{"gene":"MVP","run_date":"2026-06-10T05:19:51","timeline":{"discoveries":[{"year":2004,"finding":"Cryoelectron microscopy and single-particle image reconstruction of recombinant and tissue-derived vaults revealed that 48 copies of MVP form each half-vault (96 total), with all MVP N-termini interacting non-covalently at the vault midsection. Co-expression of MVP with VPARP or TEP1 results in their co-assembly into vaults. VPARP was localized by cryoEM difference mapping to three density bands lining the inner surface of the vault.","method":"Cryoelectron microscopy, single-particle image reconstruction, recombinant co-expression in insect cells","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct structural determination with multiple recombinant constructs and difference mapping; replicated across wild-type and TEP1-deficient mouse vaults","pmids":["15504404"],"is_preprint":false},{"year":2009,"finding":"Crystal structure of the seven N-terminal repeat domains (R1-R7) of MVP at 2.1 Å resolution, together with 8 Å vault particle structure, revealed that the interactions governing vault half-association are mediated by the N-terminal domains R1-R2, and that vault halves dissociate reversibly at acidic pH through disruption of these interactions.","method":"X-ray crystallography (2.1 Å structure of R1-R7), electron microscopy (8 Å vault particle structure)","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic resolution crystal structure with functional validation of pH-dependent dissociation mechanism","pmids":["19779459"],"is_preprint":false},{"year":2005,"finding":"Newly synthesized MVP requires more than 4 hours to be incorporated into vault particles, whereas VPARP is completely incorporated within 1.5 hours. Once incorporated, both MVP and VPARP are very stable. Expression of MVP alone in E. coli produces particles with vault morphology, and the C-terminal region of VPARP lacking polyADP-ribose polymerase activity co-sediments with MVP self-assembled vault-like particles, indicating VPARP polymerase activity is not required for interaction with MVP.","method":"Immunoprecipitation pulse-chase assay, E. coli expression reconstitution, co-sedimentation assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution in E. coli plus biochemical pulse-chase and co-sedimentation; multiple orthogonal methods in single study","pmids":["15567158"],"is_preprint":false},{"year":2005,"finding":"YB-1 (Y-box binding protein-1) directly binds the Y-box element in the MVP gene promoter and controls basal and 5-fluorouracil-induced MVP expression. 5-FU amplified YB-1 binding activity to the Y-box in a time-dependent manner. Stable YB-1 overexpression enhanced binding and increased basal and 5-FU-inducible MVP promoter-driven reporter expression. YB-1 cDNA transduction led to increased endogenous MVP protein expression.","method":"Electrophoretic mobility shift assay (EMSA), ChIP, MVP promoter-reporter deletion mutants, YB-1 stable overexpression, YB-1 cDNA transduction","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (EMSA, ChIP, reporter assays, overexpression) in a single lab study","pmids":["15750632"],"is_preprint":false},{"year":2004,"finding":"SP-family transcription factors (Sp1, Sp3) bind a conserved proximal GC-box element essential for basal human MVP promoter transactivation. Dominant-negative Sp1 and mithramycin A attenuated MVP promoter activity. HDAC inhibitors (butyrate, trichostatin A) potently stimulated MVP expression by shifting Sp1 to Sp3 occupancy at this GC-box, demonstrated by ChIP assays.","method":"EMSA, ChIP, MVP promoter deletion/mutation analysis, dominant-negative Sp1, mithramycin A treatment, HDAC inhibitor treatment","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (EMSA, ChIP, reporter mutagenesis) in a single lab with consistent results","pmids":["15047174"],"is_preprint":false},{"year":2004,"finding":"The LRP130 protein binds the invMED1 cis-element located at -148/-143 in the MVP gene promoter and is involved in transcriptional activation of MVP. SiRNA knockdown of LRP130 and transcriptional decoys targeting invMED1 reduced endogenous MVP gene activity in two unrelated human cancer cell lines.","method":"siRNA knockdown, transcriptional decoy competition, promoter-reporter assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — siRNA and reporter assays in two cell lines but single lab, no direct biochemical binding confirmation for MVP promoter","pmids":["15272088"],"is_preprint":false},{"year":2004,"finding":"Drug resistance in multi-drug resistant cancer cell lines is not caused by vault gene amplification. Treatment with HDAC inhibitors (sodium butyrate, trichostatin A) increased MVP mRNA, protein, and promoter activity, suggesting chromatin remodeling regulates MVP upregulation in MDR.","method":"Gene copy number analysis, RT-PCR, Western blot, promoter-reporter assays, HDAC inhibitor treatment","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple methods (gene copy number, promoter activity, mRNA/protein) in single lab; functional promoter assays supporting mechanism","pmids":["15093136"],"is_preprint":false},{"year":2010,"finding":"MVP physically interacts with YPEL4 and inhibits YPEL4-mediated activation of Elk-1 in the MAPK signaling pathway. The interaction was confirmed by yeast two-hybrid, mammalian two-hybrid, GST pull-down, co-immunoprecipitation, and immunocytochemistry. Reporter assays showed MVP suppresses YPEL4-driven transcriptional activity through the ERK pathway.","method":"Yeast two-hybrid, mammalian two-hybrid, GST pull-down, co-immunoprecipitation, immunocytochemistry, reporter gene assay","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal binding assays plus functional reporter readout; single lab","pmids":["20555386"],"is_preprint":false},{"year":2006,"finding":"MVP interacts with zinc finger protein ZNF540 as identified by yeast two-hybrid screening and confirmed by co-immunoprecipitation. ZNF540 represses SRE and ELK-1 transcriptional activities, and MVP is identified as a MAPK scaffold protein in this pathway.","method":"Yeast two-hybrid, co-immunoprecipitation, reporter gene assay (SRE, ELK-1), siRNA knockdown","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reciprocal co-IP with functional readout but single lab, single study","pmids":["16815308"],"is_preprint":false},{"year":2002,"finding":"MVP/LRP knockout mice are viable, healthy, and show no obvious abnormalities. MVP-deficient embryonic stem cells and bone marrow cells showed no increased sensitivity to cytostatic agents compared to wild-type cells. ABC-transporter activities (P-glycoprotein, MRP, BCRP) were unaltered upon MVP deletion. MVP knockout mice responded to doxorubicin treatment similarly to wild-type mice.","method":"MVP knockout mouse generation, cytotoxicity assays (embryonic stem cells, bone marrow), ABC-transporter activity assays, in vivo doxorubicin treatment","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple drug sensitivity readouts; negative result (no direct role in cytostatic drug resistance) replicated across cell types and in vivo","pmids":["12499273"],"is_preprint":false},{"year":2017,"finding":"MVP mediates selective sorting of miR-193a into exosomes. Knockout of MVP leads to miR-193a accumulation in donor cells instead of exosomes, inhibiting tumor progression. Accumulated miR-193a causes G1 cell cycle arrest and represses proliferation by targeting Caprin1, which upregulates Ccnd2 and c-Myc.","method":"MVP knockout, exosomal miRNA profiling, cell cycle analysis, target validation (Caprin1, Ccnd2, c-Myc)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with mechanistic pathway validation (exosomal sorting + downstream target identification) using multiple methods","pmids":["28211508"],"is_preprint":false},{"year":2018,"finding":"B7-H3 interacts with MVP as identified by immunoprecipitation and mass spectrometry. MVP enhances B-RAF and MEK interaction to activate MEK signaling. B7-H3-induced MEK activation and cancer stem cell enrichment are blocked by MVP depletion.","method":"Immunoprecipitation, mass spectrometry, MVP siRNA knockdown, MEK pathway analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP/MS identification of interaction plus siRNA functional validation; single lab","pmids":["30082909"],"is_preprint":false},{"year":2013,"finding":"14-3-3ε binds to MVP in a phosphorylation-dependent manner at both Thr52 and Ser864 of the MVP monomer. This interaction is induced by bleomycin treatment and inhibits the drug-resistant activity of MVP, enhancing the DNA damage response.","method":"LC-MS/MS proteomics, co-immunoprecipitation, phosphorylation site identification, functional drug resistance assays","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — MS-based interactome with phosphorylation site mapping and functional validation; single lab","pmids":["23590642"],"is_preprint":false},{"year":2018,"finding":"Zebrafish MVP interacts with TBK1 and recruits it from a uniformly distributed cytoplasmic state to an aggregated state, then mediates lysosome-dependent degradation of TBK1. This suppresses IFN production downstream of RIG-I-like receptor signaling.","method":"Co-immunoprecipitation, overexpression studies, lysosome inhibitor treatment, IFN reporter assays, viral infection experiments","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP with mechanistic follow-up (lysosome-dependent degradation) but single lab, zebrafish ortholog","pmids":["30530482"],"is_preprint":false},{"year":2021,"finding":"MVP negatively regulates osteoclastogenesis via inhibition of calcineurin-NFATc1 signaling. MVP deficiency enhances calcineurin-NFATc1 signaling and promotes osteoclast differentiation and bone resorption. Calcineurin inhibition with FK506 corrected the enhanced osteoclastogenesis in MVP knockout mice. MVP re-expression in knockout mice rescued calcineurin expression.","method":"Total body and monocyte-specific MVP knockout mice, micro-CT, bone histomorphometry, in vitro osteoclast differentiation assays, FK506 treatment, AAV-mediated MVP re-expression","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO (two mouse models) with pathway identification, pharmacological rescue, and AAV re-expression validation","pmids":["34158848"],"is_preprint":false},{"year":2023,"finding":"MVP interacts with death receptor Fas in osteoclasts, and the MVP-Fas signaling cascade positively regulates osteoclast apoptosis. Conditional MVP knockout in monocyte lineage inhibited osteoclast apoptosis in vivo and in vitro, leading to osteoporosis in aging and estrogen-deficient mouse models.","method":"Conditional MVP knockout mice (Mvpf/fLyz2-Cre), co-immunoprecipitation (MVP-Fas interaction), in vivo and in vitro apoptosis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined cellular phenotype plus co-IP identification of binding partner; single lab","pmids":["37704623"],"is_preprint":false},{"year":2022,"finding":"MVP translocates PTPN18 from cytoplasm to nucleus together with importin β2 in breast cancer cells. Nuclear PTPN18 (but not cytoplasmic) dephosphorylates ETS1 and promotes its degradation, suppressing TGF-β signaling and EMT.","method":"Co-immunoprecipitation, subcellular fractionation, MVP overexpression/knockdown, PTPN18 localization studies","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP and localization experiments with functional pathway validation; single lab, single study","pmids":["35982039"],"is_preprint":false},{"year":2016,"finding":"MVP is a cargo protein of the nuclear import receptor KPNA7. KPNA7 silencing hindered MVP transport to the nucleus. MVP knockdown caused marked reduction in pancreatic cancer cell growth.","method":"Protein affinity chromatography, co-immunoprecipitation, siRNA-mediated KPNA7 silencing, cell growth assays","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — affinity chromatography and co-IP for binding, siRNA for functional validation; single lab","pmids":["27664836"],"is_preprint":false},{"year":2025,"finding":"MVP binds β-TrCP and prevents β-TrCP-mediated proteasomal degradation of PD-L1, thereby stabilizing PD-L1 protein. Histone lactylation transcriptionally upregulates MVP. Site-directed mutagenesis and truncation mutants identified the binding sites of the MVP-β-TrCP complex.","method":"Co-immunoprecipitation, cycloheximide-chase analysis, ubiquitination assay, site-directed mutagenesis, truncation mutants, ChIP-seq","journal":"Journal for immunotherapy of cancer","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical reconstitution of binding with mutagenesis, ubiquitination assays, and protein stability assays; multiple orthogonal methods in single study","pmids":["40983342"],"is_preprint":false},{"year":2025,"finding":"PGAM5 directly dephosphorylates MVP at Ser873, facilitating MVP binding to LCN2 mRNA and maintaining its stability. This attenuates ferroptosis by reducing lipid peroxidation and intracellular Fe²⁺. Tenapanor disrupts the MVP-LCN2 mRNA interaction. ROS-induced STAT3 transcriptionally activates MVP expression in HCC.","method":"Phosphatase assay (PGAM5-MVP), RNA-protein binding assay (MVP-LCN2 mRNA), ferroptosis assays, STAT3 ChIP, tenapanor inhibition","journal":"Drug resistance updates","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct dephosphorylation and RNA binding assays with multiple orthogonal methods; single lab","pmids":["40262414"],"is_preprint":false},{"year":2024,"finding":"MVP binds IRF1 and interferes with IRF1 interaction with the YAP1 promoter, leading to increased NOX4 transcription and enhanced lipid peroxidation. This promotes FGF21-induced ferroptosis in HCC cells. MVP knockdown reduced NOX4 transcription and attenuated FGF21-mediated ferroptosis.","method":"Co-immunoprecipitation (MVP-IRF1), ChIP assay (IRF1-YAP1 promoter), MVP knockdown/overexpression, ferroptosis/lipid peroxidation assays, xenograft models","journal":"Clinical and translational science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP and ChIP with functional ferroptosis readout; single lab","pmids":["39143889"],"is_preprint":false},{"year":2025,"finding":"TG2 binds MVP and stabilizes it by inhibiting ubiquitin-proteasomal degradation in a transamidase activity-dependent manner. Accumulation of MVP facilitates MAPK/ERK1/2 signaling activation, inducing EMT and metastasis in basal-like bladder cancer.","method":"Co-immunoprecipitation (TG2-MVP), ubiquitination assays, proteasome inhibitor treatment, TG2 catalytic inhibitor NC9, ERK signaling analysis, patient-derived organoids, in vivo xenograft","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assays, and pharmacological inhibition with multiple functional readouts; single lab but orthogonal methods","pmids":["41238097"],"is_preprint":false},{"year":2025,"finding":"MVP undergoes succinylation modification; SIRT7 is the desuccinylase for MVP and promotes MVP protein stability in TSCC cells. Desuccinylated MVP activates JAK2/STAT3 pathway to promote TSCC cell proliferation, migration, and invasion. JAK2 agonist CA1 reversed the effects of MVP silencing.","method":"Succinylation assay, SIRT7 co-expression/knockdown, Western blot (MVP stability), JAK2/STAT3 pathway analysis, functional cell assays","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — PTM identification and desuccinylase assignment with functional rescue; single lab","pmids":["40586636"],"is_preprint":false},{"year":2023,"finding":"MVP promotes M2 macrophage polarization during fracture repair via the JAK2-STAT6 pathway. Myeloid-specific MVP knockout mice showed impaired transition from pro-inflammatory to anti-inflammatory macrophage phenotype, increased pro-inflammatory cytokines, enhanced osteoclastogenesis, and impaired fracture healing. AAV-Mvp injection rescued fracture repair.","method":"Myeloid-specific MVP knockout mice (Mvpf/fLyz2-Cre), in vivo fracture model, macrophage polarization assays, cytokine measurement, JAK2-STAT6 pathway analysis, AAV rescue","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined mechanistic pathway and AAV rescue; single lab","pmids":["37267856"],"is_preprint":false},{"year":2025,"finding":"Intercellular force activates Notch signaling which upregulates MVP expression, and MVP facilitates export of chemotherapy drugs from nuclei. Inhibition of contractile force, Notch signaling, or MVP each reversed drug export and restored chemosensitivity in vitro and in vivo.","method":"MVP knockdown, Notch inhibition, contractility manipulation, nuclear drug export assays, xenograft tumor models","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway (force→Notch→MVP→drug export) with multiple inhibition strategies and in vivo validation; single lab","pmids":["40333760"],"is_preprint":false},{"year":2015,"finding":"MVP-associated Filamin A mutations (G288R, P637Q, H743P) abolish FlnA/PTPN12 (PTP-PEST) interactions. Loss of this interaction impairs activation of PTPN12 substrates Src and p190RhoGAP, affecting focal adhesion signaling and actin cytoskeleton dynamics in the context of mitral valve prolapse pathogenesis.","method":"Yeast two-hybrid, pull-down, co-immunoprecipitation, kinase activity assays (Src, p190RhoGAP)","journal":"Journal of cardiovascular development and disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — this paper concerns MVP (mitral valve prolapse) disease-associated FLNA mutations, not the major vault protein; excluded as off-target","pmids":["26594644"],"is_preprint":false},{"year":2026,"finding":"MVP sequesters IRF1 from TRAF6, suppressing IRF1 polyubiquitination and nuclear localization during IAV infection. This prevents IRF1 transcriptional repression of the FSP1 promoter, thereby increasing FSP1 expression and plasma membrane recruitment, enabling ferroptosis suppression.","method":"Co-immunoprecipitation (MVP-IRF1, IRF1-TRAF6), ubiquitination assay, FSP1 promoter reporter, in vitro and in vivo ferroptosis assays, myristoylation/membrane recruitment assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP and mechanistic pathway validation with functional ferroptosis readout; single lab, single study","pmids":["41782382"],"is_preprint":false},{"year":2026,"finding":"MG53 interacts with MVP and promotes K63-linked ubiquitination of MVP at lysine 747, facilitating STAT6 nuclear translocation and transcriptional activation of M2 macrophage genes to promote corneal nerve regeneration.","method":"Co-immunoprecipitation (MG53-MVP), K63-ubiquitination assay, STAT6 nuclear translocation assay, genome-wide Membrane Proteome Array screen, in vivo nerve regeneration model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP with site-specific ubiquitination and functional nuclear translocation assay; single lab","pmids":["41961488"],"is_preprint":false}],"current_model":"MVP (major vault protein) is the dominant structural component (~70%) of barrel-shaped vault ribonucleoprotein particles, forming 48-subunit half-vaults whose assembly and reversible pH-dependent dissociation are governed by N-terminal repeat domains; it acts as a scaffold that recruits VPARP and TEP1 into the complex, mediates nuclear-cytoplasmic transport of cargo proteins (including PTPN18 via importin β2), facilitates exosomal sorting of miRNAs, modulates multiple signaling pathways (MAPK/ERK, calcineurin-NFATc1, JAK2-STAT6, JAK2-STAT3) through protein-protein interactions with partners including TBK1, IRF1, B7-H3, YPEL4, 14-3-3ε, and β-TrCP, undergoes post-translational modifications including phosphorylation (by upstream kinases, read by 14-3-3ε at Thr52/Ser864) and succinylation (reversed by SIRT7), and can facilitate nuclear drug export downstream of mechanosensitive Notch signaling, though direct involvement in classical multidrug resistance via ABC transporters is not supported by genetic knockout studies."},"narrative":{"mechanistic_narrative":"MVP (major vault protein) is the dominant structural subunit of barrel-shaped vault ribonucleoprotein particles, with 48 copies forming each half-vault and all N-termini interacting non-covalently at the vault midsection; co-expression with VPARP or TEP1 recruits these partners into the assembled particle [PMID:15504404]. The N-terminal repeat domains R1-R2 mediate half-vault association, and these contacts are disrupted reversibly at acidic pH, providing a pH-gated dissociation mechanism resolved at atomic resolution [PMID:19779459]. MVP alone is sufficient to self-assemble vault-shaped particles, and interaction with VPARP is independent of VPARP polymerase activity [PMID:15567158]. Beyond its structural role, MVP functions as a multipurpose protein-protein interaction scaffold that tunes signaling: it binds YPEL4 and ZNF540 to modulate MAPK/ERK–Elk-1 transcriptional output [PMID:20555386, PMID:16815308], and its stabilization (e.g., by transglutaminase TG2) drives MAPK/ERK1/2-dependent EMT and metastasis [PMID:41238097]. MVP regulates intracellular trafficking, mediating nuclear import of cargoes including PTPN18 with importin β2 to suppress TGF-β/EMT signaling [PMID:35982039], and is itself a cargo of the import receptor KPNA7 [PMID:27664836]. MVP controls protein stability of signaling effectors, binding β-TrCP to protect PD-L1 from proteasomal degradation [PMID:40983342] and shaping ferroptosis through interactions with IRF1 that redirect transcription of NOX4, YAP1, and FSP1 [PMID:39143889, PMID:41782382]. In bone and immune contexts, MVP restrains calcineurin–NFATc1 osteoclastogenesis [PMID:34158848], couples to Fas to promote osteoclast apoptosis [PMID:37704623], and promotes JAK-STAT-driven M2 macrophage polarization [PMID:37267856, PMID:41961488]. MVP also directs selective sorting of miR-193a into exosomes, with loss causing intracellular miR-193a accumulation and Caprin1-dependent cell-cycle arrest [PMID:28211508]. MVP activity is regulated by phosphorylation read by 14-3-3ε at Thr52/Ser864 [PMID:23590642] and by succinylation reversed by SIRT7 [PMID:40586636]. Notably, genetic knockout established that MVP is not required for classical ABC-transporter–mediated multidrug resistance [PMID:12499273], although it can facilitate nuclear chemotherapeutic export downstream of mechanosensitive Notch signaling [PMID:40333760].","teleology":[{"year":2004,"claim":"Established the quaternary architecture of the vault and showed MVP is the self-sufficient scaffold that recruits accessory proteins, defining the particle's building principle.","evidence":"CryoEM single-particle reconstruction of recombinant and tissue vaults with VPARP/TEP1 co-expression and difference mapping","pmids":["15504404"],"confidence":"High","gaps":["Did not resolve atomic contacts of half-vault association","Functional consequence of VPARP/TEP1 recruitment not addressed"]},{"year":2005,"claim":"Demonstrated MVP alone assembles vault-shaped particles and that VPARP incorporation does not require its polymerase activity, separating structural assembly from enzymatic function.","evidence":"E. coli expression reconstitution, pulse-chase immunoprecipitation, and co-sedimentation","pmids":["15567158"],"confidence":"High","gaps":["Slow MVP incorporation kinetics mechanism unexplained","Assembly chaperones not identified"]},{"year":2009,"claim":"Localized the half-vault association interface to N-terminal repeats R1-R2 and defined a reversible pH-dependent dissociation mechanism, providing a structural basis for vault opening/cargo release.","evidence":"2.1 Å crystal structure of R1-R7 plus 8 Å vault particle EM","pmids":["19779459"],"confidence":"High","gaps":["Physiological trigger for in vivo dissociation unknown","Cargo loading/release coupling to pH change not shown"]},{"year":2004,"claim":"Defined the transcriptional control of MVP via Sp1/Sp3 GC-box occupancy and LRP130/invMED1, and showed chromatin remodeling (HDAC inhibition) rather than gene amplification drives MVP upregulation in MDR cells.","evidence":"EMSA, ChIP, promoter mutagenesis, dominant-negative Sp1, siRNA, copy-number analysis, HDAC inhibitor treatment","pmids":["15047174","15272088","15093136"],"confidence":"Medium","gaps":["Causal link between MVP induction and drug resistance not established","Upstream signals coordinating these factors unclear"]},{"year":2005,"claim":"Identified YB-1 as a sequence-specific activator of basal and chemotherapy-inducible MVP transcription, linking stress-responsive transcription factors to MVP expression.","evidence":"EMSA, ChIP, promoter-reporter deletions, YB-1 overexpression/transduction","pmids":["15750632"],"confidence":"High","gaps":["Functional outcome of 5-FU-induced MVP on drug response not tested","Signaling that activates YB-1 binding undefined"]},{"year":2002,"claim":"Resolved whether MVP confers classical multidrug resistance: genetic knockout showed normal drug sensitivity and unchanged ABC-transporter activity, excluding MVP as a primary MDR effector.","evidence":"MVP knockout mice, cytotoxicity assays in ES/bone marrow cells, ABC-transporter activity assays, in vivo doxorubicin","pmids":["12499273"],"confidence":"High","gaps":["Context-specific drug handling roles not excluded","Compensatory mechanisms in KO not characterized"]},{"year":2010,"claim":"Recast MVP as a signaling scaffold by showing it binds YPEL4 and ZNF540 to modulate MAPK/ERK–Elk-1/SRE transcriptional activity, beyond a purely structural role.","evidence":"Yeast/mammalian two-hybrid, GST pull-down, co-IP, immunocytochemistry, SRE/ELK-1 reporter assays, siRNA","pmids":["20555386","16815308"],"confidence":"Medium","gaps":["Whether scaffolding occurs on intact vaults or free MVP unclear","Endogenous physiological relevance not established in vivo"]},{"year":2013,"claim":"Showed MVP function is regulated by phosphorylation, with 14-3-3ε binding phospho-Thr52/Ser864 to inhibit drug-resistant activity and enhance DNA damage response.","evidence":"LC-MS/MS, co-IP, phosphosite mapping, bleomycin treatment, drug resistance assays","pmids":["23590642"],"confidence":"Medium","gaps":["Upstream kinase not identified","Mechanism linking 14-3-3ε binding to DNA damage response undefined"]},{"year":2017,"claim":"Established a non-structural trafficking role: MVP selectively sorts miR-193a into exosomes, and its loss traps the miRNA intracellularly to impose Caprin1-dependent cell-cycle arrest.","evidence":"MVP knockout, exosomal miRNA profiling, cell-cycle analysis, Caprin1/Ccnd2/c-Myc target validation","pmids":["28211508"],"confidence":"High","gaps":["Selectivity determinant for miR-193a sorting unknown","Whether vault assembly is required for sorting unaddressed"]},{"year":2018,"claim":"Extended MVP scaffolding to immune signaling and oncogenic MEK activation, binding TBK1 to drive its lysosomal degradation (zebrafish) and bridging B7-H3 to B-RAF/MEK.","evidence":"Co-IP, mass spectrometry, siRNA, IFN reporter and viral infection assays, MEK pathway analysis","pmids":["30530482","30082909"],"confidence":"Medium","gaps":["TBK1 degradation finding is in zebrafish ortholog","Direct vs indirect B7-H3–MVP binding not fully resolved"]},{"year":2022,"claim":"Defined MVP as a nuclear transport mediator, importing PTPN18 with importin β2 to dephosphorylate ETS1 and suppress TGF-β/EMT, and being itself a KPNA7 cargo required for cancer growth.","evidence":"Co-IP, subcellular fractionation, overexpression/knockdown, affinity chromatography, cell growth assays","pmids":["35982039","27664836"],"confidence":"Medium","gaps":["Generality of MVP as an import adaptor for other cargoes unknown","Role of vault particle vs free MVP in transport unclear"]},{"year":2021,"claim":"Revealed MVP's physiological role in bone homeostasis, restraining calcineurin–NFATc1 osteoclastogenesis and later coupling to Fas to drive osteoclast apoptosis, with knockout causing osteoporosis.","evidence":"Total-body and monocyte-specific knockout mice, micro-CT, histomorphometry, FK506 rescue, AAV re-expression, co-IP","pmids":["34158848","37704623"],"confidence":"High","gaps":["Molecular link between MVP and calcineurin regulation not fully defined","Whether MVP-Fas acts directly or via adaptors unresolved"]},{"year":2023,"claim":"Connected MVP to macrophage fate, promoting JAK2-STAT6-driven M2 polarization important for fracture repair and corneal nerve regeneration.","evidence":"Myeloid-specific knockout mice, fracture and nerve regeneration models, macrophage polarization assays, AAV rescue, MG53-MVP K63-ubiquitination assays","pmids":["37267856","41961488"],"confidence":"Medium","gaps":["Direct MVP–STAT6 mechanistic coupling incompletely defined","Relationship of K63 ubiquitination site to function partly correlative"]},{"year":2025,"claim":"Demonstrated MVP controls effector protein stability, binding β-TrCP to stabilize PD-L1 and being itself stabilized by TG2 transamidase activity to drive ERK-dependent EMT.","evidence":"Co-IP, cycloheximide-chase, ubiquitination assays, site-directed mutagenesis/truncations, ChIP-seq, TG2 inhibitor NC9, organoids, xenografts","pmids":["40983342","41238097"],"confidence":"High","gaps":["How MVP blocks β-TrCP substrate engagement structurally unclear","Crosstalk between MVP-stabilizing PTMs not integrated"]},{"year":2025,"claim":"Established MVP as a node in ferroptosis regulation through RNA binding and transcription-factor sequestration, with PGAM5 dephosphorylation enabling LCN2 mRNA stabilization and IRF1 interactions reprogramming NOX4/YAP1/FSP1 transcription.","evidence":"Phosphatase and RNA-protein binding assays, ferroptosis/lipid peroxidation assays, ChIP, co-IP, ubiquitination assays, tenapanor inhibition, in vivo models","pmids":["40262414","39143889","41782382"],"confidence":"Medium","gaps":["Context-dependent pro- vs anti-ferroptotic roles not reconciled","RNA-binding specificity determinants on MVP undefined"]},{"year":2025,"claim":"Clarified MVP's relationship to drug handling beyond classical MDR, showing mechanosensitive Notch signaling upregulates MVP to facilitate nuclear chemotherapeutic export, and that succinylation reversed by SIRT7 regulates MVP-driven JAK2/STAT3 oncogenic signaling.","evidence":"MVP knockdown, Notch/contractility manipulation, nuclear drug export assays, succinylation/SIRT7 assays, JAK2/STAT3 analysis, xenografts","pmids":["40333760","40586636"],"confidence":"Medium","gaps":["Physical mechanism of nuclear drug export by MVP undefined","How succinylation alters MVP stability/interactions mechanistically unclear"]},{"year":null,"claim":"How MVP toggles between an assembled vault particle and a diffuse signaling/transport/RNA-binding scaffold, and which functions require intact vaults versus free MVP, remains the central unresolved question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No study directly tests vault-assembly dependence of signaling/transport roles","Unifying regulatory logic across PTMs and partners not established","Structural basis of cargo/partner selectivity unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,8,11,16]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[10,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[14,18,26]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,13,16]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[16,17]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,8,11,14,23]},{"term_id":"R-HSA-392499","term_label":"Metabolism of 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remodeling in the regulation of MVP.","date":"2004","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/15093136","citation_count":9,"is_preprint":false},{"pmid":"24490868","id":"PMC_24490868","title":"Biochemical and structural analysis of the hyperpolarization-activated K(+) channel MVP.","date":"2014","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24490868","citation_count":9,"is_preprint":false},{"pmid":"37157906","id":"PMC_37157906","title":"PD-L1 expression predicts efficacy in the phase II SPiReL trial with MVP-S, pembrolizumab, and low-dose CPA in R/R DLBCL.","date":"2023","source":"European journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/37157906","citation_count":8,"is_preprint":false},{"pmid":"35328603","id":"PMC_35328603","title":"Analysis of Multiple Drug Resistance Mechanism in Different Types of Soft Tissue Sarcomas: Assessment of the Expression of ABC-Transporters, MVP, YB-1, and Analysis of Their Correlation with Chemosensitivity of Cancer Cells.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35328603","citation_count":7,"is_preprint":false},{"pmid":"1659842","id":"PMC_1659842","title":"Influence of pretreatment clinical characteristics on the response rate to mitomycin/vindesine/cisplatin (MVP) in unresectable non-small cell lung cancer. ATTIT (Association pour le Traitement des Tumeurs Intra-Thoraciques).","date":"1991","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/1659842","citation_count":7,"is_preprint":false},{"pmid":"27301292","id":"PMC_27301292","title":"Connection between Proliferation Rate and Temozolomide Sensitivity of Primary Glioblastoma Cell Culture and Expression of YB-1 and LRP/MVP.","date":"2016","source":"Biochemistry. Biokhimiia","url":"https://pubmed.ncbi.nlm.nih.gov/27301292","citation_count":6,"is_preprint":false},{"pmid":"9570378","id":"PMC_9570378","title":"Advanced non-small cell lung cancer chemotherapy: a randomized trial of two active regimens (MVP and PE).","date":"1997","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/9570378","citation_count":6,"is_preprint":false},{"pmid":"29307622","id":"PMC_29307622","title":"MVP immunohistochemistry is a useful adjunct in distinguishing leiomyosarcoma from leiomyoma and leiomyoma with bizarre nuclei.","date":"2018","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/29307622","citation_count":6,"is_preprint":false},{"pmid":"29362508","id":"PMC_29362508","title":"Inhibition of RM-1 prostate carcinoma and eliciting robust immune responses in the mouse model by using VEGF-M2-GnRH3-hinge-MVP vaccine.","date":"2018","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/29362508","citation_count":6,"is_preprint":false},{"pmid":"8075028","id":"PMC_8075028","title":"Comparison of two chemotherapeutic regimens--mitomycin + vindesine + cisplatin (MVP) vs. mitomycin + ifosfamide + cisplatin (MIP)--in advanced non-small-cell lung cancer. ONCOPAZ Cooperative Group.","date":"1994","source":"Annals of oncology : official journal of the European Society for Medical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/8075028","citation_count":6,"is_preprint":false},{"pmid":"40333760","id":"PMC_40333760","title":"Intercellular contractile force attenuates chemosensitivity through Notch-MVP-mediated nuclear drug export.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/40333760","citation_count":5,"is_preprint":false},{"pmid":"37267856","id":"PMC_37267856","title":"Macrophage MVP regulates fracture repair by promoting M2 polarization via JAK2-STAT6 pathway.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37267856","citation_count":5,"is_preprint":false},{"pmid":"12622134","id":"PMC_12622134","title":"Major vault protein/lung resistance-related protein (MVP/LRP) expression in nervous system tumors.","date":"2002","source":"Brain tumor pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12622134","citation_count":5,"is_preprint":false},{"pmid":"35173287","id":"PMC_35173287","title":"Role of upfront autologous stem cell transplantation in patients newly diagnosed with primary CNS lymphoma treated with R-MVP: real-world data from a retrospective single-center analysis.","date":"2022","source":"Bone marrow transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/35173287","citation_count":5,"is_preprint":false},{"pmid":"8695157","id":"PMC_8695157","title":"Is the MVP regimen less active than previously described? Results of a phase II study in advanced non-small cell lung cancer.","date":"1996","source":"Acta oncologica (Stockholm, Sweden)","url":"https://pubmed.ncbi.nlm.nih.gov/8695157","citation_count":5,"is_preprint":false},{"pmid":"26476776","id":"PMC_26476776","title":"Absence of association between major vault protein (MVP) gene polymorphisms and drug resistance in Chinese Han patients with partial epilepsy.","date":"2015","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26476776","citation_count":4,"is_preprint":false},{"pmid":"39348965","id":"PMC_39348965","title":"MiR-140-3p Improves Sensitivity to Docetaxel by Suppressing PD-L1/ABCG2/MVP Expression in Lung Adenocarcinoma.","date":"2024","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/39348965","citation_count":3,"is_preprint":false},{"pmid":"38762090","id":"PMC_38762090","title":"Design and pilot results from the Million Veteran Program Return Of Actionable Results (MVP-ROAR) Study.","date":"2024","source":"American heart journal","url":"https://pubmed.ncbi.nlm.nih.gov/38762090","citation_count":3,"is_preprint":false},{"pmid":"40127180","id":"PMC_40127180","title":"DS-MVP: identifying disease-specific pathogenicity of missense variants by pre-training representation.","date":"2025","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/40127180","citation_count":2,"is_preprint":false},{"pmid":"39472282","id":"PMC_39472282","title":"Proteomic Analysis of Microsomal Proteins Reveals That MVP Is Crucial for the Secretion of GDF-15, Which in Turn Promotes the Neuroendocrine Differentiation of PCa Cells.","date":"2024","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/39472282","citation_count":2,"is_preprint":false},{"pmid":"7693990","id":"PMC_7693990","title":"Adjuvant chemotherapy for invasive urothelial cancer: experience with a methotrexate, vincristine, cisplatin, cyclophosphamide, adriamycin and bleomycin (MVP-CAB) regimen: a preliminary report.","date":"1993","source":"Japanese journal of clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/7693990","citation_count":2,"is_preprint":false},{"pmid":"1279258","id":"PMC_1279258","title":"[Adjuvant chemotherapy with MVP-CAB (methotrexate, vincristine, cisplatinum, cyclophosphamide, adriamycin and bleomycin) for epithelial tumors of the upper urinary tract].","date":"1992","source":"Nihon Hinyokika Gakkai zasshi. The japanese journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/1279258","citation_count":2,"is_preprint":false},{"pmid":"40586636","id":"PMC_40586636","title":"SIRT7-Mediated MVP Desuccinylation Facilitates Tongue Squamous Cell Carcinoma Progression by Activating JAK2/STAT3 Pathway.","date":"2025","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/40586636","citation_count":1,"is_preprint":false},{"pmid":"40840450","id":"PMC_40840450","title":"Phenome-wide association study of male and female sex chromosome trisomies in 1.5 million participants of MVP, FinnGen, and UK Biobank.","date":"2025","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40840450","citation_count":1,"is_preprint":false},{"pmid":"41238097","id":"PMC_41238097","title":"Transglutaminase 2 facilitates metastasis of basal-like bladder cancer by sustaining MVP-mediated MAPK/ERK1/2 signaling activation.","date":"2025","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/41238097","citation_count":1,"is_preprint":false},{"pmid":"41064595","id":"PMC_41064595","title":"VIRUS-MVP: a framework for comprehensive surveillance of viral mutations and their functional impacts.","date":"2025","source":"NAR genomics and bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/41064595","citation_count":1,"is_preprint":false},{"pmid":"39974076","id":"PMC_39974076","title":"Prevalence and disease risks for male and female sex chromosome trisomies: a registry-based phenome-wide association study in 1.5 million participants of MVP, FinnGen, and UK Biobank.","date":"2025","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39974076","citation_count":1,"is_preprint":false},{"pmid":"23258135","id":"PMC_23258135","title":"Does reducing unnecessary right ventricular pacing improve sympathetic activity and innervation of heart in sinus node disease patients? MVP and SafeR study.","date":"2012","source":"International heart journal","url":"https://pubmed.ncbi.nlm.nih.gov/23258135","citation_count":1,"is_preprint":false},{"pmid":"2168091","id":"PMC_2168091","title":"Preliminary experience with mitomycin, vinblastine and cisplatin (MVP) combination chemotherapy in the treatment of advanced non-small cell lung cancer at University Hospital, Kuala Lumpur.","date":"1990","source":"Singapore medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/2168091","citation_count":1,"is_preprint":false},{"pmid":"41782382","id":"PMC_41782382","title":"MVP Inhibits Influenza A Virus-Induced Ferroptosis by Targeting IRF1 and Increasing FSP1 Activity.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41782382","citation_count":0,"is_preprint":false},{"pmid":"3049286","id":"PMC_3049286","title":"Understanding mitral valve prolapse (MVP).","date":"1988","source":"Herz","url":"https://pubmed.ncbi.nlm.nih.gov/3049286","citation_count":0,"is_preprint":false},{"pmid":"40950669","id":"PMC_40950669","title":"Investigation into the sensitivity of adipocytes mediated by the major vault protein (MVP) to chemotherapy for triple-negative breast cancer.","date":"2025","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/40950669","citation_count":0,"is_preprint":false},{"pmid":"15087034","id":"PMC_15087034","title":"[Prospective randomized study of HMVP, MVP, and HVP regimens in treatment of advanced non-small cell lung cancer].","date":"2004","source":"Ai zheng = Aizheng = Chinese journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/15087034","citation_count":0,"is_preprint":false},{"pmid":"41961488","id":"PMC_41961488","title":"MG53 Coordinates Macrophage Polarization and Neuroimmune Coupling to Promote Corneal Nerve Regeneration via the MPEG1-MVP-STAT6 Axis.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41961488","citation_count":0,"is_preprint":false},{"pmid":"12520749","id":"PMC_12520749","title":"[Comparison of NP and MVP regimen in treatment of advanced non-small cell lung cancer].","date":"2002","source":"Ai zheng = Aizheng = Chinese journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/12520749","citation_count":0,"is_preprint":false},{"pmid":"12795837","id":"PMC_12795837","title":"[Establishment of human multidrug-resistant lung carcinoma cell line (D6/MVP)].","date":"2003","source":"Zhonghua zhong liu za zhi [Chinese journal of oncology]","url":"https://pubmed.ncbi.nlm.nih.gov/12795837","citation_count":0,"is_preprint":false},{"pmid":"21251408","id":"PMC_21251408","title":"[Efficacy of MVP chemotherapy combined with concurrent radiotherapy for advanced non-small cell lung cancer].","date":"2004","source":"Zhongguo fei ai za zhi = Chinese journal of lung cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21251408","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50709,"output_tokens":6822,"usd":0.127228,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16155,"output_tokens":5571,"usd":0.110025,"stage2_stop_reason":"end_turn"},"total_usd":0.237253,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"Cryoelectron microscopy and single-particle image reconstruction of recombinant and tissue-derived vaults revealed that 48 copies of MVP form each half-vault (96 total), with all MVP N-termini interacting non-covalently at the vault midsection. Co-expression of MVP with VPARP or TEP1 results in their co-assembly into vaults. VPARP was localized by cryoEM difference mapping to three density bands lining the inner surface of the vault.\",\n      \"method\": \"Cryoelectron microscopy, single-particle image reconstruction, recombinant co-expression in insect cells\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct structural determination with multiple recombinant constructs and difference mapping; replicated across wild-type and TEP1-deficient mouse vaults\",\n      \"pmids\": [\"15504404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Crystal structure of the seven N-terminal repeat domains (R1-R7) of MVP at 2.1 Å resolution, together with 8 Å vault particle structure, revealed that the interactions governing vault half-association are mediated by the N-terminal domains R1-R2, and that vault halves dissociate reversibly at acidic pH through disruption of these interactions.\",\n      \"method\": \"X-ray crystallography (2.1 Å structure of R1-R7), electron microscopy (8 Å vault particle structure)\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic resolution crystal structure with functional validation of pH-dependent dissociation mechanism\",\n      \"pmids\": [\"19779459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Newly synthesized MVP requires more than 4 hours to be incorporated into vault particles, whereas VPARP is completely incorporated within 1.5 hours. Once incorporated, both MVP and VPARP are very stable. Expression of MVP alone in E. coli produces particles with vault morphology, and the C-terminal region of VPARP lacking polyADP-ribose polymerase activity co-sediments with MVP self-assembled vault-like particles, indicating VPARP polymerase activity is not required for interaction with MVP.\",\n      \"method\": \"Immunoprecipitation pulse-chase assay, E. coli expression reconstitution, co-sedimentation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution in E. coli plus biochemical pulse-chase and co-sedimentation; multiple orthogonal methods in single study\",\n      \"pmids\": [\"15567158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"YB-1 (Y-box binding protein-1) directly binds the Y-box element in the MVP gene promoter and controls basal and 5-fluorouracil-induced MVP expression. 5-FU amplified YB-1 binding activity to the Y-box in a time-dependent manner. Stable YB-1 overexpression enhanced binding and increased basal and 5-FU-inducible MVP promoter-driven reporter expression. YB-1 cDNA transduction led to increased endogenous MVP protein expression.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), ChIP, MVP promoter-reporter deletion mutants, YB-1 stable overexpression, YB-1 cDNA transduction\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (EMSA, ChIP, reporter assays, overexpression) in a single lab study\",\n      \"pmids\": [\"15750632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SP-family transcription factors (Sp1, Sp3) bind a conserved proximal GC-box element essential for basal human MVP promoter transactivation. Dominant-negative Sp1 and mithramycin A attenuated MVP promoter activity. HDAC inhibitors (butyrate, trichostatin A) potently stimulated MVP expression by shifting Sp1 to Sp3 occupancy at this GC-box, demonstrated by ChIP assays.\",\n      \"method\": \"EMSA, ChIP, MVP promoter deletion/mutation analysis, dominant-negative Sp1, mithramycin A treatment, HDAC inhibitor treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (EMSA, ChIP, reporter mutagenesis) in a single lab with consistent results\",\n      \"pmids\": [\"15047174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The LRP130 protein binds the invMED1 cis-element located at -148/-143 in the MVP gene promoter and is involved in transcriptional activation of MVP. SiRNA knockdown of LRP130 and transcriptional decoys targeting invMED1 reduced endogenous MVP gene activity in two unrelated human cancer cell lines.\",\n      \"method\": \"siRNA knockdown, transcriptional decoy competition, promoter-reporter assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — siRNA and reporter assays in two cell lines but single lab, no direct biochemical binding confirmation for MVP promoter\",\n      \"pmids\": [\"15272088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Drug resistance in multi-drug resistant cancer cell lines is not caused by vault gene amplification. Treatment with HDAC inhibitors (sodium butyrate, trichostatin A) increased MVP mRNA, protein, and promoter activity, suggesting chromatin remodeling regulates MVP upregulation in MDR.\",\n      \"method\": \"Gene copy number analysis, RT-PCR, Western blot, promoter-reporter assays, HDAC inhibitor treatment\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple methods (gene copy number, promoter activity, mRNA/protein) in single lab; functional promoter assays supporting mechanism\",\n      \"pmids\": [\"15093136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MVP physically interacts with YPEL4 and inhibits YPEL4-mediated activation of Elk-1 in the MAPK signaling pathway. The interaction was confirmed by yeast two-hybrid, mammalian two-hybrid, GST pull-down, co-immunoprecipitation, and immunocytochemistry. Reporter assays showed MVP suppresses YPEL4-driven transcriptional activity through the ERK pathway.\",\n      \"method\": \"Yeast two-hybrid, mammalian two-hybrid, GST pull-down, co-immunoprecipitation, immunocytochemistry, reporter gene assay\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal binding assays plus functional reporter readout; single lab\",\n      \"pmids\": [\"20555386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MVP interacts with zinc finger protein ZNF540 as identified by yeast two-hybrid screening and confirmed by co-immunoprecipitation. ZNF540 represses SRE and ELK-1 transcriptional activities, and MVP is identified as a MAPK scaffold protein in this pathway.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, reporter gene assay (SRE, ELK-1), siRNA knockdown\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reciprocal co-IP with functional readout but single lab, single study\",\n      \"pmids\": [\"16815308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MVP/LRP knockout mice are viable, healthy, and show no obvious abnormalities. MVP-deficient embryonic stem cells and bone marrow cells showed no increased sensitivity to cytostatic agents compared to wild-type cells. ABC-transporter activities (P-glycoprotein, MRP, BCRP) were unaltered upon MVP deletion. MVP knockout mice responded to doxorubicin treatment similarly to wild-type mice.\",\n      \"method\": \"MVP knockout mouse generation, cytotoxicity assays (embryonic stem cells, bone marrow), ABC-transporter activity assays, in vivo doxorubicin treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple drug sensitivity readouts; negative result (no direct role in cytostatic drug resistance) replicated across cell types and in vivo\",\n      \"pmids\": [\"12499273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MVP mediates selective sorting of miR-193a into exosomes. Knockout of MVP leads to miR-193a accumulation in donor cells instead of exosomes, inhibiting tumor progression. Accumulated miR-193a causes G1 cell cycle arrest and represses proliferation by targeting Caprin1, which upregulates Ccnd2 and c-Myc.\",\n      \"method\": \"MVP knockout, exosomal miRNA profiling, cell cycle analysis, target validation (Caprin1, Ccnd2, c-Myc)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with mechanistic pathway validation (exosomal sorting + downstream target identification) using multiple methods\",\n      \"pmids\": [\"28211508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"B7-H3 interacts with MVP as identified by immunoprecipitation and mass spectrometry. MVP enhances B-RAF and MEK interaction to activate MEK signaling. B7-H3-induced MEK activation and cancer stem cell enrichment are blocked by MVP depletion.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, MVP siRNA knockdown, MEK pathway analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP/MS identification of interaction plus siRNA functional validation; single lab\",\n      \"pmids\": [\"30082909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"14-3-3ε binds to MVP in a phosphorylation-dependent manner at both Thr52 and Ser864 of the MVP monomer. This interaction is induced by bleomycin treatment and inhibits the drug-resistant activity of MVP, enhancing the DNA damage response.\",\n      \"method\": \"LC-MS/MS proteomics, co-immunoprecipitation, phosphorylation site identification, functional drug resistance assays\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — MS-based interactome with phosphorylation site mapping and functional validation; single lab\",\n      \"pmids\": [\"23590642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Zebrafish MVP interacts with TBK1 and recruits it from a uniformly distributed cytoplasmic state to an aggregated state, then mediates lysosome-dependent degradation of TBK1. This suppresses IFN production downstream of RIG-I-like receptor signaling.\",\n      \"method\": \"Co-immunoprecipitation, overexpression studies, lysosome inhibitor treatment, IFN reporter assays, viral infection experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP with mechanistic follow-up (lysosome-dependent degradation) but single lab, zebrafish ortholog\",\n      \"pmids\": [\"30530482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MVP negatively regulates osteoclastogenesis via inhibition of calcineurin-NFATc1 signaling. MVP deficiency enhances calcineurin-NFATc1 signaling and promotes osteoclast differentiation and bone resorption. Calcineurin inhibition with FK506 corrected the enhanced osteoclastogenesis in MVP knockout mice. MVP re-expression in knockout mice rescued calcineurin expression.\",\n      \"method\": \"Total body and monocyte-specific MVP knockout mice, micro-CT, bone histomorphometry, in vitro osteoclast differentiation assays, FK506 treatment, AAV-mediated MVP re-expression\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO (two mouse models) with pathway identification, pharmacological rescue, and AAV re-expression validation\",\n      \"pmids\": [\"34158848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MVP interacts with death receptor Fas in osteoclasts, and the MVP-Fas signaling cascade positively regulates osteoclast apoptosis. Conditional MVP knockout in monocyte lineage inhibited osteoclast apoptosis in vivo and in vitro, leading to osteoporosis in aging and estrogen-deficient mouse models.\",\n      \"method\": \"Conditional MVP knockout mice (Mvpf/fLyz2-Cre), co-immunoprecipitation (MVP-Fas interaction), in vivo and in vitro apoptosis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined cellular phenotype plus co-IP identification of binding partner; single lab\",\n      \"pmids\": [\"37704623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MVP translocates PTPN18 from cytoplasm to nucleus together with importin β2 in breast cancer cells. Nuclear PTPN18 (but not cytoplasmic) dephosphorylates ETS1 and promotes its degradation, suppressing TGF-β signaling and EMT.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, MVP overexpression/knockdown, PTPN18 localization studies\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP and localization experiments with functional pathway validation; single lab, single study\",\n      \"pmids\": [\"35982039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MVP is a cargo protein of the nuclear import receptor KPNA7. KPNA7 silencing hindered MVP transport to the nucleus. MVP knockdown caused marked reduction in pancreatic cancer cell growth.\",\n      \"method\": \"Protein affinity chromatography, co-immunoprecipitation, siRNA-mediated KPNA7 silencing, cell growth assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — affinity chromatography and co-IP for binding, siRNA for functional validation; single lab\",\n      \"pmids\": [\"27664836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MVP binds β-TrCP and prevents β-TrCP-mediated proteasomal degradation of PD-L1, thereby stabilizing PD-L1 protein. Histone lactylation transcriptionally upregulates MVP. Site-directed mutagenesis and truncation mutants identified the binding sites of the MVP-β-TrCP complex.\",\n      \"method\": \"Co-immunoprecipitation, cycloheximide-chase analysis, ubiquitination assay, site-directed mutagenesis, truncation mutants, ChIP-seq\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical reconstitution of binding with mutagenesis, ubiquitination assays, and protein stability assays; multiple orthogonal methods in single study\",\n      \"pmids\": [\"40983342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PGAM5 directly dephosphorylates MVP at Ser873, facilitating MVP binding to LCN2 mRNA and maintaining its stability. This attenuates ferroptosis by reducing lipid peroxidation and intracellular Fe²⁺. Tenapanor disrupts the MVP-LCN2 mRNA interaction. ROS-induced STAT3 transcriptionally activates MVP expression in HCC.\",\n      \"method\": \"Phosphatase assay (PGAM5-MVP), RNA-protein binding assay (MVP-LCN2 mRNA), ferroptosis assays, STAT3 ChIP, tenapanor inhibition\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct dephosphorylation and RNA binding assays with multiple orthogonal methods; single lab\",\n      \"pmids\": [\"40262414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MVP binds IRF1 and interferes with IRF1 interaction with the YAP1 promoter, leading to increased NOX4 transcription and enhanced lipid peroxidation. This promotes FGF21-induced ferroptosis in HCC cells. MVP knockdown reduced NOX4 transcription and attenuated FGF21-mediated ferroptosis.\",\n      \"method\": \"Co-immunoprecipitation (MVP-IRF1), ChIP assay (IRF1-YAP1 promoter), MVP knockdown/overexpression, ferroptosis/lipid peroxidation assays, xenograft models\",\n      \"journal\": \"Clinical and translational science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP and ChIP with functional ferroptosis readout; single lab\",\n      \"pmids\": [\"39143889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TG2 binds MVP and stabilizes it by inhibiting ubiquitin-proteasomal degradation in a transamidase activity-dependent manner. Accumulation of MVP facilitates MAPK/ERK1/2 signaling activation, inducing EMT and metastasis in basal-like bladder cancer.\",\n      \"method\": \"Co-immunoprecipitation (TG2-MVP), ubiquitination assays, proteasome inhibitor treatment, TG2 catalytic inhibitor NC9, ERK signaling analysis, patient-derived organoids, in vivo xenograft\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assays, and pharmacological inhibition with multiple functional readouts; single lab but orthogonal methods\",\n      \"pmids\": [\"41238097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MVP undergoes succinylation modification; SIRT7 is the desuccinylase for MVP and promotes MVP protein stability in TSCC cells. Desuccinylated MVP activates JAK2/STAT3 pathway to promote TSCC cell proliferation, migration, and invasion. JAK2 agonist CA1 reversed the effects of MVP silencing.\",\n      \"method\": \"Succinylation assay, SIRT7 co-expression/knockdown, Western blot (MVP stability), JAK2/STAT3 pathway analysis, functional cell assays\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — PTM identification and desuccinylase assignment with functional rescue; single lab\",\n      \"pmids\": [\"40586636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MVP promotes M2 macrophage polarization during fracture repair via the JAK2-STAT6 pathway. Myeloid-specific MVP knockout mice showed impaired transition from pro-inflammatory to anti-inflammatory macrophage phenotype, increased pro-inflammatory cytokines, enhanced osteoclastogenesis, and impaired fracture healing. AAV-Mvp injection rescued fracture repair.\",\n      \"method\": \"Myeloid-specific MVP knockout mice (Mvpf/fLyz2-Cre), in vivo fracture model, macrophage polarization assays, cytokine measurement, JAK2-STAT6 pathway analysis, AAV rescue\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined mechanistic pathway and AAV rescue; single lab\",\n      \"pmids\": [\"37267856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Intercellular force activates Notch signaling which upregulates MVP expression, and MVP facilitates export of chemotherapy drugs from nuclei. Inhibition of contractile force, Notch signaling, or MVP each reversed drug export and restored chemosensitivity in vitro and in vivo.\",\n      \"method\": \"MVP knockdown, Notch inhibition, contractility manipulation, nuclear drug export assays, xenograft tumor models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway (force→Notch→MVP→drug export) with multiple inhibition strategies and in vivo validation; single lab\",\n      \"pmids\": [\"40333760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MVP-associated Filamin A mutations (G288R, P637Q, H743P) abolish FlnA/PTPN12 (PTP-PEST) interactions. Loss of this interaction impairs activation of PTPN12 substrates Src and p190RhoGAP, affecting focal adhesion signaling and actin cytoskeleton dynamics in the context of mitral valve prolapse pathogenesis.\",\n      \"method\": \"Yeast two-hybrid, pull-down, co-immunoprecipitation, kinase activity assays (Src, p190RhoGAP)\",\n      \"journal\": \"Journal of cardiovascular development and disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — this paper concerns MVP (mitral valve prolapse) disease-associated FLNA mutations, not the major vault protein; excluded as off-target\",\n      \"pmids\": [\"26594644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MVP sequesters IRF1 from TRAF6, suppressing IRF1 polyubiquitination and nuclear localization during IAV infection. This prevents IRF1 transcriptional repression of the FSP1 promoter, thereby increasing FSP1 expression and plasma membrane recruitment, enabling ferroptosis suppression.\",\n      \"method\": \"Co-immunoprecipitation (MVP-IRF1, IRF1-TRAF6), ubiquitination assay, FSP1 promoter reporter, in vitro and in vivo ferroptosis assays, myristoylation/membrane recruitment assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP and mechanistic pathway validation with functional ferroptosis readout; single lab, single study\",\n      \"pmids\": [\"41782382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MG53 interacts with MVP and promotes K63-linked ubiquitination of MVP at lysine 747, facilitating STAT6 nuclear translocation and transcriptional activation of M2 macrophage genes to promote corneal nerve regeneration.\",\n      \"method\": \"Co-immunoprecipitation (MG53-MVP), K63-ubiquitination assay, STAT6 nuclear translocation assay, genome-wide Membrane Proteome Array screen, in vivo nerve regeneration model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP with site-specific ubiquitination and functional nuclear translocation assay; single lab\",\n      \"pmids\": [\"41961488\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MVP (major vault protein) is the dominant structural component (~70%) of barrel-shaped vault ribonucleoprotein particles, forming 48-subunit half-vaults whose assembly and reversible pH-dependent dissociation are governed by N-terminal repeat domains; it acts as a scaffold that recruits VPARP and TEP1 into the complex, mediates nuclear-cytoplasmic transport of cargo proteins (including PTPN18 via importin β2), facilitates exosomal sorting of miRNAs, modulates multiple signaling pathways (MAPK/ERK, calcineurin-NFATc1, JAK2-STAT6, JAK2-STAT3) through protein-protein interactions with partners including TBK1, IRF1, B7-H3, YPEL4, 14-3-3ε, and β-TrCP, undergoes post-translational modifications including phosphorylation (by upstream kinases, read by 14-3-3ε at Thr52/Ser864) and succinylation (reversed by SIRT7), and can facilitate nuclear drug export downstream of mechanosensitive Notch signaling, though direct involvement in classical multidrug resistance via ABC transporters is not supported by genetic knockout studies.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MVP (major vault protein) is the dominant structural subunit of barrel-shaped vault ribonucleoprotein particles, with 48 copies forming each half-vault and all N-termini interacting non-covalently at the vault midsection; co-expression with VPARP or TEP1 recruits these partners into the assembled particle [#0]. The N-terminal repeat domains R1-R2 mediate half-vault association, and these contacts are disrupted reversibly at acidic pH, providing a pH-gated dissociation mechanism resolved at atomic resolution [#1]. MVP alone is sufficient to self-assemble vault-shaped particles, and interaction with VPARP is independent of VPARP polymerase activity [#2]. Beyond its structural role, MVP functions as a multipurpose protein-protein interaction scaffold that tunes signaling: it binds YPEL4 and ZNF540 to modulate MAPK/ERK–Elk-1 transcriptional output [#7, #8], and its stabilization (e.g., by transglutaminase TG2) drives MAPK/ERK1/2-dependent EMT and metastasis [#21]. MVP regulates intracellular trafficking, mediating nuclear import of cargoes including PTPN18 with importin β2 to suppress TGF-β/EMT signaling [#16], and is itself a cargo of the import receptor KPNA7 [#17]. MVP controls protein stability of signaling effectors, binding β-TrCP to protect PD-L1 from proteasomal degradation [#18] and shaping ferroptosis through interactions with IRF1 that redirect transcription of NOX4, YAP1, and FSP1 [#20, #26]. In bone and immune contexts, MVP restrains calcineurin–NFATc1 osteoclastogenesis [#14], couples to Fas to promote osteoclast apoptosis [#15], and promotes JAK-STAT-driven M2 macrophage polarization [#23, #27]. MVP also directs selective sorting of miR-193a into exosomes, with loss causing intracellular miR-193a accumulation and Caprin1-dependent cell-cycle arrest [#10]. MVP activity is regulated by phosphorylation read by 14-3-3ε at Thr52/Ser864 [#12] and by succinylation reversed by SIRT7 [#22]. Notably, genetic knockout established that MVP is not required for classical ABC-transporter–mediated multidrug resistance [#9], although it can facilitate nuclear chemotherapeutic export downstream of mechanosensitive Notch signaling [#24].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the quaternary architecture of the vault and showed MVP is the self-sufficient scaffold that recruits accessory proteins, defining the particle's building principle.\",\n      \"evidence\": \"CryoEM single-particle reconstruction of recombinant and tissue vaults with VPARP/TEP1 co-expression and difference mapping\",\n      \"pmids\": [\"15504404\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve atomic contacts of half-vault association\", \"Functional consequence of VPARP/TEP1 recruitment not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated MVP alone assembles vault-shaped particles and that VPARP incorporation does not require its polymerase activity, separating structural assembly from enzymatic function.\",\n      \"evidence\": \"E. coli expression reconstitution, pulse-chase immunoprecipitation, and co-sedimentation\",\n      \"pmids\": [\"15567158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Slow MVP incorporation kinetics mechanism unexplained\", \"Assembly chaperones not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Localized the half-vault association interface to N-terminal repeats R1-R2 and defined a reversible pH-dependent dissociation mechanism, providing a structural basis for vault opening/cargo release.\",\n      \"evidence\": \"2.1 Å crystal structure of R1-R7 plus 8 Å vault particle EM\",\n      \"pmids\": [\"19779459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological trigger for in vivo dissociation unknown\", \"Cargo loading/release coupling to pH change not shown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined the transcriptional control of MVP via Sp1/Sp3 GC-box occupancy and LRP130/invMED1, and showed chromatin remodeling (HDAC inhibition) rather than gene amplification drives MVP upregulation in MDR cells.\",\n      \"evidence\": \"EMSA, ChIP, promoter mutagenesis, dominant-negative Sp1, siRNA, copy-number analysis, HDAC inhibitor treatment\",\n      \"pmids\": [\"15047174\", \"15272088\", \"15093136\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between MVP induction and drug resistance not established\", \"Upstream signals coordinating these factors unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified YB-1 as a sequence-specific activator of basal and chemotherapy-inducible MVP transcription, linking stress-responsive transcription factors to MVP expression.\",\n      \"evidence\": \"EMSA, ChIP, promoter-reporter deletions, YB-1 overexpression/transduction\",\n      \"pmids\": [\"15750632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional outcome of 5-FU-induced MVP on drug response not tested\", \"Signaling that activates YB-1 binding undefined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Resolved whether MVP confers classical multidrug resistance: genetic knockout showed normal drug sensitivity and unchanged ABC-transporter activity, excluding MVP as a primary MDR effector.\",\n      \"evidence\": \"MVP knockout mice, cytotoxicity assays in ES/bone marrow cells, ABC-transporter activity assays, in vivo doxorubicin\",\n      \"pmids\": [\"12499273\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Context-specific drug handling roles not excluded\", \"Compensatory mechanisms in KO not characterized\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Recast MVP as a signaling scaffold by showing it binds YPEL4 and ZNF540 to modulate MAPK/ERK–Elk-1/SRE transcriptional activity, beyond a purely structural role.\",\n      \"evidence\": \"Yeast/mammalian two-hybrid, GST pull-down, co-IP, immunocytochemistry, SRE/ELK-1 reporter assays, siRNA\",\n      \"pmids\": [\"20555386\", \"16815308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether scaffolding occurs on intact vaults or free MVP unclear\", \"Endogenous physiological relevance not established in vivo\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed MVP function is regulated by phosphorylation, with 14-3-3ε binding phospho-Thr52/Ser864 to inhibit drug-resistant activity and enhance DNA damage response.\",\n      \"evidence\": \"LC-MS/MS, co-IP, phosphosite mapping, bleomycin treatment, drug resistance assays\",\n      \"pmids\": [\"23590642\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream kinase not identified\", \"Mechanism linking 14-3-3ε binding to DNA damage response undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established a non-structural trafficking role: MVP selectively sorts miR-193a into exosomes, and its loss traps the miRNA intracellularly to impose Caprin1-dependent cell-cycle arrest.\",\n      \"evidence\": \"MVP knockout, exosomal miRNA profiling, cell-cycle analysis, Caprin1/Ccnd2/c-Myc target validation\",\n      \"pmids\": [\"28211508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity determinant for miR-193a sorting unknown\", \"Whether vault assembly is required for sorting unaddressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended MVP scaffolding to immune signaling and oncogenic MEK activation, binding TBK1 to drive its lysosomal degradation (zebrafish) and bridging B7-H3 to B-RAF/MEK.\",\n      \"evidence\": \"Co-IP, mass spectrometry, siRNA, IFN reporter and viral infection assays, MEK pathway analysis\",\n      \"pmids\": [\"30530482\", \"30082909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TBK1 degradation finding is in zebrafish ortholog\", \"Direct vs indirect B7-H3–MVP binding not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined MVP as a nuclear transport mediator, importing PTPN18 with importin β2 to dephosphorylate ETS1 and suppress TGF-β/EMT, and being itself a KPNA7 cargo required for cancer growth.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, overexpression/knockdown, affinity chromatography, cell growth assays\",\n      \"pmids\": [\"35982039\", \"27664836\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of MVP as an import adaptor for other cargoes unknown\", \"Role of vault particle vs free MVP in transport unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed MVP's physiological role in bone homeostasis, restraining calcineurin–NFATc1 osteoclastogenesis and later coupling to Fas to drive osteoclast apoptosis, with knockout causing osteoporosis.\",\n      \"evidence\": \"Total-body and monocyte-specific knockout mice, micro-CT, histomorphometry, FK506 rescue, AAV re-expression, co-IP\",\n      \"pmids\": [\"34158848\", \"37704623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between MVP and calcineurin regulation not fully defined\", \"Whether MVP-Fas acts directly or via adaptors unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected MVP to macrophage fate, promoting JAK2-STAT6-driven M2 polarization important for fracture repair and corneal nerve regeneration.\",\n      \"evidence\": \"Myeloid-specific knockout mice, fracture and nerve regeneration models, macrophage polarization assays, AAV rescue, MG53-MVP K63-ubiquitination assays\",\n      \"pmids\": [\"37267856\", \"41961488\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MVP–STAT6 mechanistic coupling incompletely defined\", \"Relationship of K63 ubiquitination site to function partly correlative\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated MVP controls effector protein stability, binding β-TrCP to stabilize PD-L1 and being itself stabilized by TG2 transamidase activity to drive ERK-dependent EMT.\",\n      \"evidence\": \"Co-IP, cycloheximide-chase, ubiquitination assays, site-directed mutagenesis/truncations, ChIP-seq, TG2 inhibitor NC9, organoids, xenografts\",\n      \"pmids\": [\"40983342\", \"41238097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How MVP blocks β-TrCP substrate engagement structurally unclear\", \"Crosstalk between MVP-stabilizing PTMs not integrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established MVP as a node in ferroptosis regulation through RNA binding and transcription-factor sequestration, with PGAM5 dephosphorylation enabling LCN2 mRNA stabilization and IRF1 interactions reprogramming NOX4/YAP1/FSP1 transcription.\",\n      \"evidence\": \"Phosphatase and RNA-protein binding assays, ferroptosis/lipid peroxidation assays, ChIP, co-IP, ubiquitination assays, tenapanor inhibition, in vivo models\",\n      \"pmids\": [\"40262414\", \"39143889\", \"41782382\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependent pro- vs anti-ferroptotic roles not reconciled\", \"RNA-binding specificity determinants on MVP undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Clarified MVP's relationship to drug handling beyond classical MDR, showing mechanosensitive Notch signaling upregulates MVP to facilitate nuclear chemotherapeutic export, and that succinylation reversed by SIRT7 regulates MVP-driven JAK2/STAT3 oncogenic signaling.\",\n      \"evidence\": \"MVP knockdown, Notch/contractility manipulation, nuclear drug export assays, succinylation/SIRT7 assays, JAK2/STAT3 analysis, xenografts\",\n      \"pmids\": [\"40333760\", \"40586636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physical mechanism of nuclear drug export by MVP undefined\", \"How succinylation alters MVP stability/interactions mechanistically unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MVP toggles between an assembled vault particle and a diffuse signaling/transport/RNA-binding scaffold, and which functions require intact vaults versus free MVP, remains the central unresolved question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No study directly tests vault-assembly dependence of signaling/transport roles\", \"Unifying regulatory logic across PTMs and partners not established\", \"Structural basis of cargo/partner selectivity unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 8, 11, 16]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [10, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [14, 18, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 13, 16]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [16, 17]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 8, 11, 14, 23]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [18, 21, 22]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [16, 17]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [15, 19, 20, 26]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13, 23, 26, 27]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [10, 19]}\n    ],\n    \"complexes\": [\"vault ribonucleoprotein particle\"],\n    \"partners\": [\"VPARP\", \"TEP1\", \"YPEL4\", \"14-3-3\\u03b5\", \"B7-H3\", \"IRF1\", \"BTRC\", \"TBK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":10,"faith_total":10,"faith_pct":100.0}}