Affinage

MARVELD3

MARVEL domain-containing protein 3 · UniProt Q96A59

Length
401 aa
Mass
44.9 kDa
Annotated
2026-04-28
15 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2009 High

    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

    PMID:20028514

    Open questions at the time
    • Molecular partners at the junction not yet identified
    • Mechanism by which MARVELD3 regulates TER unknown
    • In vivo relevance not tested
  2. 2010 High

    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

    PMID:20164257

    Open questions at the time
    • Structural basis for partial compensation unclear
    • Which protein–protein interactions underlie compensation not resolved
  3. 2011 Medium

    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

    PMID:21763689

    Open questions at the time
    • Transcriptional regulation mechanism (direct Snail binding to MARVELD3 promoter) not shown
    • Generalizability beyond pancreatic cancer cells untested
  4. 2012 High

    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

    PMID:23203797

    Open questions at the time
    • Trans-interactions across opposing membranes not addressed
    • Binding domains mediating cis-interactions not mapped
    • Stoichiometry of TAMP–claudin complexes undetermined
  5. 2014 High

    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

    PMID:24567356

    Open questions at the time
    • 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
  6. 2016 Medium

    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

    PMID:27870636

    Open questions at the time
    • Cell-type specificity of JNK dependence in eye development unclear
    • Mammalian developmental phenotype not assessed
  7. 2018 Medium

    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

    PMID:29352236

    Open questions at the time
    • Whether MARVELD3 acts in neural crest cells autonomously or via neighboring epithelia not determined
    • No mammalian neural crest data
  8. 2022 Medium

    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

    PMID:35563847

    Open questions at the time
    • Mechanism of colitis protection (proliferation/survival vs. barrier) not dissected
    • Which STAT family member mediates transcription not specified
  9. 2025 Medium

    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

    PMID:41319938

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No structural model of MARVELD3 or its complexes
  • No mammalian genetic knockout phenotype characterized
  • Mechanism connecting junctional pool to nuclear signaling undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-1500931 Cell-Cell communication 3 R-HSA-162582 Signal Transduction 3
Partners
CLDN1CLDN3MAP3K1MARVELD2MYBOCLN
Complex memberships
TAMP complex (with occludin and tricellulin)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 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. Immunofluorescence co-localization, RNA interference (siRNA knockdown), transepithelial electrical resistance measurements, sequence/domain analysis BMC cell biology High 20028514
2010 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. siRNA knockdown, immunofluorescence, electron microscopy, FRAP (fluorescence recovery after photobleaching), co-immunoprecipitation, in vivo immune activation model Molecular biology of the cell High 20164257
2012 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. FRET (fluorescence resonance energy transfer), FRAP, freeze-fracture electron microscopy, co-transfection in HEK-293 cells Journal of cell science High 23203797
2014 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. siRNA knockdown, overexpression in metastatic cell line, in vivo tumor formation assay, co-immunoprecipitation (MEKK1 recruitment), JNK phosphorylation assays, migration/proliferation assays The Journal of cell biology High 24567356
2011 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. siRNA knockdown, transepithelial electrical resistance, fluorescent dextran permeability assay, Snail overexpression model, TGF-β treatment Experimental cell research Medium 21763689
2016 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. Morpholino knockdown in Xenopus, small molecule JNK modulation, rescue with ectopic MarvelD3 expression, gene expression analysis Biology open Medium 27870636
2018 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. Morpholino knockdown in Xenopus, explant cultures, small molecule JNK inhibitor, mutant mRNA rescue experiments, genetic epistasis Scientific reports Medium 29352236
2021 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. MarvelD3 knockdown/overexpression in HCC cells, migration assays, Western blot for NF-κB pathway components, EMT marker analysis Cell adhesion & migration Low 34338154
2022 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. Cytokine treatment with pathway inhibitor analysis (IL13Rα1/STAT), transgenic mouse model with intestinal MD3 overexpression, DSS colitis model, electrophysiological barrier measurements Cells Medium 35563847
2023 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. MARVELD3 knockdown/overexpression in NSCLC cells, migration assays, Western blot for Wnt/β-catenin pathway components and EMT markers, TGF-β1 treatment model Thoracic cancer Low 36924014
2024 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. siRNA knockdown, RNA sequencing, MDA/Fe2+/ROS assays, BODIPY staining for lipid peroxidation, KEGG/GO pathway analysis Molecular medicine Low 39434056
2025 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. Co-immunoprecipitation (MarvelD3-MYB interaction), dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), RNA-sequencing, in vitro and in vivo knockdown models Cellular signalling Medium 41319938
2025 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. siRNA knockdown, overexpression, proliferation/colony formation/Transwell assays, RNA-seq, Western blotting, qPCR Bioorganic chemistry Low 41237572

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Tight junction-associated MARVEL proteins marveld3, tricellulin, and occludin have distinct but overlapping functions. Molecular biology of the cell 259 20164257
2009 Identification of MarvelD3 as a tight junction-associated transmembrane protein of the occludin family. BMC cell biology 145 20028514
2012 In tight junctions, claudins regulate the interactions between occludin, tricellulin and marvelD3, which, inversely, modulate claudin oligomerization. Journal of cell science 140 23203797
2014 MarvelD3 couples tight junctions to the MEKK1-JNK pathway to regulate cell behavior and survival. The Journal of cell biology 62 24567356
2011 Downregulation of tight junction-associated MARVEL protein marvelD3 during epithelial-mesenchymal transition in human pancreatic cancer cells. Experimental cell research 48 21763689
2021 Spatio-temporal expression pattern and role of the tight junction protein MarvelD3 in pancreas development and function. Scientific reports 13 34267243
2018 Control of neural crest induction by MarvelD3-mediated attenuation of JNK signalling. Scientific reports 11 29352236
2023 MARVELD3 inhibits the epithelial-mesenchymal transition and cell migration by suppressing the Wnt/β-catenin signaling pathway in non-small cell lung cancer cells. Thoracic cancer 10 36924014
2021 Role of tight junction-associated MARVEL protein marvelD3 in migration and epithelial-mesenchymal transition of hepatocellular carcinoma. Cell adhesion & migration 10 34338154
2016 MarvelD3 regulates the c-Jun N-terminal kinase pathway during eye development in Xenopus. Biology open 8 27870636
2022 MarvelD3 Is Upregulated in Ulcerative Colitis and Has Attenuating Effects during Colitis Indirectly Stabilizing the Intestinal Barrier. Cells 5 35563847
2024 Upregulation of PRRX2 by silencing Marveld3 as a protective mechanism against radiation-induced ferroptosis in skin cells. Molecular medicine (Cambridge, Mass.) 4 39434056
2025 R-loop accumulation promotes OSCC malignant progression by upregulating MARVELD3 expression. Bioorganic chemistry 1 41237572
2026 Relationship of Serum Tricellulin, MarvelD3, and Tumor Necrosis Factor-Alpha Levels With Obsessive-Compulsive Disorder Severity in Children and Adolescents. Journal of the Korean Academy of Child and Adolescent Psychiatry 0 41969415
2025 MarvelD3 regulates the radiosensitivity of Esophageal squamous cell carcinoma via the MYB/IFI6 axis. Cellular signalling 0 41319938