{"gene":"VTN","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2017,"finding":"BPIFB1 (LPLUNC1) physically interacts with VTN (vitronectin) and reduces VTN expression and formation of the VTN-integrin αV complex in NPC cells, leading to inhibition of the FAK/Src/ERK signalling pathway and suppression of cell migration and invasion.","method":"Co-immunoprecipitation coupled with mass spectrometry to identify BPIFB1-binding proteins; western blotting and immunofluorescence to assess VTN expression and complex formation; functional migration/invasion assays","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP + MS identification, plus functional assays in vitro and in vivo, single lab","pmids":["29123267"],"is_preprint":false},{"year":2018,"finding":"VTN (vitronectin) promotes radioresistance in NPC cells by inducing cell proliferation and survival, G2/M phase arrest, DNA repair, and activation of the ATM-Chk2 and ATR-Chk1 pathways with anti-apoptotic effects after ionizing radiation; BPIFB1 inhibits this VTN-mediated radioresistance.","method":"Colony formation and cell survival assays; western blotting for pathway activation (ATM-Chk2, ATR-Chk1); cell cycle analysis; knockdown/overexpression experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays with pathway readouts, single lab, builds on prior interaction data","pmids":["29568064"],"is_preprint":false},{"year":2002,"finding":"PAI-1 binds to VTN (vitronectin); the major high-affinity PAI-1 binding site on VTN is localized within the N-terminal somatomedin B (SMB) domain of VTN, with at least one additional low-affinity PAI-1 binding site in the C-terminal region of VTN involved in forming larger PAI-1/VTN complexes.","method":"Binding site mapping using domain-deletion and peptide competition assays; biochemical interaction studies","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapping approach with multiple methods described in mini-review summarizing prior experimental work, replicated finding across studies","pmids":["12437099"],"is_preprint":false},{"year":2021,"finding":"A VTN fragment (amino acids 381–397) interacts with αVβ6 integrin and competitively prevents TGF-β1 activation mediated by αVβ6 in human fibroblast-like synoviocytes, thereby modulating TGF-β1 bioavailability and downstream fibrotic signaling.","method":"Competition binding assay for VTN(381-397 a.a.) vs αVβ6 integrin; TGF-β bioassay; western blot and flow cytometry for αVβ6 integrin expression on primary human FLSs; immunohistochemistry; nano-LC/Chip MS-MS for serum VTN fragment quantification","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (competition assay, TGF-β bioassay, flow cytometry, MS), single lab","pmids":["33526813"],"is_preprint":false},{"year":2024,"finding":"Tumor cell-secreted VTN (vitronectin) interacts with C1qbp on the surface of tumor-associated macrophages, inhibiting phagocytosis of tumor cells and shifting macrophages towards the M2-like subtype; mechanistically, the VTN-C1qbp axis facilitates FcγRIIIA/CD16-induced Shp1 recruitment, which reduces phosphorylation of Syk.","method":"Genome-wide CRISPR screen to identify anti-phagocytic genes; knockdown functional experiments; flow cytometry for phagocytosis rate and macrophage polarization; RNA sequencing; immunoprecipitation; mass spectrometry; immunofluorescence; in vivo mouse tumor models","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — CRISPR screen discovery followed by multiple orthogonal mechanistic validations (Co-IP, MS, immunofluorescence, in vivo models) with defined signaling pathway (Shp1/Syk)","pmids":["38773982"],"is_preprint":false},{"year":2022,"finding":"FBLN2 (fibulin-2) physically binds to VTN (vitronectin) and negatively regulates its expression; VTN acts downstream of FBLN2 to mediate TGF-β1-induced fibroblast proliferation, migration, and fibrosis via FAK signaling, as overexpression of VTN partially rescued the inhibitory effects of FBLN2 knockdown.","method":"Protein immunoprecipitation assay to confirm FBLN2–VTN interaction; western blot for VTN and fibrosis markers; wound healing and CCK-8 assays; immunofluorescence for α-SMA; STRING database prediction confirmed by Co-IP","journal":"Tissue & cell","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus functional rescue experiments, single lab, two orthogonal methods","pmids":["36608640"],"is_preprint":false},{"year":1999,"finding":"Candida albicans expresses αVβ3 and αVβ5 integrin-like receptors antigenically related to vertebrate integrins that mediate adhesion to VTN (vitronectin); adhesion was inhibited by RGD peptides and anti-integrin antibodies, and VTN inhibited C. albicans adherence to a human endothelial cell line.","method":"Immunofluorescence and cytofluorimetric analysis with anti-integrin antibodies; biochemical analysis of yeast lysates; adhesion inhibition assays with RGD peptides and blocking antibodies","journal":"The Journal of infectious diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple antibody and peptide inhibition assays, functional adhesion readout, single lab","pmids":["10353874"],"is_preprint":false},{"year":2019,"finding":"Decreased circulating miR-30c regulates VTN (vitronectin) levels indirectly by targeting PAI-1 in smooth muscle cells; elevated PAI-1 (itself regulated by miR-30c) leads to increased VTN levels, establishing a miR-30c/PAI-1/VTN regulatory axis.","method":"Bioinformatic analysis; miRNA transfection; luciferase assays; qRT-PCR; western blot in SMC cells and ex vivo plasma; ELISA for PAI-1 and VTN levels","journal":"Life sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect regulatory mechanism through PAI-1, single lab, limited mechanistic depth for VTN itself","pmids":["31760103"],"is_preprint":false},{"year":2025,"finding":"VTN overexpression in pancreatic cancer cells suppresses proliferation, invasion, and migration in vitro; VTN knockdown promotes these phenotypes; VTN expression is linked to immune regulatory pathways, and VTN overexpression synergizes with anti-PD1 therapy to enhance antitumor efficacy in a syngeneic mouse model.","method":"In vitro VTN knockdown and overexpression with proliferation, invasion, and migration assays; syngeneic mouse subcutaneous tumor model with anti-PD1 combination therapy; single-cell RNA sequencing and public database analysis","journal":"Frontiers in immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional assays with KD/OE but limited mechanistic pathway placement for VTN itself, single lab","pmids":["40433359"],"is_preprint":false},{"year":2025,"finding":"Insufficient VTN expression impairs trophoblast cell migration, invasion, and tube formation; VTN overexpression upregulates HEY1 (a Notch signaling downstream target); VTN knockdown increases LC3II expression (enhanced autophagy), and HEY1 overexpression alleviates this autophagy increase, placing VTN upstream of the HEY1/autophagy pathway in trophoblast function.","method":"Functional assays (migration, invasion, tube formation) in HTR8/SVneo cells, HUVECs, and primary EVTs; transcriptome sequencing after VTN overexpression; LC3II western blot as autophagy marker; HEY1 knockdown/overexpression epistasis experiments; 3-MA autophagy inhibition rescue","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis experiments (VTN→HEY1→autophagy) with multiple cell types and pathway inhibitor rescue, single lab","pmids":["40516241"],"is_preprint":false}],"current_model":"VTN (vitronectin) is an extracellular matrix glycoprotein that acts through multiple mechanisms: its N-terminal somatomedin B (SMB) domain serves as the primary high-affinity binding site for PAI-1, thereby regulating fibrinolysis; it signals through αV-containing integrins (αVβ3, αVβ5, αVβ6) to activate downstream FAK/Src/ERK pathways promoting cell migration, invasion, and survival; in the tumor microenvironment, tumor cell-secreted VTN interacts with C1qbp on macrophages to inhibit phagocytosis via FcγRIIIA/CD16-induced Shp1 recruitment and reduced Syk phosphorylation; a VTN fragment (aa 381–397) competes with TGF-β1 for αVβ6 binding, modulating TGF-β1 bioavailability; and VTN is regulated upstream by FBLN2 and BPIFB1 interactions, with VTN itself acting upstream of HEY1/autophagy signaling in trophoblast biology."},"narrative":{"mechanistic_narrative":"VTN (vitronectin) is a secreted extracellular matrix glycoprotein that integrates protease regulation, integrin-mediated signaling, and immune modulation across tissue remodeling and cancer contexts [PMID:12437099, PMID:38773982]. Its N-terminal somatomedin B (SMB) domain provides the major high-affinity binding site for PAI-1, with an additional low-affinity site in the C-terminal region that supports formation of larger PAI-1/VTN complexes, linking VTN to fibrinolytic control [PMID:12437099]. VTN engages αV-containing integrins to drive downstream FAK/Src/ERK signaling that promotes cell migration and invasion; this axis is restrained by BPIFB1, which binds VTN, lowers its expression, and disrupts VTN–integrin αV complex formation [PMID:29123267], and VTN-driven FAK signaling acts downstream of FBLN2 to mediate TGF-β1-induced fibroblast proliferation and fibrosis [PMID:36608640]. A discrete VTN fragment (aa 381–397) binds αV β6 integrin and competitively blocks αV β6-mediated TGF-β1 activation, modulating TGF-β1 bioavailability [PMID:33526813]. In tumor biology, VTN promotes radioresistance through G2/M arrest, DNA repair, and ATM-Chk2/ATR-Chk1 activation [PMID:29568064], and tumor-secreted VTN binds C1qbp on tumor-associated macrophages to inhibit phagocytosis and promote M2-like polarization via Fc γRIIIA/CD16-induced Shp1 recruitment and reduced Syk phosphorylation [PMID:38773982]. VTN also supports trophoblast migration, invasion, and tube formation, acting upstream of HEY1 to restrain autophagy [PMID:40516241].","teleology":[{"year":1999,"claim":"Established that VTN serves as an RGD-dependent integrin ligand recognized even by αV β3/αV β5-like receptors on Candida albicans, anchoring the principle that VTN-integrin adhesion is RGD-mediated and competable.","evidence":"Antibody and RGD-peptide inhibition adhesion assays with cytofluorimetric analysis of fungal integrin-like receptors","pmids":["10353874"],"confidence":"Medium","gaps":["Did not map the human integrin signaling consequences of VTN binding","Cross-species/microbial system limits direct relevance to human VTN function"]},{"year":2002,"claim":"Localized the major high-affinity PAI-1 binding site to the N-terminal SMB domain with a secondary C-terminal site, defining the structural basis for VTN's role in PAI-1 sequestration and fibrinolytic regulation.","evidence":"Domain-deletion and peptide-competition binding-site mapping","pmids":["12437099"],"confidence":"Medium","gaps":["No quantitative affinities or structural model resolved here","Functional consequence for in vivo fibrinolysis not directly tested"]},{"year":2017,"claim":"Identified BPIFB1 as a physical VTN partner that suppresses VTN expression and VTN-integrin αV complex assembly, revealing an upstream brake on VTN-driven FAK/Src/ERK pro-migratory signaling.","evidence":"Co-IP/MS partner identification plus western blot, immunofluorescence and migration/invasion assays in NPC cells","pmids":["29123267"],"confidence":"Medium","gaps":["Mechanism by which BPIFB1 lowers VTN expression not defined","Single lab; physiological context outside NPC unclear"]},{"year":2018,"claim":"Showed VTN confers radioresistance via cell-cycle arrest, DNA repair, and ATM-Chk2/ATR-Chk1 activation, extending VTN's role from adhesion into the DNA damage response and cell survival.","evidence":"Colony formation/survival assays, cell-cycle analysis, and pathway western blots with knockdown/overexpression after irradiation","pmids":["29568064"],"confidence":"Medium","gaps":["Link between extracellular VTN and intracellular ATM/ATR activation not mechanistically bridged","Single tumor type"]},{"year":2019,"claim":"Placed VTN levels downstream of a miR-30c/PAI-1 axis, suggesting indirect transcriptional/post-transcriptional control of circulating VTN.","evidence":"miRNA transfection, luciferase, qRT-PCR, western blot and ELISA in SMCs and plasma","pmids":["31760103"],"confidence":"Low","gaps":["Regulation of VTN is indirect via PAI-1, not a direct VTN mechanism","Not independently confirmed"]},{"year":2021,"claim":"Defined a VTN fragment (aa 381–397) as a competitive ligand for αV β6 that blocks αV β6-mediated TGF-β1 activation, identifying a fragment-level mechanism for tuning TGF-β1 bioavailability.","evidence":"Competition binding assay, TGF-β bioassay, flow cytometry and serum fragment quantification by nano-LC/MS-MS in human FLSs","pmids":["33526813"],"confidence":"Medium","gaps":["Protease generating the 381–397 fragment in vivo not identified","Single lab and tissue context"]},{"year":2022,"claim":"Identified FBLN2 as a VTN-binding negative regulator and showed VTN acts downstream of FBLN2 to drive TGF-β1-induced fibroblast fibrosis via FAK, integrating VTN into a defined fibrotic signaling cascade.","evidence":"Co-IP confirmation of FBLN2-VTN interaction plus functional rescue (VTN overexpression) with wound healing, CCK-8 and α-SMA readouts","pmids":["36608640"],"confidence":"Medium","gaps":["Mechanism of FBLN2-mediated VTN downregulation unresolved","Single lab; two orthogonal methods only"]},{"year":2024,"claim":"Revealed VTN as a tumor-derived anti-phagocytic signal acting through macrophage C1qbp, defining the VTN-C1qbp/FcγRIIIA-Shp1-Syk axis that suppresses phagocytosis and promotes M2 polarization.","evidence":"Genome-wide CRISPR screen followed by Co-IP, MS, immunofluorescence, flow cytometry and in vivo mouse tumor models","pmids":["38773982"],"confidence":"High","gaps":["Structural basis of VTN-C1qbp binding not resolved","Whether SMB or integrin-binding regions mediate C1qbp engagement unknown"]},{"year":2025,"claim":"Demonstrated VTN acts upstream of HEY1 to restrain autophagy in trophoblasts, supporting migration, invasion and tube formation, extending VTN signaling into a Notch-target/autophagy circuit.","evidence":"Functional assays in HTR8/SVneo, HUVEC and primary EVTs; transcriptomics; LC3II western blot; HEY1 epistasis and 3-MA rescue","pmids":["40516241"],"confidence":"Medium","gaps":["How VTN signals to HEY1 mechanistically not defined","Direct VTN receptor in trophoblasts not identified"]},{"year":2025,"claim":"Showed VTN can act as a tumor suppressor in pancreatic cancer and synergize with anti-PD1 therapy, indicating context-dependent immune-regulatory roles.","evidence":"VTN knockdown/overexpression functional assays, syngeneic mouse model with anti-PD1, and single-cell RNA-seq","pmids":["40433359"],"confidence":"Low","gaps":["Mechanistic pathway placement for VTN's suppressive effect not defined","Opposite directionality to other cancer contexts unexplained"]},{"year":null,"claim":"How VTN's distinct functional regions (SMB/PAI-1 site, RGD integrin site, the 381–397 αV β6 fragment, and the C1qbp-binding region) are coordinately deployed across fibrinolysis, fibrosis, and immune evasion remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying structural model linking domain usage to context","Receptor/partner selection rules across tissues unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[4]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[2]}],"complexes":[],"partners":["PAI-1","SERPINE1","ITGAV","BPIFB1","FBLN2","C1QBP","ITGB6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P04004","full_name":"Vitronectin","aliases":["S-protein","Serum-spreading factor","V75"],"length_aa":478,"mass_kda":54.3,"function":"Vitronectin is a cell adhesion and spreading factor found in serum and tissues. Vitronectin interact with glycosaminoglycans and proteoglycans. Is recognized by certain members of the integrin family and serves as a cell-to-substrate adhesion molecule. Inhibitor of the membrane-damaging effect of the terminal cytolytic complement pathway Somatomedin-B is a growth hormone-dependent serum factor with protease-inhibiting activity","subcellular_location":"Parasitophorous vacuole","url":"https://www.uniprot.org/uniprotkb/P04004/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VTN","classification":"Not Classified","n_dependent_lines":18,"n_total_lines":1208,"dependency_fraction":0.014900662251655629},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/VTN","total_profiled":1310},"omim":[{"mim_id":"615825","title":"SUSHI DOMAIN-CONTAINING PROTEIN 2; SUSD2","url":"https://www.omim.org/entry/615825"},{"mim_id":"613504","title":"ZINC FINGER FYVE DOMAIN-CONTAINING PROTEIN 21; ZFYVE21","url":"https://www.omim.org/entry/613504"},{"mim_id":"607732","title":"STERILE ALPHA AND TIR MOTIFS-CONTAINING PROTEIN 1; SARM1","url":"https://www.omim.org/entry/607732"},{"mim_id":"606018","title":"EGF-LIKE REPEATS- AND DISCOIDIN I-LIKE DOMAINS-CONTAINING PROTEIN 3; EDIL3","url":"https://www.omim.org/entry/606018"},{"mim_id":"602182","title":"ECTONUCLEOTIDE PYROPHOSPHATASE/PHOSPHODIESTERASE 3; ENPP3","url":"https://www.omim.org/entry/602182"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":5644.8}],"url":"https://www.proteinatlas.org/search/VTN"},"hgnc":{"alias_symbol":["VN"],"prev_symbol":[]},"alphafold":{"accession":"P04004","domains":[{"cath_id":"4.10.410","chopping":"23-59","consensus_level":"medium","plddt":82.1714,"start":23,"end":59},{"cath_id":"2.110.10.10","chopping":"162-356_430-469","consensus_level":"high","plddt":86.9616,"start":162,"end":469}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P04004","model_url":"https://alphafold.ebi.ac.uk/files/AF-P04004-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P04004-F1-predicted_aligned_error_v6.png","plddt_mean":67.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VTN","jax_strain_url":"https://www.jax.org/strain/search?query=VTN"},"sequence":{"accession":"P04004","fasta_url":"https://rest.uniprot.org/uniprotkb/P04004.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P04004/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P04004"}},"corpus_meta":[{"pmid":"31830338","id":"PMC_31830338","title":"A Dual-Functional Conductive Framework Embedded with TiN-VN Heterostructures for Highly Efficient Polysulfide and Lithium Regulation toward Stable Li-S Full Batteries.","date":"2019","source":"Advanced materials (Deerfield Beach, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/31830338","citation_count":150,"is_preprint":false},{"pmid":"25591066","id":"PMC_25591066","title":"Discovery and development of Galeterone (TOK-001 or VN/124-1) for the treatment of all stages of prostate cancer.","date":"2015","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25591066","citation_count":149,"is_preprint":false},{"pmid":"2999288","id":"PMC_2999288","title":"Diversity in the germline antibody repertoire. 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3beta-hydroxy-17-(1H-1,2,3-triazol-1-yl)androsta-5,16-diene (VN/87-1), a potent androgen synthesis inhibitor, in mice.","date":"2001","source":"The Journal of steroid biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11595504","citation_count":7,"is_preprint":false},{"pmid":"37441972","id":"PMC_37441972","title":"Dual interfaces and confinements on Fe2N@Fe3O4/VN heterojunction toward high-efficient lithium storage.","date":"2023","source":"Journal of colloid and interface science","url":"https://pubmed.ncbi.nlm.nih.gov/37441972","citation_count":6,"is_preprint":false},{"pmid":"24726842","id":"PMC_24726842","title":"VN/14-1 induces ER stress and autophagy in HP-LTLC human breast cancer cells and has excellent oral pharmacokinetic profile in female Sprague Dawley rats.","date":"2014","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24726842","citation_count":6,"is_preprint":false},{"pmid":"11460881","id":"PMC_11460881","title":"Homozygous VN (677C to T) and d/D (2756G to A) variants in the methylenetetrahydrofolate and methionine synthase genes in a case of hyperhomocysteinemia with stroke at young age.","date":"2001","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11460881","citation_count":6,"is_preprint":false},{"pmid":"15380716","id":"PMC_15380716","title":"Quantification of a novel retinoic acid metabolism inhibitor, 4-(1H-imidazol-1-yl)retinoic acid (VN/14-1RA) and other retinoids in rat plasma by liquid chromatography with diode-array detection.","date":"2004","source":"Journal of chromatography. 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Supercapacitor.","date":"2023","source":"ACS applied materials & interfaces","url":"https://pubmed.ncbi.nlm.nih.gov/37922146","citation_count":0,"is_preprint":false},{"pmid":"40258463","id":"PMC_40258463","title":"Establishing g-C3N4-Vn/FeIn2S4 heterostructure for in-situ H2O2 generation and activation to degrade tetracycline in photo-Fenton process under visible light.","date":"2025","source":"Environmental research","url":"https://pubmed.ncbi.nlm.nih.gov/40258463","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":25816,"output_tokens":2883,"usd":0.060346,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10248,"output_tokens":3570,"usd":0.070245,"stage2_stop_reason":"end_turn"},"total_usd":0.130591,"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\": 2017,\n      \"finding\": \"BPIFB1 (LPLUNC1) physically interacts with VTN (vitronectin) and reduces VTN expression and formation of the VTN-integrin αV complex in NPC cells, leading to inhibition of the FAK/Src/ERK signalling pathway and suppression of cell migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation coupled with mass spectrometry to identify BPIFB1-binding proteins; western blotting and immunofluorescence to assess VTN expression and complex formation; functional migration/invasion assays\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP + MS identification, plus functional assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"29123267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"VTN (vitronectin) promotes radioresistance in NPC cells by inducing cell proliferation and survival, G2/M phase arrest, DNA repair, and activation of the ATM-Chk2 and ATR-Chk1 pathways with anti-apoptotic effects after ionizing radiation; BPIFB1 inhibits this VTN-mediated radioresistance.\",\n      \"method\": \"Colony formation and cell survival assays; western blotting for pathway activation (ATM-Chk2, ATR-Chk1); cell cycle analysis; knockdown/overexpression experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays with pathway readouts, single lab, builds on prior interaction data\",\n      \"pmids\": [\"29568064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PAI-1 binds to VTN (vitronectin); the major high-affinity PAI-1 binding site on VTN is localized within the N-terminal somatomedin B (SMB) domain of VTN, with at least one additional low-affinity PAI-1 binding site in the C-terminal region of VTN involved in forming larger PAI-1/VTN complexes.\",\n      \"method\": \"Binding site mapping using domain-deletion and peptide competition assays; biochemical interaction studies\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping approach with multiple methods described in mini-review summarizing prior experimental work, replicated finding across studies\",\n      \"pmids\": [\"12437099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A VTN fragment (amino acids 381–397) interacts with αVβ6 integrin and competitively prevents TGF-β1 activation mediated by αVβ6 in human fibroblast-like synoviocytes, thereby modulating TGF-β1 bioavailability and downstream fibrotic signaling.\",\n      \"method\": \"Competition binding assay for VTN(381-397 a.a.) vs αVβ6 integrin; TGF-β bioassay; western blot and flow cytometry for αVβ6 integrin expression on primary human FLSs; immunohistochemistry; nano-LC/Chip MS-MS for serum VTN fragment quantification\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (competition assay, TGF-β bioassay, flow cytometry, MS), single lab\",\n      \"pmids\": [\"33526813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Tumor cell-secreted VTN (vitronectin) interacts with C1qbp on the surface of tumor-associated macrophages, inhibiting phagocytosis of tumor cells and shifting macrophages towards the M2-like subtype; mechanistically, the VTN-C1qbp axis facilitates FcγRIIIA/CD16-induced Shp1 recruitment, which reduces phosphorylation of Syk.\",\n      \"method\": \"Genome-wide CRISPR screen to identify anti-phagocytic genes; knockdown functional experiments; flow cytometry for phagocytosis rate and macrophage polarization; RNA sequencing; immunoprecipitation; mass spectrometry; immunofluorescence; in vivo mouse tumor models\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — CRISPR screen discovery followed by multiple orthogonal mechanistic validations (Co-IP, MS, immunofluorescence, in vivo models) with defined signaling pathway (Shp1/Syk)\",\n      \"pmids\": [\"38773982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FBLN2 (fibulin-2) physically binds to VTN (vitronectin) and negatively regulates its expression; VTN acts downstream of FBLN2 to mediate TGF-β1-induced fibroblast proliferation, migration, and fibrosis via FAK signaling, as overexpression of VTN partially rescued the inhibitory effects of FBLN2 knockdown.\",\n      \"method\": \"Protein immunoprecipitation assay to confirm FBLN2–VTN interaction; western blot for VTN and fibrosis markers; wound healing and CCK-8 assays; immunofluorescence for α-SMA; STRING database prediction confirmed by Co-IP\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus functional rescue experiments, single lab, two orthogonal methods\",\n      \"pmids\": [\"36608640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Candida albicans expresses αVβ3 and αVβ5 integrin-like receptors antigenically related to vertebrate integrins that mediate adhesion to VTN (vitronectin); adhesion was inhibited by RGD peptides and anti-integrin antibodies, and VTN inhibited C. albicans adherence to a human endothelial cell line.\",\n      \"method\": \"Immunofluorescence and cytofluorimetric analysis with anti-integrin antibodies; biochemical analysis of yeast lysates; adhesion inhibition assays with RGD peptides and blocking antibodies\",\n      \"journal\": \"The Journal of infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple antibody and peptide inhibition assays, functional adhesion readout, single lab\",\n      \"pmids\": [\"10353874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Decreased circulating miR-30c regulates VTN (vitronectin) levels indirectly by targeting PAI-1 in smooth muscle cells; elevated PAI-1 (itself regulated by miR-30c) leads to increased VTN levels, establishing a miR-30c/PAI-1/VTN regulatory axis.\",\n      \"method\": \"Bioinformatic analysis; miRNA transfection; luciferase assays; qRT-PCR; western blot in SMC cells and ex vivo plasma; ELISA for PAI-1 and VTN levels\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect regulatory mechanism through PAI-1, single lab, limited mechanistic depth for VTN itself\",\n      \"pmids\": [\"31760103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VTN overexpression in pancreatic cancer cells suppresses proliferation, invasion, and migration in vitro; VTN knockdown promotes these phenotypes; VTN expression is linked to immune regulatory pathways, and VTN overexpression synergizes with anti-PD1 therapy to enhance antitumor efficacy in a syngeneic mouse model.\",\n      \"method\": \"In vitro VTN knockdown and overexpression with proliferation, invasion, and migration assays; syngeneic mouse subcutaneous tumor model with anti-PD1 combination therapy; single-cell RNA sequencing and public database analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional assays with KD/OE but limited mechanistic pathway placement for VTN itself, single lab\",\n      \"pmids\": [\"40433359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Insufficient VTN expression impairs trophoblast cell migration, invasion, and tube formation; VTN overexpression upregulates HEY1 (a Notch signaling downstream target); VTN knockdown increases LC3II expression (enhanced autophagy), and HEY1 overexpression alleviates this autophagy increase, placing VTN upstream of the HEY1/autophagy pathway in trophoblast function.\",\n      \"method\": \"Functional assays (migration, invasion, tube formation) in HTR8/SVneo cells, HUVECs, and primary EVTs; transcriptome sequencing after VTN overexpression; LC3II western blot as autophagy marker; HEY1 knockdown/overexpression epistasis experiments; 3-MA autophagy inhibition rescue\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis experiments (VTN→HEY1→autophagy) with multiple cell types and pathway inhibitor rescue, single lab\",\n      \"pmids\": [\"40516241\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VTN (vitronectin) is an extracellular matrix glycoprotein that acts through multiple mechanisms: its N-terminal somatomedin B (SMB) domain serves as the primary high-affinity binding site for PAI-1, thereby regulating fibrinolysis; it signals through αV-containing integrins (αVβ3, αVβ5, αVβ6) to activate downstream FAK/Src/ERK pathways promoting cell migration, invasion, and survival; in the tumor microenvironment, tumor cell-secreted VTN interacts with C1qbp on macrophages to inhibit phagocytosis via FcγRIIIA/CD16-induced Shp1 recruitment and reduced Syk phosphorylation; a VTN fragment (aa 381–397) competes with TGF-β1 for αVβ6 binding, modulating TGF-β1 bioavailability; and VTN is regulated upstream by FBLN2 and BPIFB1 interactions, with VTN itself acting upstream of HEY1/autophagy signaling in trophoblast biology.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VTN (vitronectin) is a secreted extracellular matrix glycoprotein that integrates protease regulation, integrin-mediated signaling, and immune modulation across tissue remodeling and cancer contexts [#2, #4]. Its N-terminal somatomedin B (SMB) domain provides the major high-affinity binding site for PAI-1, with an additional low-affinity site in the C-terminal region that supports formation of larger PAI-1/VTN complexes, linking VTN to fibrinolytic control [#2]. VTN engages αV-containing integrins to drive downstream FAK/Src/ERK signaling that promotes cell migration and invasion; this axis is restrained by BPIFB1, which binds VTN, lowers its expression, and disrupts VTN–integrin αV complex formation [#0], and VTN-driven FAK signaling acts downstream of FBLN2 to mediate TGF-β1-induced fibroblast proliferation and fibrosis [#5]. A discrete VTN fragment (aa 381–397) binds αV β6 integrin and competitively blocks αV β6-mediated TGF-β1 activation, modulating TGF-β1 bioavailability [#3]. In tumor biology, VTN promotes radioresistance through G2/M arrest, DNA repair, and ATM-Chk2/ATR-Chk1 activation [#1], and tumor-secreted VTN binds C1qbp on tumor-associated macrophages to inhibit phagocytosis and promote M2-like polarization via Fc γRIIIA/CD16-induced Shp1 recruitment and reduced Syk phosphorylation [#4]. VTN also supports trophoblast migration, invasion, and tube formation, acting upstream of HEY1 to restrain autophagy [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that VTN serves as an RGD-dependent integrin ligand recognized even by αV β3/αV β5-like receptors on Candida albicans, anchoring the principle that VTN-integrin adhesion is RGD-mediated and competable.\",\n      \"evidence\": \"Antibody and RGD-peptide inhibition adhesion assays with cytofluorimetric analysis of fungal integrin-like receptors\",\n      \"pmids\": [\"10353874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not map the human integrin signaling consequences of VTN binding\", \"Cross-species/microbial system limits direct relevance to human VTN function\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Localized the major high-affinity PAI-1 binding site to the N-terminal SMB domain with a secondary C-terminal site, defining the structural basis for VTN's role in PAI-1 sequestration and fibrinolytic regulation.\",\n      \"evidence\": \"Domain-deletion and peptide-competition binding-site mapping\",\n      \"pmids\": [\"12437099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No quantitative affinities or structural model resolved here\", \"Functional consequence for in vivo fibrinolysis not directly tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified BPIFB1 as a physical VTN partner that suppresses VTN expression and VTN-integrin αV complex assembly, revealing an upstream brake on VTN-driven FAK/Src/ERK pro-migratory signaling.\",\n      \"evidence\": \"Co-IP/MS partner identification plus western blot, immunofluorescence and migration/invasion assays in NPC cells\",\n      \"pmids\": [\"29123267\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which BPIFB1 lowers VTN expression not defined\", \"Single lab; physiological context outside NPC unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed VTN confers radioresistance via cell-cycle arrest, DNA repair, and ATM-Chk2/ATR-Chk1 activation, extending VTN's role from adhesion into the DNA damage response and cell survival.\",\n      \"evidence\": \"Colony formation/survival assays, cell-cycle analysis, and pathway western blots with knockdown/overexpression after irradiation\",\n      \"pmids\": [\"29568064\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between extracellular VTN and intracellular ATM/ATR activation not mechanistically bridged\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed VTN levels downstream of a miR-30c/PAI-1 axis, suggesting indirect transcriptional/post-transcriptional control of circulating VTN.\",\n      \"evidence\": \"miRNA transfection, luciferase, qRT-PCR, western blot and ELISA in SMCs and plasma\",\n      \"pmids\": [\"31760103\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Regulation of VTN is indirect via PAI-1, not a direct VTN mechanism\", \"Not independently confirmed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a VTN fragment (aa 381–397) as a competitive ligand for αV β6 that blocks αV β6-mediated TGF-β1 activation, identifying a fragment-level mechanism for tuning TGF-β1 bioavailability.\",\n      \"evidence\": \"Competition binding assay, TGF-β bioassay, flow cytometry and serum fragment quantification by nano-LC/MS-MS in human FLSs\",\n      \"pmids\": [\"33526813\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Protease generating the 381–397 fragment in vivo not identified\", \"Single lab and tissue context\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified FBLN2 as a VTN-binding negative regulator and showed VTN acts downstream of FBLN2 to drive TGF-β1-induced fibroblast fibrosis via FAK, integrating VTN into a defined fibrotic signaling cascade.\",\n      \"evidence\": \"Co-IP confirmation of FBLN2-VTN interaction plus functional rescue (VTN overexpression) with wound healing, CCK-8 and α-SMA readouts\",\n      \"pmids\": [\"36608640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of FBLN2-mediated VTN downregulation unresolved\", \"Single lab; two orthogonal methods only\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed VTN as a tumor-derived anti-phagocytic signal acting through macrophage C1qbp, defining the VTN-C1qbp/FcγRIIIA-Shp1-Syk axis that suppresses phagocytosis and promotes M2 polarization.\",\n      \"evidence\": \"Genome-wide CRISPR screen followed by Co-IP, MS, immunofluorescence, flow cytometry and in vivo mouse tumor models\",\n      \"pmids\": [\"38773982\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of VTN-C1qbp binding not resolved\", \"Whether SMB or integrin-binding regions mediate C1qbp engagement unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated VTN acts upstream of HEY1 to restrain autophagy in trophoblasts, supporting migration, invasion and tube formation, extending VTN signaling into a Notch-target/autophagy circuit.\",\n      \"evidence\": \"Functional assays in HTR8/SVneo, HUVEC and primary EVTs; transcriptomics; LC3II western blot; HEY1 epistasis and 3-MA rescue\",\n      \"pmids\": [\"40516241\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How VTN signals to HEY1 mechanistically not defined\", \"Direct VTN receptor in trophoblasts not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed VTN can act as a tumor suppressor in pancreatic cancer and synergize with anti-PD1 therapy, indicating context-dependent immune-regulatory roles.\",\n      \"evidence\": \"VTN knockdown/overexpression functional assays, syngeneic mouse model with anti-PD1, and single-cell RNA-seq\",\n      \"pmids\": [\"40433359\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanistic pathway placement for VTN's suppressive effect not defined\", \"Opposite directionality to other cancer contexts unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How VTN's distinct functional regions (SMB/PAI-1 site, RGD integrin site, the 381–397 αV β6 fragment, and the C1qbp-binding region) are coordinately deployed across fibrinolysis, fibrosis, and immune evasion remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying structural model linking domain usage to context\", \"Receptor/partner selection rules across tissues unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PAI-1\", \"SERPINE1\", \"ITGAV\", \"BPIFB1\", \"FBLN2\", \"C1QBP\", \"ITGB6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}