{"gene":"VASN","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2004,"finding":"Vasorin (VASN) is a type I transmembrane protein expressed predominantly in vascular smooth muscle cells that directly binds TGF-β through its extracellular domain, attenuating TGF-β signaling in vitro. In vivo, vasorin expression is down-regulated after arterial injury, and adenovirus-mediated restoration of vasorin expression significantly diminishes injury-induced vascular lesion formation, at least in part by inhibiting TGF-β signaling.","method":"Signal sequence trap isolation, binding assay (direct pulldown of TGF-β), in vitro TGF-β signaling assays, adenovirus-mediated in vivo gene transfer with vascular injury model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — original discovery paper with multiple orthogonal methods: binding assay, in vitro signaling, and in vivo rescue","pmids":["15247411"],"is_preprint":false},{"year":2010,"finding":"ADAM17 (TACE) cleaves the transmembrane protein VASN, generating a soluble extracellular fragment. Only the soluble (shed) form of VASN inhibits TGF-β signaling; the membrane-bound form does not. Inhibition of ADAM17 blocks VASN shedding, leading to upregulation of TGF-β signaling and enhanced TGF-β-mediated epithelial-to-mesenchymal transition.","method":"ADAM17 substrate identification, metalloprotease cleavage assay, Western blot for soluble vs. membrane-bound VASN, TGF-β signaling readouts, EMT assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 — mechanistic dissection with protease assay, domain-specific functional forms, and downstream signaling readouts in a single study","pmids":["21170088"],"is_preprint":false},{"year":2015,"finding":"VASN expressed in hepatocellular carcinoma (HepG2) cells is packaged into exosomes and transferred to human umbilical vein endothelial cells (HUVECs) via receptor-mediated endocytosis, at least in part through heparan sulfate proteoglycans (HSPGs). The VASN-containing HepG2-derived exosomes promote migration of recipient HUVECs.","method":"Exosome isolation, Western blot, live-cell imaging, endocytosis inhibition assays (HSPG blocking), HUVEC migration assay","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 — first demonstration of exosomal VASN transfer with functional consequence, single lab with multiple assays","pmids":["26157350"],"is_preprint":false},{"year":2017,"finding":"In glioblastoma, VASN is preferentially induced in glioma stem-like cells (GSCs) by a HIF-1α/STAT3 co-activator complex under hypoxia. VASN stabilizes Notch1 protein at the cell membrane by preventing Numb from binding Notch1, thereby rescuing Notch1 from Numb-mediated lysosomal degradation. This mechanism augments Notch signaling under hypoxic conditions, promotes tumor growth, and reduces survival in mouse glioblastoma models.","method":"Co-IP, Western blot, shRNA knockdown, HIF-1α/STAT3 co-activator complex studies, mouse glioblastoma model, Notch1 stability assays, Numb competition assay","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway dissection with reciprocal Co-IP, loss-of-function, in vivo model, and competition assay in one study","pmids":["29198941"],"is_preprint":false},{"year":2019,"finding":"ST3Gal1-mediated sialylation of VASN (adding α2,3-linked sialic acid to O-glycans on VASN) reduces its binding affinity for TGF-β1; desialylation of VASN (by neuraminidase treatment or ST3GAL1 silencing) enhances VASN–TGF-β1 binding by 2- to 3-fold, thereby dampening TGF-β1 signaling, impairing HUVEC tube formation, and reducing downstream Smad2/Smad3 activation.","method":"LC-MS/MS glycan analysis, neuraminidase treatment, ST3GAL1 siRNA knockdown, TGF-β1 binding assay, HUVEC tube formation assay, Smad2/3 phosphorylation Western blot","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical glycan characterization by MS, binding assay, and functional readouts with multiple orthogonal methods","pmids":["30252131"],"is_preprint":false},{"year":2019,"finding":"In thyroid cancer cells, VASN knockdown by siRNA suppresses migration, invasion, and proliferation, and decreases protein levels of YAP/TAZ pathway components and epithelial-mesenchymal transition (EMT) markers as measured by Western blot, placing VASN upstream of YAP/TAZ and EMT in thyroid carcinogenesis.","method":"siRNA knockdown, Western blot (YAP/TAZ and EMT markers), migration/invasion/proliferation assays","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, knockdown with phenotypic readout and pathway marker Western blot, no direct binding or epistasis confirmation","pmids":["31312369"],"is_preprint":false},{"year":2019,"finding":"In glioma, VASN overexpression activates STAT3 and NOTCH pathways; conditioned medium from VASN-overexpressing glioma cells promotes HUVEC migration and tubulogenesis in vitro, and ectopic VASN expression stimulates tumor growth and angiogenesis in vivo.","method":"shRNA knockdown, VASN overexpression, conditioned medium assay, HUVEC migration and tubulogenesis assay, in vivo xenograft model, GSEA pathway analysis, Western blot for STAT3/NOTCH pathway","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2–3 — in vivo and in vitro functional data with pathway markers, single lab","pmids":["31215106"],"is_preprint":false},{"year":2012,"finding":"Murine Vasn (vasorin) is highly expressed in vascular smooth muscle cells and in the developing skeletal system from the first mesenchymal condensations, as well as in developing kidneys and lungs, as determined by whole-mount in situ hybridization and β-galactosidase knock-in reporter. Mitochondria-localized Vasn protects cells from TNFα- and hypoxia-induced apoptosis, and partial deletion of the Vasn coding sequence leads to increased sensitivity of hepatocytes to TNFα-induced apoptosis.","method":"Whole-mount in situ hybridization (WISH), targeted Vasn(lacZ) knock-in reporter (β-galactosidase staining), genetic knockout/partial deletion with TNFα apoptosis assay","journal":"Gene expression patterns : GEP","confidence":"Medium","confidence_rationale":"Tier 2 — reporter knock-in confirms expression, genetic deletion with defined apoptosis phenotype; cited from prior Choksi et al. 2011 findings","pmids":["22426063"],"is_preprint":false},{"year":2020,"finding":"In prostate cancer cells (LNCaP and C4-2), VASN knockdown suppresses cell viability, clonality, and protein levels of YAP and TAZ. Overexpression of YAP rescues the attenuated viability and clonality caused by VASN knockdown, placing VASN upstream of YAP/TAZ in prostate cancer cell proliferation.","method":"siRNA knockdown, Western blot (YAP/TAZ), CCK-8 viability assay, colony formation assay, YAP overexpression rescue experiment","journal":"European review for medical and pharmacological sciences","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, knockdown + rescue epistasis with defined proliferation phenotype","pmids":["32633347"],"is_preprint":false},{"year":2023,"finding":"In colorectal cancer cells, VASN physically interacts with YAP (confirmed by co-IP and co-immunofluorescence), inhibits YAP phosphorylation, and activates both the YAP/TAZ-TEAD target gene CTGF and the PTEN/PI3K/AKT pathway. Knockdown of YAP reverses the pro-proliferative, migratory, and invasive phenotype induced by VASN overexpression.","method":"Co-IP, immunofluorescence, co-immunofluorescence, Western blot (YAP phosphorylation, CTGF, PTEN/PI3K/AKT), siRNA knockdown, overexpression, YAP knockdown rescue","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus multiple orthogonal functional assays and rescue epistasis in one study","pmids":["36468780"],"is_preprint":false},{"year":2024,"finding":"In rectal cancer cells, VASN interacts with NOTCH1 protein (confirmed by co-IP), leading to concurrent activation of the NOTCH and MAPK pathways, and promoting cell proliferation, metastasis, and drug resistance.","method":"Co-IP, immunofluorescence, Western blot (NOTCH and MAPK pathway markers), in vitro and in vivo metastasis/proliferation assays, rescue experiments","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP identifies NOTCH1 interaction; functional consequence shown in vitro and in vivo, single lab","pmids":["39107788"],"is_preprint":false},{"year":2024,"finding":"VASN level in lung adenocarcinoma is regulated by ARID1A: ARID1A depletion elevates secreted VASN, while ARID1A restoration suppresses VASN upregulation and secretion. Recombinant VASN protein promotes proliferation and invasion of lung adenocarcinoma cells, and this aggressive phenotype is blocked by Notch1 knockdown, placing VASN upstream of Notch1 in ARID1A-deficient lung adenocarcinoma.","method":"Secretome analysis, ARID1A knockdown/restoration, recombinant VASN protein addition, antibody neutralization, Notch1 siRNA knockdown, in vitro and in vivo proliferation/invasion assays","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 — recombinant protein gain-of-function with epistasis (Notch1 KD reversal), single lab","pmids":["39472811"],"is_preprint":false},{"year":2025,"finding":"KLF15 transcriptionally activates VASN expression by binding GC-rich sequences in its promoter (confirmed by ATAC-seq and ChIP-seq). VASN in turn suppresses endothelial angiogenic function by interacting with Notch1 via its EGF-like domain, activating Notch1 signaling (activation blocked by γ-secretase inhibitor). EC-specific knockout of either KLF15 or VASN promotes retinal angiogenesis and tumor vascularization in mice. VASN EGF-like domain-derived peptides activate Notch1 signaling and suppress angiogenesis.","method":"RNA-seq, ATAC-seq, ChIP-seq, Cdh5-Cre conditional knockout (EC-KLF15 KO, EC-VASN KO), retinal angiogenesis assay, tumor transplantation, Co-IP (VASN–Notch1 interaction), γ-secretase inhibitor treatment, EGF-like domain peptide treatment, endothelial cell functional assays","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1–2 — comprehensive study with ChIP-seq, conditional KO mice, Co-IP, domain peptide rescue, and γ-secretase inhibitor epistasis","pmids":["40297901"],"is_preprint":false},{"year":2025,"finding":"VASN localizes to the lysosome and is induced by TGF-β (TGFB). VASN interacts with lysosomal MTOR and STK11IP, disrupting STK11IP binding to both MTOR and the V-ATPase. This relieves STK11IP-mediated suppression of lysosomal acidification, thereby positively regulating lysosomal V-ATPase activity, autophagic flux (mitophagy), and supporting terminal erythroid differentiation and mutant KRAS-driven lung cancer progression.","method":"Lysosomal immunoprecipitation (LysoIP), Co-IP (VASN–MTOR, VASN–STK11IP, STK11IP–V-ATPase competition), correlative-light electron microscopy (CLEM), FIB-SEM, lysosomal acidification assay, autophagy/mitophagy assays, VASN knockout, TGFB induction experiments","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including LysoIP, Co-IP competition assay, CLEM/FIB-SEM structural imaging, and KO functional rescue","pmids":["41630427"],"is_preprint":false},{"year":2025,"finding":"In gastric cancer, VASN overexpression (induced by H. pylori via HIF-1α upregulation of VASN) promotes proliferation, migration, and invasion. COL4A1 (collagen type IV α1 chain) is identified as a critical downstream effector of VASN that activates the PI3K/AKT signaling pathway. VASN heterozygous-deficient mice show reduced gastric tumorigenesis.","method":"RNA-seq, proteomics, VASN knockdown/overexpression, VASN+/- mouse model, H. pylori infection model, HIF-1α induction assay, PI3K/AKT pathway Western blot, in vitro and in vivo functional assays","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 — in vivo heterozygous KO plus multi-omic downstream effector identification, single lab","pmids":["40550854"],"is_preprint":false},{"year":2025,"finding":"VASN knockout in mice leads to pathological cardiac hypertrophy that progresses to myocardial fibrosis, characterized by downregulation of non-collagen ECM genes (COL6A1, COL9A1, FRAS1) and upregulation of inflammatory factors (IL-1β, IL-6) in heart tissue.","method":"VASN knockout mouse model, histology (H&E, Masson, Sirius red staining), RNA-seq, qPCR, IHC, Western blot","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined molecular and histological phenotype, single lab","pmids":["39898320"],"is_preprint":false},{"year":2025,"finding":"VASN knockout mice develop pathological cardiac hypertrophy associated with elevated exosomal miRNAs (let-7g-5p, let-7f-5p, miR-148a-3p); bioinformatics and expression analysis indicate these miRNAs target the Calm/MLCK/p-MLC2 and RhoA/ROCK1/p-MLC2 signaling pathways, with decreased levels of related pathway proteins in VASN KO hearts.","method":"VASN knockout mouse model, exosome sequencing, bioinformatics, qPCR, IHC, Western blot (p-MLC2 pathway proteins), echocardiography, pathological staining, electron microscopy","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3–4 — pathway inference primarily bioinformatic with protein-level confirmation; miRNA-pathway links not directly validated by rescue","pmids":["41235503"],"is_preprint":false},{"year":2025,"finding":"HIF-1α activates VASN expression under hypoxia in low-grade bladder cancer cells; VASN in turn promotes cell migration and EMT, and activates YAP/TAZ and PTEN/AKT pathway proteins as shown by Western blot.","method":"HIF-1α siRNA knockdown, VASN siRNA knockdown, VASN overexpression, hypoxia cell culture model, wound healing/transwell migration assays, Western blot (YAP/TAZ, PTEN/AKT, EMT markers)","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 — upstream regulator (HIF-1α) and downstream pathway (YAP/TAZ, PTEN/AKT) defined by KD/OE with functional assays, single lab","pmids":["40594164"],"is_preprint":false},{"year":2024,"finding":"NIC-PS (a niclosamide prodrug) directly binds and suppresses VASN, leading to suppression of TGF-β signaling and reduced SMAD2/3 phosphorylation in hepatocellular carcinoma. VASN knockout models recapitulate the ~50% tumor reduction seen with NIC-PS treatment.","method":"VASN knockout HCC model, Western blot (SMAD2/3 phosphorylation), bioinformatic target analysis, HCC PDX model, direct binding assay (NIC-PS to VASN)","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint, direct binding shown but mechanistic detail limited; VASN KO phenotype supports on-target effect","pmids":[],"is_preprint":true},{"year":2024,"finding":"In preeclampsia, VASN carried in extracellular vesicles (EVs) from placenta regulates vascular endothelial function. Plasma EV VASN is decreased in severe preeclampsia; VASN-deficient EV impair HUVEC migration, tube formation, and induce apoptosis, and inhibit acetylcholine-induced vasorelaxation in murine aortic rings. VASN overexpression in HAECs counteracts these effects, and VASN modulates hundreds of vasculogenesis/endothelial-related transcripts.","method":"Unbiased proteomics of urinary EVs, VASN overexpression and knockdown in HAECs, murine aortic ring vasorelaxation assay, HUVEC migration/tube formation/apoptosis assays, placenta explant EV isolation, RNA sequencing","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint, multiple functional assays but not yet peer-reviewed; mechanistic pathway not fully delineated","pmids":[],"is_preprint":true}],"current_model":"VASN is a type I transmembrane glycoprotein that acts as a TGF-β trap via its extracellular domain (cleaved and released by ADAM17), whose sialylation by ST3Gal1 modulates TGF-β binding affinity; it also localizes to lysosomes where it interacts with MTOR and STK11IP to promote lysosomal acidification and autophagy, stabilizes Notch1 at the cell membrane by blocking Numb-mediated lysosomal degradation (acting via its EGF-like domain), and activates YAP/TAZ and PI3K/AKT signaling pathways—collectively regulating vascular smooth muscle cell responses, glioma stem cell maintenance, angiogenesis, cardiac homeostasis, and cancer progression."},"narrative":{"teleology":[{"year":2004,"claim":"The identification of VASN as a TGF-β-binding transmembrane protein in vascular smooth muscle cells established its foundational role as a ligand trap that attenuates TGF-β signaling and limits injury-induced neointima formation.","evidence":"Signal sequence trap cloning, direct TGF-β pulldown, in vitro signaling assays, and adenoviral restoration in a rat carotid injury model","pmids":["15247411"],"confidence":"High","gaps":["Mechanism by which VASN binds TGF-β at the structural level was not resolved","Whether the membrane-bound versus soluble form differed in function was unknown"]},{"year":2010,"claim":"Demonstrating that ADAM17-mediated ectodomain shedding is required for VASN's TGF-β-inhibitory activity resolved the paradox of how a transmembrane protein acts as a soluble cytokine trap and linked metalloprotease regulation to TGF-β/EMT control.","evidence":"ADAM17 substrate screen, metalloprotease cleavage assay, comparison of membrane-bound vs. soluble VASN in TGF-β signaling and EMT readouts","pmids":["21170088"],"confidence":"High","gaps":["Cleavage site on VASN not mapped at residue resolution","Regulation of ADAM17-dependent shedding in vivo not addressed"]},{"year":2012,"claim":"Reporter knock-in and partial deletion studies in mice established VASN's developmental expression pattern in vasculature, skeleton, kidney, and lung, and revealed an anti-apoptotic role against TNFα- and hypoxia-induced cell death.","evidence":"Vasn(lacZ) knock-in reporter, whole-mount in situ hybridization, partial coding deletion with TNFα apoptosis assay in hepatocytes","pmids":["22426063"],"confidence":"Medium","gaps":["Mitochondrial localization reported but mechanism of mitochondrial targeting not defined","Full knockout phenotype not described in this study"]},{"year":2017,"claim":"Discovery that VASN stabilizes Notch1 by competitively blocking Numb binding revealed a second major signaling axis — independent of TGF-β trapping — through which VASN sustains glioma stem cell self-renewal under hypoxia.","evidence":"Reciprocal Co-IP, Numb competition assay, shRNA knockdown, HIF-1α/STAT3 co-activator studies, and mouse glioblastoma survival model","pmids":["29198941"],"confidence":"High","gaps":["Whether Notch1 stabilization occurs in non-cancer vascular cells was untested","Domain on VASN required for Numb displacement was not mapped"]},{"year":2019,"claim":"Characterization of ST3Gal1-dependent sialylation as a negative regulator of VASN–TGF-β1 binding affinity introduced post-translational glycan editing as a tuning mechanism for VASN's trap function and connected it to angiogenesis via HUVEC tube formation.","evidence":"LC-MS/MS O-glycan analysis, neuraminidase and ST3GAL1 siRNA, quantitative TGF-β1 binding assay, Smad2/3 phosphorylation, HUVEC tubulogenesis","pmids":["30252131"],"confidence":"High","gaps":["In vivo relevance of sialylation-dependent modulation not tested","Whether N-glycans also regulate VASN function was not addressed"]},{"year":2019,"claim":"Linking VASN to YAP/TAZ pathway activation in thyroid and later prostate cancer broadened its oncogenic repertoire beyond TGF-β and Notch, though the direct mechanism was initially unclear.","evidence":"siRNA knockdown with YAP/TAZ and EMT marker Western blots in thyroid cancer; YAP overexpression rescue in prostate cancer cells","pmids":["31312369","32633347"],"confidence":"Medium","gaps":["No direct VASN–YAP physical interaction demonstrated in these studies","Whether YAP/TAZ activation is independent of or downstream of Notch/TGF-β was unknown"]},{"year":2023,"claim":"Co-immunoprecipitation of VASN with YAP in colorectal cancer cells, combined with demonstration that VASN inhibits YAP phosphorylation and activates PTEN/PI3K/AKT, established VASN as a direct physical regulator of Hippo pathway output.","evidence":"Reciprocal Co-IP, co-immunofluorescence, YAP phosphorylation Western blot, CTGF readout, YAP knockdown rescue in colorectal cancer cells","pmids":["36468780"],"confidence":"High","gaps":["Binding domain on VASN responsible for YAP interaction not mapped","Whether VASN–YAP interaction occurs at the membrane or in the cytosol is unresolved"]},{"year":2025,"claim":"Conditional endothelial knockout of VASN and identification of its EGF-like domain as the Notch1-interacting module unified the TGF-β-independent vascular role: KLF15-driven VASN expression in endothelium activates Notch1 signaling to suppress angiogenesis, and synthetic EGF-like domain peptides recapitulate this activity.","evidence":"Cdh5-Cre EC-specific KO of KLF15 and VASN, ChIP-seq, retinal angiogenesis assay, tumor vascularization, Co-IP, γ-secretase inhibitor epistasis, EGF-like domain peptide treatment","pmids":["40297901"],"confidence":"High","gaps":["Whether shed VASN also activates Notch1 in trans is not determined","Structural basis of EGF-like domain–Notch1 interaction unresolved"]},{"year":2025,"claim":"Discovery that VASN localizes to lysosomes and displaces STK11IP from MTOR and V-ATPase to promote lysosomal acidification and autophagic flux revealed a mechanistically distinct intracellular function connecting TGF-β-induced VASN to autophagy, mitophagy, erythropoiesis, and KRAS-driven cancer.","evidence":"LysoIP, Co-IP competition assay (VASN–STK11IP–MTOR–V-ATPase), CLEM/FIB-SEM, lysosomal acidification assay, autophagy/mitophagy flux, VASN KO, TGF-β induction","pmids":["41630427"],"confidence":"High","gaps":["How VASN is trafficked from the plasma membrane to lysosomes is not defined","Whether lysosomal VASN function is independent of its extracellular shedding is unclear","Relevance of lysosomal VASN to vascular biology not yet tested"]},{"year":2025,"claim":"VASN knockout mice develop pathological cardiac hypertrophy progressing to fibrosis, establishing a non-redundant cardioprotective role in vivo and linking VASN loss to inflammatory cytokine upregulation and ECM remodeling.","evidence":"VASN global KO mice, histology, RNA-seq, qPCR, echocardiography","pmids":["39898320"],"confidence":"Medium","gaps":["Which VASN signaling axis (TGF-β, Notch, YAP, lysosomal) mediates cardioprotection is unknown","Cell-type-specific contributions (cardiomyocyte vs. fibroblast vs. endothelial) not dissected"]},{"year":null,"claim":"Key unresolved questions include the structural basis of VASN's multi-ligand interactions (TGF-β, Notch1, YAP, STK11IP), how VASN partitions between plasma membrane shedding and lysosomal trafficking, and whether its distinct signaling outputs (TGF-β trapping, Notch1 stabilization, YAP activation, V-ATPase derepression) operate independently or are coordinated in a cell-type-specific manner.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structural data for VASN or its complexes","Trafficking itinerary from ER to plasma membrane to lysosome not mapped","Relative contribution of each signaling axis in physiological vs. pathological contexts remains undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,3,9,12,13]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,4,12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,12]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[13]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,2,4]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2,19]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,3,4,5,8,9,10,12,14]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,12]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,6,9,10,11,14]}],"complexes":[],"partners":["TGFB1","NOTCH1","YAP1","STK11IP","MTOR","ADAM17","NUMB"],"other_free_text":[]},"mechanistic_narrative":"Vasorin (VASN) is a type I transmembrane glycoprotein that functions as a multivalent signaling modulator in vascular biology, autophagy, and cancer through distinct extracellular and intracellular mechanisms. Its extracellular domain, shed by ADAM17, acts as a soluble TGF-β trap whose binding affinity is tuned by ST3Gal1-mediated sialylation, thereby attenuating TGF-β/Smad2/3 signaling in vascular smooth muscle cells and endothelial cells [PMID:15247411, PMID:21170088, PMID:30252131]. VASN stabilizes Notch1 at the plasma membrane by competitively blocking Numb-mediated lysosomal degradation through its EGF-like domain, activating Notch signaling in glioma stem cells and endothelial cells, and also physically interacts with YAP to inhibit its phosphorylation, thereby co-activating YAP/TAZ-TEAD and PI3K/AKT pathways in multiple carcinomas [PMID:29198941, PMID:40297901, PMID:36468780]. At the lysosome, VASN interacts with MTOR and STK11IP, displacing STK11IP from V-ATPase to promote lysosomal acidification, autophagic flux, and mitophagy, linking TGF-β-induced VASN to autophagy regulation in erythropoiesis and KRAS-driven tumorigenesis [PMID:41630427]."},"prefetch_data":{"uniprot":{"accession":"Q6EMK4","full_name":"Vasorin","aliases":["Protein slit-like 2"],"length_aa":673,"mass_kda":71.7,"function":"May act as an inhibitor of TGF-beta signaling","subcellular_location":"Membrane; Secreted","url":"https://www.uniprot.org/uniprotkb/Q6EMK4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VASN","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/VASN","total_profiled":1310},"omim":[{"mim_id":"608843","title":"VASORIN","url":"https://www.omim.org/entry/608843"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":118.0}],"url":"https://www.proteinatlas.org/search/VASN"},"hgnc":{"alias_symbol":[],"prev_symbol":["SLITL2"]},"alphafold":{"accession":"Q6EMK4","domains":[{"cath_id":"3.80.10.10","chopping":"26-172","consensus_level":"medium","plddt":93.4778,"start":26,"end":172},{"cath_id":"3.80.10.10","chopping":"222-350","consensus_level":"medium","plddt":93.0041,"start":222,"end":350},{"cath_id":"2.10.25.10","chopping":"412-442","consensus_level":"medium","plddt":79.6394,"start":412,"end":442},{"cath_id":"2.60.40.10","chopping":"469-556","consensus_level":"high","plddt":82.1706,"start":469,"end":556}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6EMK4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6EMK4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6EMK4-F1-predicted_aligned_error_v6.png","plddt_mean":73.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VASN","jax_strain_url":"https://www.jax.org/strain/search?query=VASN"},"sequence":{"accession":"Q6EMK4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6EMK4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6EMK4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6EMK4"}},"corpus_meta":[{"pmid":"31312369","id":"PMC_31312369","title":"VASN promotes YAP/TAZ and EMT pathway in thyroid carcinogenesis in vitro.","date":"2019","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/31312369","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22426063","id":"PMC_22426063","title":"Expression of vasorin (Vasn) during embryonic development of the mouse.","date":"2012","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/22426063","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36468780","id":"PMC_36468780","title":"VASN promotes colorectal cancer progression by activating the YAP/TAZ and AKT signaling pathways via YAP.","date":"2023","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/36468780","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35729462","id":"PMC_35729462","title":"Circ_0060077 Knockdown Alleviates High-Glucose-Induced Cell Apoptosis, Oxidative Stress, Inflammation and Fibrosis in HK-2 Cells via miR-145-5p/VASN Pathway.","date":"2022","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/35729462","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32633347","id":"PMC_32633347","title":"VASN promotes proliferation of prostate cancer through the YAP/TAZ axis.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32633347","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34565020","id":"PMC_34565020","title":"VASN promotes proliferation of laryngeal cancer cells via YAP/TAZ.","date":"2021","source":"Journal of B.U.ON. : official journal of the Balkan Union of Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34565020","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40297901","id":"PMC_40297901","title":"Endothelial KLF15/VASN Axis Inhibits Angiogenesis via Activation of Notch1 Signaling.","date":"2025","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/40297901","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39107788","id":"PMC_39107788","title":"Vasorin (VASN) overexpression promotes pulmonary metastasis and resistance to adjuvant chemotherapy in patients with locally advanced rectal cancer.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39107788","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39472811","id":"PMC_39472811","title":"VASN promotes the aggressive phenotype in ARID1A-deficient lung adenocarcinoma.","date":"2024","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39472811","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40594164","id":"PMC_40594164","title":"Hypoxia-induced HIF-1α/VASN promotes bladder cancer progression.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40594164","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39898320","id":"PMC_39898320","title":"VASN knockout induces myocardial fibrosis in mice by downregulating non-collagen fibers and promoting inflammation.","date":"2025","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39898320","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41235503","id":"PMC_41235503","title":"The Network of Exosomes miRNA and p-MLC2 Regulatory Pathway Induced Pathological Cardiac Hypertrophy in Vasn Deficient Mice.","date":"2025","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41235503","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33766234","id":"PMC_33766234","title":"[Preparation of mouse monoclonal antibody against human vasorin (VASN) protein by high-efficacy electrofusion-based protocol].","date":"2021","source":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33766234","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41630427","id":"PMC_41630427","title":"TGFB-inducible VASN (vasorin) promotes lysosomal acidification.","date":"2026","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/41630427","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40550854","id":"PMC_40550854","title":"VASN drives gastric tumorigenesis via activation of the COL4A1/PI3K/AKT axis during Helicobacter pylori infection.","date":"2025","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40550854","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2024.10.15.618538","title":"Niclosamide Prodrug Enhances Oral Bioavailability and Targets Vasorin-TGFβ Signaling in Hepatocellular Carcinoma","date":"2024-10-18","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.15.618538","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.07.08.25331050","title":"A proteogenomic approach to identifying a gene signature associated with <i>HOXB13</i> G84E carrier status in prostate cancer tumours","date":"2025-07-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.08.25331050","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2024.11.18.624213","title":"Dysregulated Proteins in Plasma Distinguishing Syndromic from Non-syndromic Heritable Thoracic Aortic Disease","date":"2024-11-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.18.624213","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2024.06.24.600441","title":"Decreased Extracellular Vesicle Vasorin in Severe Preeclampsia Plasma Mediates Endothelial Dysfunction","date":"2024-06-25","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.24.600441","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25416956","id":"PMC_25416956","title":"A proteome-scale map of the human interactome network.","date":"2014","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/25416956","citation_count":977,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29507755","id":"PMC_29507755","title":"VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation.","date":"2018","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/29507755","citation_count":829,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22939629","id":"PMC_22939629","title":"A census of human soluble protein complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19056867","id":"PMC_19056867","title":"Large-scale proteomics and phosphoproteomics of urinary exosomes.","date":"2008","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/19056867","citation_count":607,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16335952","id":"PMC_16335952","title":"Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry.","date":"2005","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/16335952","citation_count":350,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12975309","id":"PMC_12975309","title":"The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.","date":"2003","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/12975309","citation_count":285,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22863883","id":"PMC_22863883","title":"A high-throughput approach for measuring temporal changes in the interactome.","date":"2012","source":"Nature methods","url":"https://pubmed.ncbi.nlm.nih.gov/22863883","citation_count":273,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17897319","id":"PMC_17897319","title":"Integral and associated lysosomal membrane proteins.","date":"2007","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/17897319","citation_count":163,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25468996","id":"PMC_25468996","title":"E-cadherin interactome complexity and robustness resolved by quantitative proteomics.","date":"2014","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/25468996","citation_count":162,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29198941","id":"PMC_29198941","title":"Hypoxic Induction of Vasorin Regulates Notch1 Turnover to Maintain Glioma Stem-like Cells.","date":"2017","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/29198941","citation_count":149,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23533145","id":"PMC_23533145","title":"In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.","date":"2013","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/23533145","citation_count":138,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31871319","id":"PMC_31871319","title":"Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms.","date":"2019","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31871319","citation_count":137,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23376485","id":"PMC_23376485","title":"Proteomic analysis of podocyte exosome-enriched fraction from normal human urine.","date":"2013","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/23376485","citation_count":126,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15247411","id":"PMC_15247411","title":"Vasorin, a transforming growth factor beta-binding protein expressed in vascular smooth muscle cells, modulates the arterial response to injury in vivo.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15247411","citation_count":122,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35922511","id":"PMC_35922511","title":"A physical wiring diagram for the human immune system.","date":"2022","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/35922511","citation_count":92,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26157350","id":"PMC_26157350","title":"Exosomal transfer of vasorin expressed in hepatocellular carcinoma cells promotes migration of human umbilical vein endothelial cells.","date":"2015","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26157350","citation_count":81,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21170088","id":"PMC_21170088","title":"ADAM17 (TACE) regulates TGFβ signaling through the cleavage of vasorin.","date":"2010","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/21170088","citation_count":77,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30252131","id":"PMC_30252131","title":"Sialylation of vasorin by ST3Gal1 facilitates TGF-β1-mediated tumor angiogenesis and progression.","date":"2019","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30252131","citation_count":59,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30745168","id":"PMC_30745168","title":"POH1 contributes to hyperactivation of TGF-β signaling and facilitates hepatocellular carcinoma metastasis through deubiquitinating TGF-β receptors and caveolin-1.","date":"2019","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/30745168","citation_count":38,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31215106","id":"PMC_31215106","title":"Vasorin stimulates malignant progression and angiogenesis in glioma.","date":"2019","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/31215106","citation_count":37,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21082674","id":"PMC_21082674","title":"Comprehensive analysis of low-abundance proteins in human urinary exosomes using peptide ligand library technology, peptide OFFGEL fractionation and nanoHPLC-chip-MS/MS.","date":"2010","source":"Electrophoresis","url":"https://pubmed.ncbi.nlm.nih.gov/21082674","citation_count":23,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35156780","id":"PMC_35156780","title":"CFTR interactome mapping using the mammalian membrane two-hybrid high-throughput screening system.","date":"2022","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/35156780","citation_count":22,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35696571","id":"PMC_35696571","title":"ESCPE-1 mediates retrograde endosomal sorting of the SARS-CoV-2 host factor Neuropilin-1.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35696571","citation_count":22,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"36949045","id":"PMC_36949045","title":"Assessment of community efforts to advance network-based prediction of protein-protein interactions.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36949045","citation_count":22,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12422,"output_tokens":3743,"usd":0.046705},"stage2":{"model":"claude-opus-4-6","input_tokens":7210,"output_tokens":2281,"usd":0.139613},"total_usd":0.461501,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":25130,"output_tokens":5635,"usd":0.079958},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":9530,"output_tokens":3300,"usd":0.195225}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"VASN's extracellular domain functions as a TGF-β trap (referenced in Krautzberger et al. 2012 citing Ikeda et al. 2004), binding TGF-β and attenuating its signaling.\",\n      \"method\": \"Referenced binding/functional assay (cited in corpus but original paper not directly available)\",\n      \"journal\": \"Gene expression patterns : GEP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — indirect citation within corpus abstract; original experiment not directly described in retrieved papers\",\n      \"pmids\": [\"22426063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VASN knockdown in thyroid cancer cells suppresses migration, invasion, and proliferation, and reduces YAP/TAZ pathway activity and EMT marker expression, placing VASN upstream of the YAP/TAZ-EMT axis.\",\n      \"method\": \"siRNA knockdown, migration/invasion/proliferation assays, Western blot for YAP/TAZ and EMT markers\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, multiple functional assays but no direct binding or structural evidence\",\n      \"pmids\": [\"31312369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VASN interacts physically with YAP, inhibits YAP phosphorylation, and activates both the YAP/TAZ-TEAD transcriptional program (including CTGF) and the PTEN/PI3K/AKT pathway in colorectal cancer cells; YAP knockdown reverses VASN-induced phenotypes.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, Western blot, rescue experiments with YAP knockdown/overexpression, GSEA/GO analysis\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus epistasis rescue, single lab\",\n      \"pmids\": [\"36468780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"VASN promotes prostate cancer cell proliferation via the YAP/TAZ axis; VASN knockdown reduces YAP and TAZ protein levels, and YAP overexpression rescues the proliferative defect caused by VASN knockdown.\",\n      \"method\": \"siRNA knockdown, CCK-8, colony formation, Western blot, rescue overexpression of YAP\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single method class, no direct binding shown\",\n      \"pmids\": [\"32633347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VASN promotes laryngeal cancer cell proliferation via YAP/TAZ; knockdown of VASN reduces YAP/TAZ protein levels and cell viability, and YAP overexpression rescues proliferation.\",\n      \"method\": \"siRNA knockdown, overexpression, CCK-8, colony formation, Western blot, rescue experiments\",\n      \"journal\": \"Journal of B.U.ON.\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, replicates YAP/TAZ axis finding without new mechanistic depth\",\n      \"pmids\": [\"34565020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KLF15 transcriptionally activates VASN by binding GC-rich sequences in the VASN promoter (identified by ATAC-seq and ChIP-seq); VASN suppresses endothelial angiogenic function by interacting with Notch1 through its EGF-like domain to activate Notch1 signaling, and VASN EGF-like domain-derived peptides activate Notch1 and suppress angiogenesis.\",\n      \"method\": \"Endothelial cell-specific conditional KO mice (EC-KLF15 KO, EC-VASN KO), RNA-seq, ATAC-seq, ChIP-seq, cell proliferation/wound healing/tube formation/sprouting assays, retinal angiogenesis model, tumor transplantation, γ-secretase inhibitor rescue, peptide functional assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including in vivo KO, ChIP-seq, domain-specific peptide assay, and genetic rescue\",\n      \"pmids\": [\"40297901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VASN interacts with NOTCH1 protein, leading to concurrent activation of NOTCH and MAPK pathways, promoting colorectal/rectal cancer cell proliferation, metastasis, and drug resistance.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, in vitro and in vivo functional assays, rescue experiments\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus in vivo validation, single lab\",\n      \"pmids\": [\"39107788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VASN mediates the aggressive phenotype of ARID1A-deficient lung adenocarcinoma via Notch1; recombinant VASN promotes proliferation and invasion, antibody neutralization of VASN suppresses aggressiveness, and Notch1 knockdown blocks VASN-induced effects.\",\n      \"method\": \"Secretome/conditioned medium analysis, recombinant protein addition, antibody neutralization, siRNA knockdown of Notch1, in vitro and in vivo proliferation/invasion assays\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis (Notch1 KD rescues), recombinant protein gain-of-function, antibody loss-of-function\",\n      \"pmids\": [\"39472811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VASN is a TGFB-inducible transmembrane glycoprotein that localizes to lysosomes, interacts with lysosomal MTOR and STK11IP, disrupts STK11IP binding to MTOR and the V-ATPase, and thereby promotes lysosomal acidification, autophagic flux (mitophagy), and terminal erythroid differentiation.\",\n      \"method\": \"Lysosomal immunoprecipitation (LysoIP), co-immunoprecipitation, correlative-light electron microscopy (CLEM), FIB-SEM, EGFP/EYFP localization, VASN KO models, TGFB stimulation, mutagenesis/domain analysis, in vitro and in vivo functional assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — lysosomal IP, co-IP of protein complex, structural/electron microscopy localization, multiple functional readouts, in vivo KO validation\",\n      \"pmids\": [\"41630427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HIF-1α activates VASN expression under hypoxia in bladder cancer cells; VASN in turn regulates YAP/TAZ and PTEN/AKT pathways to promote EMT and cell migration.\",\n      \"method\": \"siRNA knockdown of HIF-1α and VASN, VASN overexpression, Western blot, wound healing/transwell assays under hypoxic conditions\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, shows transcriptional regulation and downstream pathway effects but no direct binding\",\n      \"pmids\": [\"40594164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VASN knockout in mice induces myocardial fibrosis characterized by downregulation of non-collagen ECM genes (COL6A1, COL9A1, FRAS1) and upregulation of inflammatory factors (IL1β, IL6) in heart tissue.\",\n      \"method\": \"VASN KO mice, histological staining (H&E, Masson, Sirius red), qPCR, IHC-P, Western blot, RNA-seq\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with multiple orthogonal readouts defining downstream effectors\",\n      \"pmids\": [\"39898320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VASN knockout in mice leads to pathological cardiac hypertrophy associated with upregulation of exosomal miRNAs (let-7g-5p, let-7f-5p, miR-148a-3p) that target the Calm/MLCK/p-MLC2 and RhoA/ROCK1/p-MLC2 signaling pathways.\",\n      \"method\": \"VASN KO mice, exosome sequencing, bioinformatics, qPCR, IHC, Western blot, electron microscopy, B-ultrasound\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — indirect mechanism via exosomal miRNA; pathway link is bioinformatic with partial experimental confirmation\",\n      \"pmids\": [\"41235503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"H. pylori infection induces HIF-1α expression, which upregulates VASN; VASN then activates COL4A1 expression and downstream PI3K/AKT signaling to promote gastric cancer cell proliferation, migration, and invasion.\",\n      \"method\": \"VASN heterozygous KO mice, VASN knockdown/overexpression in gastric cell lines, RNA-seq, proteomics, functional proliferation/migration/invasion assays\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO plus in vitro mechanistic studies with multiple omics approaches\",\n      \"pmids\": [\"40550854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VASN is packaged and transported in extracellular vesicles (EV); decreased EV-associated VASN in severe preeclampsia impairs endothelial cell migration, tube formation, and induces apoptosis; VASN overexpression in endothelial cells counteracts sPE EV-induced dysfunction and regulates transcription of hundreds of genes associated with vasculogenesis, endothelial proliferation, migration, and apoptosis.\",\n      \"method\": \"Unbiased EV proteomics, placenta explant EV generation, murine aorta ring vasorelaxation assay, human aortic endothelial cell functional assays (migration, tube formation, apoptosis), VASN overexpression/knockdown, RNA-seq, murine PE model (adeno-sFLT-1)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including in vivo model and functional rescue, but preprint\",\n      \"pmids\": [\"bio_10.1101_2024.06.24.600441\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Niclosamide prodrug (NIC-PS) directly binds and suppresses VASN, reducing TGF-β signaling (SMAD2/3 phosphorylation) and inhibiting HCC tumor growth; VASN knockout models confirm the on-target effect.\",\n      \"method\": \"Direct binding assay, Western blot (SMAD2/3 phosphorylation), VASN KO models, HCC patient-derived xenograft (PDX) models, pharmacokinetic/pharmacodynamic assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding plus KO confirmation in vivo, but preprint\",\n      \"pmids\": [\"bio_10.1101_2024.10.15.618538\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"circ_0060077 acts as a sponge for miR-145-5p, which directly targets VASN mRNA; the circ_0060077/miR-145-5p/VASN axis regulates high-glucose-induced apoptosis, oxidative stress, inflammation, and fibrosis in renal tubular cells.\",\n      \"method\": \"Dual-luciferase reporter assay, RNA pulldown assay, qRT-PCR, Western blot, functional cell assays\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding validated by dual-luciferase and RNA pulldown, epistasis rescue experiments\",\n      \"pmids\": [\"35729462\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VASN is a TGF-β-inducible transmembrane glycoprotein that (1) localizes to lysosomes and promotes lysosomal acidification by interacting with MTOR and STK11IP to disrupt V-ATPase suppression, enabling mitophagy and erythroid differentiation; (2) suppresses angiogenesis through a KLF15-driven transcriptional axis by engaging Notch1 via its EGF-like domain; (3) promotes cancer cell proliferation, EMT, and metastasis by interacting with YAP to inhibit its phosphorylation and activate YAP/TAZ-TEAD and PI3K/AKT signaling; and (4) its extracellular domain can trap TGF-β to attenuate TGF-β signaling.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"Vasorin (VASN) is a type I transmembrane protein expressed predominantly in vascular smooth muscle cells that directly binds TGF-β through its extracellular domain, attenuating TGF-β signaling in vitro. In vivo, vasorin expression is down-regulated after arterial injury, and adenovirus-mediated restoration of vasorin expression significantly diminishes injury-induced vascular lesion formation, at least in part by inhibiting TGF-β signaling.\",\n      \"method\": \"Signal sequence trap isolation, binding assay (direct pulldown of TGF-β), in vitro TGF-β signaling assays, adenovirus-mediated in vivo gene transfer with vascular injury model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — original discovery paper with multiple orthogonal methods: binding assay, in vitro signaling, and in vivo rescue\",\n      \"pmids\": [\"15247411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ADAM17 (TACE) cleaves the transmembrane protein VASN, generating a soluble extracellular fragment. Only the soluble (shed) form of VASN inhibits TGF-β signaling; the membrane-bound form does not. Inhibition of ADAM17 blocks VASN shedding, leading to upregulation of TGF-β signaling and enhanced TGF-β-mediated epithelial-to-mesenchymal transition.\",\n      \"method\": \"ADAM17 substrate identification, metalloprotease cleavage assay, Western blot for soluble vs. membrane-bound VASN, TGF-β signaling readouts, EMT assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mechanistic dissection with protease assay, domain-specific functional forms, and downstream signaling readouts in a single study\",\n      \"pmids\": [\"21170088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"VASN expressed in hepatocellular carcinoma (HepG2) cells is packaged into exosomes and transferred to human umbilical vein endothelial cells (HUVECs) via receptor-mediated endocytosis, at least in part through heparan sulfate proteoglycans (HSPGs). The VASN-containing HepG2-derived exosomes promote migration of recipient HUVECs.\",\n      \"method\": \"Exosome isolation, Western blot, live-cell imaging, endocytosis inhibition assays (HSPG blocking), HUVEC migration assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — first demonstration of exosomal VASN transfer with functional consequence, single lab with multiple assays\",\n      \"pmids\": [\"26157350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In glioblastoma, VASN is preferentially induced in glioma stem-like cells (GSCs) by a HIF-1α/STAT3 co-activator complex under hypoxia. VASN stabilizes Notch1 protein at the cell membrane by preventing Numb from binding Notch1, thereby rescuing Notch1 from Numb-mediated lysosomal degradation. This mechanism augments Notch signaling under hypoxic conditions, promotes tumor growth, and reduces survival in mouse glioblastoma models.\",\n      \"method\": \"Co-IP, Western blot, shRNA knockdown, HIF-1α/STAT3 co-activator complex studies, mouse glioblastoma model, Notch1 stability assays, Numb competition assay\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway dissection with reciprocal Co-IP, loss-of-function, in vivo model, and competition assay in one study\",\n      \"pmids\": [\"29198941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ST3Gal1-mediated sialylation of VASN (adding α2,3-linked sialic acid to O-glycans on VASN) reduces its binding affinity for TGF-β1; desialylation of VASN (by neuraminidase treatment or ST3GAL1 silencing) enhances VASN–TGF-β1 binding by 2- to 3-fold, thereby dampening TGF-β1 signaling, impairing HUVEC tube formation, and reducing downstream Smad2/Smad3 activation.\",\n      \"method\": \"LC-MS/MS glycan analysis, neuraminidase treatment, ST3GAL1 siRNA knockdown, TGF-β1 binding assay, HUVEC tube formation assay, Smad2/3 phosphorylation Western blot\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical glycan characterization by MS, binding assay, and functional readouts with multiple orthogonal methods\",\n      \"pmids\": [\"30252131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In thyroid cancer cells, VASN knockdown by siRNA suppresses migration, invasion, and proliferation, and decreases protein levels of YAP/TAZ pathway components and epithelial-mesenchymal transition (EMT) markers as measured by Western blot, placing VASN upstream of YAP/TAZ and EMT in thyroid carcinogenesis.\",\n      \"method\": \"siRNA knockdown, Western blot (YAP/TAZ and EMT markers), migration/invasion/proliferation assays\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, knockdown with phenotypic readout and pathway marker Western blot, no direct binding or epistasis confirmation\",\n      \"pmids\": [\"31312369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In glioma, VASN overexpression activates STAT3 and NOTCH pathways; conditioned medium from VASN-overexpressing glioma cells promotes HUVEC migration and tubulogenesis in vitro, and ectopic VASN expression stimulates tumor growth and angiogenesis in vivo.\",\n      \"method\": \"shRNA knockdown, VASN overexpression, conditioned medium assay, HUVEC migration and tubulogenesis assay, in vivo xenograft model, GSEA pathway analysis, Western blot for STAT3/NOTCH pathway\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — in vivo and in vitro functional data with pathway markers, single lab\",\n      \"pmids\": [\"31215106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Murine Vasn (vasorin) is highly expressed in vascular smooth muscle cells and in the developing skeletal system from the first mesenchymal condensations, as well as in developing kidneys and lungs, as determined by whole-mount in situ hybridization and β-galactosidase knock-in reporter. Mitochondria-localized Vasn protects cells from TNFα- and hypoxia-induced apoptosis, and partial deletion of the Vasn coding sequence leads to increased sensitivity of hepatocytes to TNFα-induced apoptosis.\",\n      \"method\": \"Whole-mount in situ hybridization (WISH), targeted Vasn(lacZ) knock-in reporter (β-galactosidase staining), genetic knockout/partial deletion with TNFα apoptosis assay\",\n      \"journal\": \"Gene expression patterns : GEP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter knock-in confirms expression, genetic deletion with defined apoptosis phenotype; cited from prior Choksi et al. 2011 findings\",\n      \"pmids\": [\"22426063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In prostate cancer cells (LNCaP and C4-2), VASN knockdown suppresses cell viability, clonality, and protein levels of YAP and TAZ. Overexpression of YAP rescues the attenuated viability and clonality caused by VASN knockdown, placing VASN upstream of YAP/TAZ in prostate cancer cell proliferation.\",\n      \"method\": \"siRNA knockdown, Western blot (YAP/TAZ), CCK-8 viability assay, colony formation assay, YAP overexpression rescue experiment\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, knockdown + rescue epistasis with defined proliferation phenotype\",\n      \"pmids\": [\"32633347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In colorectal cancer cells, VASN physically interacts with YAP (confirmed by co-IP and co-immunofluorescence), inhibits YAP phosphorylation, and activates both the YAP/TAZ-TEAD target gene CTGF and the PTEN/PI3K/AKT pathway. Knockdown of YAP reverses the pro-proliferative, migratory, and invasive phenotype induced by VASN overexpression.\",\n      \"method\": \"Co-IP, immunofluorescence, co-immunofluorescence, Western blot (YAP phosphorylation, CTGF, PTEN/PI3K/AKT), siRNA knockdown, overexpression, YAP knockdown rescue\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus multiple orthogonal functional assays and rescue epistasis in one study\",\n      \"pmids\": [\"36468780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In rectal cancer cells, VASN interacts with NOTCH1 protein (confirmed by co-IP), leading to concurrent activation of the NOTCH and MAPK pathways, and promoting cell proliferation, metastasis, and drug resistance.\",\n      \"method\": \"Co-IP, immunofluorescence, Western blot (NOTCH and MAPK pathway markers), in vitro and in vivo metastasis/proliferation assays, rescue experiments\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP identifies NOTCH1 interaction; functional consequence shown in vitro and in vivo, single lab\",\n      \"pmids\": [\"39107788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VASN level in lung adenocarcinoma is regulated by ARID1A: ARID1A depletion elevates secreted VASN, while ARID1A restoration suppresses VASN upregulation and secretion. Recombinant VASN protein promotes proliferation and invasion of lung adenocarcinoma cells, and this aggressive phenotype is blocked by Notch1 knockdown, placing VASN upstream of Notch1 in ARID1A-deficient lung adenocarcinoma.\",\n      \"method\": \"Secretome analysis, ARID1A knockdown/restoration, recombinant VASN protein addition, antibody neutralization, Notch1 siRNA knockdown, in vitro and in vivo proliferation/invasion assays\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — recombinant protein gain-of-function with epistasis (Notch1 KD reversal), single lab\",\n      \"pmids\": [\"39472811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KLF15 transcriptionally activates VASN expression by binding GC-rich sequences in its promoter (confirmed by ATAC-seq and ChIP-seq). VASN in turn suppresses endothelial angiogenic function by interacting with Notch1 via its EGF-like domain, activating Notch1 signaling (activation blocked by γ-secretase inhibitor). EC-specific knockout of either KLF15 or VASN promotes retinal angiogenesis and tumor vascularization in mice. VASN EGF-like domain-derived peptides activate Notch1 signaling and suppress angiogenesis.\",\n      \"method\": \"RNA-seq, ATAC-seq, ChIP-seq, Cdh5-Cre conditional knockout (EC-KLF15 KO, EC-VASN KO), retinal angiogenesis assay, tumor transplantation, Co-IP (VASN–Notch1 interaction), γ-secretase inhibitor treatment, EGF-like domain peptide treatment, endothelial cell functional assays\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — comprehensive study with ChIP-seq, conditional KO mice, Co-IP, domain peptide rescue, and γ-secretase inhibitor epistasis\",\n      \"pmids\": [\"40297901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VASN localizes to the lysosome and is induced by TGF-β (TGFB). VASN interacts with lysosomal MTOR and STK11IP, disrupting STK11IP binding to both MTOR and the V-ATPase. This relieves STK11IP-mediated suppression of lysosomal acidification, thereby positively regulating lysosomal V-ATPase activity, autophagic flux (mitophagy), and supporting terminal erythroid differentiation and mutant KRAS-driven lung cancer progression.\",\n      \"method\": \"Lysosomal immunoprecipitation (LysoIP), Co-IP (VASN–MTOR, VASN–STK11IP, STK11IP–V-ATPase competition), correlative-light electron microscopy (CLEM), FIB-SEM, lysosomal acidification assay, autophagy/mitophagy assays, VASN knockout, TGFB induction experiments\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including LysoIP, Co-IP competition assay, CLEM/FIB-SEM structural imaging, and KO functional rescue\",\n      \"pmids\": [\"41630427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In gastric cancer, VASN overexpression (induced by H. pylori via HIF-1α upregulation of VASN) promotes proliferation, migration, and invasion. COL4A1 (collagen type IV α1 chain) is identified as a critical downstream effector of VASN that activates the PI3K/AKT signaling pathway. VASN heterozygous-deficient mice show reduced gastric tumorigenesis.\",\n      \"method\": \"RNA-seq, proteomics, VASN knockdown/overexpression, VASN+/- mouse model, H. pylori infection model, HIF-1α induction assay, PI3K/AKT pathway Western blot, in vitro and in vivo functional assays\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — in vivo heterozygous KO plus multi-omic downstream effector identification, single lab\",\n      \"pmids\": [\"40550854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VASN knockout in mice leads to pathological cardiac hypertrophy that progresses to myocardial fibrosis, characterized by downregulation of non-collagen ECM genes (COL6A1, COL9A1, FRAS1) and upregulation of inflammatory factors (IL-1β, IL-6) in heart tissue.\",\n      \"method\": \"VASN knockout mouse model, histology (H&E, Masson, Sirius red staining), RNA-seq, qPCR, IHC, Western blot\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined molecular and histological phenotype, single lab\",\n      \"pmids\": [\"39898320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VASN knockout mice develop pathological cardiac hypertrophy associated with elevated exosomal miRNAs (let-7g-5p, let-7f-5p, miR-148a-3p); bioinformatics and expression analysis indicate these miRNAs target the Calm/MLCK/p-MLC2 and RhoA/ROCK1/p-MLC2 signaling pathways, with decreased levels of related pathway proteins in VASN KO hearts.\",\n      \"method\": \"VASN knockout mouse model, exosome sequencing, bioinformatics, qPCR, IHC, Western blot (p-MLC2 pathway proteins), echocardiography, pathological staining, electron microscopy\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3–4 — pathway inference primarily bioinformatic with protein-level confirmation; miRNA-pathway links not directly validated by rescue\",\n      \"pmids\": [\"41235503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HIF-1α activates VASN expression under hypoxia in low-grade bladder cancer cells; VASN in turn promotes cell migration and EMT, and activates YAP/TAZ and PTEN/AKT pathway proteins as shown by Western blot.\",\n      \"method\": \"HIF-1α siRNA knockdown, VASN siRNA knockdown, VASN overexpression, hypoxia cell culture model, wound healing/transwell migration assays, Western blot (YAP/TAZ, PTEN/AKT, EMT markers)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — upstream regulator (HIF-1α) and downstream pathway (YAP/TAZ, PTEN/AKT) defined by KD/OE with functional assays, single lab\",\n      \"pmids\": [\"40594164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NIC-PS (a niclosamide prodrug) directly binds and suppresses VASN, leading to suppression of TGF-β signaling and reduced SMAD2/3 phosphorylation in hepatocellular carcinoma. VASN knockout models recapitulate the ~50% tumor reduction seen with NIC-PS treatment.\",\n      \"method\": \"VASN knockout HCC model, Western blot (SMAD2/3 phosphorylation), bioinformatic target analysis, HCC PDX model, direct binding assay (NIC-PS to VASN)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, direct binding shown but mechanistic detail limited; VASN KO phenotype supports on-target effect\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In preeclampsia, VASN carried in extracellular vesicles (EVs) from placenta regulates vascular endothelial function. Plasma EV VASN is decreased in severe preeclampsia; VASN-deficient EV impair HUVEC migration, tube formation, and induce apoptosis, and inhibit acetylcholine-induced vasorelaxation in murine aortic rings. VASN overexpression in HAECs counteracts these effects, and VASN modulates hundreds of vasculogenesis/endothelial-related transcripts.\",\n      \"method\": \"Unbiased proteomics of urinary EVs, VASN overexpression and knockdown in HAECs, murine aortic ring vasorelaxation assay, HUVEC migration/tube formation/apoptosis assays, placenta explant EV isolation, RNA sequencing\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, multiple functional assays but not yet peer-reviewed; mechanistic pathway not fully delineated\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"VASN is a type I transmembrane glycoprotein that acts as a TGF-β trap via its extracellular domain (cleaved and released by ADAM17), whose sialylation by ST3Gal1 modulates TGF-β binding affinity; it also localizes to lysosomes where it interacts with MTOR and STK11IP to promote lysosomal acidification and autophagy, stabilizes Notch1 at the cell membrane by blocking Numb-mediated lysosomal degradation (acting via its EGF-like domain), and activates YAP/TAZ and PI3K/AKT signaling pathways—collectively regulating vascular smooth muscle cell responses, glioma stem cell maintenance, angiogenesis, cardiac homeostasis, and cancer progression.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"VASN is a TGF-β-inducible transmembrane glycoprotein that functions as a signaling hub at the intersection of Notch, Hippo-YAP/TAZ, and mTOR-lysosomal pathways. Its extracellular EGF-like domain engages Notch1 to activate Notch signaling, which in endothelial cells suppresses angiogenesis under transcriptional control of KLF15, while in cancer cells it promotes proliferation and metastasis [PMID:40297901, PMID:39472811, PMID:39107788]. VASN physically interacts with YAP, inhibits YAP phosphorylation, and thereby activates YAP/TAZ-TEAD and PI3K/AKT signaling to drive epithelial-mesenchymal transition and tumor progression across multiple cancer types [PMID:36468780, PMID:31312369]. At lysosomes, VASN interacts with mTOR and STK11IP to relieve V-ATPase suppression, promoting lysosomal acidification, mitophagy, and terminal erythroid differentiation [PMID:41630427].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that VASN's extracellular domain can sequester TGF-β identified it as a potential modulator of TGF-β signaling rather than merely a passive membrane protein.\",\n      \"evidence\": \"Binding/functional assays (cited indirectly via Krautzberger et al. 2012)\",\n      \"pmids\": [\"22426063\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Original binding assay not directly described in retrieved papers; awaits independent confirmation of binding affinity and stoichiometry\",\n        \"Physiological relevance of TGF-β trapping versus other VASN functions not delineated\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that VASN knockdown suppresses YAP/TAZ levels and EMT markers in cancer cells established VASN as an upstream activator of Hippo-YAP signaling, opening a new mechanistic axis beyond TGF-β.\",\n      \"evidence\": \"siRNA knockdown in thyroid cancer cells with Western blot for YAP/TAZ and EMT markers, migration/invasion/proliferation assays\",\n      \"pmids\": [\"31312369\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct physical interaction between VASN and YAP shown in this study\",\n        \"Mechanism by which a transmembrane protein regulates cytoplasmic YAP unclear\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Co-immunoprecipitation of VASN with YAP plus epistasis rescue established a direct physical interaction and confirmed that VASN inhibits YAP phosphorylation to activate YAP/TAZ-TEAD transcription and PTEN/PI3K/AKT signaling.\",\n      \"evidence\": \"Reciprocal co-IP, immunofluorescence, YAP knockdown/overexpression rescue in colorectal cancer cells\",\n      \"pmids\": [\"36468780\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis of VASN–YAP interaction not resolved\",\n        \"How a transmembrane glycoprotein accesses cytoplasmic YAP remains mechanistically unclear\",\n        \"Single-lab finding\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of VASN–Notch1 physical interaction revealed a second major signaling output: VASN activates Notch and MAPK pathways to drive colorectal cancer proliferation, metastasis, and drug resistance, and mediates aggressiveness of ARID1A-deficient lung adenocarcinoma.\",\n      \"evidence\": \"Co-IP plus in vivo functional assays in colorectal cancer; recombinant VASN gain-of-function, antibody neutralization, and Notch1 epistasis in lung adenocarcinoma\",\n      \"pmids\": [\"39107788\", \"39472811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Domain on VASN mediating Notch1 interaction not mapped in these studies\",\n        \"Relationship between VASN–Notch1 and VASN–YAP axes not tested in the same system\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"In vivo endothelial-cell-specific KO of VASN and KLF15, combined with ChIP-seq and EGF-like domain peptide assays, established a KLF15→VASN→Notch1 transcriptional-signaling axis that suppresses angiogenesis, pinpointing the EGF-like domain as the Notch1-binding moiety.\",\n      \"evidence\": \"EC-specific conditional KO mice, retinal angiogenesis model, ChIP-seq, ATAC-seq, domain-derived peptide assays, γ-secretase inhibitor rescue\",\n      \"pmids\": [\"40297901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How the same VASN–Notch1 interaction promotes cancer growth in some contexts but suppresses angiogenesis in endothelium is not reconciled\",\n        \"Structural details of EGF-like domain–Notch1 interface unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Lysosomal immunoprecipitation revealed that VASN localizes to lysosomes and interacts with mTOR and STK11IP, disrupting STK11IP-mediated V-ATPase suppression to promote lysosomal acidification, mitophagy, and erythroid differentiation — establishing a fundamentally distinct non-cancer function.\",\n      \"evidence\": \"LysoIP, co-IP, CLEM/FIB-SEM, VASN KO models, TGF-β stimulation, in vivo erythroid differentiation assays\",\n      \"pmids\": [\"41630427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the lysosomal function of VASN operates in non-erythroid cells is untested\",\n        \"Relative contribution of TGF-β trapping versus lysosomal activity in VASN-null phenotypes unclear\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"VASN knockout in mice produces myocardial fibrosis and pathological cardiac hypertrophy, demonstrating an essential role in cardiac homeostasis beyond cancer and erythropoiesis.\",\n      \"evidence\": \"VASN KO mice, histology, RNA-seq, Western blot, exosome miRNA profiling\",\n      \"pmids\": [\"39898320\", \"41235503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking VASN loss to cardiac fibrosis/hypertrophy not resolved at the molecular level\",\n        \"Exosomal miRNA–pathway connections are largely bioinformatic\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How VASN coordinates its distinct signaling outputs — TGF-β trapping, YAP inhibition, Notch1 activation, and lysosomal mTOR/V-ATPase regulation — in a context-dependent manner remains the central unresolved question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of VASN exists to explain multi-partner engagement\",\n        \"Relative importance of each signaling axis in physiological versus pathological settings is undefined\",\n        \"Tissue-specific trafficking of VASN to lysosomes versus plasma membrane has not been characterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 5, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 5, 6, 7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"YAP1\",\n      \"NOTCH1\",\n      \"MTOR\",\n      \"STK11IP\",\n      \"KLF15\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Vasorin (VASN) is a type I transmembrane glycoprotein that functions as a multivalent signaling modulator in vascular biology, autophagy, and cancer through distinct extracellular and intracellular mechanisms. Its extracellular domain, shed by ADAM17, acts as a soluble TGF-β trap whose binding affinity is tuned by ST3Gal1-mediated sialylation, thereby attenuating TGF-β/Smad2/3 signaling in vascular smooth muscle cells and endothelial cells [PMID:15247411, PMID:21170088, PMID:30252131]. VASN stabilizes Notch1 at the plasma membrane by competitively blocking Numb-mediated lysosomal degradation through its EGF-like domain, activating Notch signaling in glioma stem cells and endothelial cells, and also physically interacts with YAP to inhibit its phosphorylation, thereby co-activating YAP/TAZ-TEAD and PI3K/AKT pathways in multiple carcinomas [PMID:29198941, PMID:40297901, PMID:36468780]. At the lysosome, VASN interacts with MTOR and STK11IP, displacing STK11IP from V-ATPase to promote lysosomal acidification, autophagic flux, and mitophagy, linking TGF-β-induced VASN to autophagy regulation in erythropoiesis and KRAS-driven tumorigenesis [PMID:41630427].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"The identification of VASN as a TGF-β-binding transmembrane protein in vascular smooth muscle cells established its foundational role as a ligand trap that attenuates TGF-β signaling and limits injury-induced neointima formation.\",\n      \"evidence\": \"Signal sequence trap cloning, direct TGF-β pulldown, in vitro signaling assays, and adenoviral restoration in a rat carotid injury model\",\n      \"pmids\": [\"15247411\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which VASN binds TGF-β at the structural level was not resolved\",\n        \"Whether the membrane-bound versus soluble form differed in function was unknown\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that ADAM17-mediated ectodomain shedding is required for VASN's TGF-β-inhibitory activity resolved the paradox of how a transmembrane protein acts as a soluble cytokine trap and linked metalloprotease regulation to TGF-β/EMT control.\",\n      \"evidence\": \"ADAM17 substrate screen, metalloprotease cleavage assay, comparison of membrane-bound vs. soluble VASN in TGF-β signaling and EMT readouts\",\n      \"pmids\": [\"21170088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Cleavage site on VASN not mapped at residue resolution\",\n        \"Regulation of ADAM17-dependent shedding in vivo not addressed\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Reporter knock-in and partial deletion studies in mice established VASN's developmental expression pattern in vasculature, skeleton, kidney, and lung, and revealed an anti-apoptotic role against TNFα- and hypoxia-induced cell death.\",\n      \"evidence\": \"Vasn(lacZ) knock-in reporter, whole-mount in situ hybridization, partial coding deletion with TNFα apoptosis assay in hepatocytes\",\n      \"pmids\": [\"22426063\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mitochondrial localization reported but mechanism of mitochondrial targeting not defined\",\n        \"Full knockout phenotype not described in this study\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that VASN stabilizes Notch1 by competitively blocking Numb binding revealed a second major signaling axis — independent of TGF-β trapping — through which VASN sustains glioma stem cell self-renewal under hypoxia.\",\n      \"evidence\": \"Reciprocal Co-IP, Numb competition assay, shRNA knockdown, HIF-1α/STAT3 co-activator studies, and mouse glioblastoma survival model\",\n      \"pmids\": [\"29198941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Notch1 stabilization occurs in non-cancer vascular cells was untested\",\n        \"Domain on VASN required for Numb displacement was not mapped\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Characterization of ST3Gal1-dependent sialylation as a negative regulator of VASN–TGF-β1 binding affinity introduced post-translational glycan editing as a tuning mechanism for VASN's trap function and connected it to angiogenesis via HUVEC tube formation.\",\n      \"evidence\": \"LC-MS/MS O-glycan analysis, neuraminidase and ST3GAL1 siRNA, quantitative TGF-β1 binding assay, Smad2/3 phosphorylation, HUVEC tubulogenesis\",\n      \"pmids\": [\"30252131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo relevance of sialylation-dependent modulation not tested\",\n        \"Whether N-glycans also regulate VASN function was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linking VASN to YAP/TAZ pathway activation in thyroid and later prostate cancer broadened its oncogenic repertoire beyond TGF-β and Notch, though the direct mechanism was initially unclear.\",\n      \"evidence\": \"siRNA knockdown with YAP/TAZ and EMT marker Western blots in thyroid cancer; YAP overexpression rescue in prostate cancer cells\",\n      \"pmids\": [\"31312369\", \"32633347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct VASN–YAP physical interaction demonstrated in these studies\",\n        \"Whether YAP/TAZ activation is independent of or downstream of Notch/TGF-β was unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Co-immunoprecipitation of VASN with YAP in colorectal cancer cells, combined with demonstration that VASN inhibits YAP phosphorylation and activates PTEN/PI3K/AKT, established VASN as a direct physical regulator of Hippo pathway output.\",\n      \"evidence\": \"Reciprocal Co-IP, co-immunofluorescence, YAP phosphorylation Western blot, CTGF readout, YAP knockdown rescue in colorectal cancer cells\",\n      \"pmids\": [\"36468780\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Binding domain on VASN responsible for YAP interaction not mapped\",\n        \"Whether VASN–YAP interaction occurs at the membrane or in the cytosol is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Conditional endothelial knockout of VASN and identification of its EGF-like domain as the Notch1-interacting module unified the TGF-β-independent vascular role: KLF15-driven VASN expression in endothelium activates Notch1 signaling to suppress angiogenesis, and synthetic EGF-like domain peptides recapitulate this activity.\",\n      \"evidence\": \"Cdh5-Cre EC-specific KO of KLF15 and VASN, ChIP-seq, retinal angiogenesis assay, tumor vascularization, Co-IP, γ-secretase inhibitor epistasis, EGF-like domain peptide treatment\",\n      \"pmids\": [\"40297901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether shed VASN also activates Notch1 in trans is not determined\",\n        \"Structural basis of EGF-like domain–Notch1 interaction unresolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery that VASN localizes to lysosomes and displaces STK11IP from MTOR and V-ATPase to promote lysosomal acidification and autophagic flux revealed a mechanistically distinct intracellular function connecting TGF-β-induced VASN to autophagy, mitophagy, erythropoiesis, and KRAS-driven cancer.\",\n      \"evidence\": \"LysoIP, Co-IP competition assay (VASN–STK11IP–MTOR–V-ATPase), CLEM/FIB-SEM, lysosomal acidification assay, autophagy/mitophagy flux, VASN KO, TGF-β induction\",\n      \"pmids\": [\"41630427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How VASN is trafficked from the plasma membrane to lysosomes is not defined\",\n        \"Whether lysosomal VASN function is independent of its extracellular shedding is unclear\",\n        \"Relevance of lysosomal VASN to vascular biology not yet tested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"VASN knockout mice develop pathological cardiac hypertrophy progressing to fibrosis, establishing a non-redundant cardioprotective role in vivo and linking VASN loss to inflammatory cytokine upregulation and ECM remodeling.\",\n      \"evidence\": \"VASN global KO mice, histology, RNA-seq, qPCR, echocardiography\",\n      \"pmids\": [\"39898320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Which VASN signaling axis (TGF-β, Notch, YAP, lysosomal) mediates cardioprotection is unknown\",\n        \"Cell-type-specific contributions (cardiomyocyte vs. fibroblast vs. endothelial) not dissected\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of VASN's multi-ligand interactions (TGF-β, Notch1, YAP, STK11IP), how VASN partitions between plasma membrane shedding and lysosomal trafficking, and whether its distinct signaling outputs (TGF-β trapping, Notch1 stabilization, YAP activation, V-ATPase derepression) operate independently or are coordinated in a cell-type-specific manner.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structural data for VASN or its complexes\",\n        \"Trafficking itinerary from ER to plasma membrane to lysosome not mapped\",\n        \"Relative contribution of each signaling axis in physiological vs. pathological contexts remains undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 3, 9, 12, 13]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 4, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 12]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 3, 4, 5, 8, 9, 10, 12, 14]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 12]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 6, 9, 10, 11, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TGFB1\",\n      \"NOTCH1\",\n      \"YAP1\",\n      \"STK11IP\",\n      \"MTOR\",\n      \"ADAM17\",\n      \"NUMB\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}