{"gene":"MARVELD3","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2009,"finding":"MarvelD3 is a four-span transmembrane tight junction protein containing a MARVEL domain, expressed as two alternatively spliced isoforms. It co-localizes with occludin at tight junctions in intestinal and corneal epithelial cells. siRNA knockdown in Caco-2 cells increases transepithelial electrical resistance, indicating MarvelD3 functions as a determinant of epithelial paracellular permeability.","method":"Immunofluorescence co-localization, RNA interference (siRNA knockdown), transepithelial electrical resistance measurements, sequence/domain analysis","journal":"BMC cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (localization, KD, functional readout); independently corroborated by subsequent studies","pmids":["20028514"],"is_preprint":false},{"year":2010,"finding":"MarvelD3 (along with occludin and tricellulin) defines the tight junction-associated MARVEL protein (TAMP) family, with distinct but overlapping functions. MarvelD3 can partially compensate for occludin or tricellulin loss at tight junctions but cannot fully restore barrier function. Dynamic behavior was characterized by FRAP and intracellular trafficking assays, and MarvelD3 undergoes remodeling after in vivo immune activation.","method":"siRNA knockdown, immunofluorescence, electron microscopy, FRAP (fluorescence recovery after photobleaching), co-immunoprecipitation, in vivo immune activation model","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including FRAP, EM, Co-IP, and functional rescue experiments; highly cited foundational study","pmids":["20164257"],"is_preprint":false},{"year":2012,"finding":"MarvelD3 forms homophilic cis-interactions along one plasma membrane, and also cis-interacts heterophilically with occludin and tricellulin, as measured by FRET. Classic claudins (claudin-1 to -5) cis-oligomerize with MarvelD3 and other TAMPs, reducing their membrane mobility (measured by FRAP), whereas non-classic claudin-11 does not. Claudins regulate TAMP interactions and, inversely, TAMPs modulate claudin oligomerization and strand morphology.","method":"FRET (fluorescence resonance energy transfer), FRAP, freeze-fracture electron microscopy, co-transfection in HEK-293 cells","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal biophysical methods (FRET, FRAP, freeze-fracture EM) in a single study; highly cited","pmids":["23203797"],"is_preprint":false},{"year":2014,"finding":"MarvelD3 recruits MEKK1 to tight junctions, leading to down-regulation of JNK phosphorylation and inhibition of JNK-regulated transcriptional mechanisms. Loss of MarvelD3 increases cell migration and proliferation; re-expression in metastatic tumor cells inhibits migration, proliferation, and in vivo tumor formation. During osmotic stress, MarvelD3 internalization modulates MEKK1 activation and JNK activity, and MarvelD3-depleted cells undergo junction dissociation and cell death.","method":"siRNA knockdown, overexpression in metastatic cell line, in vivo tumor formation assay, co-immunoprecipitation (MEKK1 recruitment), JNK phosphorylation assays, migration/proliferation assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP showing MEKK1 interaction, multiple functional readouts (migration, proliferation, in vivo tumor), replicated in Xenopus studies","pmids":["24567356"],"is_preprint":false},{"year":2011,"finding":"MarvelD3 is transcriptionally downregulated during Snail-induced epithelial-mesenchymal transition in pancreatic cancer cells (under hypoxia, TGF-β treatment, or FOXA2 knockdown). siRNA depletion of marvelD3 in HPAC cells decreases transepithelial electrical resistance and increases paracellular permeability to fluorescent dextran, but does not affect the fence function of tight junctions.","method":"siRNA knockdown, transepithelial electrical resistance, fluorescent dextran permeability assay, Snail overexpression model, TGF-β treatment","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined functional readouts (TER, permeability), but single lab and cell-type specific","pmids":["21763689"],"is_preprint":false},{"year":2016,"finding":"MarvelD3 depletion in Xenopus causes abnormal eye pigmentation or absence of eye development, linked to deregulated expression of cell-cycle regulators and transcription factors. The eye phenotype is rescued by increased JNK activation (not inhibition), placing MarvelD3 as a negative modulator of JNK in eye morphogenesis context.","method":"Morpholino knockdown in Xenopus, small molecule JNK modulation, rescue with ectopic MarvelD3 expression, gene expression analysis","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis in Xenopus with rescue experiments; single lab","pmids":["27870636"],"is_preprint":false},{"year":2018,"finding":"MarvelD3 depletion in Xenopus disrupts neural crest formation and development of neural crest-derived tissues. MarvelD3 is required to attenuate JNK signaling during neural crest induction; inhibition of JNK pathway activation rescues the MarvelD3-depletion phenotype. Direct JNK stimulation also disrupts neural crest development, confirming the importance of MarvelD3-mediated negative regulation of JNK.","method":"Morpholino knockdown in Xenopus, explant cultures, small molecule JNK inhibitor, mutant mRNA rescue experiments, genetic epistasis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with chemical rescue in Xenopus; single lab but orthogonal approaches","pmids":["29352236"],"is_preprint":false},{"year":2021,"finding":"MarvelD3 inhibits EMT and migration of hepatocellular carcinoma cells, associated with inhibition of the NF-κB signaling pathway. TGF-β1 and Snail/Slug-induced EMT downregulates MarvelD3.","method":"MarvelD3 knockdown/overexpression in HCC cells, migration assays, Western blot for NF-κB pathway components, EMT marker analysis","journal":"Cell adhesion & migration","confidence":"Low","confidence_rationale":"Tier 3 — single lab, limited mechanistic detail on NF-κB pathway connection, no direct binding or epistasis data","pmids":["34338154"],"is_preprint":false},{"year":2022,"finding":"IL-13 increases MarvelD3 expression in HT-29/B6 colon epithelial cells via the IL-13Rα1/STAT signaling pathway. In a DSS colitis mouse model, intestinal overexpression of MarvelD3 had a protective/ameliorating effect not directly attributable to enhanced paracellular barrier permeability, suggesting regulatory mechanisms involving proliferation and cell survival.","method":"Cytokine treatment with pathway inhibitor analysis (IL13Rα1/STAT), transgenic mouse model with intestinal MD3 overexpression, DSS colitis model, electrophysiological barrier measurements","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo mouse model plus identified upstream signaling pathway (IL13Rα1/STAT); single lab","pmids":["35563847"],"is_preprint":false},{"year":2023,"finding":"MARVELD3 overexpression in NSCLC cells inhibits TGF-β1-induced EMT and cell migration by suppressing the Wnt/β-catenin signaling pathway and its target genes MYC and CCND1.","method":"MARVELD3 knockdown/overexpression in NSCLC cells, migration assays, Western blot for Wnt/β-catenin pathway components and EMT markers, TGF-β1 treatment model","journal":"Thoracic cancer","confidence":"Low","confidence_rationale":"Tier 3 — single lab, mechanism linking MarvelD3 to Wnt/β-catenin not directly demonstrated (no binding or epistasis data)","pmids":["36924014"],"is_preprint":false},{"year":2024,"finding":"Silencing Marveld3 in irradiated skin cells inhibits lipid peroxidation and reduces intracellular Fe2+ levels, protecting against radiation-induced ferroptosis. Marveld3 knockdown upregulates PRRX2, which suppresses ferroptosis by reducing ROS and Fe2+ levels.","method":"siRNA knockdown, RNA sequencing, MDA/Fe2+/ROS assays, BODIPY staining for lipid peroxidation, KEGG/GO pathway analysis","journal":"Molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 — single lab, pathway placement is indirect (PRRX2 identified by RNA-seq but mechanistic link not fully validated)","pmids":["39434056"],"is_preprint":false},{"year":2025,"finding":"MarvelD3 interacts with MYB (shown by co-immunoprecipitation), and this regulatory relationship controls IFI6 transcription; MYB directly binds the IFI6 promoter (confirmed by dual-luciferase reporter and chromatin immunoprecipitation assays), thereby modulating radiosensitivity in esophageal squamous cell carcinoma via the MYB/IFI6 axis.","method":"Co-immunoprecipitation (MarvelD3-MYB interaction), dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), RNA-sequencing, in vitro and in vivo knockdown models","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus ChIP and reporter assays providing direct mechanistic evidence; single lab","pmids":["41319938"],"is_preprint":false},{"year":2025,"finding":"In OSCC, MARVELD3 promotes MAPK signaling pathway activation by suppressing expression of TTC9; MARVELD3 knockdown reduces proliferation, migration, and invasion, while overexpression enhances these characteristics.","method":"siRNA knockdown, overexpression, proliferation/colony formation/Transwell assays, RNA-seq, Western blotting, qPCR","journal":"Bioorganic chemistry","confidence":"Low","confidence_rationale":"Tier 3 — MAPK activation via TTC9 suppression is based on expression data; no direct binding shown between MARVELD3 and TTC9","pmids":["41237572"],"is_preprint":false}],"current_model":"MARVELD3 is a four-transmembrane MARVEL domain protein that localizes to epithelial and endothelial tight junctions, where it forms cis-interactions with occludin, tricellulin, and claudins to regulate paracellular permeability; its cytoplasmic domains recruit MEKK1 to the junction, thereby suppressing JNK phosphorylation and downstream transcriptional activity to control cell migration, proliferation, and survival, while also interacting with MYB to regulate IFI6 transcription."},"narrative":{"teleology":[{"year":2009,"claim":"Identification of MARVELD3 as a tight junction-resident MARVEL domain protein established that, beyond occludin and tricellulin, a third TAMP family member contributes to epithelial paracellular permeability.","evidence":"Immunofluorescence co-localization with occludin, siRNA knockdown in Caco-2 cells with TER measurement","pmids":["20028514"],"confidence":"High","gaps":["Molecular partners at the junction not yet identified","Mechanism by which MARVELD3 regulates TER unknown","In vivo relevance not tested"]},{"year":2010,"claim":"Defining the TAMP family and showing that MARVELD3 can partially compensate for occludin or tricellulin loss demonstrated functional overlap yet non-redundancy among MARVEL proteins at tight junctions.","evidence":"siRNA, FRAP, Co-IP, EM, and functional rescue in epithelial cell lines; in vivo immune activation model","pmids":["20164257"],"confidence":"High","gaps":["Structural basis for partial compensation unclear","Which protein–protein interactions underlie compensation not resolved"]},{"year":2011,"claim":"Showing that Snail-driven EMT transcriptionally silences MARVELD3 linked tight junction remodeling to the EMT program and confirmed MARVELD3 regulates paracellular barrier but not fence function.","evidence":"siRNA in HPAC cells, TER, dextran permeability, Snail overexpression and TGF-β/hypoxia models","pmids":["21763689"],"confidence":"Medium","gaps":["Transcriptional regulation mechanism (direct Snail binding to MARVELD3 promoter) not shown","Generalizability beyond pancreatic cancer cells untested"]},{"year":2012,"claim":"FRET-based demonstration of homophilic and heterophilic cis-interactions between MARVELD3, occludin, tricellulin, and classic claudins established the biophysical framework for how TAMPs and claudins cooperatively organize tight junction strands.","evidence":"FRET, FRAP, freeze-fracture EM in HEK-293 co-transfection system","pmids":["23203797"],"confidence":"High","gaps":["Trans-interactions across opposing membranes not addressed","Binding domains mediating cis-interactions not mapped","Stoichiometry of TAMP–claudin complexes undetermined"]},{"year":2014,"claim":"Discovery that MARVELD3 recruits MEKK1 to tight junctions and suppresses JNK signaling revealed a direct signaling function, explaining how junction integrity feeds back on migration, proliferation, and tumor suppression.","evidence":"Reciprocal Co-IP for MEKK1, JNK phosphorylation assays, siRNA and overexpression, in vivo tumor formation assay in metastatic cells","pmids":["24567356"],"confidence":"High","gaps":["Domain on MARVELD3 that binds MEKK1 not mapped","How MEKK1 junctional sequestration suppresses JNK mechanistically not fully resolved","Relevance of isoform-specific differences in signaling unknown"]},{"year":2016,"claim":"Morpholino knockdown in Xenopus demonstrated that MARVELD3 is required for eye morphogenesis through JNK regulation, extending its functional role from barrier maintenance to developmental signaling in vivo.","evidence":"Morpholino knockdown in Xenopus, JNK small-molecule modulation, rescue experiments","pmids":["27870636"],"confidence":"Medium","gaps":["Cell-type specificity of JNK dependence in eye development unclear","Mammalian developmental phenotype not assessed"]},{"year":2018,"claim":"Extension of the Xenopus model to neural crest formation confirmed MARVELD3 as a negative modulator of JNK during inductive signaling, with chemical JNK inhibition rescuing neural crest defects.","evidence":"Morpholino knockdown, explant culture, JNK inhibitor rescue, genetic epistasis in Xenopus","pmids":["29352236"],"confidence":"Medium","gaps":["Whether MARVELD3 acts in neural crest cells autonomously or via neighboring epithelia not determined","No mammalian neural crest data"]},{"year":2022,"claim":"Identification of IL-13/IL-13Rα1/STAT as an upstream inducer of MARVELD3 expression, combined with protective effects of intestinal MARVELD3 overexpression in a DSS colitis model, demonstrated physiological relevance beyond barrier permeability.","evidence":"Cytokine treatment with pathway inhibitors in HT-29/B6 cells, transgenic mouse intestinal overexpression, DSS colitis model","pmids":["35563847"],"confidence":"Medium","gaps":["Mechanism of colitis protection (proliferation/survival vs. barrier) not dissected","Which STAT family member mediates transcription not specified"]},{"year":2025,"claim":"Co-immunoprecipitation of MARVELD3 with MYB and demonstration that MYB directly activates IFI6 transcription revealed a nuclear signaling axis through which MARVELD3 modulates radiosensitivity.","evidence":"Co-IP, dual-luciferase reporter, ChIP for MYB on IFI6 promoter, RNA-seq, in vivo knockdown in ESCC","pmids":["41319938"],"confidence":"Medium","gaps":["Whether MARVELD3 enters the nucleus or sequesters MYB at junctions is unknown","Single lab, no reciprocal Co-IP reported for MYB","Direct binding versus complex-mediated association not resolved"]},{"year":null,"claim":"The structural basis of MARVELD3 interactions with MEKK1, claudins, and MYB remains unresolved, no mammalian knockout phenotype has been reported, and the mechanism linking junctional MARVELD3 to nuclear transcriptional outputs (MYB/IFI6 axis) is unknown.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of MARVELD3 or its complexes","No mammalian genetic knockout phenotype characterized","Mechanism connecting junctional pool to nuclear signaling undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,5,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,6]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,1,2]}],"complexes":["TAMP complex (with occludin and tricellulin)"],"partners":["OCLN","MARVELD2","CLDN1","CLDN3","MAP3K1","MYB"],"other_free_text":[]},"mechanistic_narrative":"MARVELD3 is a four-transmembrane MARVEL domain protein that functions at epithelial tight junctions to regulate paracellular permeability and transduce junctional signals that control cell migration, proliferation, and survival. It forms homophilic and heterophilic cis-interactions with the tight junction-associated MARVEL proteins (TAMPs) occludin and tricellulin, as well as with classic claudins, thereby modulating claudin oligomerization and tight junction strand morphology [PMID:23203797, PMID:20164257]. Its cytoplasmic domain recruits MEKK1 to tight junctions, suppressing JNK phosphorylation; loss of MARVELD3 hyperactivates JNK signaling, increasing cell migration and proliferation, while re-expression in metastatic cells inhibits tumor growth in vivo [PMID:24567356, PMID:27870636, PMID:29352236]. MARVELD3 is transcriptionally downregulated during Snail-driven epithelial-mesenchymal transition, and its expression is protective in colitis models through mechanisms beyond barrier integrity alone [PMID:21763689, PMID:35563847]."},"prefetch_data":{"uniprot":{"accession":"Q96A59","full_name":"MARVEL domain-containing protein 3","aliases":[],"length_aa":401,"mass_kda":44.9,"function":"As a component of tight junctions, plays a role in paracellular ion conductivity","subcellular_location":"Membrane; Cell junction, tight junction","url":"https://www.uniprot.org/uniprotkb/Q96A59/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MARVELD3","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MARVELD3","total_profiled":1310},"omim":[{"mim_id":"614094","title":"MARVEL DOMAIN-CONTAINING PROTEIN 3; MARVELD3","url":"https://www.omim.org/entry/614094"},{"mim_id":"611162","title":"MALARIA, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/611162"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Intermediate filaments","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":31.2}],"url":"https://www.proteinatlas.org/search/MARVELD3"},"hgnc":{"alias_symbol":[],"prev_symbol":["MRVLDC3"]},"alphafold":{"accession":"Q96A59","domains":[{"cath_id":"-","chopping":"200-228_247-399","consensus_level":"high","plddt":87.352,"start":200,"end":399}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96A59","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96A59-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96A59-F1-predicted_aligned_error_v6.png","plddt_mean":66.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MARVELD3","jax_strain_url":"https://www.jax.org/strain/search?query=MARVELD3"},"sequence":{"accession":"Q96A59","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96A59.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96A59/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96A59"}},"corpus_meta":[{"pmid":"20164257","id":"PMC_20164257","title":"Tight junction-associated MARVEL proteins marveld3, tricellulin, and occludin have distinct but overlapping functions.","date":"2010","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/20164257","citation_count":259,"is_preprint":false},{"pmid":"20028514","id":"PMC_20028514","title":"Identification of MarvelD3 as a tight junction-associated transmembrane protein of the occludin family.","date":"2009","source":"BMC cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20028514","citation_count":145,"is_preprint":false},{"pmid":"23203797","id":"PMC_23203797","title":"In tight junctions, claudins regulate the interactions between occludin, tricellulin and marvelD3, which, inversely, modulate claudin oligomerization.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/23203797","citation_count":140,"is_preprint":false},{"pmid":"24567356","id":"PMC_24567356","title":"MarvelD3 couples tight junctions to the MEKK1-JNK pathway to regulate cell behavior and survival.","date":"2014","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/24567356","citation_count":62,"is_preprint":false},{"pmid":"21763689","id":"PMC_21763689","title":"Downregulation of tight junction-associated MARVEL protein marvelD3 during epithelial-mesenchymal transition in human pancreatic cancer cells.","date":"2011","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/21763689","citation_count":48,"is_preprint":false},{"pmid":"34267243","id":"PMC_34267243","title":"Spatio-temporal expression pattern and role of the tight junction protein MarvelD3 in pancreas development and function.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34267243","citation_count":13,"is_preprint":false},{"pmid":"29352236","id":"PMC_29352236","title":"Control of neural crest induction by MarvelD3-mediated attenuation of JNK signalling.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29352236","citation_count":11,"is_preprint":false},{"pmid":"34338154","id":"PMC_34338154","title":"Role of tight junction-associated MARVEL protein marvelD3 in migration and epithelial-mesenchymal transition of hepatocellular carcinoma.","date":"2021","source":"Cell adhesion & migration","url":"https://pubmed.ncbi.nlm.nih.gov/34338154","citation_count":10,"is_preprint":false},{"pmid":"36924014","id":"PMC_36924014","title":"MARVELD3 inhibits the epithelial-mesenchymal transition and cell migration by suppressing the Wnt/β-catenin signaling pathway in non-small cell lung cancer cells.","date":"2023","source":"Thoracic cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36924014","citation_count":10,"is_preprint":false},{"pmid":"27870636","id":"PMC_27870636","title":"MarvelD3 regulates the c-Jun N-terminal kinase pathway during eye development in Xenopus.","date":"2016","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/27870636","citation_count":8,"is_preprint":false},{"pmid":"35563847","id":"PMC_35563847","title":"MarvelD3 Is Upregulated in Ulcerative Colitis and Has Attenuating Effects during Colitis Indirectly Stabilizing the Intestinal Barrier.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35563847","citation_count":5,"is_preprint":false},{"pmid":"39434056","id":"PMC_39434056","title":"Upregulation of PRRX2 by silencing Marveld3 as a protective mechanism against radiation-induced ferroptosis in skin cells.","date":"2024","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/39434056","citation_count":4,"is_preprint":false},{"pmid":"41237572","id":"PMC_41237572","title":"R-loop accumulation promotes OSCC malignant progression by upregulating MARVELD3 expression.","date":"2025","source":"Bioorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41237572","citation_count":1,"is_preprint":false},{"pmid":"41319938","id":"PMC_41319938","title":"MarvelD3 regulates the radiosensitivity of Esophageal squamous cell carcinoma via the MYB/IFI6 axis.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/41319938","citation_count":0,"is_preprint":false},{"pmid":"41969415","id":"PMC_41969415","title":"Relationship of Serum Tricellulin, MarvelD3, and Tumor Necrosis Factor-Alpha Levels With Obsessive-Compulsive Disorder Severity in Children and Adolescents.","date":"2026","source":"Journal of the Korean Academy of Child and Adolescent Psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/41969415","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.27.684895","title":"Pharmacologic activation of HNF4α/γ Restores Epithelial Barrier Function in Crohn’s disease","date":"2025-10-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.27.684895","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9462,"output_tokens":3305,"usd":0.038981},"stage2":{"model":"claude-opus-4-6","input_tokens":6713,"output_tokens":2363,"usd":0.13896},"total_usd":0.177941,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"MarvelD3 is a four-span transmembrane tight junction protein containing a MARVEL domain, expressed as two alternatively spliced isoforms. It co-localizes with occludin at tight junctions in intestinal and corneal epithelial cells. siRNA knockdown in Caco-2 cells increases transepithelial electrical resistance, indicating MarvelD3 functions as a determinant of epithelial paracellular permeability.\",\n      \"method\": \"Immunofluorescence co-localization, RNA interference (siRNA knockdown), transepithelial electrical resistance measurements, sequence/domain analysis\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (localization, KD, functional readout); independently corroborated by subsequent studies\",\n      \"pmids\": [\"20028514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MarvelD3 (along with occludin and tricellulin) defines the tight junction-associated MARVEL protein (TAMP) family, with distinct but overlapping functions. MarvelD3 can partially compensate for occludin or tricellulin loss at tight junctions but cannot fully restore barrier function. Dynamic behavior was characterized by FRAP and intracellular trafficking assays, and MarvelD3 undergoes remodeling after in vivo immune activation.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, electron microscopy, FRAP (fluorescence recovery after photobleaching), co-immunoprecipitation, in vivo immune activation model\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including FRAP, EM, Co-IP, and functional rescue experiments; highly cited foundational study\",\n      \"pmids\": [\"20164257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MarvelD3 forms homophilic cis-interactions along one plasma membrane, and also cis-interacts heterophilically with occludin and tricellulin, as measured by FRET. Classic claudins (claudin-1 to -5) cis-oligomerize with MarvelD3 and other TAMPs, reducing their membrane mobility (measured by FRAP), whereas non-classic claudin-11 does not. Claudins regulate TAMP interactions and, inversely, TAMPs modulate claudin oligomerization and strand morphology.\",\n      \"method\": \"FRET (fluorescence resonance energy transfer), FRAP, freeze-fracture electron microscopy, co-transfection in HEK-293 cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biophysical methods (FRET, FRAP, freeze-fracture EM) in a single study; highly cited\",\n      \"pmids\": [\"23203797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MarvelD3 recruits MEKK1 to tight junctions, leading to down-regulation of JNK phosphorylation and inhibition of JNK-regulated transcriptional mechanisms. Loss of MarvelD3 increases cell migration and proliferation; re-expression in metastatic tumor cells inhibits migration, proliferation, and in vivo tumor formation. During osmotic stress, MarvelD3 internalization modulates MEKK1 activation and JNK activity, and MarvelD3-depleted cells undergo junction dissociation and cell death.\",\n      \"method\": \"siRNA knockdown, overexpression in metastatic cell line, in vivo tumor formation assay, co-immunoprecipitation (MEKK1 recruitment), JNK phosphorylation assays, migration/proliferation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP showing MEKK1 interaction, multiple functional readouts (migration, proliferation, in vivo tumor), replicated in Xenopus studies\",\n      \"pmids\": [\"24567356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MarvelD3 is transcriptionally downregulated during Snail-induced epithelial-mesenchymal transition in pancreatic cancer cells (under hypoxia, TGF-β treatment, or FOXA2 knockdown). siRNA depletion of marvelD3 in HPAC cells decreases transepithelial electrical resistance and increases paracellular permeability to fluorescent dextran, but does not affect the fence function of tight junctions.\",\n      \"method\": \"siRNA knockdown, transepithelial electrical resistance, fluorescent dextran permeability assay, Snail overexpression model, TGF-β treatment\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined functional readouts (TER, permeability), but single lab and cell-type specific\",\n      \"pmids\": [\"21763689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MarvelD3 depletion in Xenopus causes abnormal eye pigmentation or absence of eye development, linked to deregulated expression of cell-cycle regulators and transcription factors. The eye phenotype is rescued by increased JNK activation (not inhibition), placing MarvelD3 as a negative modulator of JNK in eye morphogenesis context.\",\n      \"method\": \"Morpholino knockdown in Xenopus, small molecule JNK modulation, rescue with ectopic MarvelD3 expression, gene expression analysis\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis in Xenopus with rescue experiments; single lab\",\n      \"pmids\": [\"27870636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MarvelD3 depletion in Xenopus disrupts neural crest formation and development of neural crest-derived tissues. MarvelD3 is required to attenuate JNK signaling during neural crest induction; inhibition of JNK pathway activation rescues the MarvelD3-depletion phenotype. Direct JNK stimulation also disrupts neural crest development, confirming the importance of MarvelD3-mediated negative regulation of JNK.\",\n      \"method\": \"Morpholino knockdown in Xenopus, explant cultures, small molecule JNK inhibitor, mutant mRNA rescue experiments, genetic epistasis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with chemical rescue in Xenopus; single lab but orthogonal approaches\",\n      \"pmids\": [\"29352236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MarvelD3 inhibits EMT and migration of hepatocellular carcinoma cells, associated with inhibition of the NF-κB signaling pathway. TGF-β1 and Snail/Slug-induced EMT downregulates MarvelD3.\",\n      \"method\": \"MarvelD3 knockdown/overexpression in HCC cells, migration assays, Western blot for NF-κB pathway components, EMT marker analysis\",\n      \"journal\": \"Cell adhesion & migration\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, limited mechanistic detail on NF-κB pathway connection, no direct binding or epistasis data\",\n      \"pmids\": [\"34338154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-13 increases MarvelD3 expression in HT-29/B6 colon epithelial cells via the IL-13Rα1/STAT signaling pathway. In a DSS colitis mouse model, intestinal overexpression of MarvelD3 had a protective/ameliorating effect not directly attributable to enhanced paracellular barrier permeability, suggesting regulatory mechanisms involving proliferation and cell survival.\",\n      \"method\": \"Cytokine treatment with pathway inhibitor analysis (IL13Rα1/STAT), transgenic mouse model with intestinal MD3 overexpression, DSS colitis model, electrophysiological barrier measurements\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse model plus identified upstream signaling pathway (IL13Rα1/STAT); single lab\",\n      \"pmids\": [\"35563847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MARVELD3 overexpression in NSCLC cells inhibits TGF-β1-induced EMT and cell migration by suppressing the Wnt/β-catenin signaling pathway and its target genes MYC and CCND1.\",\n      \"method\": \"MARVELD3 knockdown/overexpression in NSCLC cells, migration assays, Western blot for Wnt/β-catenin pathway components and EMT markers, TGF-β1 treatment model\",\n      \"journal\": \"Thoracic cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, mechanism linking MarvelD3 to Wnt/β-catenin not directly demonstrated (no binding or epistasis data)\",\n      \"pmids\": [\"36924014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Silencing Marveld3 in irradiated skin cells inhibits lipid peroxidation and reduces intracellular Fe2+ levels, protecting against radiation-induced ferroptosis. Marveld3 knockdown upregulates PRRX2, which suppresses ferroptosis by reducing ROS and Fe2+ levels.\",\n      \"method\": \"siRNA knockdown, RNA sequencing, MDA/Fe2+/ROS assays, BODIPY staining for lipid peroxidation, KEGG/GO pathway analysis\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, pathway placement is indirect (PRRX2 identified by RNA-seq but mechanistic link not fully validated)\",\n      \"pmids\": [\"39434056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MarvelD3 interacts with MYB (shown by co-immunoprecipitation), and this regulatory relationship controls IFI6 transcription; MYB directly binds the IFI6 promoter (confirmed by dual-luciferase reporter and chromatin immunoprecipitation assays), thereby modulating radiosensitivity in esophageal squamous cell carcinoma via the MYB/IFI6 axis.\",\n      \"method\": \"Co-immunoprecipitation (MarvelD3-MYB interaction), dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), RNA-sequencing, in vitro and in vivo knockdown models\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus ChIP and reporter assays providing direct mechanistic evidence; single lab\",\n      \"pmids\": [\"41319938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In OSCC, MARVELD3 promotes MAPK signaling pathway activation by suppressing expression of TTC9; MARVELD3 knockdown reduces proliferation, migration, and invasion, while overexpression enhances these characteristics.\",\n      \"method\": \"siRNA knockdown, overexpression, proliferation/colony formation/Transwell assays, RNA-seq, Western blotting, qPCR\",\n      \"journal\": \"Bioorganic chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — MAPK activation via TTC9 suppression is based on expression data; no direct binding shown between MARVELD3 and TTC9\",\n      \"pmids\": [\"41237572\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MARVELD3 is a four-transmembrane MARVEL domain protein that localizes to epithelial and endothelial tight junctions, where it forms cis-interactions with occludin, tricellulin, and claudins to regulate paracellular permeability; its cytoplasmic domains recruit MEKK1 to the junction, thereby suppressing JNK phosphorylation and downstream transcriptional activity to control cell migration, proliferation, and survival, while also interacting with MYB to regulate IFI6 transcription.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MARVELD3 is a four-transmembrane MARVEL domain protein that functions at epithelial tight junctions to regulate paracellular permeability and transduce junctional signals that control cell migration, proliferation, and survival. It forms homophilic and heterophilic cis-interactions with the tight junction-associated MARVEL proteins (TAMPs) occludin and tricellulin, as well as with classic claudins, thereby modulating claudin oligomerization and tight junction strand morphology [PMID:23203797, PMID:20164257]. Its cytoplasmic domain recruits MEKK1 to tight junctions, suppressing JNK phosphorylation; loss of MARVELD3 hyperactivates JNK signaling, increasing cell migration and proliferation, while re-expression in metastatic cells inhibits tumor growth in vivo [PMID:24567356, PMID:27870636, PMID:29352236]. MARVELD3 is transcriptionally downregulated during Snail-driven epithelial-mesenchymal transition, and its expression is protective in colitis models through mechanisms beyond barrier integrity alone [PMID:21763689, PMID:35563847].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of MARVELD3 as a tight junction-resident MARVEL domain protein established that, beyond occludin and tricellulin, a third TAMP family member contributes to epithelial paracellular permeability.\",\n      \"evidence\": \"Immunofluorescence co-localization with occludin, siRNA knockdown in Caco-2 cells with TER measurement\",\n      \"pmids\": [\"20028514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners at the junction not yet identified\", \"Mechanism by which MARVELD3 regulates TER unknown\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defining the TAMP family and showing that MARVELD3 can partially compensate for occludin or tricellulin loss demonstrated functional overlap yet non-redundancy among MARVEL proteins at tight junctions.\",\n      \"evidence\": \"siRNA, FRAP, Co-IP, EM, and functional rescue in epithelial cell lines; in vivo immune activation model\",\n      \"pmids\": [\"20164257\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for partial compensation unclear\", \"Which protein–protein interactions underlie compensation not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showing that Snail-driven EMT transcriptionally silences MARVELD3 linked tight junction remodeling to the EMT program and confirmed MARVELD3 regulates paracellular barrier but not fence function.\",\n      \"evidence\": \"siRNA in HPAC cells, TER, dextran permeability, Snail overexpression and TGF-β/hypoxia models\",\n      \"pmids\": [\"21763689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional regulation mechanism (direct Snail binding to MARVELD3 promoter) not shown\", \"Generalizability beyond pancreatic cancer cells untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"FRET-based demonstration of homophilic and heterophilic cis-interactions between MARVELD3, occludin, tricellulin, and classic claudins established the biophysical framework for how TAMPs and claudins cooperatively organize tight junction strands.\",\n      \"evidence\": \"FRET, FRAP, freeze-fracture EM in HEK-293 co-transfection system\",\n      \"pmids\": [\"23203797\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trans-interactions across opposing membranes not addressed\", \"Binding domains mediating cis-interactions not mapped\", \"Stoichiometry of TAMP–claudin complexes undetermined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that MARVELD3 recruits MEKK1 to tight junctions and suppresses JNK signaling revealed a direct signaling function, explaining how junction integrity feeds back on migration, proliferation, and tumor suppression.\",\n      \"evidence\": \"Reciprocal Co-IP for MEKK1, JNK phosphorylation assays, siRNA and overexpression, in vivo tumor formation assay in metastatic cells\",\n      \"pmids\": [\"24567356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain on MARVELD3 that binds MEKK1 not mapped\", \"How MEKK1 junctional sequestration suppresses JNK mechanistically not fully resolved\", \"Relevance of isoform-specific differences in signaling unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Morpholino knockdown in Xenopus demonstrated that MARVELD3 is required for eye morphogenesis through JNK regulation, extending its functional role from barrier maintenance to developmental signaling in vivo.\",\n      \"evidence\": \"Morpholino knockdown in Xenopus, JNK small-molecule modulation, rescue experiments\",\n      \"pmids\": [\"27870636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-type specificity of JNK dependence in eye development unclear\", \"Mammalian developmental phenotype not assessed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extension of the Xenopus model to neural crest formation confirmed MARVELD3 as a negative modulator of JNK during inductive signaling, with chemical JNK inhibition rescuing neural crest defects.\",\n      \"evidence\": \"Morpholino knockdown, explant culture, JNK inhibitor rescue, genetic epistasis in Xenopus\",\n      \"pmids\": [\"29352236\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MARVELD3 acts in neural crest cells autonomously or via neighboring epithelia not determined\", \"No mammalian neural crest data\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of IL-13/IL-13Rα1/STAT as an upstream inducer of MARVELD3 expression, combined with protective effects of intestinal MARVELD3 overexpression in a DSS colitis model, demonstrated physiological relevance beyond barrier permeability.\",\n      \"evidence\": \"Cytokine treatment with pathway inhibitors in HT-29/B6 cells, transgenic mouse intestinal overexpression, DSS colitis model\",\n      \"pmids\": [\"35563847\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of colitis protection (proliferation/survival vs. barrier) not dissected\", \"Which STAT family member mediates transcription not specified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Co-immunoprecipitation of MARVELD3 with MYB and demonstration that MYB directly activates IFI6 transcription revealed a nuclear signaling axis through which MARVELD3 modulates radiosensitivity.\",\n      \"evidence\": \"Co-IP, dual-luciferase reporter, ChIP for MYB on IFI6 promoter, RNA-seq, in vivo knockdown in ESCC\",\n      \"pmids\": [\"41319938\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MARVELD3 enters the nucleus or sequesters MYB at junctions is unknown\", \"Single lab, no reciprocal Co-IP reported for MYB\", \"Direct binding versus complex-mediated association not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of MARVELD3 interactions with MEKK1, claudins, and MYB remains unresolved, no mammalian knockout phenotype has been reported, and the mechanism linking junctional MARVELD3 to nuclear transcriptional outputs (MYB/IFI6 axis) is unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of MARVELD3 or its complexes\", \"No mammalian genetic knockout phenotype characterized\", \"Mechanism connecting junctional pool to nuclear signaling undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 6]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [\n      \"TAMP complex (with occludin and tricellulin)\"\n    ],\n    \"partners\": [\n      \"OCLN\",\n      \"MARVELD2\",\n      \"CLDN1\",\n      \"CLDN3\",\n      \"MAP3K1\",\n      \"MYB\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}