{"gene":"ADAMTS9","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2003,"finding":"ADAMTS9 is activated by selective proprotein convertase (furin) cleavage at the Arg287-Phe288 bond; the ancillary domains (including TSRs) are required for cell-surface localization and for versicanase/aggrecanase activity, whereas the catalytic domain alone is insufficient for these functions.","method":"Pulse-chase analysis, site-directed mutagenesis, amino acid sequencing, COS-1/HEK293 cell transfection with catalytic domain vs. full-length constructs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro/cell-based reconstitution with mutagenesis and biochemical sequencing; foundational paper with 272 citations","pmids":["12514189"],"is_preprint":false},{"year":2006,"finding":"Pro-ADAMTS9 zymogen is secreted intact to the cell surface and processed there by furin (not intracellularly); furin-deficient cells fail to process pro-ADAMTS9, and furin rescue restores processing. PC5A can also process pro-ADAMTS9 but similarly only at the cell surface.","method":"Pulse-chase analysis, PC inhibitors, furin-deficient cell lines, furin rescue, furin siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal biochemical methods in defined cell systems; directly replicated mechanistic finding","pmids":["16537537"],"is_preprint":false},{"year":2007,"finding":"The ADAMTS9 propeptide acts as an intramolecular chaperone required for secretion; N-linked glycosylation of the propeptide at three consensus sites is essential for secretion. Paradoxically, furin processing of the propeptide reduces catalytic activity, and propeptide fragments retain non-covalent association with the catalytic domain after cleavage, constituting an unusual inhibitory regulatory mechanism.","method":"Ala-substitution mutagenesis of glycosylation sites and furin cleavage sites, pulse-chase, versican cleavage assays, proprotein convertase inhibitor treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with systematic mutagenesis and biochemical activity assays in defined cell systems","pmids":["17403680"],"is_preprint":false},{"year":2009,"finding":"The ER chaperone GRP94 (gp96) and BiP (GRP78) form an immunoprecipitable complex with pro-ADAMTS9 and furin at the cell surface; gp96 inhibition by geldanamycin or gp96 siRNA reduces furin processing and cell-surface levels of pro-ADAMTS9, identifying gp96 as a regulator of pro-ADAMTS9 biosynthesis and cell-surface processing.","method":"Chemical cross-linking, mass spectrometry, co-immunoprecipitation, geldanamycin treatment, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, MS interactome, orthogonal siRNA and inhibitor validation","pmids":["19875450"],"is_preprint":false},{"year":2010,"finding":"ADAMTS9 is a cell-autonomous angiogenesis inhibitor expressed by capillary endothelial cells; its proteolytic activity (not catalytically inactive mutant) suppresses tube formation. ADAMTS9 does not cleave thrombospondins 1/2 nor bind VEGF165, distinguishing its mechanism from ADAMTS1.","method":"ADAMTS9 siRNA in human microvascular endothelial cells, overexpression of catalytically active vs. inactive ADAMTS9, Matrigel tube formation assay, heterotopic tumor model in ADAMTS9+/- mice, β-galactosidase lineage tracing","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 1–2 — active-site mutagenesis, loss- and gain-of-function, in vivo and in vitro corroboration","pmids":["20093484"],"is_preprint":false},{"year":2010,"finding":"Adamts9 haploinsufficiency in mice causes accumulation of versican and decreased cleaved versican in cardiac valves and aortic wall, leading to cardiovascular developmental anomalies including myxomatous valve degeneration and left ventricular non-compaction, demonstrating that ADAMTS9-mediated versican proteolysis is required for cardiovascular ECM homeostasis.","method":"Adamts9+/LacZ mouse model, histological analysis, immunostaining for versican and cleaved versican","journal":"Matrix biology","confidence":"High","confidence_rationale":"Tier 2 — defined genetic loss-of-function with specific molecular readout (versican cleavage) and structural phenotype; 127 citations","pmids":["20096780"],"is_preprint":false},{"year":2010,"finding":"ADAMTS9 suppresses tumor formation and angiogenesis in esophageal and nasopharyngeal carcinoma by reducing expression of pro-angiogenic factors MMP9 and VEGFA; ADAMTS9 knockdown reverts cells to tumorigenic phenotype.","method":"Nude mouse tumorigenicity assay, Matrigel plug angiogenesis assay, ADAMTS9 knockdown and overexpression, conditioned medium HUVEC tube-formation assay, MMP9/VEGFA expression analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal gain/loss-of-function with in vivo and in vitro angiogenesis readouts; 72 citations","pmids":["20551050"],"is_preprint":false},{"year":2012,"finding":"ADAMTS9 (and its C. elegans ortholog GON-1) has a protease-independent function in promoting ER-to-Golgi protein transport, mediated by the C-terminal GON domain; expression of the GON domain in the ER rescues the trafficking defect caused by ADAMTS9/GON-1 knockdown.","method":"siRNA knockdown of human ADAMTS9, C. elegans GON-1 loss-of-function, domain rescue experiments, ER-to-Golgi trafficking assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 — domain rescue experiments with loss-of-function in two organisms establishing protease-independent GON domain function","pmids":["22419820"],"is_preprint":false},{"year":2015,"finding":"ADAMTS9 produced by mesenchymal cells acts non-cell-autonomously on smooth muscle cells (SMCs) of the umbilical cord vasculature: versican proteolysis by ADAMTS9 is required for SMC proliferation, differentiation, and orthogonal reorientation. Loss of ADAMTS9 impairs PDGFRβ/MAPK-ERK signaling and disrupts Shh signaling and mesenchymal primary cilium orientation.","method":"Gene trap allele (Adamts9Gt), conditional Adamts9 deletion, versican knockdown, proteolysis manipulation, immunostaining, signaling pathway analysis in mouse umbilical cord","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — conditional genetics with multiple pathway readouts and mechanistic epistasis","pmids":["26027930"],"is_preprint":false},{"year":2016,"finding":"POFUT2-mediated O-fucosylation of ADAMTS9 TSRs is required for ADAMTS9 secretion; CRISPR/Cas9 knockout of POFUT2 in HEK293T cells blocks ADAMTS9 secretion. Loss of ADAMTS9 in extra-embryonic tissues (not epiblast) is responsible for gastrulation defects in Pofut2 mutant mice.","method":"CRISPR/Cas9 knockout of POFUT2, Cre-mediated conditional deletion of Pofut2 and Adamts9, secretion assays, comparative phenotype analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1–2 — CRISPR-validated biochemical secretion assay plus genetic epistasis via conditional knockouts","pmids":["27297885"],"is_preprint":false},{"year":2018,"finding":"ADAMTS9-mediated pericellular versican proteolysis is required for maintenance of smooth muscle cell focal adhesions; loss of ADAMTS9 in uterine SMCs causes failure of myometrial activation and parturition. Pericellular versican acts upstream of cytoskeletal (actin) assembly and SMC differentiation by regulating focal adhesion formation.","method":"Conditional Adamts9 deletion in myometrium, ADAMTS9 siRNA in uterine SMCs, versican knockdown, proteolysis manipulation, focal adhesion imaging, cytoskeletal analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — conditional genetic deletion with mechanistic dissection of focal adhesion–cytoskeleton pathway","pmids":["29642006"],"is_preprint":false},{"year":2019,"finding":"ADAMTS9 binds directly to fibronectin through multiple sites in both molecules (identified by yeast two-hybrid, solid-phase binding, and surface plasmon resonance); proteolytically active but not catalytically inactive ADAMTS9 disrupts fibronectin fibril networks, and ADAMTS9 cleaves fibronectin at Gly2196-Leu2197 in the III17-I10 linker region.","method":"Yeast two-hybrid screen, solid-phase binding assays, surface plasmon resonance, fibronectin fibril disruption assays in fibroblasts, targeted LC-MS for cleavage site identification","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct binding demonstrated by SPR and solid-phase assays, cleavage site mapped by LC-MS, catalytic mutant control","pmids":["31085586"],"is_preprint":false},{"year":2019,"finding":"ADAMTS9 overexpression selectively in skeletal muscle impairs insulin signaling via disruption of the integrin β1 signaling pathway and cytoskeletal organization, leading to decreased insulin sensitivity and mitochondrial dysfunction. Conversely, muscle-specific Adamts9 knockout improves insulin sensitivity in mice.","method":"Muscle-specific transgenic overexpression and conditional knockout of Adamts9 in mice, insulin signaling assays, integrin β1 pathway analysis, mitochondrial function assays, correlation with human skeletal muscle expression data","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 — reciprocal gain- and loss-of-function genetic models with defined pathway readout; translational human correlation","pmids":["30626608"],"is_preprint":false},{"year":2019,"finding":"ADAMTS9 has aggrecanase activity in mouse cartilage distinct from ADAMTS-4 and ADAMTS-5, cleaving primarily at E↓G bonds rather than E↓A bonds in the aggrecan core protein, and is upregulated by retinoic acid but not IL-1α in ADAMTS-4/5 double-deficient cartilage explants.","method":"Microarray of femoral head cartilage explants from ADAMTS-4/5 catalytic domain double-knockout mice, immunohistochemistry, aggrecan cleavage assays with cleavage-site characterization","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — genetic loss-of-function model plus biochemical cleavage characterization, single lab","pmids":["30699963"],"is_preprint":false},{"year":2019,"finding":"B3GLCT-mediated extension of O-fucose on ADAMTS9 TSRs differentially affects ADAMTS9 and ADAMTS20 function; B3glct knockout mouse eye abnormalities result from partial reduction of ADAMTS9 function, providing genetic and biochemical evidence that O-glycosylation modulates ADAMTS9 activity in vivo.","method":"B3glct knockout mouse models, genetic complementation, biochemical secretion assays, phenotype comparison with Adamts9 and Adamts20 mutants","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple knockout models with biochemical validation; strong genetic evidence","pmids":["31600785"],"is_preprint":false},{"year":2008,"finding":"IL-1β activates ADAMTS9 expression through NFATc1 transcription factor; NFATc1 directly binds distal and proximal ADAMTS9 promoter regions (demonstrated by ChIP), and NFAT inhibitors (FK506, 11R-VIVIT) block IL-1β-induced ADAMTS9 upregulation.","method":"ADAMTS9 promoter cloning and reporter assays, ChIP assay demonstrating NFATc1 binding, NFAT inhibitor treatment in OUMS-27 and human chondrocytes","journal":"Molecular and cellular biochemistry","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP plus promoter-reporter assays with pharmacological validation","pmids":["19052845"],"is_preprint":false},{"year":2005,"finding":"ADAMTS9 expression is synergistically induced by IL-1β and TNFα in chondrocytes; MAPK inhibitors SB203580 (p38) and PD98059 (MEK) decrease IL-1β-induced ADAMTS9 upregulation, identifying MAPK signaling pathways as mediators of cytokine-driven ADAMTS9 expression.","method":"Quantitative RT-PCR, Northern blotting, Western blotting, MAPK inhibitor treatment in OUMS-27 and human chondrocytes","journal":"Arthritis and rheumatism","confidence":"Medium","confidence_rationale":"Tier 2–3 — pharmacological pathway inhibition with protein-level confirmation; single lab but multiple methods","pmids":["15880812"],"is_preprint":false},{"year":2023,"finding":"ADAMTS9 and ADAMTS20 shed membrane type 1-matrix metalloproteinase (MT1-MMP) by cleaving its ectodomain at the Tyr314-Gly315 bond in the hinge region and at a second site in the hemopexin domain; this shedding requires hinge O-glycosylation. Loss of ADAMTS9/ADAMTS20 increases cell-surface MT1-MMP retention and enhances pro-MMP2 activation.","method":"Quantitative terminomics (TAILS) on ADAMTS9-knockout RPE-1 cells vs. parental cells, orthogonal validation by detecting catalytic domain fragment in medium, ADAMTS9/ADAMTS20 re-expression rescue, MT1-MMP knockdown epistasis, pro-MMP2 activation assays","journal":"Molecular & cellular proteomics","confidence":"High","confidence_rationale":"Tier 1 — unbiased quantitative proteomics with orthogonal biochemical validation, re-expression rescue, and epistasis experiments","pmids":["37169079"],"is_preprint":false},{"year":2022,"finding":"METTL3-mediated m6A modification leads to YTHDF2-dependent degradation of ADAMTS9 mRNA in gastric cancer, suppressing ADAMTS9 protein levels and facilitating tumor angiogenesis and carcinogenesis via the PI3K/AKT pathway.","method":"METTL3 overexpression/knockdown, YTHDF2-dependent mRNA degradation assays, phenotypic angiogenesis and proliferation experiments, PI3K/AKT pathway analysis","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 — mechanistic m6A-YTHDF2 axis supported by functional assays; single lab","pmids":["35574388"],"is_preprint":false},{"year":2021,"finding":"DNMT3A is responsible for promoter hypermethylation-mediated silencing of ADAMTS9 in gastric cancer; RNF180 ubiquitinates DNMT3A for proteasomal degradation, thereby de-repressing ADAMTS9. ADAMTS9 restoration suppresses gastric cancer cell viability and motility.","method":"Chromatin immunoprecipitation for DNMT3A at ADAMTS9 promoter, ubiquitination assays, proteasome inhibitor treatment, ADAMTS9 re-expression in gastric cancer cells, RNA-seq after ADAMTS9 restoration","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and ubiquitination assays establish RNF180/DNMT3A/ADAMTS9 regulatory axis; single lab","pmids":["33931579"],"is_preprint":false},{"year":2023,"finding":"ADAMTS9 knockout in human iPSC-derived kidney organoids reduces primary cilia number, recapitulating renal ciliopathy; single-cell RNA sequencing reveals ADAMTS9 is highest in podocytes and proximal tubules, and ADAMTS9 loss increases Wnt/PCP signaling in podocyte clusters.","method":"ADAMTS9 knockout in hiPSCs, kidney organoid differentiation, primary cilia quantification, single-cell RNA sequencing, signaling pathway analysis","journal":"Frontiers in medicine","confidence":"Medium","confidence_rationale":"Tier 2 — defined genetic KO in organoid model with single-cell transcriptomic pathway analysis","pmids":["37035301"],"is_preprint":false},{"year":2018,"finding":"ADAMTS9 is required cell-autonomously for melanocyte development in mouse tail epidermis; dominant ENU mutations in Adamts9 cause loss of melanocytes at ~E18.5. TAILS N-terminomics in skin identified new candidate ADAMTS9 substrates in the ECM.","method":"ENU mutagenesis, conditional allele analysis, TAILS N-terminomics proteomics for substrate identification, histological and pigmentation analysis","journal":"Pigment cell & melanoma research","confidence":"Medium","confidence_rationale":"Tier 2 — conditional genetic allele with cell-autonomous demonstration and proteomics substrate screen","pmids":["29781574"],"is_preprint":false}],"current_model":"ADAMTS9 is a secreted zinc metalloprotease that undergoes cell-surface furin processing (facilitated by GRP94/gp96 chaperone), with its propeptide serving as both an intramolecular chaperone (requiring N-glycosylation for secretion) and an unusual activity attenuator; the active enzyme cleaves versican and aggrecan (at distinct bonds from ADAMTS-4/5), fibronectin, and MT1-MMP, requiring its ancillary TSR/GON domains for ECM localization and substrate recognition, while its protease-independent GON domain additionally promotes ER-to-Golgi trafficking; through ECM remodeling ADAMTS9 regulates cardiovascular development, smooth muscle differentiation via focal adhesion/PDGFRβ-MAPK signaling, primary ciliogenesis, angiogenesis inhibition, melanocyte development, and skeletal muscle insulin sensitivity via integrin β1 signaling, and its expression is transcriptionally activated by IL-1β/TNFα through NFATc1 and repressed by METTL3-mediated m6A/YTHDF2 mRNA degradation or promoter hypermethylation via DNMT3A."},"narrative":{"teleology":[{"year":2003,"claim":"Establishing that ADAMTS9 requires furin-mediated propeptide cleavage at a specific bond and that ancillary TSR domains—not the catalytic domain alone—are necessary for substrate activity and cell-surface localization resolved the fundamental activation and domain-architecture requirements of this protease.","evidence":"Pulse-chase analysis, site-directed mutagenesis, and amino acid sequencing in COS-1/HEK293 cells comparing full-length versus catalytic-domain-only constructs","pmids":["12514189"],"confidence":"High","gaps":["Precise contributions of individual TSR repeats to substrate engagement were not defined","Whether propeptide cleavage is required in vivo was not tested"]},{"year":2006,"claim":"Demonstrating that pro-ADAMTS9 is processed by furin exclusively at the cell surface (not intracellularly) distinguished its activation mechanism from most ADAMTS family members and explained why the zymogen must reach the plasma membrane intact.","evidence":"Pulse-chase in furin-deficient LoVo cells with furin rescue and siRNA knockdown","pmids":["16537537"],"confidence":"High","gaps":["Structural basis for the cell-surface selectivity of furin processing was not determined","Whether other cell types use alternative convertases in vivo remained open"]},{"year":2007,"claim":"Revealing that the ADAMTS9 propeptide is both an intramolecular chaperone (requiring N-glycosylation for secretion) and an unusual activity attenuator that remains associated after cleavage overturned the classical model of propeptide removal as simple activation.","evidence":"Systematic Ala-substitution of glycosylation and furin sites, pulse-chase, and versican cleavage activity assays","pmids":["17403680"],"confidence":"High","gaps":["Stoichiometry and affinity of propeptide–catalytic domain reassociation not quantified","Whether displacement of the propeptide by substrate is the physiological activation mechanism was not tested"]},{"year":2008,"claim":"Identifying NFATc1 as the transcription factor that mediates IL-1β-induced ADAMTS9 expression, and MAPK pathways (p38, MEK) as upstream mediators, established the cytokine-responsive transcriptional control of this protease in inflammation.","evidence":"ChIP showing NFATc1 binding to ADAMTS9 promoter, promoter-reporter assays, and pharmacological inhibition with FK506/VIVIT/MAPK inhibitors in chondrocytes","pmids":["19052845","15880812"],"confidence":"High","gaps":["Whether NFATc1 is the sole mediator or cooperates with other transcription factors in vivo was not resolved","Direct link between MAPK-driven expression and cartilage catabolism not shown"]},{"year":2009,"claim":"Identifying the ER chaperone GRP94 as a cell-surface co-complex partner that facilitates furin processing of pro-ADAMTS9 added a quality-control checkpoint to the activation pathway.","evidence":"Chemical cross-linking with MS identification, reciprocal co-IP, geldanamycin inhibition, and gp96 siRNA in HEK293F cells","pmids":["19875450"],"confidence":"High","gaps":["Whether GRP94 acts catalytically or as a scaffold for the furin–ADAMTS9 encounter was not distinguished","Role of BiP versus GRP94 not separated"]},{"year":2010,"claim":"Demonstrating that Adamts9 haploinsufficiency causes versican accumulation and cardiovascular malformations, and that ADAMTS9 catalytic activity (not inactive mutant) suppresses angiogenesis in endothelial cells, connected ADAMTS9 proteolysis to two major developmental/vascular programs.","evidence":"Adamts9+/LacZ mouse phenotyping with versican immunostaining; ADAMTS9 siRNA and catalytic-mutant overexpression in microvascular endothelial cells with Matrigel tube formation and heterotopic tumor assays","pmids":["20096780","20093484","20551050"],"confidence":"High","gaps":["Identity of the anti-angiogenic substrate was not determined","Whether angiogenesis inhibition and versican cleavage are mechanistically linked was not established"]},{"year":2012,"claim":"Discovering that the ADAMTS9 GON domain promotes ER-to-Golgi trafficking independently of protease activity—conserved from C. elegans GON-1—revealed a fundamentally non-catalytic cellular function for this metalloprotease.","evidence":"siRNA knockdown and GON-domain rescue of ER-to-Golgi trafficking defects in human cells and C. elegans gon-1 mutants","pmids":["22419820"],"confidence":"High","gaps":["Molecular mechanism by which the GON domain promotes vesicle trafficking was not identified","Cargo specificity of the trafficking function was not defined"]},{"year":2015,"claim":"Showing that mesenchymal ADAMTS9-mediated versican proteolysis is required non-cell-autonomously for smooth muscle PDGFRβ-MAPK signaling, cilium orientation, and cell reorientation established versican processing as a signaling-competent ECM event upstream of multiple pathways.","evidence":"Gene-trap and conditional Adamts9 deletion in mouse umbilical cord with immunostaining and signaling pathway analysis","pmids":["26027930"],"confidence":"High","gaps":["Whether versican fragments themselves or exposure of underlying matrix signals activate PDGFRβ was not distinguished","Role of primary cilium orientation in downstream signaling not fully separated from focal adhesion effects"]},{"year":2016,"claim":"Establishing that POFUT2-dependent O-fucosylation of TSRs is required for ADAMTS9 secretion, and that loss of ADAMTS9 in extra-embryonic tissues explains Pofut2-mutant gastrulation defects, placed glycosylation as a biosynthetic gatekeeper for ADAMTS9 function in early development.","evidence":"CRISPR knockout of POFUT2 in HEK293T with secretion assays; conditional deletion of Pofut2 and Adamts9 in epiblast versus extra-embryonic tissues","pmids":["27297885"],"confidence":"High","gaps":["Whether O-fucosylation affects ADAMTS9 folding, stability, or receptor interactions was not separated","Other POFUT2 client proteins may contribute to the phenotype"]},{"year":2018,"claim":"Demonstrating that ADAMTS9-mediated pericellular versican proteolysis controls focal adhesion assembly in uterine smooth muscle, and that ADAMTS9 cell-autonomously regulates melanocyte survival, broadened the in vivo substrate-to-phenotype map to parturition and pigmentation.","evidence":"Conditional Adamts9 deletion in myometrium with focal adhesion/cytoskeletal imaging; ENU-induced dominant Adamts9 mutations with melanocyte analysis and TAILS proteomics in skin","pmids":["29642006","29781574"],"confidence":"High","gaps":["ECM substrates responsible for melanocyte survival were not validated beyond the proteomics screen","Whether focal adhesion effects are versican-specific or also involve fibronectin cleavage was not resolved"]},{"year":2019,"claim":"Identifying fibronectin as a direct ADAMTS9 substrate cleaved at Gly2196-Leu2197, aggrecan cleavage at E↓G bonds distinct from ADAMTS-4/5, and integrin β1 signaling disruption as the mechanism of ADAMTS9-driven insulin resistance in skeletal muscle substantially expanded the substrate repertoire and linked ECM remodeling to metabolic regulation.","evidence":"SPR/solid-phase binding and LC-MS cleavage-site mapping for fibronectin; ADAMTS-4/5 double-KO cartilage explants for aggrecan; reciprocal muscle-specific transgenic overexpression and knockout in mice with insulin signaling and integrin β1 pathway analysis","pmids":["31085586","30699963","30626608"],"confidence":"High","gaps":["Whether fibronectin cleavage occurs in vivo and contributes to specific developmental phenotypes was not shown","Structural basis for distinct aggrecan cleavage-site selectivity versus ADAMTS-4/5 was not determined"]},{"year":2019,"claim":"Showing that B3GLCT-mediated extension of O-fucose on TSRs differentially modulates ADAMTS9 versus ADAMTS20 function, with B3glct knockout causing renal phenotypes through partial ADAMTS9 reduction, refined the glycosylation hierarchy controlling ADAMTS9 activity.","evidence":"B3glct knockout mouse models with genetic complementation, biochemical secretion assays, and phenotype comparison with Adamts9 and Adamts20 mutants","pmids":["31600785"],"confidence":"High","gaps":["Quantitative impact of B3GLCT on ADAMTS9 catalytic rate versus secretion was not measured","Whether the eye and kidney phenotypes are entirely ADAMTS9-dependent or involve other TSR-containing proteins was not excluded"]},{"year":2021,"claim":"Identifying DNMT3A-mediated promoter methylation as a silencing mechanism for ADAMTS9 in gastric cancer, regulated upstream by RNF180-mediated DNMT3A ubiquitination, established an epigenetic axis controlling ADAMTS9 tumor-suppressive function.","evidence":"ChIP for DNMT3A at ADAMTS9 promoter, ubiquitination assays for RNF180–DNMT3A, proteasome inhibitor treatment, ADAMTS9 re-expression in gastric cancer cells","pmids":["33931579"],"confidence":"Medium","gaps":["Single-lab finding not independently replicated","Whether DNMT3A methylation of ADAMTS9 promoter occurs in non-cancer tissues was not tested"]},{"year":2022,"claim":"Demonstrating METTL3-mediated m6A modification leading to YTHDF2-dependent ADAMTS9 mRNA degradation added an epitranscriptomic layer of regulation and connected ADAMTS9 downregulation to PI3K/AKT-driven tumor angiogenesis.","evidence":"METTL3 overexpression/knockdown with YTHDF2-dependent mRNA stability assays and angiogenesis/proliferation readouts in gastric cancer cells","pmids":["35574388"],"confidence":"Medium","gaps":["Specific m6A sites on ADAMTS9 mRNA were not mapped","In vivo relevance of the METTL3/YTHDF2 axis for ADAMTS9 regulation not demonstrated"]},{"year":2023,"claim":"Identifying MT1-MMP as a direct ADAMTS9/ADAMTS20 substrate shed at specific ectodomain sites, and demonstrating that ADAMTS9 loss reduces primary cilia in kidney organoids via increased Wnt/PCP signaling, connected ADAMTS9 to metalloproteinase network regulation and renal ciliopathy-relevant biology.","evidence":"TAILS quantitative terminomics on ADAMTS9-KO RPE-1 cells with re-expression rescue and MMP2 activation epistasis; ADAMTS9-KO iPSC kidney organoids with cilia quantification and scRNA-seq pathway analysis","pmids":["37169079","37035301"],"confidence":"High","gaps":["Whether MT1-MMP shedding is the mechanism underlying ADAMTS9's anti-angiogenic activity was not tested","Whether ciliogenesis defect is versican-dependent or involves other substrates was not resolved"]},{"year":null,"claim":"The structural basis for ADAMTS9's distinct substrate selectivity (versus ADAMTS-4/5), the mechanism by which the GON domain promotes vesicle trafficking, and whether MT1-MMP shedding explains ADAMTS9's anti-angiogenic and developmental roles remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of ADAMTS9 or its catalytic/GON domains","Cargo identity and molecular mechanism of GON-domain-mediated ER-to-Golgi transport unknown","Relative in vivo contributions of versican, fibronectin, and MT1-MMP cleavage to specific phenotypes not disentangled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,4,5,8,10,11,13,17]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,11,13,17]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,5,11]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,7]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[5,8,10,11]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[5,8,10,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,8,9,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,12,20]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2,9,14]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[7]}],"complexes":[],"partners":["FN1","VCAN","ACAN","MMP14","FURIN","HSP90B1","POFUT2","B3GLCT"],"other_free_text":[]},"mechanistic_narrative":"ADAMTS9 is a secreted zinc metalloprotease that remodels the extracellular matrix to regulate cardiovascular morphogenesis, smooth muscle differentiation, primary ciliogenesis, angiogenesis, melanocyte development, and skeletal muscle insulin sensitivity. The zymogen is secreted intact to the cell surface, where furin cleaves the propeptide at Arg287-Phe288 in a GRP94-chaperoned complex; paradoxically, the cleaved propeptide remains non-covalently associated and attenuates catalytic activity, while N-glycosylation and POFUT2-mediated O-fucosylation of the TSR domains are required for secretion [PMID:12514189, PMID:16537537, PMID:17403680, PMID:19875450, PMID:27297885]. The mature protease cleaves versican, aggrecan (at E↓G bonds distinct from ADAMTS-4/5), fibronectin (at Gly2196-Leu2197), and the MT1-MMP ectodomain, with ancillary TSR/GON domains essential for substrate recognition and ECM localization; versican proteolysis controls focal adhesion assembly, PDGFRβ-MAPK signaling, and smooth muscle cytoskeletal organization, while the C-terminal GON domain independently promotes ER-to-Golgi trafficking [PMID:31085586, PMID:37169079, PMID:26027930, PMID:29642006, PMID:22419820]. ADAMTS9 transcription is induced by IL-1β/TNFα through NFATc1 and MAPK pathways and silenced by DNMT3A-mediated promoter methylation or METTL3/YTHDF2-dependent m6A mRNA degradation [PMID:19052845, PMID:33931579, PMID:35574388]."},"prefetch_data":{"uniprot":{"accession":"Q9P2N4","full_name":"A disintegrin and metalloproteinase with thrombospondin motifs 9","aliases":[],"length_aa":1935,"mass_kda":216.5,"function":"Cleaves the large aggregating proteoglycans, aggrecan (at the '1838-Glu-|-Ala-1839' site) and versican (at the '1428-Glu-|-Ala-1429' site). Has a protease-independent function in promoting the transport from the endoplasmic reticulum to the Golgi apparatus of a variety of secretory cargos","subcellular_location":"Secreted, extracellular space, extracellular matrix; Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/Q9P2N4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADAMTS9","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADAMTS9","total_profiled":1310},"omim":[{"mim_id":"611681","title":"A DISINTEGRIN-LIKE AND METALLOPROTEINASE WITH THROMBOSPONDIN TYPE 1 MOTIF, 20; ADAMTS20","url":"https://www.omim.org/entry/611681"},{"mim_id":"605421","title":"A DISINTEGRIN-LIKE AND METALLOPROTEINASE WITH THROMBOSPONDIN TYPE 1 MOTIF, 9; ADAMTS9","url":"https://www.omim.org/entry/605421"},{"mim_id":"603075","title":"MACULAR DEGENERATION, AGE-RELATED, 1; ARMD1","url":"https://www.omim.org/entry/603075"},{"mim_id":"162060","title":"GROWTH-ASSOCIATED PROTEIN 43; GAP43","url":"https://www.omim.org/entry/162060"},{"mim_id":"133239","title":"ESOPHAGEAL CANCER","url":"https://www.omim.org/entry/133239"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":39.1}],"url":"https://www.proteinatlas.org/search/ADAMTS9"},"hgnc":{"alias_symbol":["KIAA1312"],"prev_symbol":[]},"alphafold":{"accession":"Q9P2N4","domains":[{"cath_id":"-","chopping":"32-61_97-135_142-191_203-209","consensus_level":"medium","plddt":64.4648,"start":32,"end":209},{"cath_id":"3.40.390.10","chopping":"293-326_350-452_459-501","consensus_level":"high","plddt":78.8126,"start":293,"end":501},{"cath_id":"-","chopping":"600-726","consensus_level":"medium","plddt":77.5857,"start":600,"end":726},{"cath_id":"2.60.120.830","chopping":"753-887","consensus_level":"high","plddt":83.4204,"start":753,"end":887},{"cath_id":"-","chopping":"1782-1935","consensus_level":"high","plddt":84.2121,"start":1782,"end":1935}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2N4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2N4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2N4-F1-predicted_aligned_error_v6.png","plddt_mean":69.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADAMTS9","jax_strain_url":"https://www.jax.org/strain/search?query=ADAMTS9"},"sequence":{"accession":"Q9P2N4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P2N4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P2N4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2N4"}},"corpus_meta":[{"pmid":"12514189","id":"PMC_12514189","title":"Characterization of ADAMTS-9 and ADAMTS-20 as a distinct ADAMTS subfamily related to Caenorhabditis elegans GON-1.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12514189","citation_count":272,"is_preprint":false},{"pmid":"32516127","id":"PMC_32516127","title":"LncRNA ADAMTS9-AS2 inhibits gastric cancer (GC) development and sensitizes chemoresistant GC cells to cisplatin by regulating miR-223-3p/NLRP3 axis.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32516127","citation_count":141,"is_preprint":false},{"pmid":"20096780","id":"PMC_20096780","title":"Reduced versican cleavage due to Adamts9 haploinsufficiency is associated with cardiac and aortic anomalies.","date":"2010","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/20096780","citation_count":127,"is_preprint":false},{"pmid":"18567820","id":"PMC_18567820","title":"Association testing of novel type 2 diabetes risk alleles in the JAZF1, CDC123/CAMK1D, TSPAN8, THADA, ADAMTS9, and NOTCH2 loci with insulin release, insulin sensitivity, and obesity in a population-based sample of 4,516 glucose-tolerant middle-aged Danes.","date":"2008","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/18567820","citation_count":120,"is_preprint":false},{"pmid":"24833086","id":"PMC_24833086","title":"A new tumor suppressor LncRNA ADAMTS9-AS2 is regulated by DNMT1 and inhibits migration of glioma cells.","date":"2014","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24833086","citation_count":112,"is_preprint":false},{"pmid":"19833888","id":"PMC_19833888","title":"Gene variants in the novel type 2 diabetes loci CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B affect different aspects of pancreatic beta-cell function.","date":"2009","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/19833888","citation_count":106,"is_preprint":false},{"pmid":"15939373","id":"PMC_15939373","title":"Adamts9 is widely expressed during mouse embryo development.","date":"2005","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/15939373","citation_count":85,"is_preprint":false},{"pmid":"20093484","id":"PMC_20093484","title":"ADAMTS9 is a cell-autonomously acting, anti-angiogenic metalloprotease expressed by microvascular endothelial cells.","date":"2010","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/20093484","citation_count":84,"is_preprint":false},{"pmid":"31632968","id":"PMC_31632968","title":"Novel Function of lncRNA ADAMTS9-AS2 in Promoting Temozolomide Resistance in Glioblastoma via Upregulating the FUS/MDM2 Ubiquitination Axis.","date":"2019","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/31632968","citation_count":84,"is_preprint":false},{"pmid":"10936055","id":"PMC_10936055","title":"ADAMTS9, a novel member of the ADAM-TS/ metallospondin gene family.","date":"2000","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10936055","citation_count":82,"is_preprint":false},{"pmid":"15880812","id":"PMC_15880812","title":"ADAMTS-9 is synergistically induced by interleukin-1beta and tumor necrosis factor alpha in OUMS-27 chondrosarcoma cells and in human chondrocytes.","date":"2005","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/15880812","citation_count":80,"is_preprint":false},{"pmid":"29707897","id":"PMC_29707897","title":"Upregulated lncRNA ADAMTS9-AS2 suppresses progression of lung cancer through inhibition of miR-223-3p and promotion of TGFBR3.","date":"2018","source":"IUBMB life","url":"https://pubmed.ncbi.nlm.nih.gov/29707897","citation_count":78,"is_preprint":false},{"pmid":"30268751","id":"PMC_30268751","title":"LncRNA ADAMTS9-AS2 regulates ovarian cancer progression by targeting miR-182-5p/FOXF2 signaling pathway.","date":"2018","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/30268751","citation_count":72,"is_preprint":false},{"pmid":"20551050","id":"PMC_20551050","title":"Extracellular protease ADAMTS9 suppresses esophageal and nasopharyngeal carcinoma tumor formation by inhibiting angiogenesis.","date":"2010","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/20551050","citation_count":72,"is_preprint":false},{"pmid":"30217729","id":"PMC_30217729","title":"Upregulation of lncRNA ADAMTS9-AS2 Promotes Salivary Adenoid Cystic Carcinoma Metastasis via PI3K/Akt and MEK/Erk Signaling.","date":"2018","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30217729","citation_count":66,"is_preprint":false},{"pmid":"25045124","id":"PMC_25045124","title":"Leptin induces ADAMTS-4, ADAMTS-5, and ADAMTS-9 genes expression by mitogen-activated protein kinases and NF-ĸB signaling pathways in human chondrocytes.","date":"2014","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/25045124","citation_count":64,"is_preprint":false},{"pmid":"16799631","id":"PMC_16799631","title":"Identification of a tumor suppressive critical region mapping to 3p14.2 in esophageal squamous cell carcinoma and studies of a candidate tumor suppressor gene, ADAMTS9.","date":"2006","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/16799631","citation_count":62,"is_preprint":false},{"pmid":"32889785","id":"PMC_32889785","title":"Long non-coding RNA ADAMTS9-AS1 suppresses colorectal cancer by inhibiting the Wnt/β-catenin signalling pathway and is a potential diagnostic biomarker.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32889785","citation_count":57,"is_preprint":false},{"pmid":"16537537","id":"PMC_16537537","title":"Cell-surface processing of pro-ADAMTS9 by furin.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16537537","citation_count":56,"is_preprint":false},{"pmid":"17403680","id":"PMC_17403680","title":"Regulation of ADAMTS9 secretion and enzymatic activity by its propeptide.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17403680","citation_count":52,"is_preprint":false},{"pmid":"30970517","id":"PMC_30970517","title":"LncRNA ADAMTS9-AS2 promotes tongue squamous cell carcinoma proliferation, migration and EMT via the miR-600/EZH2 axis.","date":"2019","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/30970517","citation_count":51,"is_preprint":false},{"pmid":"26027930","id":"PMC_26027930","title":"ADAMTS9-Mediated Extracellular Matrix Dynamics Regulates Umbilical Cord Vascular Smooth Muscle Differentiation and Rotation.","date":"2015","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26027930","citation_count":50,"is_preprint":false},{"pmid":"31400752","id":"PMC_31400752","title":"LncRNA ADAMTS9-AS2 inhibits cell proliferation and decreases chemoresistance in clear cell renal cell carcinoma via the miR-27a-3p/FOXO1 axis.","date":"2019","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/31400752","citation_count":50,"is_preprint":false},{"pmid":"18449890","id":"PMC_18449890","title":"Characterization of a novel epigenetically-silenced, growth-suppressive gene, ADAMTS9, and its association with lymph node metastases in nasopharyngeal carcinoma.","date":"2008","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/18449890","citation_count":48,"is_preprint":false},{"pmid":"34428588","id":"PMC_34428588","title":"lncRNA ADAMTS9-AS1 promotes bladder cancer cell invasion, migration, and inhibits apoptosis and autophagy through PI3K/AKT/mTOR signaling pathway.","date":"2021","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/34428588","citation_count":48,"is_preprint":false},{"pmid":"19789630","id":"PMC_19789630","title":"Variant near ADAMTS9 known to associate with type 2 diabetes is related to insulin resistance in offspring of type 2 diabetes patients--EUGENE2 study.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19789630","citation_count":45,"is_preprint":false},{"pmid":"31621118","id":"PMC_31621118","title":"Long noncoding RNA ADAMTS9-AS2 suppresses the progression of esophageal cancer by mediating CDH3 promoter methylation.","date":"2019","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/31621118","citation_count":44,"is_preprint":false},{"pmid":"30840279","id":"PMC_30840279","title":"Downregulated lncRNA ADAMTS9-AS2 in breast cancer enhances tamoxifen resistance by activating microRNA-130a-5p.","date":"2019","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30840279","citation_count":44,"is_preprint":false},{"pmid":"29642006","id":"PMC_29642006","title":"ADAMTS9-Regulated Pericellular Matrix Dynamics Governs Focal Adhesion-Dependent Smooth Muscle Differentiation.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29642006","citation_count":44,"is_preprint":false},{"pmid":"30089248","id":"PMC_30089248","title":"RETRACTED: Down-regulation of lncRNA ADAMTS9-AS2 contributes to gastric cancer development via activation of PI3K/Akt pathway.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/30089248","citation_count":43,"is_preprint":false},{"pmid":"32153626","id":"PMC_32153626","title":"Data Mining and Expression Analysis of Differential lncRNA ADAMTS9-AS1 in Prostate Cancer.","date":"2020","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32153626","citation_count":43,"is_preprint":false},{"pmid":"19052845","id":"PMC_19052845","title":"ADAMTS9 activation by interleukin 1 beta via NFATc1 in OUMS-27 chondrosarcoma cells and in human chondrocytes.","date":"2008","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19052845","citation_count":40,"is_preprint":false},{"pmid":"33345447","id":"PMC_33345447","title":"Exosome-derived long non-coding RNA ADAMTS9-AS2 suppresses progression of oral submucous fibrosis via AKT signalling pathway.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33345447","citation_count":39,"is_preprint":false},{"pmid":"35311457","id":"PMC_35311457","title":"Long non-coding RNA ADAMTS9-AS1 attenuates ferroptosis by Targeting microRNA-587/solute carrier family 7 member 11 axis in epithelial ovarian cancer.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35311457","citation_count":39,"is_preprint":false},{"pmid":"27297885","id":"PMC_27297885","title":"Genetic and biochemical evidence that gastrulation defects in Pofut2 mutants result from defects in ADAMTS9 secretion.","date":"2016","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/27297885","citation_count":39,"is_preprint":false},{"pmid":"31671346","id":"PMC_31671346","title":"lncRNA ADAMTS9-AS2 Controls Human Mesenchymal Stem Cell Chondrogenic Differentiation and Functions as a ceRNA.","date":"2019","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/31671346","citation_count":37,"is_preprint":false},{"pmid":"19875450","id":"PMC_19875450","title":"Cell-surface processing of the metalloprotease pro-ADAMTS9 is influenced by the chaperone GRP94/gp96.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19875450","citation_count":37,"is_preprint":false},{"pmid":"23562508","id":"PMC_23562508","title":"ADAMTS1, ADAMTS5, ADAMTS9 and aggrecanase-generated proteoglycan fragments are induced following spinal cord injury in mouse.","date":"2013","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/23562508","citation_count":37,"is_preprint":false},{"pmid":"35574388","id":"PMC_35574388","title":"METTL3-Mediated ADAMTS9 Suppression Facilitates Angiogenesis and Carcinogenesis in Gastric Cancer.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35574388","citation_count":35,"is_preprint":false},{"pmid":"27146815","id":"PMC_27146815","title":"Clinical significance of ADAMTS1, ADAMTS5, ADAMTS9 aggrecanases and IL-17A, IL-23, IL-33 cytokines in polycystic ovary syndrome.","date":"2016","source":"Journal of endocrinological investigation","url":"https://pubmed.ncbi.nlm.nih.gov/27146815","citation_count":35,"is_preprint":false},{"pmid":"35173188","id":"PMC_35173188","title":"Long noncoding RNA ADAMTS9-AS1 represses ferroptosis of endometrial stromal cells by regulating the miR-6516-5p/GPX4 axis in endometriosis.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35173188","citation_count":32,"is_preprint":false},{"pmid":"32744323","id":"PMC_32744323","title":"Lnc RNA ZFAS1 regulates the proliferation, apoptosis, inflammatory response and autophagy of fibroblast-like synoviocytes via miR-2682-5p/ADAMTS9 axis in rheumatoid arthritis.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/32744323","citation_count":32,"is_preprint":false},{"pmid":"23161442","id":"PMC_23161442","title":"PPARG2 Pro12Ala and ADAMTS9 rs4607103 as \"insulin resistance loci\" and \"insulin secretion loci\" in Italian individuals. The GENFIEV study and the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 4.","date":"2012","source":"Acta diabetologica","url":"https://pubmed.ncbi.nlm.nih.gov/23161442","citation_count":30,"is_preprint":false},{"pmid":"29575055","id":"PMC_29575055","title":"MicroRNA-190b regulates lipid metabolism and insulin sensitivity by targeting IGF-1 and ADAMTS9 in non-alcoholic fatty liver disease.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29575055","citation_count":27,"is_preprint":false},{"pmid":"25080592","id":"PMC_25080592","title":"Perlecan antagonizes collagen IV and ADAMTS9/GON-1 in restricting the growth of presynaptic boutons.","date":"2014","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25080592","citation_count":27,"is_preprint":false},{"pmid":"33931579","id":"PMC_33931579","title":"DNMT3A-mediated silence in ADAMTS9 expression is restored by RNF180 to inhibit viability and motility in gastric cancer cells.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33931579","citation_count":25,"is_preprint":false},{"pmid":"28225792","id":"PMC_28225792","title":"The ADAMTS9 gene is associated with cognitive aging in the elderly in a Taiwanese population.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28225792","citation_count":25,"is_preprint":false},{"pmid":"32160650","id":"PMC_32160650","title":"LncRNA ADAMTS9-AS2 suppresses the proliferation of gastric cancer cells and the tumorigenicity of cancer stem cells through regulating SPOP.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32160650","citation_count":25,"is_preprint":false},{"pmid":"30626608","id":"PMC_30626608","title":"ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations.","date":"2019","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/30626608","citation_count":25,"is_preprint":false},{"pmid":"31600785","id":"PMC_31600785","title":"ADAMTS9 and ADAMTS20 are differentially affected by loss of B3GLCT in mouse model of Peters plus syndrome.","date":"2019","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31600785","citation_count":25,"is_preprint":false},{"pmid":"34900984","id":"PMC_34900984","title":"ADAMTS9-AS1 Constrains Breast Cancer Cell Invasion and Proliferation via Sequestering miR-301b-3p.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34900984","citation_count":24,"is_preprint":false},{"pmid":"32781068","id":"PMC_32781068","title":"Upregulation of TNF-α and IL-6 induces preterm premature rupture of membranes by activation of ADAMTS-9 in embryonic membrane cells.","date":"2020","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32781068","citation_count":24,"is_preprint":false},{"pmid":"31415758","id":"PMC_31415758","title":"Mechanical strain attenuates cytokine-induced ADAMTS9 expression via transient receptor potential vanilloid type 1.","date":"2019","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/31415758","citation_count":23,"is_preprint":false},{"pmid":"29186710","id":"PMC_29186710","title":"ADAMTS9 is Silenced by Epigenetic Disruption in Colorectal Cancer and Inhibits Cell Growth and Metastasis by Regulating Akt/p53 Signaling.","date":"2017","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29186710","citation_count":23,"is_preprint":false},{"pmid":"22419820","id":"PMC_22419820","title":"Identification of a novel ADAMTS9/GON-1 function for protein transport from the ER to the Golgi.","date":"2012","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/22419820","citation_count":22,"is_preprint":false},{"pmid":"19963134","id":"PMC_19963134","title":"High-resolution melting analysis of ADAMTS9 methylation levels in gastric, colorectal, and pancreatic cancers.","date":"2010","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/19963134","citation_count":22,"is_preprint":false},{"pmid":"30446843","id":"PMC_30446843","title":"Abnormal expressions of ADAMTS-1, ADAMTS-9 and progesterone receptors are associated with lower oocyte maturation in women with polycystic ovary syndrome.","date":"2018","source":"Archives of gynecology and obstetrics","url":"https://pubmed.ncbi.nlm.nih.gov/30446843","citation_count":21,"is_preprint":false},{"pmid":"31085586","id":"PMC_31085586","title":"A disintegrin-like and metalloproteinase domain with thrombospondin type 1 motif 9 (ADAMTS9) regulates fibronectin fibrillogenesis and turnover.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31085586","citation_count":21,"is_preprint":false},{"pmid":"29193730","id":"PMC_29193730","title":"The 3p14.2 tumour suppressor ADAMTS9 is inactivated by promoter CpG methylation and inhibits tumour cell growth in breast cancer.","date":"2017","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29193730","citation_count":21,"is_preprint":false},{"pmid":"25990289","id":"PMC_25990289","title":"A deletion at ADAMTS9-MAGI1 locus is associated with psoriatic arthritis risk.","date":"2015","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/25990289","citation_count":20,"is_preprint":false},{"pmid":"33149676","id":"PMC_33149676","title":"LncRNA ADAMTS9-AS1 Restrains the Aggressive Traits of Breast Carcinoma Cells via Sponging miR-513a-5p.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/33149676","citation_count":19,"is_preprint":false},{"pmid":"33704879","id":"PMC_33704879","title":"Long non-coding RNA ADAMTS9-AS1 inhibits the progression of prostate cancer by modulating the miR-142-5p/CCND1 axis.","date":"2021","source":"The journal of gene medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33704879","citation_count":18,"is_preprint":false},{"pmid":"29781574","id":"PMC_29781574","title":"Melanocyte development in the mouse tail epidermis requires the Adamts9 metalloproteinase.","date":"2018","source":"Pigment cell & melanoma research","url":"https://pubmed.ncbi.nlm.nih.gov/29781574","citation_count":18,"is_preprint":false},{"pmid":"33850531","id":"PMC_33850531","title":"Long non-coding RNA ADAMTS9-AS2 inhibits liver cancer cell proliferation, migration and invasion.","date":"2021","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33850531","citation_count":18,"is_preprint":false},{"pmid":"30951722","id":"PMC_30951722","title":"Adamts9 is necessary for ovarian development in zebrafish.","date":"2019","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30951722","citation_count":18,"is_preprint":false},{"pmid":"35503407","id":"PMC_35503407","title":"ADAMTS9-AS2 regulates PPP1R12B by adsorbing miR-196b-5p and affects cell cycle-related signaling pathways inhibiting the malignant process of esophageal cancer.","date":"2022","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/35503407","citation_count":17,"is_preprint":false},{"pmid":"37991019","id":"PMC_37991019","title":"N6-methyladenosine-mediated overexpression of long noncoding RNA ADAMTS9-AS2 triggers neuroblastoma differentiation via regulating LIN28B/let-7/MYCN signaling.","date":"2023","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/37991019","citation_count":17,"is_preprint":false},{"pmid":"33042449","id":"PMC_33042449","title":"Long non-coding RNA ADAMTS9-AS1 exacerbates cell proliferation, migration, and invasion via triggering of the PI3K/AKT/mTOR pathway in hepatocellular carcinoma cells.","date":"2020","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/33042449","citation_count":17,"is_preprint":false},{"pmid":"31586455","id":"PMC_31586455","title":"Upregulation of adamts9 by gonadotropin in preovulatory follicles of zebrafish.","date":"2019","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/31586455","citation_count":16,"is_preprint":false},{"pmid":"36941991","id":"PMC_36941991","title":"Exosomal miR-93-5p regulated the progression of osteoarthritis by targeting ADAMTS9.","date":"2023","source":"Open medicine (Warsaw, Poland)","url":"https://pubmed.ncbi.nlm.nih.gov/36941991","citation_count":16,"is_preprint":false},{"pmid":"35098480","id":"PMC_35098480","title":"ADAMTS9-AS2 Promotes Angiogenesis of Brain Microvascular Endothelial Cells Through Regulating miR-185-5p/IGFBP-2 Axis in Ischemic Stroke.","date":"2022","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/35098480","citation_count":16,"is_preprint":false},{"pmid":"30699963","id":"PMC_30699963","title":"ADAMTS-9 in Mouse Cartilage Has Aggrecanase Activity That Is Distinct from ADAMTS-4 and ADAMTS-5.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30699963","citation_count":15,"is_preprint":false},{"pmid":"19348733","id":"PMC_19348733","title":"ADAMTS-9 expression is up-regulated following transient middle cerebral artery occlusion (tMCAo) in the rat.","date":"2009","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/19348733","citation_count":15,"is_preprint":false},{"pmid":"34178640","id":"PMC_34178640","title":"The lncRNA ADAMTS9-AS2 Regulates RPL22 to Modulate TNBC Progression via Controlling the TGF-β Signaling Pathway.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34178640","citation_count":14,"is_preprint":false},{"pmid":"37258203","id":"PMC_37258203","title":"The lncRNA ADAMTS9-AS1/miR-185-5p/KAT7 ceRNA network inhibits cardiomyocyte hypertrophy in hypertrophic obstructive cardiomyopathy.","date":"2023","source":"Biomedical research (Tokyo, Japan)","url":"https://pubmed.ncbi.nlm.nih.gov/37258203","citation_count":12,"is_preprint":false},{"pmid":"36535531","id":"PMC_36535531","title":"Melittin inhibits the proliferation migration and invasion of HCC cells by regulating ADAMTS9-AS2 demethylation.","date":"2022","source":"Toxicon : official journal of the International Society on Toxinology","url":"https://pubmed.ncbi.nlm.nih.gov/36535531","citation_count":12,"is_preprint":false},{"pmid":"32801743","id":"PMC_32801743","title":"Long Noncoding RNA ADAMTS9-AS2 Inhibits the Proliferation, Migration, and Invasion in Bladder Tumor Cells.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32801743","citation_count":12,"is_preprint":false},{"pmid":"28850027","id":"PMC_28850027","title":"MiR-338-5p suppresses rheumatoid arthritis synovial fibroblast proliferation and invasion by targeting ADAMTS-9.","date":"2017","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/28850027","citation_count":12,"is_preprint":false},{"pmid":"37169079","id":"PMC_37169079","title":"Degradomic Identification of Membrane Type 1-Matrix Metalloproteinase as an ADAMTS9 and ADAMTS20 Substrate.","date":"2023","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/37169079","citation_count":11,"is_preprint":false},{"pmid":"29137610","id":"PMC_29137610","title":"Hemoglobin stimulates the expression of ADAMTS-5 and ADAMTS-9 by synovial cells: a possible cause of articular cartilage damage after intra-articular hemorrhage.","date":"2017","source":"BMC musculoskeletal disorders","url":"https://pubmed.ncbi.nlm.nih.gov/29137610","citation_count":11,"is_preprint":false},{"pmid":"36870548","id":"PMC_36870548","title":"LncRNA ADAMTS9-AS1 inhibits the stemness of lung adenocarcinoma cells by regulating miR-5009-3p/NPNT axis.","date":"2023","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/36870548","citation_count":11,"is_preprint":false},{"pmid":"33823762","id":"PMC_33823762","title":"ADAMTS9-AS2: A Functional Long Non-coding RNA in Tumorigenesis.","date":"2021","source":"Current pharmaceutical design","url":"https://pubmed.ncbi.nlm.nih.gov/33823762","citation_count":10,"is_preprint":false},{"pmid":"35401927","id":"PMC_35401927","title":"lncRNA ADAMTS9-AS1/circFN1 Competitively Binds to miR-206 to Elevate the Expression of ACTB, Thus Inducing Hypertrophic Cardiomyopathy.","date":"2022","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/35401927","citation_count":10,"is_preprint":false},{"pmid":"23358566","id":"PMC_23358566","title":"Epigenetic inactivation of ADAMTS9 via promoter methylation in multiple myeloma.","date":"2013","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/23358566","citation_count":10,"is_preprint":false},{"pmid":"28244876","id":"PMC_28244876","title":"Adaptive sequence convergence of the tumor suppressor ADAMTS9 between small-bodied mammals displaying exceptional longevity.","date":"2017","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/28244876","citation_count":10,"is_preprint":false},{"pmid":"34923953","id":"PMC_34923953","title":"LncRNA ADAMTS9-AS1 knockdown suppresses cell proliferation and migration in glioma through downregulating Wnt/β-catenin signaling pathway.","date":"2022","source":"Bosnian journal of basic medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34923953","citation_count":10,"is_preprint":false},{"pmid":"29935379","id":"PMC_29935379","title":"ADAMTS9, a member of the ADAMTS family, in Xenopus development.","date":"2018","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/29935379","citation_count":10,"is_preprint":false},{"pmid":"36746036","id":"PMC_36746036","title":"A review on the role of ADAMTS9-AS2 in different disorders.","date":"2023","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/36746036","citation_count":9,"is_preprint":false},{"pmid":"33879810","id":"PMC_33879810","title":"Delay in primordial germ cell migration in adamts9 knockout zebrafish.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33879810","citation_count":9,"is_preprint":false},{"pmid":"33621133","id":"PMC_33621133","title":"Long-Chain Noncoding RNA ADAMTS9-AS2 Regulates Proliferation, Migration, and Apoptosis in Bladder Cancer Cells Through Regulating miR-182-5p.","date":"2021","source":"Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research","url":"https://pubmed.ncbi.nlm.nih.gov/33621133","citation_count":8,"is_preprint":false},{"pmid":"31413211","id":"PMC_31413211","title":"[Overexpression of the long non-coding RNA ADAMTS9-AS2 suppresses colorectal cancer proliferation and metastasis].","date":"2019","source":"Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31413211","citation_count":8,"is_preprint":false},{"pmid":"34312940","id":"PMC_34312940","title":"The diagnostic significance of circulating lncRNA ADAMTS9-AS2 tumor biomarker in non-small cell lung cancer among the Egyptian population.","date":"2021","source":"The journal of gene medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34312940","citation_count":8,"is_preprint":false},{"pmid":"26218657","id":"PMC_26218657","title":"Loss of C. elegans GON-1, an ADAMTS9 Homolog, Decreases Secretion Resulting in Altered Lifespan and Dauer Formation.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26218657","citation_count":8,"is_preprint":false},{"pmid":"36449154","id":"PMC_36449154","title":"ADAMTS9-AS1 Long Non‑coding RNA Sponges miR‑128 and miR-150 to Regulate Ras/MAPK Signaling Pathway in Glioma.","date":"2022","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/36449154","citation_count":8,"is_preprint":false},{"pmid":"37035301","id":"PMC_37035301","title":"Disease modeling of ADAMTS9-related nephropathy using kidney organoids reveals its roles in tubular cells and podocytes.","date":"2023","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37035301","citation_count":7,"is_preprint":false},{"pmid":"27230574","id":"PMC_27230574","title":"Relationship between cytosine-adenine repeat polymorphism of ADAMTS9 gene and clinical and radiologic severity of knee osteoarthritis.","date":"2016","source":"International journal of rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/27230574","citation_count":7,"is_preprint":false},{"pmid":"34085704","id":"PMC_34085704","title":"LncRNA ADAMTS9-AS1 knockdown restricts cell proliferation and EMT in non-small cell lung cancer.","date":"2021","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/34085704","citation_count":6,"is_preprint":false},{"pmid":"27485821","id":"PMC_27485821","title":"Maternal serum ADAMTS-9 levels in gestational diabetes: a pilot study.","date":"2016","source":"The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians","url":"https://pubmed.ncbi.nlm.nih.gov/27485821","citation_count":6,"is_preprint":false},{"pmid":"40143747","id":"PMC_40143747","title":"The lncRNAs PART1 and ADAMTS9-AS2 act in an antithetic manner on AR signaling and induction of cellular senescence in prostate cancer cells.","date":"2025","source":"International journal of surgery (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/40143747","citation_count":5,"is_preprint":false},{"pmid":"32335142","id":"PMC_32335142","title":"The ADAMTS9 gene is associated with mandibular retrusion in a Chinese population.","date":"2020","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/32335142","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54513,"output_tokens":5542,"usd":0.123334},"stage2":{"model":"claude-opus-4-6","input_tokens":9142,"output_tokens":4372,"usd":0.232515},"total_usd":0.355849,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"ADAMTS9 is activated by selective proprotein convertase (furin) cleavage at the Arg287-Phe288 bond; the ancillary domains (including TSRs) are required for cell-surface localization and for versicanase/aggrecanase activity, whereas the catalytic domain alone is insufficient for these functions.\",\n      \"method\": \"Pulse-chase analysis, site-directed mutagenesis, amino acid sequencing, COS-1/HEK293 cell transfection with catalytic domain vs. full-length constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro/cell-based reconstitution with mutagenesis and biochemical sequencing; foundational paper with 272 citations\",\n      \"pmids\": [\"12514189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Pro-ADAMTS9 zymogen is secreted intact to the cell surface and processed there by furin (not intracellularly); furin-deficient cells fail to process pro-ADAMTS9, and furin rescue restores processing. PC5A can also process pro-ADAMTS9 but similarly only at the cell surface.\",\n      \"method\": \"Pulse-chase analysis, PC inhibitors, furin-deficient cell lines, furin rescue, furin siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal biochemical methods in defined cell systems; directly replicated mechanistic finding\",\n      \"pmids\": [\"16537537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The ADAMTS9 propeptide acts as an intramolecular chaperone required for secretion; N-linked glycosylation of the propeptide at three consensus sites is essential for secretion. Paradoxically, furin processing of the propeptide reduces catalytic activity, and propeptide fragments retain non-covalent association with the catalytic domain after cleavage, constituting an unusual inhibitory regulatory mechanism.\",\n      \"method\": \"Ala-substitution mutagenesis of glycosylation sites and furin cleavage sites, pulse-chase, versican cleavage assays, proprotein convertase inhibitor treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with systematic mutagenesis and biochemical activity assays in defined cell systems\",\n      \"pmids\": [\"17403680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The ER chaperone GRP94 (gp96) and BiP (GRP78) form an immunoprecipitable complex with pro-ADAMTS9 and furin at the cell surface; gp96 inhibition by geldanamycin or gp96 siRNA reduces furin processing and cell-surface levels of pro-ADAMTS9, identifying gp96 as a regulator of pro-ADAMTS9 biosynthesis and cell-surface processing.\",\n      \"method\": \"Chemical cross-linking, mass spectrometry, co-immunoprecipitation, geldanamycin treatment, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, MS interactome, orthogonal siRNA and inhibitor validation\",\n      \"pmids\": [\"19875450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ADAMTS9 is a cell-autonomous angiogenesis inhibitor expressed by capillary endothelial cells; its proteolytic activity (not catalytically inactive mutant) suppresses tube formation. ADAMTS9 does not cleave thrombospondins 1/2 nor bind VEGF165, distinguishing its mechanism from ADAMTS1.\",\n      \"method\": \"ADAMTS9 siRNA in human microvascular endothelial cells, overexpression of catalytically active vs. inactive ADAMTS9, Matrigel tube formation assay, heterotopic tumor model in ADAMTS9+/- mice, β-galactosidase lineage tracing\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — active-site mutagenesis, loss- and gain-of-function, in vivo and in vitro corroboration\",\n      \"pmids\": [\"20093484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Adamts9 haploinsufficiency in mice causes accumulation of versican and decreased cleaved versican in cardiac valves and aortic wall, leading to cardiovascular developmental anomalies including myxomatous valve degeneration and left ventricular non-compaction, demonstrating that ADAMTS9-mediated versican proteolysis is required for cardiovascular ECM homeostasis.\",\n      \"method\": \"Adamts9+/LacZ mouse model, histological analysis, immunostaining for versican and cleaved versican\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — defined genetic loss-of-function with specific molecular readout (versican cleavage) and structural phenotype; 127 citations\",\n      \"pmids\": [\"20096780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ADAMTS9 suppresses tumor formation and angiogenesis in esophageal and nasopharyngeal carcinoma by reducing expression of pro-angiogenic factors MMP9 and VEGFA; ADAMTS9 knockdown reverts cells to tumorigenic phenotype.\",\n      \"method\": \"Nude mouse tumorigenicity assay, Matrigel plug angiogenesis assay, ADAMTS9 knockdown and overexpression, conditioned medium HUVEC tube-formation assay, MMP9/VEGFA expression analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal gain/loss-of-function with in vivo and in vitro angiogenesis readouts; 72 citations\",\n      \"pmids\": [\"20551050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ADAMTS9 (and its C. elegans ortholog GON-1) has a protease-independent function in promoting ER-to-Golgi protein transport, mediated by the C-terminal GON domain; expression of the GON domain in the ER rescues the trafficking defect caused by ADAMTS9/GON-1 knockdown.\",\n      \"method\": \"siRNA knockdown of human ADAMTS9, C. elegans GON-1 loss-of-function, domain rescue experiments, ER-to-Golgi trafficking assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — domain rescue experiments with loss-of-function in two organisms establishing protease-independent GON domain function\",\n      \"pmids\": [\"22419820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ADAMTS9 produced by mesenchymal cells acts non-cell-autonomously on smooth muscle cells (SMCs) of the umbilical cord vasculature: versican proteolysis by ADAMTS9 is required for SMC proliferation, differentiation, and orthogonal reorientation. Loss of ADAMTS9 impairs PDGFRβ/MAPK-ERK signaling and disrupts Shh signaling and mesenchymal primary cilium orientation.\",\n      \"method\": \"Gene trap allele (Adamts9Gt), conditional Adamts9 deletion, versican knockdown, proteolysis manipulation, immunostaining, signaling pathway analysis in mouse umbilical cord\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional genetics with multiple pathway readouts and mechanistic epistasis\",\n      \"pmids\": [\"26027930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"POFUT2-mediated O-fucosylation of ADAMTS9 TSRs is required for ADAMTS9 secretion; CRISPR/Cas9 knockout of POFUT2 in HEK293T cells blocks ADAMTS9 secretion. Loss of ADAMTS9 in extra-embryonic tissues (not epiblast) is responsible for gastrulation defects in Pofut2 mutant mice.\",\n      \"method\": \"CRISPR/Cas9 knockout of POFUT2, Cre-mediated conditional deletion of Pofut2 and Adamts9, secretion assays, comparative phenotype analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — CRISPR-validated biochemical secretion assay plus genetic epistasis via conditional knockouts\",\n      \"pmids\": [\"27297885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ADAMTS9-mediated pericellular versican proteolysis is required for maintenance of smooth muscle cell focal adhesions; loss of ADAMTS9 in uterine SMCs causes failure of myometrial activation and parturition. Pericellular versican acts upstream of cytoskeletal (actin) assembly and SMC differentiation by regulating focal adhesion formation.\",\n      \"method\": \"Conditional Adamts9 deletion in myometrium, ADAMTS9 siRNA in uterine SMCs, versican knockdown, proteolysis manipulation, focal adhesion imaging, cytoskeletal analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional genetic deletion with mechanistic dissection of focal adhesion–cytoskeleton pathway\",\n      \"pmids\": [\"29642006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADAMTS9 binds directly to fibronectin through multiple sites in both molecules (identified by yeast two-hybrid, solid-phase binding, and surface plasmon resonance); proteolytically active but not catalytically inactive ADAMTS9 disrupts fibronectin fibril networks, and ADAMTS9 cleaves fibronectin at Gly2196-Leu2197 in the III17-I10 linker region.\",\n      \"method\": \"Yeast two-hybrid screen, solid-phase binding assays, surface plasmon resonance, fibronectin fibril disruption assays in fibroblasts, targeted LC-MS for cleavage site identification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct binding demonstrated by SPR and solid-phase assays, cleavage site mapped by LC-MS, catalytic mutant control\",\n      \"pmids\": [\"31085586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADAMTS9 overexpression selectively in skeletal muscle impairs insulin signaling via disruption of the integrin β1 signaling pathway and cytoskeletal organization, leading to decreased insulin sensitivity and mitochondrial dysfunction. Conversely, muscle-specific Adamts9 knockout improves insulin sensitivity in mice.\",\n      \"method\": \"Muscle-specific transgenic overexpression and conditional knockout of Adamts9 in mice, insulin signaling assays, integrin β1 pathway analysis, mitochondrial function assays, correlation with human skeletal muscle expression data\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal gain- and loss-of-function genetic models with defined pathway readout; translational human correlation\",\n      \"pmids\": [\"30626608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADAMTS9 has aggrecanase activity in mouse cartilage distinct from ADAMTS-4 and ADAMTS-5, cleaving primarily at E↓G bonds rather than E↓A bonds in the aggrecan core protein, and is upregulated by retinoic acid but not IL-1α in ADAMTS-4/5 double-deficient cartilage explants.\",\n      \"method\": \"Microarray of femoral head cartilage explants from ADAMTS-4/5 catalytic domain double-knockout mice, immunohistochemistry, aggrecan cleavage assays with cleavage-site characterization\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function model plus biochemical cleavage characterization, single lab\",\n      \"pmids\": [\"30699963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"B3GLCT-mediated extension of O-fucose on ADAMTS9 TSRs differentially affects ADAMTS9 and ADAMTS20 function; B3glct knockout mouse eye abnormalities result from partial reduction of ADAMTS9 function, providing genetic and biochemical evidence that O-glycosylation modulates ADAMTS9 activity in vivo.\",\n      \"method\": \"B3glct knockout mouse models, genetic complementation, biochemical secretion assays, phenotype comparison with Adamts9 and Adamts20 mutants\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple knockout models with biochemical validation; strong genetic evidence\",\n      \"pmids\": [\"31600785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IL-1β activates ADAMTS9 expression through NFATc1 transcription factor; NFATc1 directly binds distal and proximal ADAMTS9 promoter regions (demonstrated by ChIP), and NFAT inhibitors (FK506, 11R-VIVIT) block IL-1β-induced ADAMTS9 upregulation.\",\n      \"method\": \"ADAMTS9 promoter cloning and reporter assays, ChIP assay demonstrating NFATc1 binding, NFAT inhibitor treatment in OUMS-27 and human chondrocytes\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP plus promoter-reporter assays with pharmacological validation\",\n      \"pmids\": [\"19052845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ADAMTS9 expression is synergistically induced by IL-1β and TNFα in chondrocytes; MAPK inhibitors SB203580 (p38) and PD98059 (MEK) decrease IL-1β-induced ADAMTS9 upregulation, identifying MAPK signaling pathways as mediators of cytokine-driven ADAMTS9 expression.\",\n      \"method\": \"Quantitative RT-PCR, Northern blotting, Western blotting, MAPK inhibitor treatment in OUMS-27 and human chondrocytes\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — pharmacological pathway inhibition with protein-level confirmation; single lab but multiple methods\",\n      \"pmids\": [\"15880812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ADAMTS9 and ADAMTS20 shed membrane type 1-matrix metalloproteinase (MT1-MMP) by cleaving its ectodomain at the Tyr314-Gly315 bond in the hinge region and at a second site in the hemopexin domain; this shedding requires hinge O-glycosylation. Loss of ADAMTS9/ADAMTS20 increases cell-surface MT1-MMP retention and enhances pro-MMP2 activation.\",\n      \"method\": \"Quantitative terminomics (TAILS) on ADAMTS9-knockout RPE-1 cells vs. parental cells, orthogonal validation by detecting catalytic domain fragment in medium, ADAMTS9/ADAMTS20 re-expression rescue, MT1-MMP knockdown epistasis, pro-MMP2 activation assays\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — unbiased quantitative proteomics with orthogonal biochemical validation, re-expression rescue, and epistasis experiments\",\n      \"pmids\": [\"37169079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL3-mediated m6A modification leads to YTHDF2-dependent degradation of ADAMTS9 mRNA in gastric cancer, suppressing ADAMTS9 protein levels and facilitating tumor angiogenesis and carcinogenesis via the PI3K/AKT pathway.\",\n      \"method\": \"METTL3 overexpression/knockdown, YTHDF2-dependent mRNA degradation assays, phenotypic angiogenesis and proliferation experiments, PI3K/AKT pathway analysis\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — mechanistic m6A-YTHDF2 axis supported by functional assays; single lab\",\n      \"pmids\": [\"35574388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DNMT3A is responsible for promoter hypermethylation-mediated silencing of ADAMTS9 in gastric cancer; RNF180 ubiquitinates DNMT3A for proteasomal degradation, thereby de-repressing ADAMTS9. ADAMTS9 restoration suppresses gastric cancer cell viability and motility.\",\n      \"method\": \"Chromatin immunoprecipitation for DNMT3A at ADAMTS9 promoter, ubiquitination assays, proteasome inhibitor treatment, ADAMTS9 re-expression in gastric cancer cells, RNA-seq after ADAMTS9 restoration\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and ubiquitination assays establish RNF180/DNMT3A/ADAMTS9 regulatory axis; single lab\",\n      \"pmids\": [\"33931579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ADAMTS9 knockout in human iPSC-derived kidney organoids reduces primary cilia number, recapitulating renal ciliopathy; single-cell RNA sequencing reveals ADAMTS9 is highest in podocytes and proximal tubules, and ADAMTS9 loss increases Wnt/PCP signaling in podocyte clusters.\",\n      \"method\": \"ADAMTS9 knockout in hiPSCs, kidney organoid differentiation, primary cilia quantification, single-cell RNA sequencing, signaling pathway analysis\",\n      \"journal\": \"Frontiers in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined genetic KO in organoid model with single-cell transcriptomic pathway analysis\",\n      \"pmids\": [\"37035301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ADAMTS9 is required cell-autonomously for melanocyte development in mouse tail epidermis; dominant ENU mutations in Adamts9 cause loss of melanocytes at ~E18.5. TAILS N-terminomics in skin identified new candidate ADAMTS9 substrates in the ECM.\",\n      \"method\": \"ENU mutagenesis, conditional allele analysis, TAILS N-terminomics proteomics for substrate identification, histological and pigmentation analysis\",\n      \"journal\": \"Pigment cell & melanoma research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional genetic allele with cell-autonomous demonstration and proteomics substrate screen\",\n      \"pmids\": [\"29781574\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADAMTS9 is a secreted zinc metalloprotease that undergoes cell-surface furin processing (facilitated by GRP94/gp96 chaperone), with its propeptide serving as both an intramolecular chaperone (requiring N-glycosylation for secretion) and an unusual activity attenuator; the active enzyme cleaves versican and aggrecan (at distinct bonds from ADAMTS-4/5), fibronectin, and MT1-MMP, requiring its ancillary TSR/GON domains for ECM localization and substrate recognition, while its protease-independent GON domain additionally promotes ER-to-Golgi trafficking; through ECM remodeling ADAMTS9 regulates cardiovascular development, smooth muscle differentiation via focal adhesion/PDGFRβ-MAPK signaling, primary ciliogenesis, angiogenesis inhibition, melanocyte development, and skeletal muscle insulin sensitivity via integrin β1 signaling, and its expression is transcriptionally activated by IL-1β/TNFα through NFATc1 and repressed by METTL3-mediated m6A/YTHDF2 mRNA degradation or promoter hypermethylation via DNMT3A.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ADAMTS9 is a secreted zinc metalloprotease that remodels the extracellular matrix to regulate cardiovascular morphogenesis, smooth muscle differentiation, primary ciliogenesis, angiogenesis, melanocyte development, and skeletal muscle insulin sensitivity. The zymogen is secreted intact to the cell surface, where furin cleaves the propeptide at Arg287-Phe288 in a GRP94-chaperoned complex; paradoxically, the cleaved propeptide remains non-covalently associated and attenuates catalytic activity, while N-glycosylation and POFUT2-mediated O-fucosylation of the TSR domains are required for secretion [PMID:12514189, PMID:16537537, PMID:17403680, PMID:19875450, PMID:27297885]. The mature protease cleaves versican, aggrecan (at E↓G bonds distinct from ADAMTS-4/5), fibronectin (at Gly2196-Leu2197), and the MT1-MMP ectodomain, with ancillary TSR/GON domains essential for substrate recognition and ECM localization; versican proteolysis controls focal adhesion assembly, PDGFRβ-MAPK signaling, and smooth muscle cytoskeletal organization, while the C-terminal GON domain independently promotes ER-to-Golgi trafficking [PMID:31085586, PMID:37169079, PMID:26027930, PMID:29642006, PMID:22419820]. ADAMTS9 transcription is induced by IL-1β/TNFα through NFATc1 and MAPK pathways and silenced by DNMT3A-mediated promoter methylation or METTL3/YTHDF2-dependent m6A mRNA degradation [PMID:19052845, PMID:33931579, PMID:35574388].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that ADAMTS9 requires furin-mediated propeptide cleavage at a specific bond and that ancillary TSR domains—not the catalytic domain alone—are necessary for substrate activity and cell-surface localization resolved the fundamental activation and domain-architecture requirements of this protease.\",\n      \"evidence\": \"Pulse-chase analysis, site-directed mutagenesis, and amino acid sequencing in COS-1/HEK293 cells comparing full-length versus catalytic-domain-only constructs\",\n      \"pmids\": [\"12514189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise contributions of individual TSR repeats to substrate engagement were not defined\", \"Whether propeptide cleavage is required in vivo was not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that pro-ADAMTS9 is processed by furin exclusively at the cell surface (not intracellularly) distinguished its activation mechanism from most ADAMTS family members and explained why the zymogen must reach the plasma membrane intact.\",\n      \"evidence\": \"Pulse-chase in furin-deficient LoVo cells with furin rescue and siRNA knockdown\",\n      \"pmids\": [\"16537537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for the cell-surface selectivity of furin processing was not determined\", \"Whether other cell types use alternative convertases in vivo remained open\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealing that the ADAMTS9 propeptide is both an intramolecular chaperone (requiring N-glycosylation for secretion) and an unusual activity attenuator that remains associated after cleavage overturned the classical model of propeptide removal as simple activation.\",\n      \"evidence\": \"Systematic Ala-substitution of glycosylation and furin sites, pulse-chase, and versican cleavage activity assays\",\n      \"pmids\": [\"17403680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and affinity of propeptide–catalytic domain reassociation not quantified\", \"Whether displacement of the propeptide by substrate is the physiological activation mechanism was not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identifying NFATc1 as the transcription factor that mediates IL-1β-induced ADAMTS9 expression, and MAPK pathways (p38, MEK) as upstream mediators, established the cytokine-responsive transcriptional control of this protease in inflammation.\",\n      \"evidence\": \"ChIP showing NFATc1 binding to ADAMTS9 promoter, promoter-reporter assays, and pharmacological inhibition with FK506/VIVIT/MAPK inhibitors in chondrocytes\",\n      \"pmids\": [\"19052845\", \"15880812\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NFATc1 is the sole mediator or cooperates with other transcription factors in vivo was not resolved\", \"Direct link between MAPK-driven expression and cartilage catabolism not shown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying the ER chaperone GRP94 as a cell-surface co-complex partner that facilitates furin processing of pro-ADAMTS9 added a quality-control checkpoint to the activation pathway.\",\n      \"evidence\": \"Chemical cross-linking with MS identification, reciprocal co-IP, geldanamycin inhibition, and gp96 siRNA in HEK293F cells\",\n      \"pmids\": [\"19875450\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GRP94 acts catalytically or as a scaffold for the furin–ADAMTS9 encounter was not distinguished\", \"Role of BiP versus GRP94 not separated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that Adamts9 haploinsufficiency causes versican accumulation and cardiovascular malformations, and that ADAMTS9 catalytic activity (not inactive mutant) suppresses angiogenesis in endothelial cells, connected ADAMTS9 proteolysis to two major developmental/vascular programs.\",\n      \"evidence\": \"Adamts9+/LacZ mouse phenotyping with versican immunostaining; ADAMTS9 siRNA and catalytic-mutant overexpression in microvascular endothelial cells with Matrigel tube formation and heterotopic tumor assays\",\n      \"pmids\": [\"20096780\", \"20093484\", \"20551050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the anti-angiogenic substrate was not determined\", \"Whether angiogenesis inhibition and versican cleavage are mechanistically linked was not established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovering that the ADAMTS9 GON domain promotes ER-to-Golgi trafficking independently of protease activity—conserved from C. elegans GON-1—revealed a fundamentally non-catalytic cellular function for this metalloprotease.\",\n      \"evidence\": \"siRNA knockdown and GON-domain rescue of ER-to-Golgi trafficking defects in human cells and C. elegans gon-1 mutants\",\n      \"pmids\": [\"22419820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which the GON domain promotes vesicle trafficking was not identified\", \"Cargo specificity of the trafficking function was not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showing that mesenchymal ADAMTS9-mediated versican proteolysis is required non-cell-autonomously for smooth muscle PDGFRβ-MAPK signaling, cilium orientation, and cell reorientation established versican processing as a signaling-competent ECM event upstream of multiple pathways.\",\n      \"evidence\": \"Gene-trap and conditional Adamts9 deletion in mouse umbilical cord with immunostaining and signaling pathway analysis\",\n      \"pmids\": [\"26027930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether versican fragments themselves or exposure of underlying matrix signals activate PDGFRβ was not distinguished\", \"Role of primary cilium orientation in downstream signaling not fully separated from focal adhesion effects\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Establishing that POFUT2-dependent O-fucosylation of TSRs is required for ADAMTS9 secretion, and that loss of ADAMTS9 in extra-embryonic tissues explains Pofut2-mutant gastrulation defects, placed glycosylation as a biosynthetic gatekeeper for ADAMTS9 function in early development.\",\n      \"evidence\": \"CRISPR knockout of POFUT2 in HEK293T with secretion assays; conditional deletion of Pofut2 and Adamts9 in epiblast versus extra-embryonic tissues\",\n      \"pmids\": [\"27297885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether O-fucosylation affects ADAMTS9 folding, stability, or receptor interactions was not separated\", \"Other POFUT2 client proteins may contribute to the phenotype\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that ADAMTS9-mediated pericellular versican proteolysis controls focal adhesion assembly in uterine smooth muscle, and that ADAMTS9 cell-autonomously regulates melanocyte survival, broadened the in vivo substrate-to-phenotype map to parturition and pigmentation.\",\n      \"evidence\": \"Conditional Adamts9 deletion in myometrium with focal adhesion/cytoskeletal imaging; ENU-induced dominant Adamts9 mutations with melanocyte analysis and TAILS proteomics in skin\",\n      \"pmids\": [\"29642006\", \"29781574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ECM substrates responsible for melanocyte survival were not validated beyond the proteomics screen\", \"Whether focal adhesion effects are versican-specific or also involve fibronectin cleavage was not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying fibronectin as a direct ADAMTS9 substrate cleaved at Gly2196-Leu2197, aggrecan cleavage at E↓G bonds distinct from ADAMTS-4/5, and integrin β1 signaling disruption as the mechanism of ADAMTS9-driven insulin resistance in skeletal muscle substantially expanded the substrate repertoire and linked ECM remodeling to metabolic regulation.\",\n      \"evidence\": \"SPR/solid-phase binding and LC-MS cleavage-site mapping for fibronectin; ADAMTS-4/5 double-KO cartilage explants for aggrecan; reciprocal muscle-specific transgenic overexpression and knockout in mice with insulin signaling and integrin β1 pathway analysis\",\n      \"pmids\": [\"31085586\", \"30699963\", \"30626608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether fibronectin cleavage occurs in vivo and contributes to specific developmental phenotypes was not shown\", \"Structural basis for distinct aggrecan cleavage-site selectivity versus ADAMTS-4/5 was not determined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing that B3GLCT-mediated extension of O-fucose on TSRs differentially modulates ADAMTS9 versus ADAMTS20 function, with B3glct knockout causing renal phenotypes through partial ADAMTS9 reduction, refined the glycosylation hierarchy controlling ADAMTS9 activity.\",\n      \"evidence\": \"B3glct knockout mouse models with genetic complementation, biochemical secretion assays, and phenotype comparison with Adamts9 and Adamts20 mutants\",\n      \"pmids\": [\"31600785\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative impact of B3GLCT on ADAMTS9 catalytic rate versus secretion was not measured\", \"Whether the eye and kidney phenotypes are entirely ADAMTS9-dependent or involve other TSR-containing proteins was not excluded\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying DNMT3A-mediated promoter methylation as a silencing mechanism for ADAMTS9 in gastric cancer, regulated upstream by RNF180-mediated DNMT3A ubiquitination, established an epigenetic axis controlling ADAMTS9 tumor-suppressive function.\",\n      \"evidence\": \"ChIP for DNMT3A at ADAMTS9 promoter, ubiquitination assays for RNF180–DNMT3A, proteasome inhibitor treatment, ADAMTS9 re-expression in gastric cancer cells\",\n      \"pmids\": [\"33931579\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding not independently replicated\", \"Whether DNMT3A methylation of ADAMTS9 promoter occurs in non-cancer tissues was not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating METTL3-mediated m6A modification leading to YTHDF2-dependent ADAMTS9 mRNA degradation added an epitranscriptomic layer of regulation and connected ADAMTS9 downregulation to PI3K/AKT-driven tumor angiogenesis.\",\n      \"evidence\": \"METTL3 overexpression/knockdown with YTHDF2-dependent mRNA stability assays and angiogenesis/proliferation readouts in gastric cancer cells\",\n      \"pmids\": [\"35574388\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific m6A sites on ADAMTS9 mRNA were not mapped\", \"In vivo relevance of the METTL3/YTHDF2 axis for ADAMTS9 regulation not demonstrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying MT1-MMP as a direct ADAMTS9/ADAMTS20 substrate shed at specific ectodomain sites, and demonstrating that ADAMTS9 loss reduces primary cilia in kidney organoids via increased Wnt/PCP signaling, connected ADAMTS9 to metalloproteinase network regulation and renal ciliopathy-relevant biology.\",\n      \"evidence\": \"TAILS quantitative terminomics on ADAMTS9-KO RPE-1 cells with re-expression rescue and MMP2 activation epistasis; ADAMTS9-KO iPSC kidney organoids with cilia quantification and scRNA-seq pathway analysis\",\n      \"pmids\": [\"37169079\", \"37035301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MT1-MMP shedding is the mechanism underlying ADAMTS9's anti-angiogenic activity was not tested\", \"Whether ciliogenesis defect is versican-dependent or involves other substrates was not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for ADAMTS9's distinct substrate selectivity (versus ADAMTS-4/5), the mechanism by which the GON domain promotes vesicle trafficking, and whether MT1-MMP shedding explains ADAMTS9's anti-angiogenic and developmental roles remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of ADAMTS9 or its catalytic/GON domains\", \"Cargo identity and molecular mechanism of GON-domain-mediated ER-to-Golgi transport unknown\", \"Relative in vivo contributions of versican, fibronectin, and MT1-MMP cleavage to specific phenotypes not disentangled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 4, 5, 8, 10, 11, 13, 17]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 11, 13, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 5, 11]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [5, 8, 10, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [5, 8, 10, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 8, 9, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 12, 20]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2, 9, 14]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"FN1\",\n      \"VCAN\",\n      \"ACAN\",\n      \"MMP14\",\n      \"FURIN\",\n      \"HSP90B1\",\n      \"POFUT2\",\n      \"B3GLCT\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}