3 signaling required for lymphatic endothelial cell differentiation and function.\",\n      \"method\": \"Whole-exome sequencing; in vitro expression of mutant proteins with assessment of processing and pro-VEGFC cleavage activity\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human disease genetics combined with in vitro functional assay demonstrating abolished pro-VEGFC activation\",\n      \"pmids\": [\"28985353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Reducing ADAMTS-3 expression in App knock-in AD model mice inhibited Aβ deposition. Conditional knockout of ADAMTS-3 (drug-inducible) crossed into AppNL-F mice significantly reduced wild-type Aβ deposition, consistent with the mechanism whereby ADAMTS-3 cleaves and inactivates Reelin, and reduced Reelin activity promotes Aβ accumulation.\",\n      \"method\": \"Drug-inducible conditional knockout mice crossed with next-generation AD model; quantification of Aβ deposition\",\n      \"journal\": \"Biological & pharmaceutical bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic KO with defined molecular phenotype, single lab\",\n      \"pmids\": [\"30828067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ADAMTS2 and ADAMTS14 can substitute for ADAMTS3 in processing pro-VEGFC into active VEGFC in adults. In vitro, ADAMTS2 and ADAMTS14 processed pro-VEGFC as efficiently as ADAMTS3. Adult Adamts2-KO mice developed skin lymphedema with reduced lymphatic vessel density and diameter, while Adamts14-KO had no effect; Adamts2/Adamts14 double-KO further reduced lymphangiogenesis in a corneal model.\",\n      \"method\": \"In vitro pro-VEGFC cleavage assay; Adamts2-KO, Adamts14-KO, and double-KO mice with lymphatic phenotype analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution of pro-VEGFC cleavage plus multiple genetic KO models with defined vascular phenotypes\",\n      \"pmids\": [\"35316211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ADAMTS3 restricts breast cancer invasion by degrading fibronectin. In a heterocellular spheroid model, loss of myoepithelial ADAMTS3 directed invasion of luminal cells through matrix. Degradomic analysis (TAILS) identified fibronectin as an ADAMTS3 substrate; loss of ADAMTS3 increased fibronectin levels and promoted invasion via integrin α5β1 activation.\",\n      \"method\": \"Heterocellular spheroid invasion assay; TAILS degradomics; functional assays with fibronectin and integrin α5β1\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — substrate identified by degradomics and validated functionally with mechanistic pathway placement, multiple orthogonal methods\",\n      \"pmids\": [\"37336268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ADAMTS-14, a novel family member with striking homology to ADAMTS-2 and ADAMTS-3, has aminoprocollagen peptidase activity capable of cleaving the aminopropeptide of type I procollagen at the ADAMTS-2 cleavage site, potentially accounting for residual procollagen I processing observed in the absence of ADAMTS-2.\",\n      \"method\": \"cDNA cloning; recombinant enzyme activity assay against procollagen I substrate\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — recombinant enzyme activity assay in single paper, contextualizes ADAMTS-3 family function\",\n      \"pmids\": [\"11741898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"An ADAMTS3 missense variant (c.2786G>A in exon 20) is associated with Upper Airway Syndrome in Norwich Terriers and enriched in BOAS-susceptible flat-faced dog breeds, suggesting that disruption of ADAMTS3 function causes airway edema via lymphedema, predisposing to respiratory obstruction.\",\n      \"method\": \"Genome-wide association study; whole-genome resequencing; segregation analysis in 401 Norwich Terriers\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic association with functional inference from ADAMTS3 loss-of-function literature, no direct enzymatic validation\",\n      \"pmids\": [\"31095560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USF1 transcription factor negatively regulates ADAMTS-3 promoter activity in osteosarcoma cells. Ectopic overexpression of USF1 decreased ADAMTS-3 mRNA and protein; co-transfection showed USF1 suppressed ADAMTS-3 promoter activity; EMSA demonstrated direct USF1 binding to the ADAMTS-3 promoter region.\",\n      \"method\": \"Overexpression, promoter-reporter assay, EMSA, Western blot\",\n      \"journal\": \"Molekuliarnaia biologiia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter binding shown by EMSA plus functional reporter assay, single lab\",\n      \"pmids\": [\"34432781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Downregulation of ADAMTS3 in glioma stem cells (GSCs) disrupted GSC proliferation, self-renewal activity, and tumor formation in orthotopic xenograft models, establishing a role for ADAMTS3 in supporting GSC stemness and tumorigenicity.\",\n      \"method\": \"shRNA knockdown in GSC lines; alamarBlue viability assay; in vitro limiting dilution assay; orthotopic xenograft\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined cellular and in vivo phenotypic readouts, single lab\",\n      \"pmids\": [\"36514188\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADAMTS3 is a secreted metalloproteinase that functions as a procollagen II N-propeptidase in cartilage, as the major Reelin-inactivating protease in cerebral cortex and hippocampus (cleaving Reelin at the N-t site to reduce its signaling activity), and as a critical activator of pro-VEGFC (processing it into active VEGFC to drive VEGFR3 signaling and lymphangiogenesis); loss-of-function mutations in ADAMTS3 cause Hennekam lymphangiectasia-lymphedema syndrome, and the enzyme additionally degrades fibronectin to suppress breast cancer invasion.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"ADAMTS-3 has procollagen II N-propeptidase activity: stable transfection of ADAMTS-3 into RCS-LTC cells (which fail to process procollagen II N-propeptide) partially rescued the processing defect, demonstrating that ADAMTS-3 can cleave the procollagen II N-propeptide. ADAMTS-3 mRNA is expressed 5-fold higher than ADAMTS-2 in human cartilage, suggesting it is the physiologically more relevant procollagen II N-propeptidase in cartilage.\",\n      \"method\": \"Stable transfection rescue assay in RCS-LTC cells; RT-PCR mRNA expression analysis in human tissues\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — functional rescue experiment in cells with defined processing defect, corroborated by tissue expression data\",\n      \"pmids\": [\"11408482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ADAMTS-3 is the major enzyme that cleaves and inactivates Reelin in the cerebral cortex and hippocampus. Recombinant ADAMTS-3 cleaved Reelin at the N-t site (within Reelin repeat 3). N-t cleavage of Reelin was markedly decreased in the embryonic cerebral cortex of ADAMTS-3 knock-out mice. ADAMTS-3 KO mice showed decreased Dab1 levels and decreased Tau phosphorylation (indicative of increased Reelin signaling), and conditional KO of ADAMTS-3 in excitatory neurons increased dendritic branching and elongation in the postnatal cerebral cortex.\",\n      \"method\": \"Partial purification and identification of the Reelin-cleaving enzyme from cortical neuron supernatant; recombinant ADAMTS-3 in vitro cleavage assay; ADAMTS-3 knock-out mice with biochemical and morphological readouts; conditional KO in excitatory neurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods: in vitro cleavage, KO mice with biochemical phenotype, conditional KO with cellular phenotype\",\n      \"pmids\": [\"28213441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss-of-function mutations in ADAMTS3 cause Hennekam lymphangiectasia-lymphedema syndrome 3 (HKLLS3). Bi-allelic missense mutations affecting conserved residues in the prodomain and peptidase domain of ADAMTS3 result in abnormal processing and intracellular sequestration of the mutant proteins, abolishing proteolytic activation of pro-VEGFC. This places ADAMTS3 as a key activator of the VEGFC/VEGFR3 lymphangiogenic signaling axis, functionally interacting with CCBE1.\",\n      \"method\": \"Whole-exome sequencing; in vitro expression and processing assays of mutant proteins; pro-VEGFC activation assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — patient mutations with in vitro functional validation demonstrating loss of pro-VEGFC processing\",\n      \"pmids\": [\"28985353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Reducing ADAMTS-3 inhibits amyloid β (Aβ) deposition in AppNL-F knock-in mice (which produce human wild-type Aβ), consistent with ADAMTS-3-mediated Reelin inactivation promoting Aβ accumulation. No effect was observed in AppNL-G-F mice producing the Arctic mutant Aβ, suggesting the protective mechanism is specific to wild-type Aβ pathology.\",\n      \"method\": \"Drug-inducible conditional ADAMTS-3 knock-out mice crossed with next-generation AD model mice; Aβ deposition quantification\",\n      \"journal\": \"Biological & pharmaceutical bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model with defined readout, single lab, single method\",\n      \"pmids\": [\"30828067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ADAMTS2 and ADAMTS14 can substitute for ADAMTS3 in processing pro-VEGFC into active VEGFC in adults. In vitro, both cleave pro-VEGFC as efficiently as ADAMTS3. In vivo, adult Adamts2-KO mice develop skin lymphedema due to reduced lymphatic vessel density/diameter, while Adamts14-KO had no phenotype alone but combined Adamts2/Adamts14 double-KO further reduced lymphangiogenesis in a corneal injury model.\",\n      \"method\": \"In vitro pro-VEGFC processing assays with recombinant proteins; Adamts2-KO, Adamts14-KO, and double-KO mice; lymphatic vessel imaging; corneal lymphangiogenesis model\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstitution in vitro plus multiple KO mouse models with functional lymphatic readouts\",\n      \"pmids\": [\"35316211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A missense variant (c.2786G>A) in ADAMTS3 is associated with Upper Airway Syndrome in Norwich Terriers and enriched in BOAS-susceptible French and English Bulldogs, suggesting that disruption of ADAMTS3 function causes airway oedema (consistent with its role in lymphatic development/function) that predisposes to respiratory obstruction.\",\n      \"method\": \"Genome-wide association analysis; whole genome resequencing; Sanger sequencing; genotyping in 401 dogs\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic association with functional inference based on known ADAMTS3 biology, no direct in vitro/in vivo mechanistic validation of the variant\",\n      \"pmids\": [\"31095560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ADAMTS3 acts as a tumour suppressor in early breast cancer by mediating fibronectin degradation. Loss of myoepithelial ADAMTS3 enhances fibronectin levels in the microenvironment, promoting invasion through canonical integrin α5β1 activation. Degradomic analysis (TAILS) identified fibronectin as an ADAMTS3 substrate.\",\n      \"method\": \"Heterocellular spheroid invasion model; TAILS degradomics; functional invasion assays; integrin α5β1 blocking experiments\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (degradomics + functional assays) in a single study\",\n      \"pmids\": [\"37336268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USF1 transcription factor negatively regulates ADAMTS-3 expression: overexpression of USF1 in osteosarcoma cells decreased ADAMTS-3 mRNA and protein levels, suppressed ADAMTS-3 promoter activity in co-transfection studies, and USF1 binding to the ADAMTS-3 promoter region was confirmed by EMSA.\",\n      \"method\": \"Ectopic USF1 overexpression; co-transfection promoter-reporter assays; EMSA\",\n      \"journal\": \"Molekuliarnaia biologiia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple methods (overexpression, reporter, EMSA) in a single lab\",\n      \"pmids\": [\"34432781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A splice site variant in ADAMTS3 (single nucleotide deletion 3 bp downstream from a donor splice site in exon 14) is the likely causal variant for pulmonary hypoplasia with anasarca (hydrops fetalis) in Persian/Persian-cross sheep, introducing an early splice site and loss of 6 amino acids at the exon14/intron14-15 junction, segregating with disease in 209 animals.\",\n      \"method\": \"SNP genotyping (homozygosity mapping); whole genome sequencing; Sanger sequencing of cDNA; genotyping assay\",\n      \"journal\": \"Animals\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic segregation with cDNA-level splice validation, no in vitro functional assay of protein activity\",\n      \"pmids\": [\"39409761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ADAMTS3 (then called ADAM-TS3/KIAA0366) was identified as a member of the ADAMTS family of zinc metalloproteinases, characterized by a preproregion, reprolysin-type catalytic domain, disintegrin-like domain, thrombospondin type-1 module, cysteine-rich domain, and spacer domain, with differential expression during mouse embryogenesis.\",\n      \"method\": \"cDNA cloning; domain architecture analysis; Northern blot/in situ expression profiling during embryogenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — initial molecular characterization by cloning and expression analysis\",\n      \"pmids\": [\"10464288\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADAMTS3 is a secreted zinc metalloproteinase that functions as a procollagen II N-propeptidase in cartilage, cleaves and inactivates the neuronal guidance protein Reelin (thereby modulating brain development and Aβ deposition), activates pro-VEGFC (a prerequisite for lymphangiogenesis and lymphatic homeostasis in cooperation with CCBE1), and degrades fibronectin to restrain cancer invasion — loss-of-function mutations in ADAMTS3 cause Hennekam lymphangiectasia-lymphedema syndrome 3 and related lymphatic dysplasias.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ADAMTS3 is a secreted zinc metalloproteinase with diverse extracellular substrates that link it to collagen maturation, lymphangiogenesis, neuronal signaling, and extracellular matrix remodeling. It functions as the principal procollagen II N-propeptidase in cartilage and processes pro-VEGFC into its active form, thereby driving VEGFR3-dependent lymphatic endothelial differentiation; bi-allelic loss-of-function mutations abolish pro-VEGFC activation and cause Hennekam lymphangiectasia–lymphedema syndrome [PMID:11408482, PMID:28985353]. In cerebral cortex and hippocampus, ADAMTS3 is the major Reelin-inactivating protease, cleaving Reelin at its N-t site to attenuate Reelin–Dab1 signaling, regulate dendritic morphology, and modulate amyloid-β deposition [PMID:28213441, PMID:30828067]. ADAMTS3 also degrades fibronectin in the breast microenvironment, restricting integrin α5β1–mediated luminal cell invasion [PMID:37336268].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that ADAMTS3 possesses procollagen II N-propeptidase activity and is likely the physiologically relevant enzyme for this cleavage in cartilage resolved the identity of the enzyme responsible for aminoprocollagen processing in non-type-I collagen tissues.\",\n      \"evidence\": \"Stable transfection rescue of processing-defective RCS-LTC cells; tissue mRNA quantification showing 5-fold enrichment over ADAMTS2 in cartilage\",\n      \"pmids\": [\"11408482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No in vivo genetic loss-of-function confirmation in cartilage at this stage\",\n        \"Relative contributions of ADAMTS2, ADAMTS3, and ADAMTS14 to procollagen processing in other tissues unresolved\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of ADAMTS3 as the major Reelin-inactivating protease in cerebral cortex and hippocampus established a previously unknown extracellular regulatory step controlling Reelin signaling strength and dendritic morphogenesis.\",\n      \"evidence\": \"Recombinant ADAMTS3 cleaved Reelin at the N-t site in vitro; germline and conditional forebrain KO mice showed reduced N-t cleavage, altered Dab1/phospho-Tau, and abnormal dendritic branching\",\n      \"pmids\": [\"28213441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether other ADAMTS family members contribute to Reelin cleavage in vivo remains unaddressed\",\n        \"Structural basis for substrate specificity at the N-t cleavage site unknown\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that bi-allelic ADAMTS3 loss-of-function mutations cause Hennekam syndrome type 3 by abolishing pro-VEGFC activation connected ADAMTS3 enzymatic activity to VEGFR3-dependent lymphangiogenesis and a human Mendelian disorder.\",\n      \"evidence\": \"Whole-exome sequencing of affected families; in vitro expression of mutant proteins showed aberrant processing, intracellular retention, and loss of pro-VEGFC cleavage\",\n      \"pmids\": [\"28985353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No Adamts3-null mouse lymphatic phenotype described at this time point\",\n        \"Whether partial enzymatic activity from milder mutations can rescue lymphangiogenesis unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that conditional ADAMTS3 knockout in an Alzheimer model reduced Aβ deposition linked Reelin inactivation by ADAMTS3 to amyloid pathology, suggesting a disease-modifying role for the enzyme.\",\n      \"evidence\": \"Drug-inducible conditional ADAMTS3 KO crossed into AppNL-F knock-in mice; Aβ plaque quantification\",\n      \"pmids\": [\"30828067\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding; independent replication in additional AD models needed\",\n        \"Downstream mechanism connecting preserved Reelin activity to reduced Aβ deposition not fully delineated\",\n        \"Cognitive or behavioral consequences not assessed\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstration that ADAMTS2 and ADAMTS14 process pro-VEGFC with comparable efficiency in vitro and can partially compensate for ADAMTS3 loss in adult lymphangiogenesis clarified the functional redundancy within the ADAMTS procollagen N-propeptidase subclade.\",\n      \"evidence\": \"In vitro pro-VEGFC cleavage assays with recombinant enzymes; Adamts2-KO, Adamts14-KO, and double-KO mice with lymphatic phenotyping\",\n      \"pmids\": [\"35316211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Why ADAMTS3 is non-redundant during embryonic lymphangiogenesis but dispensable in some adult contexts remains mechanistically unclear\",\n        \"Tissue-specific expression patterns governing compensation not mapped quantitatively\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of fibronectin as an ADAMTS3 substrate via degradomics revealed a tumor-suppressive mechanism in which myoepithelial ADAMTS3 degrades fibronectin to limit integrin α5β1-driven breast cancer invasion.\",\n      \"evidence\": \"TAILS degradomics in heterocellular spheroid model; functional validation with fibronectin reconstitution and integrin blocking\",\n      \"pmids\": [\"37336268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo validation of fibronectin cleavage by ADAMTS3 in breast tissue not performed\",\n        \"Whether this anti-invasive role extends to other cancer types untested\",\n        \"Cleavage site(s) within fibronectin not precisely mapped\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for ADAMTS3 substrate selectivity across its diverse substrates (procollagen II, pro-VEGFC, Reelin, fibronectin) and the regulatory mechanisms controlling its expression and activity in different tissues remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of ADAMTS3 or its substrate complexes\",\n        \"In vivo Adamts3-null lymphatic phenotype in mice not fully reported\",\n        \"Transcriptional regulation beyond USF1 largely unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"VEGFC\",\n      \"RELN\",\n      \"FN1\",\n      \"COL2A1\",\n      \"ADAMTS2\",\n      \"ADAMTS14\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ADAMTS3 is a secreted zinc metalloproteinase with multiple physiologically important substrates, functioning in collagen maturation, lymphangiogenesis, neuronal Reelin signaling, and extracellular matrix remodeling. It cleaves the N-propeptide of procollagen II and is the predominant procollagen II N-propeptidase in cartilage [PMID:11408482]; it proteolytically activates pro-VEGFC in cooperation with CCBE1, a step essential for VEGFC/VEGFR3-driven lymphangiogenesis, and bi-allelic loss-of-function mutations cause Hennekam lymphangiectasia-lymphedema syndrome 3 [PMID:28985353, PMID:35316211]. In the brain, ADAMTS3 is the principal protease that cleaves and inactivates Reelin at the N-t site, thereby modulating dendritic morphogenesis and amyloid-β deposition [PMID:28213441, PMID:30828067]. ADAMTS3 also degrades fibronectin in the breast tumor microenvironment, restraining integrin α5β1-mediated invasion [PMID:37336268].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Molecular cloning established ADAMTS3 as a new member of the ADAMTS zinc metalloproteinase family with a characteristic multi-domain architecture, addressing the question of gene identity and domain organization.\",\n      \"evidence\": \"cDNA cloning, domain analysis, and Northern blot/in situ hybridization during mouse embryogenesis\",\n      \"pmids\": [\"10464288\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No enzymatic activity demonstrated at this stage\", \"Physiological substrates unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"A functional rescue experiment showed that ADAMTS3 possesses procollagen II N-propeptidase activity and is the likely dominant enzyme for this function in cartilage, answering whether ADAMTS family members beyond ADAMTS2 could process procollagen II.\",\n      \"evidence\": \"Stable transfection of ADAMTS3 into RCS-LTC cells rescued procollagen II N-propeptide processing; RT-PCR showed 5-fold higher ADAMTS3 than ADAMTS2 mRNA in human cartilage\",\n      \"pmids\": [\"11408482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No in vivo knockout confirmation of cartilage phenotype\", \"Relative contribution versus ADAMTS2 and ADAMTS14 not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of ADAMTS3 as the principal Reelin-cleaving enzyme in the cerebral cortex resolved a long-standing question about how Reelin signaling is terminated, revealing roles in dendritic morphogenesis and cortical development.\",\n      \"evidence\": \"Purification of Reelin-cleaving activity from cortical neuron supernatants; recombinant ADAMTS3 cleavage assay; global and conditional ADAMTS3 KO mice with biochemical (Dab1, Tau phosphorylation) and morphological (dendritic branching) readouts\",\n      \"pmids\": [\"28213441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other ADAMTS proteases contribute to Reelin cleavage in vivo\", \"Mechanism of ADAMTS3 regulation in neurons not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Human genetic evidence demonstrated that ADAMTS3 is the essential activator of pro-VEGFC for lymphangiogenesis, placing it in the CCBE1–ADAMTS3–VEGFC–VEGFR3 signaling axis and establishing a Mendelian disease mechanism.\",\n      \"evidence\": \"Whole-exome sequencing identified bi-allelic ADAMTS3 mutations in Hennekam syndrome patients; in vitro expression showed mutant proteins were retained intracellularly and failed to activate pro-VEGFC\",\n      \"pmids\": [\"28985353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CCBE1–ADAMTS3 cooperation unresolved\", \"Whether residual pro-VEGFC activation occurs through ADAMTS2/14 in these patients\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linking ADAMTS3-mediated Reelin inactivation to amyloid-β pathology showed that reducing ADAMTS3 protects against Aβ deposition in a wild-type Aβ model, extending the enzyme's relevance to neurodegeneration.\",\n      \"evidence\": \"Drug-inducible conditional ADAMTS3 KO crossed with AppNL-F and AppNL-G-F knock-in mice; quantification of Aβ deposits\",\n      \"pmids\": [\"30828067\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking enhanced Reelin signaling to reduced Aβ deposition not dissected\", \"Effect limited to wild-type Aβ; no benefit with Arctic mutant Aβ\", \"Single study, not independently replicated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstration that ADAMTS2 and ADAMTS14 can substitute for ADAMTS3 in pro-VEGFC activation in adults clarified redundancy within the ADAMTS procollagen N-propeptidase subclade for lymphangiogenesis.\",\n      \"evidence\": \"Recombinant in vitro cleavage assays; Adamts2-KO mice with skin lymphedema; Adamts2/Adamts14 double-KO corneal lymphangiogenesis model\",\n      \"pmids\": [\"35316211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of ADAMTS3 versus ADAMTS2/14 during embryonic versus adult lymphangiogenesis not fully delineated\", \"No triple-KO model\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of fibronectin as a novel ADAMTS3 substrate revealed a tumor-suppressive role in breast cancer, showing that myoepithelial ADAMTS3 limits invasion by preventing fibronectin-driven integrin α5β1 activation.\",\n      \"evidence\": \"TAILS degradomics; heterocellular spheroid invasion assays; integrin-blocking experiments\",\n      \"pmids\": [\"37336268\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo validation of tumor-suppressive role lacking\", \"Whether fibronectin degradation is relevant outside breast cancer not tested\", \"Single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions include the structural basis of CCBE1-dependent ADAMTS3 activation of pro-VEGFC, whether ADAMTS3 has additional physiological substrates, the regulation of ADAMTS3 activity in the brain, and the in vivo significance of fibronectin cleavage in cancer.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure or cryo-EM model of ADAMTS3 or ADAMTS3–CCBE1 complex\", \"Full substrate repertoire not systematically mapped\", \"Transcriptional and post-translational regulation largely unexplored beyond USF1\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 4, 6]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CCBE1\",\n      \"VEGFC\",\n      \"RELN\",\n      \"FN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}