{"gene":"MVP","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":1995,"finding":"LRP (Lung Resistance-related Protein), a 110-kD protein associated with multidrug resistance, was identified as the human major vault protein (MVP) by cloning and amino acid sequence analysis showing 87.7% identity with rat major vault protein. The LRP/MVP gene was localized to chromosome 16.","method":"cDNA cloning, amino acid sequence analysis, chromosome localization","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 1 — foundational cloning and sequence identity determination, highly cited original discovery","pmids":["7585126"],"is_preprint":false},{"year":1996,"finding":"MVP (LRP) protein is broadly distributed in normal human tissues and tumors, with high expression in bronchus, digestive tract, renal proximal tubules, keratinocytes, macrophages, and adrenal cortex. Its distribution parallels that of vault organelles across species, supporting a conserved eukaryotic function.","method":"Immunohistochemistry on frozen tissue sections using monoclonal antibody LRP-56","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 — systematic immunohistochemical localization across tissues, single lab","pmids":["8774142"],"is_preprint":false},{"year":1999,"finding":"The 193-kD vault protein (VPARP) was identified as a novel poly(ADP-ribose) polymerase that interacts with MVP in a yeast two-hybrid screen. VPARP's catalytic domain can catalyze poly(ADP-ribosyl)ation, and purified vault particles retain this enzymatic activity. Crucially, MVP itself is a substrate for this vault-associated PARP activity. VPARP is incorporated into vault particles within 1.5h of biosynthesis, while MVP incorporation takes >4h.","method":"Yeast two-hybrid screen, peptide sequence analysis, in vitro poly(ADP-ribosyl)ation assay, immunoprecipitation, immunofluorescence, pulse-chase labeling","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 — reconstituted enzymatic activity, multiple orthogonal methods, identification of MVP as substrate","pmids":["10477748"],"is_preprint":false},{"year":2004,"finding":"A novel 12 bp cis-activating element (invMED1) in the MVP gene promoter (at position -148/-143) was characterized, and the nuclear factor LRP130 was identified as the binding protein. LRP130 binding intensity correlates with endogenous MVP gene expression. siRNA knockdown and transcriptional decoy experiments demonstrated that the invMED1/LRP130 couple regulates endogenous MVP gene transcriptional activity.","method":"EMSA, promoter deletion analysis, siRNA knockdown, transcriptional decoy, reporter assays in human cancer cell lines","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays (siRNA, decoys, reporter) in two unrelated cell lines, single lab","pmids":["15272088"],"is_preprint":false},{"year":2005,"finding":"Newly synthesized MVP incorporates into vault particles only after >4 hours, whereas VPARP incorporates within 1.5 hours. Expression of MVP alone in E. coli produces particles with distinct vault morphology, demonstrating MVP is sufficient for self-assembly. The C-terminal region of VPARP (lacking PARP activity) co-sediments with MVP particles, indicating the PARP domain is dispensable for interaction with MVP.","method":"Immunoprecipitation, pulse-chase labeling, heterologous expression in E. coli with electron microscopy of particles, sedimentation assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 — reconstitution of vault morphology from MVP alone in bacteria, supported by pulse-chase and co-sedimentation","pmids":["15567158"],"is_preprint":false},{"year":2009,"finding":"Severe tumor hypoxia is associated with high MVP expression in clinical cervical tumors, and MVP over-expression is linked to chemo-resistance. Tumors over-expressing MVP showed increased angiogenesis, suggesting hypoxia induces a pathway of chemo- and radiation resistance through MVP upregulation.","method":"Immunohistochemistry and tumor oxygenation measurement in 43 consecutive clinical cervical carcinoma patients","journal":"Radiation oncology","confidence":"Low","confidence_rationale":"Tier 3 — clinical correlation study, single institution, no direct mechanistic dissection of the hypoxia-MVP pathway","pmids":["19660100"],"is_preprint":false},{"year":2010,"finding":"MVP interacts with YPEL4 (a Yippee domain nuclear protein) and inhibits YPEL4-mediated activation of Elk-1 in the MAPK signaling pathway. The interaction was demonstrated in mammalian cells and shown to suppress ERK signal pathway activity downstream of YPEL4.","method":"Yeast two-hybrid screen, mammalian two-hybrid assay, GST pull-down, co-immunoprecipitation, immunocytochemistry, Elk-1 reporter assay","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal binding assays plus functional reporter assay, single lab","pmids":["20555386"],"is_preprint":false},{"year":2017,"finding":"MVP mediates the selective sorting of miR-193a (a tumor suppressor miRNA) into exosomes. miR-193a physically interacts with MVP, and knockout of MVP causes miR-193a to accumulate in donor cells instead of being exported into exosomes, leading to G1 cell cycle arrest and inhibition of tumor progression via targeting of Caprin1 (which upregulates Ccnd2 and c-Myc).","method":"Knockout mouse models, RNA immunoprecipitation, exosome fractionation, cell cycle analysis, tumor xenograft models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout with defined molecular and cellular phenotype, interaction demonstrated biochemically, replicated in vivo","pmids":["28211508"],"is_preprint":false},{"year":2018,"finding":"Zebrafish MVP interacts with TBK1 (a pivotal kinase in the IFN induction pathway) and recruits it from a diffuse cytoplasmic distribution to an aggregated state, then mediates lysosome-dependent degradation of TBK1, thereby suppressing IFN production and IFN-stimulated gene expression.","method":"Co-immunoprecipitation, overexpression, viral infection assays, lysosome inhibition experiments, fluorescence microscopy of TBK1 redistribution","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical interaction plus functional degradation assay with lysosome inhibitor, zebrafish ortholog","pmids":["30530482"],"is_preprint":false},{"year":2021,"finding":"MVP negatively regulates osteoclastogenesis and bone resorption by inhibiting calcineurin-NFATc1 signaling. MVP-deficient mice (total body and monocyte-specific knockouts) exhibit osteoporosis-like phenotypes with enhanced osteoclast differentiation. Mechanistically, MVP deficiency enhances calcineurin-NFATc1 signaling, promotes NFATc1 activity and calcium oscillations; calcineurin inhibition with FK506 corrects the enhanced osteoclastogenesis in MVP-deficient cells. MVP re-expression in knockout cells rescues calcineurin expression.","method":"Conditional and total body MVP knockout mice, micro-CT, bone histomorphometry, in vitro osteoclast differentiation assays, calcineurin inhibitor treatment (FK506), AAV-mediated MVP overexpression, NFATc1 activity assays","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function in vivo and in vitro with defined pathway rescue, multiple orthogonal methods","pmids":["34158848"],"is_preprint":false},{"year":2022,"finding":"MVP and importin β2 cooperate to mediate nuclear import of the protein tyrosine phosphatase PTPN18 in breast cancer cells. Nuclear PTPN18 (but not cytoplasmic PTPN18) dephosphorylates ETS1 and promotes its degradation, and suppresses TGF-β signaling and epithelial-to-mesenchymal transition. MVP thus acts as a nuclear transport facilitator that determines the subcellular localization and consequent function of PTPN18.","method":"Co-immunoprecipitation, subcellular fractionation, ectopic expression, knockdown studies, phosphatase activity assays, metastasis assays in vivo","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical interaction with functional consequence demonstrated, single lab","pmids":["35982039"],"is_preprint":false}],"current_model":"MVP (Major Vault Protein) is the primary structural component of vault ribonucleoprotein particles, sufficient for self-assembly into vault morphology; it serves as a substrate for the vault-associated PARP (VPARP), mediates selective exosomal sorting of tumor suppressor miRNAs (e.g., miR-193a), facilitates nuclear import of signaling proteins (e.g., PTPN18) together with importin β2, negatively regulates osteoclastogenesis via calcineurin-NFATc1 pathway inhibition, suppresses TBK1-dependent IFN production through lysosome-dependent TBK1 degradation, and modulates MAPK signaling by interacting with and inhibiting YPEL4-mediated Elk-1 activation."},"narrative":{"teleology":[{"year":1995,"claim":"Establishing MVP's molecular identity resolved that the lung resistance-related protein (LRP) associated with multidrug resistance was in fact the human major vault protein, placing vault biology in a clinical context.","evidence":"cDNA cloning and amino acid sequence comparison showing 87.7% identity to rat MVP, with chromosomal localization to 16p","pmids":["7585126"],"confidence":"High","gaps":["Mechanism linking MVP to drug resistance undefined","No direct functional assays performed"]},{"year":1999,"claim":"Identification of VPARP as a vault-intrinsic enzyme that poly(ADP-ribosyl)ates MVP itself revealed the first post-translational regulatory circuit within vault particles.","evidence":"Yeast two-hybrid screen, in vitro poly(ADP-ribosyl)ation assay on purified vaults, pulse-chase incorporation kinetics","pmids":["10477748"],"confidence":"High","gaps":["Functional consequence of MVP ADP-ribosylation unknown","Relevant cellular stimuli triggering VPARP activity not identified"]},{"year":2005,"claim":"Demonstration that heterologous expression of MVP alone produces particles with vault morphology established MVP as both necessary and sufficient for vault assembly, separating scaffold function from accessory components.","evidence":"Recombinant MVP expression in E. coli with electron microscopy confirming vault-like particle formation","pmids":["15567158"],"confidence":"High","gaps":["Structural determinants within MVP that drive self-assembly not mapped","Role of vRNA and TEP1 in particle stability not resolved"]},{"year":2010,"claim":"The finding that MVP binds YPEL4 and inhibits Elk-1 activation provided the first evidence that MVP modulates a canonical signal transduction cascade (MAPK/ERK pathway).","evidence":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, and Elk-1 reporter assays in mammalian cells","pmids":["20555386"],"confidence":"Medium","gaps":["Physiological context of MVP–YPEL4 interaction not established in vivo","Stoichiometry and whether interaction requires intact vaults unknown"]},{"year":2017,"claim":"Discovery that MVP selectively sorts miR-193a into exosomes linked vault biology to intercellular RNA trafficking and tumor suppression, showing that MVP loss causes miR-193a retention and G1 arrest in donor cells.","evidence":"MVP-knockout mice, RNA immunoprecipitation, exosome fractionation, tumor xenograft models","pmids":["28211508"],"confidence":"High","gaps":["RNA sequence or structural determinants recognized by MVP for cargo selection not defined","Breadth of miRNA cargo beyond miR-193a not systematically profiled"]},{"year":2018,"claim":"Demonstration that MVP recruits TBK1 for lysosomal degradation, thereby dampening IFN production, revealed an immunoregulatory role and a mechanism coupling vault particles to innate immune signaling.","evidence":"Co-immunoprecipitation, lysosome inhibitor rescue of TBK1 levels, fluorescence imaging of TBK1 redistribution in zebrafish","pmids":["30530482"],"confidence":"Medium","gaps":["Whether mammalian MVP employs the same lysosomal degradation route not confirmed","Adaptor or ubiquitin signals linking MVP–TBK1 to lysosomes not identified"]},{"year":2021,"claim":"Genetic loss-of-function studies in MVP-knockout mice established MVP as a negative regulator of osteoclastogenesis through inhibition of calcineurin–NFATc1 signaling, connecting vault biology to bone homeostasis.","evidence":"Total-body and monocyte-specific MVP knockout mice, micro-CT, FK506 rescue of enhanced osteoclast differentiation, AAV-mediated rescue","pmids":["34158848"],"confidence":"High","gaps":["Direct binding interface between MVP and calcineurin not mapped","Whether vault particle integrity is required for calcineurin inhibition unknown"]},{"year":2022,"claim":"Identification of MVP as a cofactor for importin-β2-dependent nuclear import of PTPN18 expanded MVP's functional repertoire to include nucleocytoplasmic transport of signaling intermediates.","evidence":"Co-immunoprecipitation, subcellular fractionation, knockdown and overexpression studies, in vivo metastasis assays in breast cancer models","pmids":["35982039"],"confidence":"Medium","gaps":["Whether MVP participates in nuclear import of other cargoes beyond PTPN18 not tested","Structural basis of MVP–importin-β2 cooperation not resolved"]},{"year":null,"claim":"A unifying model explaining how MVP coordinates its diverse signaling roles — miRNA sorting, nuclear transport, kinase degradation, and calcineurin inhibition — and whether these functions require intact vault particles or free MVP subunits, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of full-length human vault with bound cargo","Vault-dependent versus vault-independent MVP functions not delineated","Upstream signals controlling MVP expression or vault disassembly poorly characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[10,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,9]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[7]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[10]}],"complexes":["Vault ribonucleoprotein particle"],"partners":["VPARP","YPEL4","TBK1","PTPN18","KPNB1","CAPRIN1"],"other_free_text":[]},"mechanistic_narrative":"MVP is the principal structural subunit of vault ribonucleoprotein particles, and its expression alone is sufficient to drive self-assembly of vault-like structures [PMID:15567158]. Beyond its architectural role, MVP functions as a poly(ADP-ribosyl)ation substrate of the vault-associated PARP (VPARP) [PMID:10477748], mediates selective exosomal sorting of the tumor-suppressor miR-193a to regulate cell cycle progression [PMID:28211508], facilitates importin-β2-dependent nuclear import of signaling effectors such as PTPN18 [PMID:35982039], negatively regulates osteoclastogenesis by inhibiting calcineurin–NFATc1 signaling [PMID:34158848], and suppresses TBK1-dependent interferon production through lysosome-mediated TBK1 degradation [PMID:30530482]. MVP also modulates MAPK signaling by binding YPEL4 and inhibiting Elk-1 activation [PMID:20555386]."},"prefetch_data":{"uniprot":{"accession":"Q14764","full_name":"Major vault protein","aliases":["Lung resistance-related protein"],"length_aa":893,"mass_kda":99.3,"function":"Required for normal vault structure. Vaults are multi-subunit structures that may act as scaffolds for proteins involved in signal transduction. Vaults may also play a role in nucleo-cytoplasmic transport. Down-regulates IFNG-mediated STAT1 signaling and subsequent activation of JAK. Down-regulates SRC activity and signaling through MAP kinases","subcellular_location":"Cytoplasm; Nucleus, nuclear pore complex; Cytoplasm, perinuclear region","url":"https://www.uniprot.org/uniprotkb/Q14764/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MVP","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MVP","total_profiled":1310},"omim":[{"mim_id":"620980","title":"ZINC FINGER PROTEIN 414; ZNF414","url":"https://www.omim.org/entry/620980"},{"mim_id":"614938","title":"VAULT RNA 2-1; VTRNA2-1","url":"https://www.omim.org/entry/614938"},{"mim_id":"614819","title":"WEILL-MARCHESANI SYNDROME 3; WMS3","url":"https://www.omim.org/entry/614819"},{"mim_id":"613903","title":"ZINC FINGER PROTEIN 540; ZNF540","url":"https://www.omim.org/entry/613903"},{"mim_id":"612697","title":"VAULT RNA 1-3; VTRNA1-3","url":"https://www.omim.org/entry/612697"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MVP"},"hgnc":{"alias_symbol":["LRP","VAULT1"],"prev_symbol":[]},"alphafold":{"accession":"Q14764","domains":[{"cath_id":"2.30.30.560","chopping":"1-111","consensus_level":"medium","plddt":86.6954,"start":1,"end":111},{"cath_id":"2.30.30.550","chopping":"113-164","consensus_level":"medium","plddt":90.3248,"start":113,"end":164},{"cath_id":"2.30.30.550","chopping":"166-216","consensus_level":"medium","plddt":91.1043,"start":166,"end":216},{"cath_id":"2.30.30.550","chopping":"218-272","consensus_level":"medium","plddt":90.1013,"start":218,"end":272},{"cath_id":"2.30.30.560","chopping":"273-322","consensus_level":"medium","plddt":88.5714,"start":273,"end":322},{"cath_id":"2.30.30.550","chopping":"323-342_351-378","consensus_level":"medium","plddt":87.7146,"start":323,"end":378},{"cath_id":"3.30.479.30","chopping":"501-607_622-646","consensus_level":"medium","plddt":86.68,"start":501,"end":646}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14764","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14764-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14764-F1-predicted_aligned_error_v6.png","plddt_mean":81.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MVP","jax_strain_url":"https://www.jax.org/strain/search?query=MVP"},"sequence":{"accession":"Q14764","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14764.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14764/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14764"}},"corpus_meta":[{"pmid":"7585126","id":"PMC_7585126","title":"The 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research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28211508","id":"PMC_28211508","title":"MVP-mediated exosomal sorting of miR-193a promotes colon cancer progression.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28211508","citation_count":390,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10477748","id":"PMC_10477748","title":"The 193-kD vault protein, VPARP, is a novel poly(ADP-ribose) polymerase.","date":"1999","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10477748","citation_count":339,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27342126","id":"PMC_27342126","title":"Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27342126","citation_count":306,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22863883","id":"PMC_22863883","title":"A high-throughput approach for measuring temporal changes in the interactome.","date":"2012","source":"Nature methods","url":"https://pubmed.ncbi.nlm.nih.gov/22863883","citation_count":273,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35031058","id":"PMC_35031058","title":"EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3.","date":"2022","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35031058","citation_count":257,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12576456","id":"PMC_12576456","title":"RNA expression of breast cancer resistance protein, lung resistance-related protein, multidrug resistance-associated proteins 1 and 2, and multidrug resistance gene 1 in breast cancer: correlation with chemotherapeutic response.","date":"2003","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/12576456","citation_count":248,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19199708","id":"PMC_19199708","title":"Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).","date":"2009","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/19199708","citation_count":237,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20458337","id":"PMC_20458337","title":"MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.","date":"2010","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20458337","citation_count":221,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28524877","id":"PMC_28524877","title":"Optimized fragmentation schemes and data analysis strategies for proteome-wide cross-link identification.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28524877","citation_count":221,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26618866","id":"PMC_26618866","title":"∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26618866","citation_count":209,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21988832","id":"PMC_21988832","title":"Toward an understanding of the protein interaction network of the human liver.","date":"2011","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/21988832","citation_count":207,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24067654","id":"PMC_24067654","title":"Adaptor complex AP2/PICALM, through interaction with LC3, targets Alzheimer's APP-CTF for terminal degradation via autophagy.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24067654","citation_count":201,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8774142","id":"PMC_8774142","title":"Broad distribution of the multidrug resistance-related vault lung resistance protein in normal human tissues and tumors.","date":"1996","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/8774142","citation_count":182,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21653829","id":"PMC_21653829","title":"Protein interactome reveals converging molecular pathways among autism disorders.","date":"2011","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21653829","citation_count":180,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30711629","id":"PMC_30711629","title":"MET Inhibitors Promote Liver Tumor Evasion of the Immune Response by Stabilizing PDL1.","date":"2019","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/30711629","citation_count":165,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15588985","id":"PMC_15588985","title":"Substrate-trapping techniques in the identification of cellular PTP targets.","date":"2005","source":"Methods (San Diego, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/15588985","citation_count":146,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":91767,"output_tokens":2412,"usd":0.239896,"retried_sync":true},"stage2":{"model":"claude-opus-4-6","input_tokens":4977,"output_tokens":2221,"usd":0.120615},"total_usd":0.685195,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":58626,"output_tokens":3545,"usd":0.114527},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6321,"output_tokens":4340,"usd":0.210157}},"stage1_raw":"Looking at the corpus, I need to identify papers about the human gene MVP (Major Vault Protein). The corpus contains many papers about LRP1 (Low Density Lipoprotein Receptor-related Protein), LRP (Leucine-responsive Regulatory Protein in bacteria), and other unrelated proteins. I need to focus on papers specifically about MVP (Major Vault Protein).\n\nKey MVP papers I identify:\n- PMID:7585126 - MVP is LRP (lung resistance protein), the major vault protein\n- PMID:15567158 - Characterization of MVP and VPARP assembly into vault ribonucleoprotein complexes\n- PMID:20555386 - MVP interacts with YPEL4 and inhibits ERK/MAPK signaling\n- PMID:34158848 - MVP negatively regulates osteoclastogenesis via calcineurin-NFATc1 pathway\n- PMID:30530482 - Zebrafish MVP recruits and degrades TBK1 to suppress IFN production\n- PMID:35982039 - MVP and importin β2 mediate nuclear import of PTPN18\n- PMID:19660100 - MVP overexpression associated with chemoresistance under hypoxia\n- PMID:15272088 - LRP130 protein binds invMED1 element to regulate MVP gene promoter\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"The drug resistance-related protein LRP (Lung Resistance-related Protein) is the human major vault protein (MVP), a component of multi-subunit vault structures potentially involved in nucleo-cytoplasmic transport; its gene was cloned and mapped to chromosome 16.\",\n      \"method\": \"Gene cloning, amino acid sequence comparison (87.7% identity with rat major vault protein), chromosome localization\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — foundational cloning paper with sequence identity, replicated widely (573 citations)\",\n      \"pmids\": [\"7585126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MVP self-assembles into vault-like particles when expressed alone in E. coli, and the C-terminal region of VPARP (lacking poly(ADP-ribose)polymerase activity) co-sediments with MVP particles; newly synthesized MVPs require >4 hours to incorporate into vault particles whereas VPARP incorporates within 1.5 hours.\",\n      \"method\": \"Immunoprecipitation pulse-chase labeling, expression of MVP in E. coli, co-sedimentation assay, electron microscopy\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstitution of MVP-only vault-like particles in bacteria plus biochemical co-sedimentation, single paper with multiple orthogonal methods\",\n      \"pmids\": [\"15567158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MVP interacts with YPEL4 in mammalian cells and inhibits YPEL4-mediated activation of Elk-1 in the MAPK/ERK signaling pathway.\",\n      \"method\": \"Yeast two-hybrid screen, mammalian two-hybrid assay, GST pull-down, co-immunoprecipitation, immunocytochemistry, Elk-1 reporter assay\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal binding assays plus functional reporter, single lab\",\n      \"pmids\": [\"20555386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MVP negatively regulates osteoclast differentiation and bone resorption by inhibiting the calcineurin-NFATc1 signaling pathway; MVP-deficient mice exhibit osteoporosis-like phenotypes with enhanced NFATc1 activity, and calcineurin inhibition with FK506 rescues enhanced osteoclastogenesis in MVP knockout cells.\",\n      \"method\": \"Total body and monocyte-specific MVP knockout mice, micro-CT, bone histomorphometry, in vitro osteoclast differentiation assays, FK506 rescue experiment, AAV-mediated MVP overexpression in vivo\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined cellular phenotype, epistasis via pharmacological rescue, multiple orthogonal in vivo and in vitro methods\",\n      \"pmids\": [\"34158848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Zebrafish major vault protein (MVP) recruits TBK1 from a dispersed cytoplasmic state to an aggregated state and promotes lysosome-dependent degradation of TBK1, thereby suppressing IFN production in response to viral infection.\",\n      \"method\": \"Overexpression of MVP, co-immunoprecipitation of MVP and TBK1, confocal microscopy of TBK1 redistribution, lysosomal inhibitor experiments, IFN reporter assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP binding, localization, functional readout (IFN suppression), lysosome dependence confirmed, single lab in zebrafish ortholog\",\n      \"pmids\": [\"30530482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MVP mediates nuclear import of PTPN18 together with importin β2 in breast cancer cells; nuclear PTPN18 transported via this mechanism dephosphorylates ETS1 and suppresses TGF-β signaling and epithelial-to-mesenchymal transition.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, ectopic expression and nuclear localization assays, ETS1 phosphorylation and degradation assays, TGF-β signaling reporter\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of MVP with importin β2 and PTPN18, functional nuclear import consequence demonstrated, single lab\",\n      \"pmids\": [\"35982039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The LRP130 protein binds to the invMED1 cis-element in the MVP gene promoter (at position -148/-143) and is required for transcriptional activation of the MVP gene; siRNA knockdown of LRP130 or transcriptional decoys against invMED1 reduced endogenous MVP gene activity.\",\n      \"method\": \"DNA-protein binding characterization, siRNA knockdown of LRP130, transcriptional decoy experiments, promoter-reporter assays in human cancer cell lines\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional promoter dissection with siRNA knockdown and decoys, identifies a transcriptional regulator of MVP, single lab with multiple methods\",\n      \"pmids\": [\"15272088\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MVP (Major Vault Protein) is the primary structural component of vault ribonucleoprotein particles, capable of self-assembling into vault-like structures; it functions as a negative regulator of osteoclastogenesis via calcineurin-NFATc1 pathway inhibition, suppresses innate immune signaling by recruiting and promoting lysosomal degradation of TBK1, mediates nuclear import of cargo proteins (e.g., PTPN18) together with importin β2, interacts with YPEL4 to inhibit ERK/MAPK signaling, and its own transcription is regulated by the LRP130 protein binding the invMED1 element in its promoter.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper before extracting discoveries.\n\n**Classification:**\n\nThe target gene is **MVP** = Major Vault Protein (human, also known as LRP/lung resistance protein in the drug resistance context).\n\n**EXCLUDE - Alias collisions:**\n- Papers [1-13, 15-16, 18-19, 22, 24, 29-31, 33, 34, 41, 44, 45, 47, 49, 50, 52, 56, 57, 58, 60, 61, 63, 70, 76, 80, 81, 83, 86, 90, 94] from main corpus — these describe LRP1/LDL receptor-related protein, not MVP/major vault protein\n- Papers [14, 17, 20, 21, 25, 26, 27, 28, 32, 36, 37, 38, 39, 43, 48, 53, 55, 59, 65, 68, 71, 73, 77, 78, 85, 87, 88, 92, 97] — these describe bacterial/archaeal Lrp (leucine-responsive regulatory protein), a completely different protein\n- Paper [23] — describes MVP 12 (mutagenised Rift Valley fever virus strain), not the protein\n- Paper [67] — describes MVP chemotherapy regimen (mitomycin, vinblastine, cisplatin), not the protein\n- Paper [75] — \"MVP\" used as abbreviation for \"most valuable player\" in TLR context\n- Papers [2] (additional) — BioPlex interactome, no specific MVP mechanism\n- Additional papers [1,3,4,5,6,7,8,9,10,11,12,13,14,18,19,21,22,23,24,25,26,28,29,30] — large-scale proteomics/interactome studies with no specific MVP mechanism\n\n**KEEP - Papers about canonical MVP (Major Vault Protein):**\n- Main [1]: LRP = human major vault protein identification\n- Main [34]: LRP/major vault protein in MDR context\n- Main [42, 64, 95, 99]: MVP expression in cancer (mostly expression studies)\n- Main [66]: MVP and hypoxia/chemo-resistance\n- Main [72]: MVP interacts with YPEL4, inhibits ERK signaling\n- Main [79]: MVP negatively regulates osteoclastogenesis via calcineurin-NFATc1\n- Main [84]: invMED1/LRP130 regulates MVP gene promoter\n- Main [91]: MVP and importin β2 mediate nuclear import of PTPN18\n- Main [93]: Characterization of MVP and VPARP assembly into vault RNP complexes\n- Main [98]: Zebrafish MVP recruits and degrades TBK1\n- Additional [15]: MVP-mediated exosomal sorting of miR-193a\n- Additional [16]: VPARP identified as vault component interacting with MVP; MVP is substrate for vault-associated PARP\n- Additional [20, 27]: Expression studies (EXCLUDE - no mechanism)\n- Additional [17]: RNAi screen identifying ZIKV/DENV dependency factors - no specific MVP mechanism\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"LRP (Lung Resistance-related Protein), a 110-kD protein associated with multidrug resistance, was identified as the human major vault protein (MVP) by cloning and amino acid sequence analysis showing 87.7% identity with rat major vault protein. The LRP/MVP gene was localized to chromosome 16.\",\n      \"method\": \"cDNA cloning, amino acid sequence analysis, chromosome localization\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — foundational cloning and sequence identity determination, highly cited original discovery\",\n      \"pmids\": [\"7585126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"MVP (LRP) protein is broadly distributed in normal human tissues and tumors, with high expression in bronchus, digestive tract, renal proximal tubules, keratinocytes, macrophages, and adrenal cortex. Its distribution parallels that of vault organelles across species, supporting a conserved eukaryotic function.\",\n      \"method\": \"Immunohistochemistry on frozen tissue sections using monoclonal antibody LRP-56\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic immunohistochemical localization across tissues, single lab\",\n      \"pmids\": [\"8774142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The 193-kD vault protein (VPARP) was identified as a novel poly(ADP-ribose) polymerase that interacts with MVP in a yeast two-hybrid screen. VPARP's catalytic domain can catalyze poly(ADP-ribosyl)ation, and purified vault particles retain this enzymatic activity. Crucially, MVP itself is a substrate for this vault-associated PARP activity. VPARP is incorporated into vault particles within 1.5h of biosynthesis, while MVP incorporation takes >4h.\",\n      \"method\": \"Yeast two-hybrid screen, peptide sequence analysis, in vitro poly(ADP-ribosyl)ation assay, immunoprecipitation, immunofluorescence, pulse-chase labeling\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted enzymatic activity, multiple orthogonal methods, identification of MVP as substrate\",\n      \"pmids\": [\"10477748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A novel 12 bp cis-activating element (invMED1) in the MVP gene promoter (at position -148/-143) was characterized, and the nuclear factor LRP130 was identified as the binding protein. LRP130 binding intensity correlates with endogenous MVP gene expression. siRNA knockdown and transcriptional decoy experiments demonstrated that the invMED1/LRP130 couple regulates endogenous MVP gene transcriptional activity.\",\n      \"method\": \"EMSA, promoter deletion analysis, siRNA knockdown, transcriptional decoy, reporter assays in human cancer cell lines\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays (siRNA, decoys, reporter) in two unrelated cell lines, single lab\",\n      \"pmids\": [\"15272088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Newly synthesized MVP incorporates into vault particles only after >4 hours, whereas VPARP incorporates within 1.5 hours. Expression of MVP alone in E. coli produces particles with distinct vault morphology, demonstrating MVP is sufficient for self-assembly. The C-terminal region of VPARP (lacking PARP activity) co-sediments with MVP particles, indicating the PARP domain is dispensable for interaction with MVP.\",\n      \"method\": \"Immunoprecipitation, pulse-chase labeling, heterologous expression in E. coli with electron microscopy of particles, sedimentation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution of vault morphology from MVP alone in bacteria, supported by pulse-chase and co-sedimentation\",\n      \"pmids\": [\"15567158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Severe tumor hypoxia is associated with high MVP expression in clinical cervical tumors, and MVP over-expression is linked to chemo-resistance. Tumors over-expressing MVP showed increased angiogenesis, suggesting hypoxia induces a pathway of chemo- and radiation resistance through MVP upregulation.\",\n      \"method\": \"Immunohistochemistry and tumor oxygenation measurement in 43 consecutive clinical cervical carcinoma patients\",\n      \"journal\": \"Radiation oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — clinical correlation study, single institution, no direct mechanistic dissection of the hypoxia-MVP pathway\",\n      \"pmids\": [\"19660100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MVP interacts with YPEL4 (a Yippee domain nuclear protein) and inhibits YPEL4-mediated activation of Elk-1 in the MAPK signaling pathway. The interaction was demonstrated in mammalian cells and shown to suppress ERK signal pathway activity downstream of YPEL4.\",\n      \"method\": \"Yeast two-hybrid screen, mammalian two-hybrid assay, GST pull-down, co-immunoprecipitation, immunocytochemistry, Elk-1 reporter assay\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal binding assays plus functional reporter assay, single lab\",\n      \"pmids\": [\"20555386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MVP mediates the selective sorting of miR-193a (a tumor suppressor miRNA) into exosomes. miR-193a physically interacts with MVP, and knockout of MVP causes miR-193a to accumulate in donor cells instead of being exported into exosomes, leading to G1 cell cycle arrest and inhibition of tumor progression via targeting of Caprin1 (which upregulates Ccnd2 and c-Myc).\",\n      \"method\": \"Knockout mouse models, RNA immunoprecipitation, exosome fractionation, cell cycle analysis, tumor xenograft models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with defined molecular and cellular phenotype, interaction demonstrated biochemically, replicated in vivo\",\n      \"pmids\": [\"28211508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Zebrafish MVP interacts with TBK1 (a pivotal kinase in the IFN induction pathway) and recruits it from a diffuse cytoplasmic distribution to an aggregated state, then mediates lysosome-dependent degradation of TBK1, thereby suppressing IFN production and IFN-stimulated gene expression.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, viral infection assays, lysosome inhibition experiments, fluorescence microscopy of TBK1 redistribution\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical interaction plus functional degradation assay with lysosome inhibitor, zebrafish ortholog\",\n      \"pmids\": [\"30530482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MVP negatively regulates osteoclastogenesis and bone resorption by inhibiting calcineurin-NFATc1 signaling. MVP-deficient mice (total body and monocyte-specific knockouts) exhibit osteoporosis-like phenotypes with enhanced osteoclast differentiation. Mechanistically, MVP deficiency enhances calcineurin-NFATc1 signaling, promotes NFATc1 activity and calcium oscillations; calcineurin inhibition with FK506 corrects the enhanced osteoclastogenesis in MVP-deficient cells. MVP re-expression in knockout cells rescues calcineurin expression.\",\n      \"method\": \"Conditional and total body MVP knockout mice, micro-CT, bone histomorphometry, in vitro osteoclast differentiation assays, calcineurin inhibitor treatment (FK506), AAV-mediated MVP overexpression, NFATc1 activity assays\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function in vivo and in vitro with defined pathway rescue, multiple orthogonal methods\",\n      \"pmids\": [\"34158848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MVP and importin β2 cooperate to mediate nuclear import of the protein tyrosine phosphatase PTPN18 in breast cancer cells. Nuclear PTPN18 (but not cytoplasmic PTPN18) dephosphorylates ETS1 and promotes its degradation, and suppresses TGF-β signaling and epithelial-to-mesenchymal transition. MVP thus acts as a nuclear transport facilitator that determines the subcellular localization and consequent function of PTPN18.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, ectopic expression, knockdown studies, phosphatase activity assays, metastasis assays in vivo\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical interaction with functional consequence demonstrated, single lab\",\n      \"pmids\": [\"35982039\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MVP (Major Vault Protein) is the primary structural component of vault ribonucleoprotein particles, sufficient for self-assembly into vault morphology; it serves as a substrate for the vault-associated PARP (VPARP), mediates selective exosomal sorting of tumor suppressor miRNAs (e.g., miR-193a), facilitates nuclear import of signaling proteins (e.g., PTPN18) together with importin β2, negatively regulates osteoclastogenesis via calcineurin-NFATc1 pathway inhibition, suppresses TBK1-dependent IFN production through lysosome-dependent TBK1 degradation, and modulates MAPK signaling by interacting with and inhibiting YPEL4-mediated Elk-1 activation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MVP is the principal structural subunit of vault ribonucleoprotein particles, capable of self-assembling into vault-like structures when expressed alone in bacteria [PMID:15567158]. Beyond its architectural role, MVP functions as a signaling modulator: it negatively regulates osteoclastogenesis by inhibiting the calcineurin–NFATc1 pathway, as demonstrated by osteoporosis-like phenotypes in MVP-knockout mice rescued by calcineurin inhibition [PMID:34158848]; it suppresses innate antiviral interferon production by recruiting TBK1 for lysosomal degradation [PMID:30530482]; and it inhibits ERK/MAPK signaling through interaction with YPEL4 [PMID:20555386]. MVP also participates in nucleo-cytoplasmic transport by mediating importin-β2-dependent nuclear import of the phosphatase PTPN18, which in turn suppresses TGF-β signaling [PMID:35982039].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing the molecular identity of the drug-resistance-associated protein LRP as human MVP resolved a longstanding question about the gene encoding the major structural vault subunit and linked it to potential nucleo-cytoplasmic transport functions.\",\n      \"evidence\": \"Gene cloning and amino acid sequence comparison (87.7% identity with rat MVP), chromosome 16 mapping\",\n      \"pmids\": [\"7585126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether MVP itself is sufficient for vault assembly was unknown\",\n        \"No direct functional assay for MVP's role in transport was performed\",\n        \"Mechanism linking MVP to drug resistance was uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of LRP130 binding to the invMED1 promoter element as a transcriptional activator of the MVP gene provided the first cis-regulatory mechanism controlling MVP expression levels.\",\n      \"evidence\": \"DNA-protein binding assays, siRNA knockdown of LRP130, transcriptional decoy experiments, promoter-reporter assays in human cancer cells\",\n      \"pmids\": [\"15272088\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether LRP130-dependent transcription is the dominant pathway regulating MVP in non-cancer contexts is unknown\",\n        \"No chromatin-level (ChIP) confirmation of LRP130 occupancy was shown\",\n        \"Upstream signals controlling LRP130 binding to MVP promoter were not identified\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating that MVP self-assembles into vault-like particles in E. coli without other vault components established it as the minimal structural unit of vaults and defined a slow maturation kinetics for particle incorporation.\",\n      \"evidence\": \"Recombinant MVP expression in E. coli, electron microscopy of vault-like particles, pulse-chase labeling of vault assembly kinetics\",\n      \"pmids\": [\"15567158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural determinants within MVP required for self-assembly were not mapped\",\n        \"How VPARP and TEP1 integrate into MVP-only shells was incompletely resolved\",\n        \"Whether assembled MVP-only particles are functionally equivalent to native vaults was not tested\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery of the MVP–YPEL4 interaction and its inhibition of Elk-1-dependent transcription revealed a vault-independent signaling role for MVP in dampening ERK/MAPK output.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, Elk-1 reporter assay in mammalian cells\",\n      \"pmids\": [\"20555386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether this interaction occurs in the context of assembled vaults or free MVP is unclear\",\n        \"Physiological consequence of MVP–YPEL4 interaction in vivo was not tested\",\n        \"Mechanism by which MVP sequesters or modifies YPEL4 activity was not defined\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing that MVP recruits TBK1 into aggregates for lysosomal degradation established MVP as a negative regulator of innate antiviral immunity by controlling TBK1 protein turnover.\",\n      \"evidence\": \"Co-immunoprecipitation, confocal microscopy of TBK1 redistribution, lysosomal inhibitor rescue, IFN reporter assays in zebrafish\",\n      \"pmids\": [\"30530482\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism was demonstrated with zebrafish MVP; conservation of the TBK1 degradation pathway in mammalian systems was not shown\",\n        \"How MVP targets TBK1 specifically to lysosomes (adaptor, ubiquitination) is unknown\",\n        \"Whether this function requires intact vault particles or free MVP monomers was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic deletion of MVP in mice revealed its role as a physiological brake on osteoclastogenesis via calcineurin–NFATc1 inhibition, providing the first in vivo loss-of-function phenotype for MVP.\",\n      \"evidence\": \"Total body and monocyte-specific MVP knockout mice, micro-CT, bone histomorphometry, FK506 rescue, AAV-mediated MVP overexpression\",\n      \"pmids\": [\"34158848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct biochemical mechanism by which MVP inhibits calcineurin was not identified\",\n        \"Whether vault particle integrity is required for osteoclast regulation is unknown\",\n        \"Relevance to human bone disease was not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of MVP as a carrier that mediates importin-β2-dependent nuclear import of PTPN18 provided a direct molecular mechanism for vault-associated nucleo-cytoplasmic transport.\",\n      \"evidence\": \"Co-immunoprecipitation, subcellular fractionation, nuclear localization assays, ETS1 dephosphorylation and TGF-β reporter assays in breast cancer cells\",\n      \"pmids\": [\"35982039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether MVP shuttles other cargoes via importin-β2 was not investigated\",\n        \"The structural basis for MVP–importin-β2–PTPN18 ternary complex formation is unknown\",\n        \"Generalizability beyond breast cancer cell lines was not demonstrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unifying framework explaining how MVP's structural (vault assembly), transport (nuclear import), and signaling-regulatory (calcineurin, TBK1, ERK) functions are coordinated — and whether they require assembled vault particles versus free MVP — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or biophysical study distinguishes vault-dependent from vault-independent functions of MVP\",\n        \"No systematic cargo identification for MVP-mediated nuclear import has been performed\",\n        \"The mechanism linking MVP to multidrug resistance in cancer remains molecularly undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"Vault particle\"\n    ],\n    \"partners\": [\n      \"VPARP\",\n      \"YPEL4\",\n      \"TBK1\",\n      \"PTPN18\",\n      \"KPNB1\",\n      \"LRP130\",\n      \"NFATc1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"MVP is the principal structural subunit of vault ribonucleoprotein particles, and its expression alone is sufficient to drive self-assembly of vault-like structures [PMID:15567158]. Beyond its architectural role, MVP functions as a poly(ADP-ribosyl)ation substrate of the vault-associated PARP (VPARP) [PMID:10477748], mediates selective exosomal sorting of the tumor-suppressor miR-193a to regulate cell cycle progression [PMID:28211508], facilitates importin-β2-dependent nuclear import of signaling effectors such as PTPN18 [PMID:35982039], negatively regulates osteoclastogenesis by inhibiting calcineurin–NFATc1 signaling [PMID:34158848], and suppresses TBK1-dependent interferon production through lysosome-mediated TBK1 degradation [PMID:30530482]. MVP also modulates MAPK signaling by binding YPEL4 and inhibiting Elk-1 activation [PMID:20555386].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing MVP's molecular identity resolved that the lung resistance-related protein (LRP) associated with multidrug resistance was in fact the human major vault protein, placing vault biology in a clinical context.\",\n      \"evidence\": \"cDNA cloning and amino acid sequence comparison showing 87.7% identity to rat MVP, with chromosomal localization to 16p\",\n      \"pmids\": [\"7585126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking MVP to drug resistance undefined\", \"No direct functional assays performed\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of VPARP as a vault-intrinsic enzyme that poly(ADP-ribosyl)ates MVP itself revealed the first post-translational regulatory circuit within vault particles.\",\n      \"evidence\": \"Yeast two-hybrid screen, in vitro poly(ADP-ribosyl)ation assay on purified vaults, pulse-chase incorporation kinetics\",\n      \"pmids\": [\"10477748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of MVP ADP-ribosylation unknown\", \"Relevant cellular stimuli triggering VPARP activity not identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstration that heterologous expression of MVP alone produces particles with vault morphology established MVP as both necessary and sufficient for vault assembly, separating scaffold function from accessory components.\",\n      \"evidence\": \"Recombinant MVP expression in E. coli with electron microscopy confirming vault-like particle formation\",\n      \"pmids\": [\"15567158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural determinants within MVP that drive self-assembly not mapped\", \"Role of vRNA and TEP1 in particle stability not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The finding that MVP binds YPEL4 and inhibits Elk-1 activation provided the first evidence that MVP modulates a canonical signal transduction cascade (MAPK/ERK pathway).\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, and Elk-1 reporter assays in mammalian cells\",\n      \"pmids\": [\"20555386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological context of MVP–YPEL4 interaction not established in vivo\", \"Stoichiometry and whether interaction requires intact vaults unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that MVP selectively sorts miR-193a into exosomes linked vault biology to intercellular RNA trafficking and tumor suppression, showing that MVP loss causes miR-193a retention and G1 arrest in donor cells.\",\n      \"evidence\": \"MVP-knockout mice, RNA immunoprecipitation, exosome fractionation, tumor xenograft models\",\n      \"pmids\": [\"28211508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA sequence or structural determinants recognized by MVP for cargo selection not defined\", \"Breadth of miRNA cargo beyond miR-193a not systematically profiled\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstration that MVP recruits TBK1 for lysosomal degradation, thereby dampening IFN production, revealed an immunoregulatory role and a mechanism coupling vault particles to innate immune signaling.\",\n      \"evidence\": \"Co-immunoprecipitation, lysosome inhibitor rescue of TBK1 levels, fluorescence imaging of TBK1 redistribution in zebrafish\",\n      \"pmids\": [\"30530482\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether mammalian MVP employs the same lysosomal degradation route not confirmed\", \"Adaptor or ubiquitin signals linking MVP–TBK1 to lysosomes not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic loss-of-function studies in MVP-knockout mice established MVP as a negative regulator of osteoclastogenesis through inhibition of calcineurin–NFATc1 signaling, connecting vault biology to bone homeostasis.\",\n      \"evidence\": \"Total-body and monocyte-specific MVP knockout mice, micro-CT, FK506 rescue of enhanced osteoclast differentiation, AAV-mediated rescue\",\n      \"pmids\": [\"34158848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface between MVP and calcineurin not mapped\", \"Whether vault particle integrity is required for calcineurin inhibition unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of MVP as a cofactor for importin-β2-dependent nuclear import of PTPN18 expanded MVP's functional repertoire to include nucleocytoplasmic transport of signaling intermediates.\",\n      \"evidence\": \"Co-immunoprecipitation, subcellular fractionation, knockdown and overexpression studies, in vivo metastasis assays in breast cancer models\",\n      \"pmids\": [\"35982039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MVP participates in nuclear import of other cargoes beyond PTPN18 not tested\", \"Structural basis of MVP–importin-β2 cooperation not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unifying model explaining how MVP coordinates its diverse signaling roles — miRNA sorting, nuclear transport, kinase degradation, and calcineurin inhibition — and whether these functions require intact vault particles or free MVP subunits, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of full-length human vault with bound cargo\", \"Vault-dependent versus vault-independent MVP functions not delineated\", \"Upstream signals controlling MVP expression or vault disassembly poorly characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005515\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\"Vault ribonucleoprotein particle\"],\n    \"partners\": [\"VPARP\", \"YPEL4\", \"TBK1\", \"PTPN18\", \"KPNB1\", \"CAPRIN1\"],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait — I need to fix a mistake in the pathway section. I included an invalid entry `GO:0005515` which is not in the allowed Reactome pathways list. Let me correct:\n\n```json\n{\n  \"mechanistic_narrative\": \"MVP is the principal structural subunit of vault ribonucleoprotein particles, and its expression alone is sufficient to drive self-assembly of vault-like structures [PMID:15567158]. Beyond its architectural role, MVP functions as a poly(ADP-ribosyl)ation substrate of the vault-associated PARP (VPARP) [PMID:10477748], mediates selective exosomal sorting of the tumor-suppressor miR-193a to regulate cell cycle progression [PMID:28211508], facilitates importin-β2-dependent nuclear import of signaling effectors such as PTPN18 [PMID:35982039], negatively regulates osteoclastogenesis by inhibiting calcineurin–NFATc1 signaling [PMID:34158848], and suppresses TBK1-dependent interferon production through lysosome-mediated TBK1 degradation [PMID:30530482]. MVP also modulates MAPK signaling by binding YPEL4 and inhibiting Elk-1 activation [PMID:20555386].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing MVP's molecular identity resolved that the lung resistance-related protein (LRP) associated with multidrug resistance was in fact the human major vault protein, placing vault biology in a clinical context.\",\n      \"evidence\": \"cDNA cloning and amino acid sequence comparison showing 87.7% identity to rat MVP, with chromosomal localization to 16p\",\n      \"pmids\": [\"7585126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking MVP to drug resistance undefined\", \"No direct functional assays performed\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of VPARP as a vault-intrinsic enzyme that poly(ADP-ribosyl)ates MVP itself revealed the first post-translational regulatory circuit within vault particles.\",\n      \"evidence\": \"Yeast two-hybrid screen, in vitro poly(ADP-ribosyl)ation assay on purified vaults, pulse-chase incorporation kinetics\",\n      \"pmids\": [\"10477748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of MVP ADP-ribosylation unknown\", \"Relevant cellular stimuli triggering VPARP activity not identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstration that heterologous expression of MVP alone produces particles with vault morphology established MVP as both necessary and sufficient for vault assembly, separating scaffold function from accessory components.\",\n      \"evidence\": \"Recombinant MVP expression in E. coli with electron microscopy confirming vault-like particle formation\",\n      \"pmids\": [\"15567158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural determinants within MVP that drive self-assembly not mapped\", \"Role of vRNA and TEP1 in particle stability not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The finding that MVP binds YPEL4 and inhibits Elk-1 activation provided the first evidence that MVP modulates a canonical signal transduction cascade (MAPK/ERK pathway).\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, and Elk-1 reporter assays in mammalian cells\",\n      \"pmids\": [\"20555386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological context of MVP–YPEL4 interaction not established in vivo\", \"Stoichiometry and whether interaction requires intact vaults unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that MVP selectively sorts miR-193a into exosomes linked vault biology to intercellular RNA trafficking and tumor suppression, showing that MVP loss causes miR-193a retention and G1 arrest in donor cells.\",\n      \"evidence\": \"MVP-knockout mice, RNA immunoprecipitation, exosome fractionation, tumor xenograft models\",\n      \"pmids\": [\"28211508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA sequence or structural determinants recognized by MVP for cargo selection not defined\", \"Breadth of miRNA cargo beyond miR-193a not systematically profiled\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstration that MVP recruits TBK1 for lysosomal degradation, thereby dampening IFN production, revealed an immunoregulatory role and a mechanism coupling vault particles to innate immune signaling.\",\n      \"evidence\": \"Co-immunoprecipitation, lysosome inhibitor rescue of TBK1 levels, fluorescence imaging of TBK1 redistribution in zebrafish\",\n      \"pmids\": [\"30530482\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether mammalian MVP employs the same lysosomal degradation route not confirmed\", \"Adaptor or ubiquitin signals linking MVP–TBK1 to lysosomes not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic loss-of-function studies in MVP-knockout mice established MVP as a negative regulator of osteoclastogenesis through inhibition of calcineurin–NFATc1 signaling, connecting vault biology to bone homeostasis.\",\n      \"evidence\": \"Total-body and monocyte-specific MVP knockout mice, micro-CT, FK506 rescue of enhanced osteoclast differentiation, AAV-mediated rescue\",\n      \"pmids\": [\"34158848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface between MVP and calcineurin not mapped\", \"Whether vault particle integrity is required for calcineurin inhibition unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of MVP as a cofactor for importin-β2-dependent nuclear import of PTPN18 expanded MVP's functional repertoire to include nucleocytoplasmic transport of signaling intermediates.\",\n      \"evidence\": \"Co-immunoprecipitation, subcellular fractionation, knockdown and overexpression studies, in vivo metastasis assays in breast cancer models\",\n      \"pmids\": [\"35982039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MVP participates in nuclear import of other cargoes beyond PTPN18 not tested\", \"Structural basis of MVP–importin-β2 cooperation not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unifying model explaining how MVP coordinates its diverse signaling roles — miRNA sorting, nuclear transport, kinase degradation, and calcineurin inhibition — and whether these functions require intact vault particles or free MVP subunits, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of full-length human vault with bound cargo\", \"Vault-dependent versus vault-independent MVP functions not delineated\", \"Upstream signals controlling MVP expression or vault disassembly poorly characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\"Vault ribonucleoprotein particle\"],\n    \"partners\": [\"VPARP\", \"YPEL4\", \"TBK1\", \"PTPN18\", \"KPNB1\", \"CAPRIN1\"],\n    \"other_free_text\": []\n  }\n}\n```"}