{"gene":"ADAMTS3","run_date":"2026-06-09T22:02:41","timeline":{"discoveries":[{"year":2001,"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 that ADAMTS-3 can cleave the procollagen II N-propeptide.","method":"Stable transfection of RCS-LTC chondrosarcoma cells with human ADAMTS-3 expression construct; rescue of procollagen II N-propeptide processing assessed by cell biology assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro reconstitution of enzymatic activity in cell-based system, single lab but with clear functional readout and comparison to ADAMTS-2 positive control","pmids":["11408482"],"is_preprint":false},{"year":2017,"finding":"ADAMTS-3 is the major protease 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 was markedly decreased in ADAMTS-3 knockout mouse embryonic cerebral cortex; ADAMTS-3 is expressed in excitatory neurons; conditional KO of ADAMTS-3 in excitatory forebrain neurons increased dendritic branching and elongation postnatally.","method":"Partial purification and identification of the N-t Reelin-cleaving enzyme from cortical neuron conditioned medium; recombinant ADAMTS-3 cleavage assay; ADAMTS-3 knockout mice (full KO and conditional KO); immunohistochemistry; Dab1 and Tau phosphorylation quantification","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — identified by biochemical purification, confirmed with recombinant protein cleavage assay, validated in vivo with KO mice using multiple orthogonal readouts (Dab1 levels, Tau phosphorylation, dendritic morphology)","pmids":["28213441"],"is_preprint":false},{"year":2017,"finding":"Loss-of-function bi-allelic missense mutations in ADAMTS3 cause Hennekam lymphangiectasia-lymphedema syndrome type 3; the mutant proteins were abnormally processed and sequestered within cells, abolishing proteolytic activation of pro-VEGFC, linking ADAMTS3 to the CCBE1/VEGFC/VEGFR3 lymphangiogenic signaling axis.","method":"Whole-exome sequencing of affected family; in vitro characterization of mutant ADAMTS3 proteins (processing assay, cellular localization, pro-VEGFC activation assay)","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics combined with in vitro functional validation of mutant protein processing and pro-VEGFC activation defect; consistent with independent mouse model data cited","pmids":["28985353"],"is_preprint":false},{"year":2001,"finding":"ADAMTS-14, a paralog highly homologous to ADAMTS-2 and ADAMTS-3, can cleave the aminopropeptide of type I procollagen in vivo in the absence of ADAMTS-2 activity, suggesting that ADAMTS-3 (and ADAMTS-14) can substitute as procollagen aminopropeptidases.","method":"Cloning of ADAMTS-14 cDNA; in vivo processing of procollagen I aminopropeptide in ADAMTS-2-deficient context; recombinant ADAMTS-14 activity assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzyme activity shown for ADAMTS-14, inferring parallel role for ADAMTS-3 by homology/context; single lab; ADAMTS-3 activity itself not directly re-tested here but corroborates PMID 11408482","pmids":["11741898"],"is_preprint":false},{"year":2019,"finding":"Reducing ADAMTS-3 inhibits amyloid-β deposition in AppNL-F knock-in mice (producing wild-type human Aβ), consistent with ADAMTS-3 inactivating Reelin whose activity opposes Aβ deposition; no effect was seen in AppNL-G-F mice producing Arctic mutant Aβ.","method":"Drug-inducible conditional ADAMTS-3 knockout mice crossed with AppNL-F and AppNL-G-F knock-in AD model mice; Aβ deposition quantified by immunohistochemistry","journal":"Biological & pharmaceutical bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic KO with quantitative phenotypic readout in two model backgrounds; single lab, pathway placement via epistasis with Reelin/Aβ axis","pmids":["30828067"],"is_preprint":false},{"year":2022,"finding":"ADAMTS2 and ADAMTS14 can process pro-VEGFC into active VEGFC as efficiently as ADAMTS3; adult Adamts2-KO mice develop skin lymphedema due to reduced lymphatic vessel density and diameter, while Adamts14-KO alone has no impact; double Adamts2/Adamts14-KO further reduces corneal lymphangiogenesis, indicating that ADAMTS2 and ADAMTS14 substitute for ADAMTS3 in adult lymphatic homeostasis.","method":"In vitro pro-VEGFC processing assay with recombinant ADAMTS2, ADAMTS14, and ADAMTS3; single and double gene knockout mice; lymphatic vessel density/diameter measurement; corneal lymphangiogenesis model","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution of pro-VEGFC cleavage combined with multiple KO mouse models and functional lymphatic assays; directly confirms ADAMTS3 catalytic function and its redundancy","pmids":["35316211"],"is_preprint":false},{"year":2023,"finding":"ADAMTS3 mediates fibronectin degradation and acts as a tumour suppressor in early breast cancer: loss of ADAMTS3 in myoepithelial cells enhances fibronectin levels in the microenvironment, promoting invasion through integrin α5β1 activation; degradomic analysis (TAILS) identified fibronectin as an ADAMTS3 substrate.","method":"Heterocellular spheroid invasion model; TAILS (terminal amine isotopic labelling of substrates) degradomics; fibronectin functional assays; integrin α5β1 blocking experiments; ADAMTS3 loss-of-function","journal":"Matrix biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate identification by unbiased degradomics validated by functional invasion assay with pathway placement; single lab","pmids":["37336268"],"is_preprint":false},{"year":2019,"finding":"An ADAMTS3 missense variant (c.2786G>A in exon 20) is associated with Norwich Terrier Upper Airway Syndrome, and the risk allele is enriched in BOAS-susceptible French and English Bulldogs; the mechanism is proposed to be airway oedema caused by disruption of ADAMTS3 (lymphoedema pathway), predisposing to respiratory obstruction.","method":"Genome-wide association study; whole-genome resequencing; Sanger sequencing; segregation analysis in 401 Norwich Terriers","journal":"PLoS genetics","confidence":"Low","confidence_rationale":"Tier 4 / Moderate — genetic association with variant identification, but functional mechanism of the specific variant not experimentally validated in this paper; pathway inference from prior literature","pmids":["31095560"],"is_preprint":false},{"year":2021,"finding":"USF1 overexpression decreases ADAMTS-3 mRNA and protein expression in osteosarcoma cells and negatively regulates ADAMTS-3 promoter activity; EMSA studies showed USF1 directly binds to the ADAMTS-3 promoter region.","method":"Ectopic USF1 expression in Saos-2 and MG-63 cells; RT-PCR and western blot for ADAMTS-3; co-transfection promoter-reporter assay; electrophoretic mobility shift assay (EMSA)","journal":"Molekuliarnaia biologiia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter-reporter and EMSA provide direct evidence for USF1 binding and transcriptional repression of ADAMTS3; single lab, two orthogonal methods","pmids":["34432781"],"is_preprint":false},{"year":2026,"finding":"TNF-α induces ADAMTS-3 transcription in osteosarcoma cells via MEK, PI3K, JNK, and NF-κB pathways, with STAT3 and NF-κB enhancing ADAMTS-3 promoter activity; ADAMTS-3 expression correlates with ECM remodeling and inflammatory gene signatures in osteosarcoma.","method":"Pharmacological pathway inhibitors (MEK, PI3K, JNK, NF-κB) in osteosarcoma cell lines; promoter-reporter assays; TCGA genomic and transcriptomic analysis; co-expression analysis","journal":"Journal of cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter-reporter assays with pathway inhibitors establish transcriptional regulatory mechanism; single lab, multiple complementary approaches","pmids":["42083632"],"is_preprint":false},{"year":2026,"finding":"VEGF₁₆₅ robustly enhances ADAMTS3 expression in endothelial cells (~46-fold at 3 h); hypoxia amplifies this VEGF response; defined ADAMTS3 promoter fragments (-131/+40; -1340/+40) show strong VEGF responsiveness under hypoxic conditions; JNK, MAPK/ERK, p38, and PI3K pathways each partially contribute to VEGF-mediated ADAMTS3 transcription.","method":"CoCl₂-induced hypoxia in HUVECs; VEGF stimulation; RT-PCR and protein expression; promoter-reporter assays with defined promoter fragments; pharmacological inhibitors of JNK, MAPK/ERK, p38, PI3K; RNA-seq analysis","journal":"Tissue & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter-reporter assays identify regulatory elements; multiple pathway inhibitors tested; single lab with multiple orthogonal methods","pmids":["42224870"],"is_preprint":false}],"current_model":"ADAMTS3 is a secreted zinc metalloproteinase that functions as a procollagen II N-propeptidase (cleaving procollagen II at the N-propeptide), as a pro-VEGFC activator required for lymphangiogenesis (loss-of-function causes Hennekam lymphangiectasia-lymphedema syndrome), and as the principal Reelin-inactivating protease in the cerebral cortex and hippocampus (cleaving Reelin within repeat 3 to abolish its signaling); it also degrades fibronectin to suppress invasion in early breast cancer, and its transcription is regulated by USF1 (repressor), NF-κB/STAT3, and VEGF/hypoxia signaling."},"narrative":{"mechanistic_narrative":"ADAMTS3 is a secreted zinc metalloproteinase that shapes extracellular matrix and signaling processes across cartilage, the lymphatic vasculature, and the developing brain through substrate-specific proteolysis [PMID:11408482, PMID:28213441, PMID:28985353]. It acts as a procollagen II N-propeptidase, rescuing N-propeptide processing in chondrosarcoma cells deficient in this activity [PMID:11408482]. In the lymphatic axis it proteolytically activates pro-VEGFC, feeding the CCBE1/VEGFC/VEGFR3 lymphangiogenic pathway; bi-allelic loss-of-function missense mutations that cause abnormal intracellular sequestration of the enzyme and abolish pro-VEGFC activation cause Hennekam lymphangiectasia-lymphedema syndrome type 3 [PMID:28985353]. This catalytic role is functionally shared with the close paralogs ADAMTS2 and ADAMTS14, which process pro-VEGFC as efficiently as ADAMTS3 and substitute for it in adult lymphatic homeostasis [PMID:35316211]. In the cerebral cortex and hippocampus, ADAMTS3 is the principal Reelin-inactivating protease, cleaving Reelin within repeat 3, and its loss in excitatory forebrain neurons increases dendritic branching and elongation, with downstream consequences for the Reelin/amyloid-β axis [PMID:28213441, PMID:30828067]. ADAMTS3 also degrades fibronectin to restrain integrin α5β1-driven invasion, acting as a tumour suppressor in early breast cancer [PMID:37336268]. Its transcription is controlled by USF1 (repressor) and induced by TNF-α/NF-κB/STAT3 and VEGF/hypoxia signaling [PMID:34432781, PMID:42083632, PMID:42224870].","teleology":[{"year":2001,"claim":"Established that ADAMTS3 possesses procollagen II N-propeptidase activity, defining its first known catalytic substrate and placing it among the procollagen-processing ADAMTS enzymes.","evidence":"Stable transfection of processing-defective RCS-LTC chondrosarcoma cells with human ADAMTS-3 and rescue of N-propeptide processing","pmids":["11408482"],"confidence":"High","gaps":["Only partial rescue shown in one cell system","No kinetic characterization or cleavage-site mapping in this work"]},{"year":2001,"claim":"Showed that the closely related paralog ADAMTS14 can process procollagen aminopropeptide in the absence of ADAMTS2, raising the possibility of functional redundancy among ADAMTS2/3/14 procollagen N-propeptidases.","evidence":"Cloning of ADAMTS-14 and procollagen I aminopropeptide processing in ADAMTS-2-deficient context","pmids":["11741898"],"confidence":"Medium","gaps":["ADAMTS3 activity itself not directly re-tested here","Redundancy inferred by homology rather than demonstrated for ADAMTS3"]},{"year":2017,"claim":"Identified ADAMTS3 as the major Reelin-inactivating protease in cortex and hippocampus, connecting its proteolysis to neuronal Reelin signaling and dendritic development.","evidence":"Biochemical purification from cortical neuron conditioned medium, recombinant cleavage assay, and full/conditional ADAMTS-3 knockout mice with Dab1, Tau phosphorylation, and dendritic morphology readouts","pmids":["28213441"],"confidence":"High","gaps":["Other proteases contributing to residual Reelin cleavage not fully resolved","Structural basis of repeat-3 cleavage specificity not determined"]},{"year":2017,"claim":"Linked ADAMTS3 to human disease by showing loss-of-function mutations abolish pro-VEGFC activation, defining its role in the VEGFC/VEGFR3 lymphangiogenic axis.","evidence":"Whole-exome sequencing of an affected family plus in vitro processing, localization, and pro-VEGFC activation assays of mutant proteins","pmids":["28985353"],"confidence":"High","gaps":["Mechanism of intracellular sequestration of mutant protein not detailed","Relationship between residual activity and phenotype severity unresolved"]},{"year":2019,"claim":"Placed ADAMTS3 within the Reelin/amyloid-β axis, showing that reducing its activity decreases Aβ deposition in an Alzheimer model.","evidence":"Drug-inducible conditional ADAMTS-3 knockout crossed with AppNL-F and AppNL-G-F knock-in mice; Aβ immunohistochemistry","pmids":["30828067"],"confidence":"Medium","gaps":["Effect absent in Arctic-mutant Aβ background, limiting generality","Pathway placement via epistasis rather than direct biochemistry"]},{"year":2019,"claim":"Associated an ADAMTS3 missense variant with canine upper airway syndrome, proposing a lymphoedema-driven mechanism but without functional validation.","evidence":"GWAS, whole-genome resequencing, and segregation analysis in Norwich Terriers and bulldogs","pmids":["31095560"],"confidence":"Low","gaps":["Functional consequence of the specific variant not experimentally tested","Causal mechanism inferred from prior literature only"]},{"year":2021,"claim":"Defined USF1 as a direct transcriptional repressor of ADAMTS3, opening study of its upstream regulation.","evidence":"Ectopic USF1 expression in osteosarcoma cells, promoter-reporter assays, and EMSA in Saos-2 and MG-63 cells","pmids":["34432781"],"confidence":"Medium","gaps":["Physiological context where USF1 controls ADAMTS3 not established","Single lab, no in vivo validation"]},{"year":2022,"claim":"Demonstrated that ADAMTS2 and ADAMTS14 process pro-VEGFC as efficiently as ADAMTS3 and substitute for it in adult lymphatic homeostasis, refining the redundancy among the three enzymes.","evidence":"In vitro pro-VEGFC processing assays and single/double knockout mice with lymphatic vessel and corneal lymphangiogenesis assays","pmids":["35316211"],"confidence":"High","gaps":["Developmental vs adult-specific contributions of each paralog not fully separated","Tissue-specific division of labor incompletely mapped"]},{"year":2023,"claim":"Identified fibronectin as an ADAMTS3 substrate and established a tumour-suppressive role in early breast cancer through restraint of integrin-driven invasion.","evidence":"TAILS degradomics, heterocellular spheroid invasion model, and integrin α5β1 blocking with ADAMTS3 loss-of-function","pmids":["37336268"],"confidence":"Medium","gaps":["Direct cleavage-site verification of fibronectin not detailed","Single lab; in vivo tumour data not shown"]},{"year":2026,"claim":"Characterized inflammatory transcriptional induction of ADAMTS3 via MEK/PI3K/JNK/NF-κB and STAT3 signaling in osteosarcoma.","evidence":"Pharmacological pathway inhibitors, promoter-reporter assays, and TCGA co-expression analysis in osteosarcoma cell lines","pmids":["42083632"],"confidence":"Medium","gaps":["Direct transcription-factor binding to promoter not all mapped","Functional consequence of induced ADAMTS3 in osteosarcoma not tested"]},{"year":2026,"claim":"Showed VEGF and hypoxia strongly induce ADAMTS3 in endothelial cells through defined promoter elements, creating a feed-forward link between VEGF signaling and the VEGFC-activating protease.","evidence":"CoCl2-induced hypoxia in HUVECs, VEGF stimulation, promoter-reporter assays with defined fragments, and pathway inhibitors","pmids":["42224870"],"confidence":"Medium","gaps":["Specific transcription factors binding the VEGF-responsive elements not identified","In vivo relevance of the VEGF/hypoxia induction not tested"]},{"year":null,"claim":"How ADAMTS3 substrate selectivity, subcellular processing, and tissue-specific deployment are coordinated across its collagen, VEGFC, Reelin, and fibronectin roles remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model explaining multi-substrate specificity","Determinants partitioning ADAMTS3 vs ADAMTS2/14 between tissues unclear","Regulation of enzyme activity (vs transcription) post-secretion uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,5,6]},{"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":[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":[2,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[8,9,10]}],"complexes":[],"partners":["VEGFC","RELN","FN1","USF1","ITGA5"],"other_free_text":[]}},"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},{"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":334,"is_preprint":false},{"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},{"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},{"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},{"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},{"pmid":"11408482","id":"PMC_11408482","title":"Procollagen II amino propeptide processing by ADAMTS-3. 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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 that ADAMTS-3 can cleave the procollagen II N-propeptide.\",\n      \"method\": \"Stable transfection of RCS-LTC chondrosarcoma cells with human ADAMTS-3 expression construct; rescue of procollagen II N-propeptide processing assessed by cell biology assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro reconstitution of enzymatic activity in cell-based system, single lab but with clear functional readout and comparison to ADAMTS-2 positive control\",\n      \"pmids\": [\"11408482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ADAMTS-3 is the major protease 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 was markedly decreased in ADAMTS-3 knockout mouse embryonic cerebral cortex; ADAMTS-3 is expressed in excitatory neurons; conditional KO of ADAMTS-3 in excitatory forebrain neurons increased dendritic branching and elongation postnatally.\",\n      \"method\": \"Partial purification and identification of the N-t Reelin-cleaving enzyme from cortical neuron conditioned medium; recombinant ADAMTS-3 cleavage assay; ADAMTS-3 knockout mice (full KO and conditional KO); immunohistochemistry; Dab1 and Tau phosphorylation quantification\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — identified by biochemical purification, confirmed with recombinant protein cleavage assay, validated in vivo with KO mice using multiple orthogonal readouts (Dab1 levels, Tau phosphorylation, dendritic morphology)\",\n      \"pmids\": [\"28213441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss-of-function bi-allelic missense mutations in ADAMTS3 cause Hennekam lymphangiectasia-lymphedema syndrome type 3; the mutant proteins were abnormally processed and sequestered within cells, abolishing proteolytic activation of pro-VEGFC, linking ADAMTS3 to the CCBE1/VEGFC/VEGFR3 lymphangiogenic signaling axis.\",\n      \"method\": \"Whole-exome sequencing of affected family; in vitro characterization of mutant ADAMTS3 proteins (processing assay, cellular localization, pro-VEGFC activation assay)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics combined with in vitro functional validation of mutant protein processing and pro-VEGFC activation defect; consistent with independent mouse model data cited\",\n      \"pmids\": [\"28985353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ADAMTS-14, a paralog highly homologous to ADAMTS-2 and ADAMTS-3, can cleave the aminopropeptide of type I procollagen in vivo in the absence of ADAMTS-2 activity, suggesting that ADAMTS-3 (and ADAMTS-14) can substitute as procollagen aminopropeptidases.\",\n      \"method\": \"Cloning of ADAMTS-14 cDNA; in vivo processing of procollagen I aminopropeptide in ADAMTS-2-deficient context; recombinant ADAMTS-14 activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzyme activity shown for ADAMTS-14, inferring parallel role for ADAMTS-3 by homology/context; single lab; ADAMTS-3 activity itself not directly re-tested here but corroborates PMID 11408482\",\n      \"pmids\": [\"11741898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Reducing ADAMTS-3 inhibits amyloid-β deposition in AppNL-F knock-in mice (producing wild-type human Aβ), consistent with ADAMTS-3 inactivating Reelin whose activity opposes Aβ deposition; no effect was seen in AppNL-G-F mice producing Arctic mutant Aβ.\",\n      \"method\": \"Drug-inducible conditional ADAMTS-3 knockout mice crossed with AppNL-F and AppNL-G-F knock-in AD model mice; Aβ deposition quantified by immunohistochemistry\",\n      \"journal\": \"Biological & pharmaceutical bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic KO with quantitative phenotypic readout in two model backgrounds; single lab, pathway placement via epistasis with Reelin/Aβ axis\",\n      \"pmids\": [\"30828067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ADAMTS2 and ADAMTS14 can process pro-VEGFC into active VEGFC as efficiently as ADAMTS3; adult Adamts2-KO mice develop skin lymphedema due to reduced lymphatic vessel density and diameter, while Adamts14-KO alone has no impact; double Adamts2/Adamts14-KO further reduces corneal lymphangiogenesis, indicating that ADAMTS2 and ADAMTS14 substitute for ADAMTS3 in adult lymphatic homeostasis.\",\n      \"method\": \"In vitro pro-VEGFC processing assay with recombinant ADAMTS2, ADAMTS14, and ADAMTS3; single and double gene knockout mice; lymphatic vessel density/diameter measurement; corneal lymphangiogenesis model\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution of pro-VEGFC cleavage combined with multiple KO mouse models and functional lymphatic assays; directly confirms ADAMTS3 catalytic function and its redundancy\",\n      \"pmids\": [\"35316211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ADAMTS3 mediates fibronectin degradation and acts as a tumour suppressor in early breast cancer: loss of ADAMTS3 in myoepithelial cells enhances fibronectin levels in the microenvironment, promoting invasion through integrin α5β1 activation; degradomic analysis (TAILS) identified fibronectin as an ADAMTS3 substrate.\",\n      \"method\": \"Heterocellular spheroid invasion model; TAILS (terminal amine isotopic labelling of substrates) degradomics; fibronectin functional assays; integrin α5β1 blocking experiments; ADAMTS3 loss-of-function\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identification by unbiased degradomics validated by functional invasion assay with pathway placement; single lab\",\n      \"pmids\": [\"37336268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"An ADAMTS3 missense variant (c.2786G>A in exon 20) is associated with Norwich Terrier Upper Airway Syndrome, and the risk allele is enriched in BOAS-susceptible French and English Bulldogs; the mechanism is proposed to be airway oedema caused by disruption of ADAMTS3 (lymphoedema pathway), predisposing to respiratory obstruction.\",\n      \"method\": \"Genome-wide association study; whole-genome resequencing; Sanger sequencing; segregation analysis in 401 Norwich Terriers\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Moderate — genetic association with variant identification, but functional mechanism of the specific variant not experimentally validated in this paper; pathway inference from prior literature\",\n      \"pmids\": [\"31095560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USF1 overexpression decreases ADAMTS-3 mRNA and protein expression in osteosarcoma cells and negatively regulates ADAMTS-3 promoter activity; EMSA studies showed USF1 directly binds to the ADAMTS-3 promoter region.\",\n      \"method\": \"Ectopic USF1 expression in Saos-2 and MG-63 cells; RT-PCR and western blot for ADAMTS-3; co-transfection promoter-reporter assay; electrophoretic mobility shift assay (EMSA)\",\n      \"journal\": \"Molekuliarnaia biologiia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter-reporter and EMSA provide direct evidence for USF1 binding and transcriptional repression of ADAMTS3; single lab, two orthogonal methods\",\n      \"pmids\": [\"34432781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TNF-α induces ADAMTS-3 transcription in osteosarcoma cells via MEK, PI3K, JNK, and NF-κB pathways, with STAT3 and NF-κB enhancing ADAMTS-3 promoter activity; ADAMTS-3 expression correlates with ECM remodeling and inflammatory gene signatures in osteosarcoma.\",\n      \"method\": \"Pharmacological pathway inhibitors (MEK, PI3K, JNK, NF-κB) in osteosarcoma cell lines; promoter-reporter assays; TCGA genomic and transcriptomic analysis; co-expression analysis\",\n      \"journal\": \"Journal of cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter-reporter assays with pathway inhibitors establish transcriptional regulatory mechanism; single lab, multiple complementary approaches\",\n      \"pmids\": [\"42083632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"VEGF₁₆₅ robustly enhances ADAMTS3 expression in endothelial cells (~46-fold at 3 h); hypoxia amplifies this VEGF response; defined ADAMTS3 promoter fragments (-131/+40; -1340/+40) show strong VEGF responsiveness under hypoxic conditions; JNK, MAPK/ERK, p38, and PI3K pathways each partially contribute to VEGF-mediated ADAMTS3 transcription.\",\n      \"method\": \"CoCl₂-induced hypoxia in HUVECs; VEGF stimulation; RT-PCR and protein expression; promoter-reporter assays with defined promoter fragments; pharmacological inhibitors of JNK, MAPK/ERK, p38, PI3K; RNA-seq analysis\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter-reporter assays identify regulatory elements; multiple pathway inhibitors tested; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"42224870\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADAMTS3 is a secreted zinc metalloproteinase that functions as a procollagen II N-propeptidase (cleaving procollagen II at the N-propeptide), as a pro-VEGFC activator required for lymphangiogenesis (loss-of-function causes Hennekam lymphangiectasia-lymphedema syndrome), and as the principal Reelin-inactivating protease in the cerebral cortex and hippocampus (cleaving Reelin within repeat 3 to abolish its signaling); it also degrades fibronectin to suppress invasion in early breast cancer, and its transcription is regulated by USF1 (repressor), NF-κB/STAT3, and VEGF/hypoxia signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADAMTS3 is a secreted zinc metalloproteinase that shapes extracellular matrix and signaling processes across cartilage, the lymphatic vasculature, and the developing brain through substrate-specific proteolysis [#0, #1, #2]. It acts as a procollagen II N-propeptidase, rescuing N-propeptide processing in chondrosarcoma cells deficient in this activity [#0]. In the lymphatic axis it proteolytically activates pro-VEGFC, feeding the CCBE1/VEGFC/VEGFR3 lymphangiogenic pathway; bi-allelic loss-of-function missense mutations that cause abnormal intracellular sequestration of the enzyme and abolish pro-VEGFC activation cause Hennekam lymphangiectasia-lymphedema syndrome type 3 [#2]. This catalytic role is functionally shared with the close paralogs ADAMTS2 and ADAMTS14, which process pro-VEGFC as efficiently as ADAMTS3 and substitute for it in adult lymphatic homeostasis [#5]. In the cerebral cortex and hippocampus, ADAMTS3 is the principal Reelin-inactivating protease, cleaving Reelin within repeat 3, and its loss in excitatory forebrain neurons increases dendritic branching and elongation, with downstream consequences for the Reelin/amyloid-\\u03b2 axis [#1, #4]. ADAMTS3 also degrades fibronectin to restrain integrin \\u03b15\\u03b21-driven invasion, acting as a tumour suppressor in early breast cancer [#6]. Its transcription is controlled by USF1 (repressor) and induced by TNF-\\u03b1/NF-\\u03baB/STAT3 and VEGF/hypoxia signaling [#8, #9, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that ADAMTS3 possesses procollagen II N-propeptidase activity, defining its first known catalytic substrate and placing it among the procollagen-processing ADAMTS enzymes.\",\n      \"evidence\": \"Stable transfection of processing-defective RCS-LTC chondrosarcoma cells with human ADAMTS-3 and rescue of N-propeptide processing\",\n      \"pmids\": [\"11408482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Only partial rescue shown in one cell system\", \"No kinetic characterization or cleavage-site mapping in this work\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed that the closely related paralog ADAMTS14 can process procollagen aminopropeptide in the absence of ADAMTS2, raising the possibility of functional redundancy among ADAMTS2/3/14 procollagen N-propeptidases.\",\n      \"evidence\": \"Cloning of ADAMTS-14 and procollagen I aminopropeptide processing in ADAMTS-2-deficient context\",\n      \"pmids\": [\"11741898\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ADAMTS3 activity itself not directly re-tested here\", \"Redundancy inferred by homology rather than demonstrated for ADAMTS3\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified ADAMTS3 as the major Reelin-inactivating protease in cortex and hippocampus, connecting its proteolysis to neuronal Reelin signaling and dendritic development.\",\n      \"evidence\": \"Biochemical purification from cortical neuron conditioned medium, recombinant cleavage assay, and full/conditional ADAMTS-3 knockout mice with Dab1, Tau phosphorylation, and dendritic morphology readouts\",\n      \"pmids\": [\"28213441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other proteases contributing to residual Reelin cleavage not fully resolved\", \"Structural basis of repeat-3 cleavage specificity not determined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked ADAMTS3 to human disease by showing loss-of-function mutations abolish pro-VEGFC activation, defining its role in the VEGFC/VEGFR3 lymphangiogenic axis.\",\n      \"evidence\": \"Whole-exome sequencing of an affected family plus in vitro processing, localization, and pro-VEGFC activation assays of mutant proteins\",\n      \"pmids\": [\"28985353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of intracellular sequestration of mutant protein not detailed\", \"Relationship between residual activity and phenotype severity unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed ADAMTS3 within the Reelin/amyloid-\\u03b2 axis, showing that reducing its activity decreases A\\u03b2 deposition in an Alzheimer model.\",\n      \"evidence\": \"Drug-inducible conditional ADAMTS-3 knockout crossed with AppNL-F and AppNL-G-F knock-in mice; A\\u03b2 immunohistochemistry\",\n      \"pmids\": [\"30828067\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect absent in Arctic-mutant A\\u03b2 background, limiting generality\", \"Pathway placement via epistasis rather than direct biochemistry\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Associated an ADAMTS3 missense variant with canine upper airway syndrome, proposing a lymphoedema-driven mechanism but without functional validation.\",\n      \"evidence\": \"GWAS, whole-genome resequencing, and segregation analysis in Norwich Terriers and bulldogs\",\n      \"pmids\": [\"31095560\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Functional consequence of the specific variant not experimentally tested\", \"Causal mechanism inferred from prior literature only\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined USF1 as a direct transcriptional repressor of ADAMTS3, opening study of its upstream regulation.\",\n      \"evidence\": \"Ectopic USF1 expression in osteosarcoma cells, promoter-reporter assays, and EMSA in Saos-2 and MG-63 cells\",\n      \"pmids\": [\"34432781\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological context where USF1 controls ADAMTS3 not established\", \"Single lab, no in vivo validation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that ADAMTS2 and ADAMTS14 process pro-VEGFC as efficiently as ADAMTS3 and substitute for it in adult lymphatic homeostasis, refining the redundancy among the three enzymes.\",\n      \"evidence\": \"In vitro pro-VEGFC processing assays and single/double knockout mice with lymphatic vessel and corneal lymphangiogenesis assays\",\n      \"pmids\": [\"35316211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Developmental vs adult-specific contributions of each paralog not fully separated\", \"Tissue-specific division of labor incompletely mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified fibronectin as an ADAMTS3 substrate and established a tumour-suppressive role in early breast cancer through restraint of integrin-driven invasion.\",\n      \"evidence\": \"TAILS degradomics, heterocellular spheroid invasion model, and integrin \\u03b15\\u03b21 blocking with ADAMTS3 loss-of-function\",\n      \"pmids\": [\"37336268\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cleavage-site verification of fibronectin not detailed\", \"Single lab; in vivo tumour data not shown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Characterized inflammatory transcriptional induction of ADAMTS3 via MEK/PI3K/JNK/NF-\\u03baB and STAT3 signaling in osteosarcoma.\",\n      \"evidence\": \"Pharmacological pathway inhibitors, promoter-reporter assays, and TCGA co-expression analysis in osteosarcoma cell lines\",\n      \"pmids\": [\"42083632\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcription-factor binding to promoter not all mapped\", \"Functional consequence of induced ADAMTS3 in osteosarcoma not tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed VEGF and hypoxia strongly induce ADAMTS3 in endothelial cells through defined promoter elements, creating a feed-forward link between VEGF signaling and the VEGFC-activating protease.\",\n      \"evidence\": \"CoCl2-induced hypoxia in HUVECs, VEGF stimulation, promoter-reporter assays with defined fragments, and pathway inhibitors\",\n      \"pmids\": [\"42224870\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific transcription factors binding the VEGF-responsive elements not identified\", \"In vivo relevance of the VEGF/hypoxia induction not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ADAMTS3 substrate selectivity, subcellular processing, and tissue-specific deployment are coordinated across its collagen, VEGFC, Reelin, and fibronectin roles remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model explaining multi-substrate specificity\", \"Determinants partitioning ADAMTS3 vs ADAMTS2/14 between tissues unclear\", \"Regulation of enzyme activity (vs transcription) post-secretion uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 5, 6]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [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, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [8, 9, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VEGFC\", \"RELN\", \"FN1\", \"USF1\", \"ITGA5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}