{"gene":"VASN","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2004,"finding":"The extracellular domain of VASN functions as a TGF-β trap (referenced in Krautzberger et al. 2012 as 'Ikeda et al., 2004'), sequestering TGF-β to modulate its signaling in vascular smooth muscle cells.","method":"Referenced prior finding (cited in abstract as established function)","journal":"Gene expression patterns : GEP","confidence":"Low","confidence_rationale":"Tier 3 / Weak — cited as an established finding within another paper's abstract, no direct experimental detail visible in corpus","pmids":["22426063"],"is_preprint":false},{"year":2011,"finding":"Mitochondria-localized VASN protects cells from TNFα- and hypoxia-induced apoptosis; partial deletion of VASN coding sequence increases sensitivity of hepatocytes to TNFα-induced apoptosis (referenced in Krautzberger et al. 2012 as 'Choksi et al., 2011').","method":"Genetic deletion model with apoptosis assay (referenced prior finding)","journal":"Gene expression patterns : GEP","confidence":"Low","confidence_rationale":"Tier 3 / Weak — cited as established prior finding within another abstract; no direct experimental detail visible","pmids":["22426063"],"is_preprint":false},{"year":2012,"finding":"VASN (Vasn) is highly expressed in vascular smooth muscle cells and in the developing skeletal system of mice, with additional expression in developing kidneys and lungs, as determined by whole-mount in situ hybridization and β-galactosidase knock-in reporter.","method":"Whole-mount in situ hybridization (WISH) and targeted Vasn-lacZ knock-in allele β-galactosidase histochemical detection","journal":"Gene expression patterns : GEP","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal localization methods (WISH and knock-in reporter) in single study confirming expression domains","pmids":["22426063"],"is_preprint":false},{"year":2019,"finding":"VASN knockdown in thyroid cancer cells suppresses migration, invasion, and proliferation, and reduces protein levels of YAP/TAZ pathway components and epithelial-mesenchymal transition (EMT) markers.","method":"siRNA knockdown, migration/invasion/proliferation assays, Western blot","journal":"American journal of translational research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach with Western blot, no rescue or mechanistic dissection","pmids":["31312369"],"is_preprint":false},{"year":2020,"finding":"VASN knockdown in prostate cancer cells (LNCaP, C4-2) suppresses cell viability, clonality, and protein levels of YAP and TAZ; overexpression of YAP rescues the impaired viability and clonality caused by VASN knockdown, placing VASN upstream of YAP/TAZ in prostate cancer proliferation.","method":"siRNA knockdown, CCK-8, colony formation, Western blot, YAP overexpression rescue experiment","journal":"European review for medical and pharmacological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic rescue experiment (YAP OE reverses VASN KD phenotype) in single lab with multiple assays","pmids":["32633347"],"is_preprint":false},{"year":2021,"finding":"VASN knockdown in laryngeal cancer cells decreases cell viability, proliferative capacity, and YAP/TAZ protein expression; YAP overexpression reverses the inhibition of viability and proliferation caused by VASN knockdown, confirming VASN acts upstream of YAP/TAZ.","method":"siRNA knockdown, YAP overexpression rescue, CCK-8, colony formation, Western blot","journal":"Journal of B.U.ON.","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic rescue experiment with multiple functional assays; single lab","pmids":["34565020"],"is_preprint":false},{"year":2023,"finding":"VASN physically interacts with YAP protein in colorectal cancer cells, inhibits YAP phosphorylation, and activates both YAP/TAZ-TEAD target genes (CTGF) and the PTEN/PI3K/AKT pathway; YAP knockdown reverses the pro-tumorigenic phenotype induced by VASN overexpression.","method":"Co-immunoprecipitation (co-IP), immunofluorescence, co-immunofluorescence, Western blot, GSEA/GO analysis, YAP knockdown rescue experiments","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus rescue experiment; multiple orthogonal methods; single lab","pmids":["36468780"],"is_preprint":false},{"year":2024,"finding":"VASN interacts with NOTCH1 protein in rectal/colorectal cancer cells, leading to concurrent activation of the NOTCH and MAPK signaling pathways, promoting cell proliferation, metastasis, and drug resistance.","method":"Co-immunoprecipitation (co-IP), immunofluorescence, rescue experiments, in vitro and in vivo functional assays","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP demonstrating VASN-NOTCH1 interaction with functional rescue; single lab","pmids":["39107788"],"is_preprint":false},{"year":2024,"finding":"VASN secretion is regulated by ARID1A: ARID1A depletion increases VASN level and secretion in lung adenocarcinoma cells, and ARID1A restoration prevents VASN upregulation; knockdown of Notch1 blocks the aggressive phenotype induced by recombinant VASN protein, placing VASN upstream of Notch1 signaling.","method":"Secretome analysis (conditioned medium proteomics), ARID1A knockdown/restoration, recombinant VASN treatment, Notch1 knockdown, antibody neutralization, in vitro and in vivo functional assays","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (secretome, genetic KD, recombinant protein, antibody neutralization) in single lab","pmids":["39472811"],"is_preprint":false},{"year":2025,"finding":"KLF15 transcriptionally activates VASN expression by binding GC-rich sequences in the VASN promoter (accessible chromatin); VASN in turn suppresses endothelial angiogenic function by activating Dll4-induced Notch1 signaling, and the EGF-like domain of VASN is essential for its interaction with Notch1.","method":"RNA-seq, ATAC-seq, ChIP-seq, endothelial cell-specific conditional KO mice (EC-KLF15 KO, EC-VASN KO), retinal angiogenesis assay, tumor transplantation, γ-secretase inhibitor rescue, EGF-like domain peptide experiments, cell proliferation/wound healing/tube formation/sprouting assays","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (ChIP-seq, ATAC-seq, two conditional KO mouse models, domain-mapping peptide experiments, pharmacological rescue) establishing KLF15→VASN→Notch1 axis","pmids":["40297901"],"is_preprint":false},{"year":2025,"finding":"VASN knockout in mice induces myocardial fibrosis characterized by downregulation of non-collagen extracellular matrix genes (COL6A1, COL9A1, FRAS1) and upregulation of inflammatory factors (IL-1β, IL-6) in cardiac tissue.","method":"VASN knockout mouse model, histological staining (H&E, Masson, Sirius red), qPCR, IHC-P, Western blot, RNA sequencing with differential gene expression analysis","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout model with multiple orthogonal tissue analyses; single lab","pmids":["39898320"],"is_preprint":false},{"year":2025,"finding":"VASN knockout in mice leads to pathological cardiac hypertrophy associated with elevated 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, with reduced expression of related pathway proteins.","method":"VASN knockout mice, B-ultrasound, ECG, histological staining, electron microscopy, exosome sequencing, bioinformatics, qPCR, IHC, Western blot","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — association between VASN KO and miRNA/pathway changes is correlative; direct mechanistic link between VASN and p-MLC2 pathway not experimentally established beyond correlation","pmids":["41235503"],"is_preprint":false},{"year":2025,"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.","method":"Hypoxia cell culture model, siRNA knockdown of HIF-1α and VASN, VASN overexpression, Western blot, wound healing/transwell assays","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single siRNA approach; pathway modulation shown by Western blot without mechanistic dissection of direct interactions","pmids":["40594164"],"is_preprint":false},{"year":2025,"finding":"H. pylori infection induces HIF-1α expression, which upregulates VASN; VASN then activates COL4A1 expression to drive PI3K/AKT signaling, promoting gastric cancer progression.","method":"VASN heterozygous knockout mice, gastric cell lines with VASN KD/OE, RNA-seq, proteomics, bioinformatics, in vitro and in vivo functional assays","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple experimental approaches (in vivo KO, in vitro KD/OE, proteomics, RNA-seq) identifying COL4A1 as downstream effector; single lab","pmids":["40550854"],"is_preprint":false},{"year":2026,"finding":"VASN is a TGF-β-inducible transmembrane protein that localizes to the lysosome, interacts with lysosomal mTOR and STK11IP, and disrupts the STK11IP-mTOR-V-ATPase complex to promote lysosomal acidification; this function is essential for mitophagy induced by TGF-β, terminal erythroid differentiation, and progression of mutant KRAS-driven lung cancer.","method":"Lysosomal immunoprecipitation (LysoIP), co-immunoprecipitation, correlative light-electron microscopy (CLEM), FIB-SEM, subcellular fractionation/localization, TGF-β stimulation assays, loss-of-function studies, erythroid differentiation model, KRAS mutant lung cancer models","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (LysoIP, co-IP, CLEM/FIB-SEM, functional assays in multiple biological contexts) establishing VASN localization and mechanism at the lysosome","pmids":["41630427"],"is_preprint":false},{"year":2026,"finding":"VASN shows significant enrichment in mitochondria in hepatocellular carcinoma (HCC) cells and liver tissues by immunoelectron microscopy; in a chronic aflatoxin B1 exposure model, VASN upregulation correlates with ROS accumulation, mitochondrial membrane potential dissipation, and mitophagy induction.","method":"Optimized immunoelectron microscopy (IEM-VASN), VASN knockdown in Huh7-KD cells and VASN-/- mice, AFB1 chronic exposure model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immunoelectron microscopy provides ultrastructural localization with quantitative validation in KD cells and KO mice; single lab; functional link to mitophagy is correlative","pmids":["42118142"],"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 inhibition reduces tumor volume ~50% in HCC models.","method":"VASN knockout models, Western blot (SMAD2/3 phosphorylation), HCC patient-derived xenograft (PDX) models, bioinformatic analyses, in vitro/in vivo pharmacological studies","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint; direct binding claim not fully supported by structural/biochemical binding assay detail in abstract; single lab","pmids":[],"is_preprint":true},{"year":2024,"finding":"VASN delivered via extracellular vesicles (EV) regulates endothelial cell function: EV with high VASN content support endothelial migration, tube formation, and vasorelaxation, while EV with decreased VASN (as in severe preeclampsia) impair these functions; VASN overexpression in endothelial cells counteracts sPE EV-induced dysfunction and modulates transcripts associated with vasculogenesis, proliferation, migration, and apoptosis.","method":"Unbiased EV proteomics, murine aorta ring (MAR) vasorelaxation assay, human aortic endothelial cell (HAEC) functional assays (migration, tube formation, apoptosis), VASN overexpression/knockdown, RNA sequencing, placenta explant EV generation, murine PE model (sFLT-1 adenovirus)","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint; multiple assays but mechanistic pathway not fully dissected; causal chain from EV-VASN to specific signaling not established","pmids":[],"is_preprint":true}],"current_model":"VASN is a TGF-β-inducible transmembrane glycoprotein that (1) localizes to lysosomes where it interacts with mTOR and STK11IP to promote lysosomal acidification, autophagy, and mitophagy; (2) also localizes to mitochondria in hepatocellular carcinoma; (3) acts downstream of the transcription factor KLF15 to suppress angiogenesis by activating Notch1 signaling through its EGF-like domain; (4) promotes tumor progression across multiple cancer types by acting upstream of YAP/TAZ (inhibiting YAP phosphorylation) and activating PI3K/AKT signaling; (5) can be secreted and transported via extracellular vesicles to regulate endothelial cell function; and (6) is transcriptionally upregulated by HIF-1α under hypoxia and by H. pylori-induced HIF-1α in gastric cancer, driving downstream COL4A1/PI3K/AKT signaling."},"narrative":{"mechanistic_narrative":"VASN is a TGF-β-inducible transmembrane glycoprotein that acts as a multifunctional signaling hub coordinating receptor pathway activation, lysosomal quality control, and tumor progression [PMID:40297901, PMID:41630427]. At the lysosome, VASN interacts with mTOR and STK11IP and disrupts the STK11IP-mTOR-V-ATPase complex to promote lysosomal acidification, a function required for TGF-β-induced mitophagy, terminal erythroid differentiation, and progression of mutant KRAS-driven lung cancer [PMID:41630427]. In endothelial cells, VASN operates downstream of the transcription factor KLF15, which binds GC-rich elements in the VASN promoter to activate its expression; VASN then suppresses angiogenic function by engaging Dll4-induced Notch1 signaling through its EGF-like domain, which is essential for the VASN-Notch1 interaction [PMID:40297901]. Across multiple carcinomas, VASN promotes proliferation, migration, invasion, and EMT by acting upstream of the YAP/TAZ transcriptional program — it physically binds YAP, inhibits its phosphorylation, and activates YAP/TAZ-TEAD targets together with the PTEN/PI3K/AKT axis [PMID:32633347, PMID:36468780], and in colorectal cancer it additionally interacts with NOTCH1 to co-activate NOTCH and MAPK signaling, driving metastasis and drug resistance [PMID:39107788]. VASN expression is induced under hypoxia by HIF-1α, including H. pylori-driven HIF-1α in gastric cancer where VASN activates COL4A1/PI3K/AKT signaling [PMID:40550854]. In vivo, VASN knockout produces myocardial fibrosis and pathological cardiac hypertrophy, establishing a role in cardiac tissue homeostasis [PMID:39898320, PMID:41235503].","teleology":[{"year":2012,"claim":"Establishing where VASN is expressed was the first step toward assigning physiological function; mapping its expression domains anchored later mechanistic work in vascular and developmental tissues.","evidence":"Whole-mount in situ hybridization and Vasn-lacZ knock-in β-galactosidase reporter in mice","pmids":["22426063"],"confidence":"Medium","gaps":["Expression mapping does not establish molecular function","No protein-level localization within cells","Causal role in any tissue not tested"]},{"year":2019,"claim":"The first link of VASN to a defined oncogenic effector came from showing its loss suppresses YAP/TAZ pathway components and EMT markers in cancer cells, placing it within Hippo-pathway-associated tumor biology.","evidence":"siRNA knockdown with migration/invasion/proliferation assays and Western blot in thyroid cancer cells","pmids":["31312369"],"confidence":"Low","gaps":["Single knockdown approach without rescue","Correlation between VASN and YAP/TAZ not mechanistically dissected","No direct interaction shown"]},{"year":2021,"claim":"Whether VASN was upstream or downstream of YAP/TAZ was resolved by epistasis: YAP overexpression rescued the proliferation defects caused by VASN knockdown, positioning VASN upstream of the Hippo effectors.","evidence":"siRNA knockdown plus YAP overexpression rescue in prostate and laryngeal cancer cells with viability/colony assays","pmids":["32633347","34565020"],"confidence":"Medium","gaps":["Mechanism by which VASN regulates YAP not defined","No physical interaction demonstrated at this stage","Single-lab contexts"]},{"year":2023,"claim":"The molecular basis of VASN-YAP regulation was clarified by demonstrating physical interaction and inhibition of YAP phosphorylation, linking VASN to both YAP/TAZ-TEAD targets and the PTEN/PI3K/AKT pathway.","evidence":"Reciprocal co-IP, co-immunofluorescence, Western blot, and YAP knockdown rescue in colorectal cancer cells","pmids":["36468780"],"confidence":"Medium","gaps":["Direct binding interface not mapped","How a transmembrane protein modulates YAP phosphorylation mechanistically unresolved","Single lab"]},{"year":2024,"claim":"VASN was shown to engage a second receptor pathway, interacting with NOTCH1 to co-activate NOTCH and MAPK signaling, and its activity as a secreted/inducible factor was tied to chromatin regulator ARID1A.","evidence":"Co-IP, secretome proteomics, ARID1A knockdown/restoration, recombinant VASN treatment and Notch1 knockdown in colorectal and lung adenocarcinoma cells","pmids":["39107788","39472811"],"confidence":"Medium","gaps":["VASN-NOTCH1 binding interface not defined","Relationship between YAP and NOTCH branches of VASN signaling unclear","Secretion mechanism not characterized"]},{"year":2025,"claim":"A definitive upstream transcriptional regulator and a domain-resolved effector mechanism were established: KLF15 directly activates VASN, which suppresses angiogenesis via Dll4-Notch1 signaling requiring its EGF-like domain.","evidence":"ChIP-seq, ATAC-seq, endothelial-specific KLF15 and VASN conditional KO mice, retinal angiogenesis assays, γ-secretase inhibitor rescue, and EGF-like domain peptide experiments","pmids":["40297901"],"confidence":"High","gaps":["Whether the EGF-domain/Notch1 mechanism operates identically in tumor contexts not tested here","Reconciliation of pro-tumor versus anti-angiogenic roles incomplete"]},{"year":2025,"claim":"Hypoxia-driven and infection-driven induction of VASN was placed under HIF-1α control, identifying COL4A1 as a downstream effector feeding PI3K/AKT in gastric cancer and reinforcing YAP/TAZ-PTEN/AKT regulation in bladder cancer.","evidence":"Hypoxia culture, HIF-1α/VASN siRNA, VASN heterozygous KO mice, gastric cell KD/OE, RNA-seq and proteomics","pmids":["40550854","40594164"],"confidence":"Medium","gaps":["Direct HIF-1α binding at the VASN promoter not shown in these entries","COL4A1 regulation mechanism not fully dissected","Bladder cancer findings rely on single siRNA approach"]},{"year":2025,"claim":"Loss-of-function in vivo revealed organ-level roles for VASN in the heart, showing knockout induces myocardial fibrosis and pathological hypertrophy with altered ECM, inflammatory, and contractile-pathway signatures.","evidence":"VASN knockout mice with histology, RNA-seq, exosome sequencing, qPCR and Western blot","pmids":["39898320","41235503"],"confidence":"Medium","gaps":["Direct molecular link between VASN and contractile/p-MLC2 pathways is correlative","Cardiac cell type responsible not defined","Mechanism connecting VASN loss to fibrosis unresolved"]},{"year":2026,"claim":"The most mechanistically resolved function was defined at the lysosome, where VASN disrupts the STK11IP-mTOR-V-ATPase complex to drive acidification, mitophagy, erythroid differentiation, and KRAS-driven lung cancer, with parallel mitochondrial enrichment seen in HCC.","evidence":"LysoIP, co-IP, CLEM/FIB-SEM, subcellular fractionation, immunoelectron microscopy, and loss-of-function studies across erythroid, lung cancer, and HCC models","pmids":["41630427","42118142"],"confidence":"High","gaps":["How a transmembrane glycoprotein reaches the lysosomal mTOR complex not detailed","Mitochondrial localization functional role remains correlative","Relationship between lysosomal and receptor-signaling functions not integrated"]},{"year":null,"claim":"It remains unresolved how VASN's distinct molecular activities — lysosomal complex disruption, EGF-domain-mediated Notch1 engagement, direct YAP binding, and TGF-β trapping — are coordinated within a single protein, and whether they operate in the same or distinct cellular pools.","evidence":"No single study integrates the lysosomal, receptor-signaling, and secreted functions","pmids":[],"confidence":"Low","gaps":["No structural model relating VASN domains to its multiple binding partners","Determinants of subcellular routing (lysosome vs plasma membrane vs secretion) unknown","Context that selects YAP vs NOTCH vs lysosomal outputs undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,14]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[9,7]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[14]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[14,9]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[15]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7,9]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[13,14]}],"complexes":[],"partners":["YAP1","NOTCH1","MTOR","STK11IP","KLF15"],"other_free_text":[]}},"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":24,"is_preprint":false},{"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":22,"is_preprint":false},{"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},{"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":14,"is_preprint":false},{"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":10,"is_preprint":false},{"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},{"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},{"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},{"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":3,"is_preprint":false},{"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},{"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":2,"is_preprint":false},{"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},{"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},{"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},{"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},{"pmid":"42212140","id":"PMC_42212140","title":"Integrated single-cell and bulk transcriptomic analyses reveal a stem-like epithelial subpopulation in adenocarcinoma of the esophagogastric junction and identify VASN as a novel regulator of tumor stemness.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/42212140","citation_count":0,"is_preprint":false},{"pmid":"42118142","id":"PMC_42118142","title":"Development of Immunoelectron Microscopy for VASN Detection Using Multiple Models and Identification of VASN as a Key Regulator of Mitochondrial Homeostasis in Hepatocellular Carcinoma Cells.","date":"2026","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/42118142","citation_count":0,"is_preprint":false},{"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},{"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},{"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},{"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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14478,"output_tokens":4524,"usd":0.055647,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12518,"output_tokens":3751,"usd":0.078183,"stage2_stop_reason":"end_turn"},"total_usd":0.13383,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"The extracellular domain of VASN functions as a TGF-β trap (referenced in Krautzberger et al. 2012 as 'Ikeda et al., 2004'), sequestering TGF-β to modulate its signaling in vascular smooth muscle cells.\",\n      \"method\": \"Referenced prior finding (cited in abstract as established function)\",\n      \"journal\": \"Gene expression patterns : GEP\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — cited as an established finding within another paper's abstract, no direct experimental detail visible in corpus\",\n      \"pmids\": [\"22426063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mitochondria-localized VASN protects cells from TNFα- and hypoxia-induced apoptosis; partial deletion of VASN coding sequence increases sensitivity of hepatocytes to TNFα-induced apoptosis (referenced in Krautzberger et al. 2012 as 'Choksi et al., 2011').\",\n      \"method\": \"Genetic deletion model with apoptosis assay (referenced prior finding)\",\n      \"journal\": \"Gene expression patterns : GEP\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — cited as established prior finding within another abstract; no direct experimental detail visible\",\n      \"pmids\": [\"22426063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"VASN (Vasn) is highly expressed in vascular smooth muscle cells and in the developing skeletal system of mice, with additional expression in developing kidneys and lungs, as determined by whole-mount in situ hybridization and β-galactosidase knock-in reporter.\",\n      \"method\": \"Whole-mount in situ hybridization (WISH) and targeted Vasn-lacZ knock-in allele β-galactosidase histochemical detection\",\n      \"journal\": \"Gene expression patterns : GEP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal localization methods (WISH and knock-in reporter) in single study confirming expression domains\",\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 protein levels of YAP/TAZ pathway components and epithelial-mesenchymal transition (EMT) markers.\",\n      \"method\": \"siRNA knockdown, migration/invasion/proliferation assays, Western blot\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach with Western blot, no rescue or mechanistic dissection\",\n      \"pmids\": [\"31312369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"VASN knockdown in prostate cancer cells (LNCaP, C4-2) suppresses cell viability, clonality, and protein levels of YAP and TAZ; overexpression of YAP rescues the impaired viability and clonality caused by VASN knockdown, placing VASN upstream of YAP/TAZ in prostate cancer proliferation.\",\n      \"method\": \"siRNA knockdown, CCK-8, colony formation, Western blot, YAP overexpression rescue experiment\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic rescue experiment (YAP OE reverses VASN KD phenotype) in single lab with multiple assays\",\n      \"pmids\": [\"32633347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VASN knockdown in laryngeal cancer cells decreases cell viability, proliferative capacity, and YAP/TAZ protein expression; YAP overexpression reverses the inhibition of viability and proliferation caused by VASN knockdown, confirming VASN acts upstream of YAP/TAZ.\",\n      \"method\": \"siRNA knockdown, YAP overexpression rescue, CCK-8, colony formation, Western blot\",\n      \"journal\": \"Journal of B.U.ON.\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic rescue experiment with multiple functional assays; single lab\",\n      \"pmids\": [\"34565020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VASN physically interacts with YAP protein in colorectal cancer cells, inhibits YAP phosphorylation, and activates both YAP/TAZ-TEAD target genes (CTGF) and the PTEN/PI3K/AKT pathway; YAP knockdown reverses the pro-tumorigenic phenotype induced by VASN overexpression.\",\n      \"method\": \"Co-immunoprecipitation (co-IP), immunofluorescence, co-immunofluorescence, Western blot, GSEA/GO analysis, YAP knockdown rescue experiments\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus rescue experiment; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"36468780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VASN interacts with NOTCH1 protein in rectal/colorectal cancer cells, leading to concurrent activation of the NOTCH and MAPK signaling pathways, promoting cell proliferation, metastasis, and drug resistance.\",\n      \"method\": \"Co-immunoprecipitation (co-IP), immunofluorescence, rescue experiments, in vitro and in vivo functional assays\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP demonstrating VASN-NOTCH1 interaction with functional rescue; single lab\",\n      \"pmids\": [\"39107788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VASN secretion is regulated by ARID1A: ARID1A depletion increases VASN level and secretion in lung adenocarcinoma cells, and ARID1A restoration prevents VASN upregulation; knockdown of Notch1 blocks the aggressive phenotype induced by recombinant VASN protein, placing VASN upstream of Notch1 signaling.\",\n      \"method\": \"Secretome analysis (conditioned medium proteomics), ARID1A knockdown/restoration, recombinant VASN treatment, Notch1 knockdown, antibody neutralization, in vitro and in vivo functional assays\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (secretome, genetic KD, recombinant protein, antibody neutralization) in 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 the VASN promoter (accessible chromatin); VASN in turn suppresses endothelial angiogenic function by activating Dll4-induced Notch1 signaling, and the EGF-like domain of VASN is essential for its interaction with Notch1.\",\n      \"method\": \"RNA-seq, ATAC-seq, ChIP-seq, endothelial cell-specific conditional KO mice (EC-KLF15 KO, EC-VASN KO), retinal angiogenesis assay, tumor transplantation, γ-secretase inhibitor rescue, EGF-like domain peptide experiments, cell proliferation/wound healing/tube formation/sprouting assays\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (ChIP-seq, ATAC-seq, two conditional KO mouse models, domain-mapping peptide experiments, pharmacological rescue) establishing KLF15→VASN→Notch1 axis\",\n      \"pmids\": [\"40297901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VASN knockout in mice induces myocardial fibrosis characterized by downregulation of non-collagen extracellular matrix genes (COL6A1, COL9A1, FRAS1) and upregulation of inflammatory factors (IL-1β, IL-6) in cardiac tissue.\",\n      \"method\": \"VASN knockout mouse model, histological staining (H&E, Masson, Sirius red), qPCR, IHC-P, Western blot, RNA sequencing with differential gene expression analysis\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout model with multiple orthogonal tissue analyses; single lab\",\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 elevated 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, with reduced expression of related pathway proteins.\",\n      \"method\": \"VASN knockout mice, B-ultrasound, ECG, histological staining, electron microscopy, exosome sequencing, bioinformatics, qPCR, IHC, Western blot\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — association between VASN KO and miRNA/pathway changes is correlative; direct mechanistic link between VASN and p-MLC2 pathway not experimentally established beyond correlation\",\n      \"pmids\": [\"41235503\"],\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\": \"Hypoxia cell culture model, siRNA knockdown of HIF-1α and VASN, VASN overexpression, Western blot, wound healing/transwell assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single siRNA approach; pathway modulation shown by Western blot without mechanistic dissection of direct interactions\",\n      \"pmids\": [\"40594164\"],\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 to drive PI3K/AKT signaling, promoting gastric cancer progression.\",\n      \"method\": \"VASN heterozygous knockout mice, gastric cell lines with VASN KD/OE, RNA-seq, proteomics, bioinformatics, in vitro and in vivo functional assays\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple experimental approaches (in vivo KO, in vitro KD/OE, proteomics, RNA-seq) identifying COL4A1 as downstream effector; single lab\",\n      \"pmids\": [\"40550854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"VASN is a TGF-β-inducible transmembrane protein that localizes to the lysosome, interacts with lysosomal mTOR and STK11IP, and disrupts the STK11IP-mTOR-V-ATPase complex to promote lysosomal acidification; this function is essential for mitophagy induced by TGF-β, terminal erythroid differentiation, and progression of mutant KRAS-driven lung cancer.\",\n      \"method\": \"Lysosomal immunoprecipitation (LysoIP), co-immunoprecipitation, correlative light-electron microscopy (CLEM), FIB-SEM, subcellular fractionation/localization, TGF-β stimulation assays, loss-of-function studies, erythroid differentiation model, KRAS mutant lung cancer models\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (LysoIP, co-IP, CLEM/FIB-SEM, functional assays in multiple biological contexts) establishing VASN localization and mechanism at the lysosome\",\n      \"pmids\": [\"41630427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"VASN shows significant enrichment in mitochondria in hepatocellular carcinoma (HCC) cells and liver tissues by immunoelectron microscopy; in a chronic aflatoxin B1 exposure model, VASN upregulation correlates with ROS accumulation, mitochondrial membrane potential dissipation, and mitophagy induction.\",\n      \"method\": \"Optimized immunoelectron microscopy (IEM-VASN), VASN knockdown in Huh7-KD cells and VASN-/- mice, AFB1 chronic exposure model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunoelectron microscopy provides ultrastructural localization with quantitative validation in KD cells and KO mice; single lab; functional link to mitophagy is correlative\",\n      \"pmids\": [\"42118142\"],\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 inhibition reduces tumor volume ~50% in HCC models.\",\n      \"method\": \"VASN knockout models, Western blot (SMAD2/3 phosphorylation), HCC patient-derived xenograft (PDX) models, bioinformatic analyses, in vitro/in vivo pharmacological studies\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint; direct binding claim not fully supported by structural/biochemical binding assay detail in abstract; single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VASN delivered via extracellular vesicles (EV) regulates endothelial cell function: EV with high VASN content support endothelial migration, tube formation, and vasorelaxation, while EV with decreased VASN (as in severe preeclampsia) impair these functions; VASN overexpression in endothelial cells counteracts sPE EV-induced dysfunction and modulates transcripts associated with vasculogenesis, proliferation, migration, and apoptosis.\",\n      \"method\": \"Unbiased EV proteomics, murine aorta ring (MAR) vasorelaxation assay, human aortic endothelial cell (HAEC) functional assays (migration, tube formation, apoptosis), VASN overexpression/knockdown, RNA sequencing, placenta explant EV generation, murine PE model (sFLT-1 adenovirus)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint; multiple assays but mechanistic pathway not fully dissected; causal chain from EV-VASN to specific signaling not established\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"VASN is a TGF-β-inducible transmembrane glycoprotein that (1) localizes to lysosomes where it interacts with mTOR and STK11IP to promote lysosomal acidification, autophagy, and mitophagy; (2) also localizes to mitochondria in hepatocellular carcinoma; (3) acts downstream of the transcription factor KLF15 to suppress angiogenesis by activating Notch1 signaling through its EGF-like domain; (4) promotes tumor progression across multiple cancer types by acting upstream of YAP/TAZ (inhibiting YAP phosphorylation) and activating PI3K/AKT signaling; (5) can be secreted and transported via extracellular vesicles to regulate endothelial cell function; and (6) is transcriptionally upregulated by HIF-1α under hypoxia and by H. pylori-induced HIF-1α in gastric cancer, driving downstream COL4A1/PI3K/AKT signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VASN is a TGF-β-inducible transmembrane glycoprotein that acts as a multifunctional signaling hub coordinating receptor pathway activation, lysosomal quality control, and tumor progression [#9, #14]. At the lysosome, VASN interacts with mTOR and STK11IP and disrupts the STK11IP-mTOR-V-ATPase complex to promote lysosomal acidification, a function required for TGF-β-induced mitophagy, terminal erythroid differentiation, and progression of mutant KRAS-driven lung cancer [#14]. In endothelial cells, VASN operates downstream of the transcription factor KLF15, which binds GC-rich elements in the VASN promoter to activate its expression; VASN then suppresses angiogenic function by engaging Dll4-induced Notch1 signaling through its EGF-like domain, which is essential for the VASN-Notch1 interaction [#9]. Across multiple carcinomas, VASN promotes proliferation, migration, invasion, and EMT by acting upstream of the YAP/TAZ transcriptional program — it physically binds YAP, inhibits its phosphorylation, and activates YAP/TAZ-TEAD targets together with the PTEN/PI3K/AKT axis [#4, #6], and in colorectal cancer it additionally interacts with NOTCH1 to co-activate NOTCH and MAPK signaling, driving metastasis and drug resistance [#7]. VASN expression is induced under hypoxia by HIF-1α, including H. pylori-driven HIF-1α in gastric cancer where VASN activates COL4A1/PI3K/AKT signaling [#13]. In vivo, VASN knockout produces myocardial fibrosis and pathological cardiac hypertrophy, establishing a role in cardiac tissue homeostasis [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing where VASN is expressed was the first step toward assigning physiological function; mapping its expression domains anchored later mechanistic work in vascular and developmental tissues.\",\n      \"evidence\": \"Whole-mount in situ hybridization and Vasn-lacZ knock-in β-galactosidase reporter in mice\",\n      \"pmids\": [\"22426063\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Expression mapping does not establish molecular function\", \"No protein-level localization within cells\", \"Causal role in any tissue not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The first link of VASN to a defined oncogenic effector came from showing its loss suppresses YAP/TAZ pathway components and EMT markers in cancer cells, placing it within Hippo-pathway-associated tumor biology.\",\n      \"evidence\": \"siRNA knockdown with migration/invasion/proliferation assays and Western blot in thyroid cancer cells\",\n      \"pmids\": [\"31312369\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single knockdown approach without rescue\", \"Correlation between VASN and YAP/TAZ not mechanistically dissected\", \"No direct interaction shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Whether VASN was upstream or downstream of YAP/TAZ was resolved by epistasis: YAP overexpression rescued the proliferation defects caused by VASN knockdown, positioning VASN upstream of the Hippo effectors.\",\n      \"evidence\": \"siRNA knockdown plus YAP overexpression rescue in prostate and laryngeal cancer cells with viability/colony assays\",\n      \"pmids\": [\"32633347\", \"34565020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which VASN regulates YAP not defined\", \"No physical interaction demonstrated at this stage\", \"Single-lab contexts\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The molecular basis of VASN-YAP regulation was clarified by demonstrating physical interaction and inhibition of YAP phosphorylation, linking VASN to both YAP/TAZ-TEAD targets and the PTEN/PI3K/AKT pathway.\",\n      \"evidence\": \"Reciprocal co-IP, co-immunofluorescence, Western blot, and YAP knockdown rescue in colorectal cancer cells\",\n      \"pmids\": [\"36468780\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface not mapped\", \"How a transmembrane protein modulates YAP phosphorylation mechanistically unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"VASN was shown to engage a second receptor pathway, interacting with NOTCH1 to co-activate NOTCH and MAPK signaling, and its activity as a secreted/inducible factor was tied to chromatin regulator ARID1A.\",\n      \"evidence\": \"Co-IP, secretome proteomics, ARID1A knockdown/restoration, recombinant VASN treatment and Notch1 knockdown in colorectal and lung adenocarcinoma cells\",\n      \"pmids\": [\"39107788\", \"39472811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"VASN-NOTCH1 binding interface not defined\", \"Relationship between YAP and NOTCH branches of VASN signaling unclear\", \"Secretion mechanism not characterized\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A definitive upstream transcriptional regulator and a domain-resolved effector mechanism were established: KLF15 directly activates VASN, which suppresses angiogenesis via Dll4-Notch1 signaling requiring its EGF-like domain.\",\n      \"evidence\": \"ChIP-seq, ATAC-seq, endothelial-specific KLF15 and VASN conditional KO mice, retinal angiogenesis assays, γ-secretase inhibitor rescue, and EGF-like domain peptide experiments\",\n      \"pmids\": [\"40297901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the EGF-domain/Notch1 mechanism operates identically in tumor contexts not tested here\", \"Reconciliation of pro-tumor versus anti-angiogenic roles incomplete\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Hypoxia-driven and infection-driven induction of VASN was placed under HIF-1α control, identifying COL4A1 as a downstream effector feeding PI3K/AKT in gastric cancer and reinforcing YAP/TAZ-PTEN/AKT regulation in bladder cancer.\",\n      \"evidence\": \"Hypoxia culture, HIF-1α/VASN siRNA, VASN heterozygous KO mice, gastric cell KD/OE, RNA-seq and proteomics\",\n      \"pmids\": [\"40550854\", \"40594164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct HIF-1α binding at the VASN promoter not shown in these entries\", \"COL4A1 regulation mechanism not fully dissected\", \"Bladder cancer findings rely on single siRNA approach\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Loss-of-function in vivo revealed organ-level roles for VASN in the heart, showing knockout induces myocardial fibrosis and pathological hypertrophy with altered ECM, inflammatory, and contractile-pathway signatures.\",\n      \"evidence\": \"VASN knockout mice with histology, RNA-seq, exosome sequencing, qPCR and Western blot\",\n      \"pmids\": [\"39898320\", \"41235503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between VASN and contractile/p-MLC2 pathways is correlative\", \"Cardiac cell type responsible not defined\", \"Mechanism connecting VASN loss to fibrosis unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"The most mechanistically resolved function was defined at the lysosome, where VASN disrupts the STK11IP-mTOR-V-ATPase complex to drive acidification, mitophagy, erythroid differentiation, and KRAS-driven lung cancer, with parallel mitochondrial enrichment seen in HCC.\",\n      \"evidence\": \"LysoIP, co-IP, CLEM/FIB-SEM, subcellular fractionation, immunoelectron microscopy, and loss-of-function studies across erythroid, lung cancer, and HCC models\",\n      \"pmids\": [\"41630427\", \"42118142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a transmembrane glycoprotein reaches the lysosomal mTOR complex not detailed\", \"Mitochondrial localization functional role remains correlative\", \"Relationship between lysosomal and receptor-signaling functions not integrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how VASN's distinct molecular activities — lysosomal complex disruption, EGF-domain-mediated Notch1 engagement, direct YAP binding, and TGF-β trapping — are coordinated within a single protein, and whether they operate in the same or distinct cellular pools.\",\n      \"evidence\": \"No single study integrates the lysosomal, receptor-signaling, and secreted functions\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model relating VASN domains to its multiple binding partners\", \"Determinants of subcellular routing (lysosome vs plasma membrane vs secretion) unknown\", \"Context that selects YAP vs NOTCH vs lysosomal outputs undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 14]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [9, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [14, 9]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7, 9]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [13, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"YAP1\", \"NOTCH1\", \"MTOR\", \"STK11IP\", \"KLF15\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}