Affinage

POPDC1

Popeye domain-containing protein 1 · UniProt Q8NE79

Round 2 corrected
Length
360 aa
Mass
41.5 kDa
Annotated
2026-04-28
118 papers in source corpus 35 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

POPDC1 (BVES) is a three-transmembrane-domain protein that functions as a high-affinity cAMP effector, scaffolding adaptor, and regulator of cell junction integrity in striated muscle, epithelial tissues, and the cardiac conduction system. Its conserved cytoplasmic Popeye domain binds cAMP and nucleates a macromolecular complex with adenylyl cyclase 9 (AC9) and the TREK-1 potassium channel, thereby coupling β-adrenergic signaling to cardiac pacemaker activity; knockout or loss-of-function mutations cause stress-induced sinus node dysfunction, AV block, and limb-girdle muscular dystrophy (LGMDR25) (PMID:22354168, PMID:26642364, PMID:36254885). POPDC1 additionally maintains epithelial barrier integrity by interacting with ZO-1 and organizing the PAR polarity complex, suppresses Rho-family GTPase signaling through GEFT, facilitates VAMP3-dependent vesicular recycling of integrins and receptors, and negatively regulates ADCY9-cAMP-PKA-FoxO signaling to preserve skeletal muscle mass (PMID:16188940, PMID:18541910, PMID:20057356, PMID:36997581). In intestinal and cancer epithelia, POPDC1 acts as a tumour suppressor by restraining Wnt/β-catenin-driven stemness and promoting c-Myc degradation via PP2A (PMID:26891025, PMID:28389570, PMID:21911938).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1999 Medium

    Identification of POPDC1 as a conserved transmembrane protein enriched in developing heart and epicardium established it as a candidate cardiac/vascular differentiation marker whose function was unknown.

    Evidence Subtractive hybridization cloning with in situ and Northern blot in chick and mouse embryos; chromosomal mapping and topology prediction in human

    PMID:10208750 PMID:10441744

    Open questions at the time
    • No functional assay performed
    • Three-TM topology was predicted, not biochemically confirmed
  2. 2001 High

    Demonstration that POPDC1 localizes to lateral membranes at cell-cell contacts and confers adhesive behavior when expressed in non-adherent cells established it as a novel cell adhesion molecule required for epicardial cell migration.

    Evidence L-cell adhesion gain-of-function assay, antibody inhibition of proepicardial migration, immunofluorescence in polarized epithelial cells

    PMID:11493530

    Open questions at the time
    • Binding partner mediating adhesion unknown
    • Mechanism of adhesion (homophilic vs. heterophilic) not resolved
  3. 2003 High

    Biochemical resolution of POPDC1 membrane topology (extracellular N-terminus, three TM helices, cytoplasmic C-terminus) and identification of C-terminal-mediated homodimerization provided a structural framework for understanding how it organizes signaling complexes.

    Evidence N-linked glycosylation assays, engineered glycosylation sites, co-expression of C-terminal fragments, detergent permeabilization

    PMID:12815060

    Open questions at the time
    • Atomic structure of the Popeye domain not determined
    • Stoichiometry of homodimer unknown
  4. 2005 High

    Discovery of a direct ZO-1 interaction and the requirement for POPDC1 in maintaining transepithelial resistance linked POPDC1 to tight junction regulation, answering how a transmembrane adhesion molecule connects to junctional signaling.

    Evidence GST pull-down of ZO-1 with POPDC1 C-terminus, siRNA knockdown with TER measurement, co-localization with ZO-1 and occludin

    PMID:16188940

    Open questions at the time
    • Binding site on ZO-1 not mapped
    • Whether POPDC1 recruits ZO-1 or stabilizes existing complexes unclear
  5. 2008 High

    Mapping of the homodimerization motif (aa 268–274, K272/K273) and identification of GEFT as a binding partner that mediates Rac1/Cdc42 suppression revealed how POPDC1 integrates junction assembly with Rho-family GTPase signaling.

    Evidence SPOTs peptide array mutagenesis, TER and EMT readouts for dimerization mutants; co-IP of GEFT with Rac1/Cdc42 activity assays

    PMID:18493308 PMID:18541910

    Open questions at the time
    • Whether GEFT and ZO-1 bind simultaneously or competitively not tested
    • RhoA regulation showed conflicting directions across cell types (suppressed vs. enhanced depending on context)
  6. 2010 High

    Identification of VAMP3 as a direct POPDC1 partner and demonstration that POPDC1 is required for transferrin receptor and β1-integrin recycling established POPDC1 as a regulator of vesicular trafficking, explaining its role in cell migration and gastrulation.

    Evidence Co-immunoprecipitation with VAMP3, transferrin and integrin recycling assays, Xenopus morpholino knockdown with gastrulation phenotype

    PMID:20057356

    Open questions at the time
    • Whether POPDC1 acts as cargo adaptor or fusion factor not resolved
    • Connection between VAMP3-mediated recycling and tight junction maintenance not explored
  7. 2012 High

    The breakthrough discovery that the Popeye domain is a high-affinity cAMP-binding module and that POPDC1 regulates TREK-1 channel surface expression in a cAMP-dependent manner, with knockout mice developing stress-induced sinus bradycardia, unified POPDC1's molecular identity as a cAMP effector controlling cardiac pacemaking.

    Evidence Competitive radiolabeled cAMP-binding assays, co-IP with TREK-1, electrophysiology, Popdc1 and Popdc2 KO mice with ECG telemetry

    PMID:22354168

    Open questions at the time
    • Crystal structure of Popeye domain–cAMP complex unavailable
    • Whether POPDC1 directly gates TREK-1 or acts through trafficking only not fully resolved
  8. 2013 High

    Discovery that POPDC1 co-immunoprecipitates with caveolin-3 and is required for caveolae biogenesis (70% reduction in KO hearts) explained how POPDC1 loss increases cardiac vulnerability to ischemia/reperfusion injury.

    Evidence Co-IP and density-gradient co-sedimentation with caveolin-3, electron microscopy of caveolae, Langendorff I/R injury model in KO mice

    PMID:24066022

    Open questions at the time
    • Whether caveolae loss is cause or consequence of POPDC1 absence not distinguished
    • Stoichiometry and direct binding site between POPDC1 and caveolin-3 not mapped
  9. 2015 High

    Identification of a homozygous POPDC1(S201F) mutation in patients with cardiac arrhythmia and limb-girdle muscular dystrophy (LGMDR25), with 50% reduced cAMP affinity and impaired membrane trafficking of POPDC1-POPDC2 complexes, provided the first human genetic proof that POPDC1 cAMP-binding is essential for striated muscle and cardiac function.

    Evidence Whole-exome sequencing in patient family, cAMP-binding affinity assays, patient muscle immunofluorescence, HL-1 electrophysiology, zebrafish knock-in model

    PMID:26642364

    Open questions at the time
    • Whether S201F fully phenocopies null or is hypomorphic not resolved
    • Genotype-phenotype correlation across different POPDC1 mutations incomplete
  10. 2016 High

    Studies in intestinal epithelium and colitis-associated cancer demonstrated that POPDC1 negatively regulates Wnt-driven intestinal stem cell programs and promotes c-Myc degradation through PP2A, establishing a tumour-suppressive mechanism operating through two distinct pathways.

    Evidence Bves KO mice with Lgr5-EGFP reporter, 3D enteroid culture, AOM/DSS cancer model, yeast two-hybrid identification of PP2A interaction, c-Myc Western blot

    PMID:26891025 PMID:28389570

    Open questions at the time
    • How POPDC1-PP2A interaction is regulated by cAMP not tested
    • Whether Wnt suppression and c-Myc degradation are mechanistically linked or parallel not clarified
  11. 2022 High

    Reconstitution of the POPDC1–AC9–TREK-1 macromolecular complex showed that POPDC1 scaffolds AC9 independently of cAMP while β-adrenergic stimulation triggers AC9-dependent release of TREK-1, providing a detailed mechanism for how the sinoatrial pacemaker integrates sympathetic input.

    Evidence Co-purification with AC9 activity, TREK-1 current recordings, AC9 KO mice with ECG telemetry, β-adrenergic stimulation

    PMID:36254885

    Open questions at the time
    • Structural basis for AC9–POPDC1 interaction not resolved
    • Whether this ternary complex exists in non-cardiac tissues unknown
  12. 2022 High

    Mapping of the POPDC1-POPDC2 heteromeric interface to conserved hydrophobic residues at the Popeye domain C-terminus, using four independent interaction methods, revealed that disease-causing mutations disrupting this interface impair membrane trafficking more severely than those preserving it.

    Evidence Co-IP, PLA, BRET, BiFC with site-directed mutagenesis of conserved hydrophobic residues; patient biopsy immunostaining

    PMID:36624536

    Open questions at the time
    • Atomic-resolution structure of POPDC1-POPDC2 heterodimer unavailable
    • Whether POPDC3 uses the same interface not tested
  13. 2023 High

    Demonstration that POPDC1 negatively regulates ADCY9-cAMP-PKA signaling in skeletal muscle and that its loss activates FoxO-mediated proteolysis and autophagy causing muscle wasting—reversible by AAV-BVES gene replacement—defined the molecular basis of LGMDR25 muscle pathology.

    Evidence BVES KO mice, co-IP with ADCY9, cAMP/PKA activity assays, FoxO/proteasome/autophagy pathway analysis, AAV-mediated rescue of muscle mass and function

    PMID:36997581

    Open questions at the time
    • Whether POPDC1 directly inhibits AC9 catalytic activity or sequesters substrate not distinguished
    • Relative contributions of proteasome vs. autophagy to muscle loss not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic structure of the Popeye domain in complex with cAMP and partner proteins, the mechanistic basis for tissue-specific regulation of Rho GTPases versus cAMP/PKA pathways, and whether the diverse functions (junction maintenance, vesicular recycling, pacemaking, tumour suppression) are cAMP-dependent or represent cAMP-independent scaffolding roles.
  • No crystal or cryo-EM structure of the Popeye domain available
  • cAMP-dependence of ZO-1, VAMP3, and PP2A interactions not tested
  • Systematic interactome across tissues not performed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 3 GO:0098631 cell adhesion mediator activity 3
Localization
GO:0005886 plasma membrane 5 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1500931 Cell-Cell communication 3 R-HSA-1643685 Disease 3 R-HSA-397014 Muscle contraction 3 R-HSA-5653656 Vesicle-mediated transport 2
Partners
ADCY9CAV3GEFTKCNK2POPDC2TJP1VAMP3XIRP1
Complex memberships
POPDC1-AC9-TREK-1 pacemaker complexPOPDC1-POPDC2 heterodimer

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 BVES (blood vessel/epicardial substance, POPDC1) was identified as a novel, highly conserved transmembrane protein expressed at high levels in the developing heart, proepicardial organ, migrating epicardium, epicardial-derived mesenchyme, and smooth muscle of developing coronary arteries, suggesting a role as an early marker of vascular smooth muscle differentiation. Subtractive hybridization cloning, Northern blot, anti-Bves antibody immunostaining in chick and mouse embryos Developmental biology Medium 10208750
1999 Human BVES (hbves) maps to chromosome 6q21 and is predicted to encode a protein with three transmembrane helices, establishing POPDC1 as a multi-pass transmembrane protein conserved across chick, mouse, and human. cDNA cloning, BLAST database analysis, Northern/dot blot, computer topology prediction Mammalian genome Medium 10441744
2000 Three Popeye (POPDC1, POPDC2, POPDC3) genes were identified as a novel vertebrate gene family encoding proteins with three conserved transmembrane domains, preferentially expressed in developing and adult striated muscle, with individual members showing distinct cardiac chamber and temporal expression patterns. cDNA library screening, chromosomal mapping, in situ hybridization, Northern blot Developmental biology Medium 10882522
2001 Bves/POPDC1 is a membrane protein with three transmembrane helices confined to the lateral membrane compartment of epithelial epicardial cells; it accumulates in a perinuclear region when cells are dissociated and traffics to the cell membrane and points of cell-cell contact upon cellular contact. Transfection of Bves into non-adherent L-cells confers adhesive behavior, identifying it as a novel cell adhesion molecule. Anti-Bves antibodies inhibit epithelial migration from the proepicardium. Immunofluorescence, transfection into L-cells (adhesion assay), antibody inhibition of proepicardial cell migration in vitro Development High 11493530
2002 Genetic deletion of mouse Pop1/POPDC1 (null mice) impairs skeletal muscle regeneration after cardiotoxin injury, with persistence of Pop1-LacZ expression and retarded regeneration in homozygotes. Beta-adrenergic agonist (isoproterenol) treatment causes post-translational stabilization of the POPDC1 protein without transcriptional induction. LacZ knock-in null mouse, cardiotoxin muscle injury model, isoproterenol administration, LacZ staining, histology Molecular and cellular biology High 11839816
2003 The membrane topology of Bves/POPDC1 was established biochemically: the amino terminus is extracellular (glycosylated via N-linked sites), there are three transmembrane domains, and the carboxyl terminus is cytoplasmic. Bves-Bves homotypic interactions occur in the cytoplasmic compartment, mediated by the C-terminal tail. Glycosylation assays, exogenous glycosylation site insertion, co-expression of C-terminal constructs in different subcellular compartments, immunoreactivity enhancement with detergent Journal of biological chemistry High 12815060
2005 Bves/POPDC1 localizes with tight junction markers ZO-1 and occludin in polarized epithelial cells and in vivo. GST pull-down experiments demonstrate a direct physical interaction between ZO-1 and the intracellular C-terminal tail of Bves. Bves knockdown causes loss of transepithelial resistance and disruption of junction protein membrane localization, demonstrating that Bves modulates tight junction integrity. Immunolocalization with TJ markers, Ca2+ chelation/TPA treatment, GST pull-down with C-terminal Bves tail and ZO-1, siRNA knockdown with transepithelial electrical resistance measurement Journal of cell science High 16188940
2007 In Drosophila, bves (DmBves/POPDC1 homolog) expression in anterior-dorsal follicle cells is repressed by the Grk/EGFR signaling pathway during oogenesis. Loss of bves function via antisense RNA causes embryonic lethality with pole cell migration defects and abnormal germband extension, establishing bves as essential for embryonic development downstream of EGFR signaling. In situ hybridization, genetic epistasis with Grk/EGFR pathway mutants, antisense RNA expression, pole cell migration analysis International journal of developmental biology Medium 17183463
2008 Bves/POPDC1 homodimerizes through an intracellular domain mapped to amino acids 268-274, with lysines 272 and 273 being essential for homodimerization and cell adhesion. Mutations at these positions abolish junctional complex formation (loss of ZO-1 and E-cadherin at membrane), reduce transepithelial electrical resistance, and promote epithelial-to-mesenchymal transition. GST pull-down, SPOTs peptide array, site-directed mutagenesis, transfection into corneal epithelial cells, TER measurement, immunofluorescence PLoS One High 18493308
2008 Bves/POPDC1 directly interacts with GEFT, a GEF for Rho-family GTPases. Exogenous Bves expression reduces Rac1 and Cdc42 activity (but not RhoA), and produces corresponding changes in cell locomotion speed and cell roundness. Bves and GEFT co-localize in adult skeletal muscle. Co-immunoprecipitation/pulldown, co-localization in adult skeletal muscle, Rac1/Cdc42/RhoA activity assays (G-LISA/pulldown), cell motility and morphology assays upon Bves overexpression PNAS High 18541910
2009 Increased Bves/POPDC1 expression in trabecular meshwork cells leads to increased tight junction formation (elevated occludin, cingulin, ZO-1), decreased RhoA activation (measured by FRET), and decreased myosin light chain phosphorylation, establishing a regulatory pathway upstream of RhoA in these cells. Stable transfection, TER measurement, FRET-based RhoA activity probe, Western blot for MLC phosphorylation Investigative ophthalmology & visual science Medium 19628742
2010 Bves/POPDC1 directly interacts with VAMP3, a SNARE protein mediating vesicular transport, and facilitates recycling of transferrin receptor and β1-integrin. Cells expressing a mutated Bves are severely impaired in recycling of these molecules. Morpholino knockdown of Bves in Xenopus inhibits transferrin receptor recycling and causes gastrulation defects related to impaired integrin-dependent cell movements. Two independent co-immunoprecipitation/interaction assays, transferrin and integrin recycling assays, Morpholino knockdown in Xenopus laevis, kymographic analysis of cell spreading EMBO journal High 20057356
2011 BVES/POPDC1 regulates tight junction formation and suppresses EMT in human corneal and colon cancer cells. BVES reexpression in colorectal carcinoma cells promotes epithelial phenotype, decreases proliferation/migration/invasion, and blocks metastasis in orthotopic xenografts. Expression of a dominant-negative BVES mutant induces mesenchymal features in corneal epithelial cells. Re-expression in CRC cell lines, dominant-negative mutant expression, orthotopic xenograft mouse model, cell migration/invasion/proliferation assays, AJ/TJ composition analysis Journal of clinical investigation High 21911938
2011 Bves/POPDC1 modulates RhoA activation and ZONAB/DbpA transcriptional activity through its regulatory effect on tight junction formation; C-terminus truncated Bves disrupts ZO-1 interaction, causes loss of TJ protein localization, increases RhoA activity (30% increase by FRET), and increases ZONAB/DbpA transcriptional activity. Stable transfection of full-length vs. C-terminus truncated Bves, TER measurement, FRET-based RhoA activity, luciferase reporter for ZONAB/DbpA transcriptional activity, immunofluorescence PLoS One Medium 21283798
2012 Popeye domain-containing proteins (POPDC1 and POPDC2) are essential regulators of cardiac pacemaking under stress. The conserved Popeye domain functions as a high-affinity cAMP-binding site. POPDC proteins interact with the potassium channel TREK-1, increasing its cell surface expression and current density; both effects are negatively modulated by cAMP. POPDC1 or POPDC2 knockout mice develop stress-induced sinus node dysfunction and age-dependent bradyarrhythmia. Popdc1/Popdc2 knockout mice, ECG telemetry under stress, cAMP-binding assays (competitive binding with radiolabeled cAMP), co-immunoprecipitation with TREK-1, electrophysiology (current density measurements), cell surface expression assays Journal of clinical investigation High 22354168
2012 Bves/POPDC1 knockdown in zebrafish disrupts atypical PKC (aPKC) localization at cell junctions and affects the PAR junctional complex (par-3, par-6, prkci/aPKC), leading to loss of epidermal barrier function and osmotic sensitivity. Rescue experiments with ZO-2, par-3, par-6, and aPKC mRNAs partially restore survival, establishing that Bves acts upstream of the PAR complex at the tight junction. Morpholino knockdown in zebrafish, osmotic stress assay, mRNA rescue experiments, immunofluorescence for aPKC and claudins Journal of biological chemistry High 23019331
2013 POPDC1/Bves is a caveolae-associated protein that co-localizes and co-immunoprecipitates with caveolin-3 at the sarcolemma, intercalated discs, and T-tubules. POPDC1-null hearts show a 70% reduction in caveolae number, impaired Ca2+ transients, increased vulnerability to oxidative stress, no pharmacological preconditioning, and greater ischemia/reperfusion injury with larger infarct size, indicating POPDC1 is required for caveolae structural and functional integrity. Co-immunoprecipitation and co-sedimentation in density gradients (caveolae isolation), electron microscopy (caveolae quantification), confocal co-localization, Ca2+ transient measurements, Langendorff heart perfusion with I/R injury PLoS One High 24066022
2013 A novel protein-protein interaction between Bves/POPDC1 and NDRG4 is required for autocrine ECM deposition and epicardial cell directional movement. The Bves/NDRG4 interaction is required for fibronectin recycling through the autocrine ECM pathway, and TIRFM shows the interaction is needed for fusion of recycling endosomes with the basal cell surface. Co-immunoprecipitation, siRNA disruption, fibronectin recycling assay, total internal reflectance fluorescence microscopy (TIRFM), directional migration assay Molecular biology of the cell High 24048452
2015 A homozygous missense mutation POPDC1(S201F) causes cardiac arrhythmia and limb-girdle muscular dystrophy. The S201F variant displays a 50% reduction in cAMP-binding affinity. In patient skeletal muscle, both POPDC1(S201F) and WT POPDC2 show impaired membrane trafficking. Expression of POPDC1(S201F) in HL-1 cardiac cells increases hyperpolarization and action potential upstroke velocity. The homologous zebrafish mutation (popdc1S191F) recapitulates heart and skeletal muscle phenotypes. Whole-exome sequencing, cAMP-binding affinity assay, immunofluorescence of patient muscle biopsies, electrophysiology in HL-1 cells, zebrafish knock-in model Journal of clinical investigation High 26642364
2016 BVES/POPDC1 interacts with PR61α (a PP2A regulatory subunit) to mediate c-Myc destruction. Loss of Bves in mouse colitis-associated cancer model leads to increased c-Myc levels, Wnt activation, and increased tumor multiplicity. The BVES-PP2A interaction was identified by yeast two-hybrid screen. Yeast two-hybrid screen, co-immunoprecipitation, AOM/DSS mouse colitis-cancer model, immunohistochemistry, Western blot for c-Myc Gut Medium 28389570
2016 Popdc1/BVES siRNA-mediated knockdown in cardiomyocytes under serum deprivation causes cell injury and death, upregulation of pro-apoptotic Bnip3, and reduction of Rac1-GTPase activity and Akt phosphorylation. Combined POPDC1/Bnip3 silencing attenuates this injury. Chromatin immunoprecipitation showed increased FoxO3 binding to the Bnip3 promoter and decreased NFκB nuclear presence in POPDC1-deficient cardiomyocytes. siRNA knockdown, cell viability assays, Western blot (Bnip3, Rac1-GTP, pAkt), chromatin immunoprecipitation (FoxO3 and NFκB at Bnip3 promoter), combined double-knockdown Journal of cellular biochemistry Medium 27886395
2016 BVES/POPDC1 regulates intestinal stem cell programs; Bves-/- mice show expanded crypt height, elevated Lgr5 stem cell marker, and increased proliferation. Bves-/- enteroids show increased stemness, amplified Wnt signaling, and responsiveness to Wnt activation. After radiation, Bves-/- mice show greater crypt viability and amplified Wnt signaling, identifying BVES as a negative regulator of Wnt-dependent intestinal stem cell programs. Bves KO mice, Lgr5-EGFP reporter intercross, 3D enteroid culture, proliferation and stem cell marker analysis, Wnt pathway activation assays, radiation injury model Stem cells High 26891025
2017 POPDC1 is negatively regulated by EGFR signaling in breast cancer cells; EGFR activation reduces POPDC1 expression, and POPDC1 overexpression attenuates EGF-mediated cell migration and proliferation in MCF7, MDA231 and SKBR3 cells. Functional suppression of POPDC1 promotes breast cancer cell migration and proliferation, while cAMP upregulates POPDC1 expression. EGFR inhibitor/activator treatment with Western blot for POPDC1, POPDC1 overexpression and siRNA knockdown, EGF-stimulated migration and proliferation assays, cAMP treatment Cancer letters / Bioscience reports Medium 28807821 28954821
2020 POPDC1 and POPDC2 interact with XIRP1 (Xin actin-binding repeat-containing protein 1) in human skeletal myotubes, confirmed by proteomic pull-down and co-immunoprecipitation from adult rat heart. Both XIRP1 and POPDC1/2 localize together at intercalated discs and T-tubules in human and rat heart. Bead-based pull-down with proteomic analysis (mass spectrometry), co-immunoprecipitation from rat heart, immunofluorescence with new monoclonal antibodies in human skeletal muscle and cardiac tissue BMC molecular and cell biology Medium 33261556
2021 ANO5 and BVES/POPDC1 directly interact; the N-terminus of ANO5 mediates interaction with the C-terminus of BVES. Both proteins co-localize at the ER membrane in muscle cells. Genome editing-mediated deletion of either ANO5 or BVES significantly suppresses C2C12 myoblast differentiation with little effect on proliferation, placing BVES in the same functional pathway as ANO5 in myogenesis. BioID2 proximity labeling with mass spectrometry, co-immunoprecipitation, domain-mapping co-IP with truncation mutants, CRISPR/Cas9 knockout, myoblast differentiation assays Cell & bioscience High 34963485
2022 POPDC1 scaffolds a macromolecular complex containing adenylyl cyclase 9 (AC9) and the potassium channel TREK-1 in the heart. TREK-1 binds the AC9:POPDC1 complex and co-purifies in a POPDC1-dependent manner with AC9 activity. The AC9:POPDC1 interaction is cAMP-independent, but TREK-1 association with the complex is reduced upon β-adrenergic receptor stimulation in an AC9 activity-dependent manner. Deletion of AC9 causes bradycardia and stress-induced heart rate variability. Co-immunoprecipitation, co-purification with AC9 activity measurements, TREK-1 current recordings in transfected cells, AC9 knockout mice (ECG telemetry), β-adrenergic stimulation experiments EMBO reports High 36254885
2022 In POPDC1-KO hippocampal slices, CA1 long-term potentiation (LTP) is enhanced in a PKA-dependent manner in response to weaker stimulation paradigms. POPDC1 is widely expressed in brain regions including hippocampus. Loss of POPDC1 enhances forskolin-induced potentiation without affecting basal transmission. These findings identify POPDC1 as a novel negative regulator of hippocampal synaptic plasticity through cAMP-PKA signaling. Popdc1 KO mice, acute hippocampal slice electrophysiology (field recordings), pharmacological PKA inhibition, forskolin-induced potentiation assays Cerebral cortex Medium 34937090
2022 POPDC1 mutations causing LGMDR25 show differential effects on heteromeric POPDC1-POPDC2 complex formation and membrane trafficking. POPDC proteins interact through a helix-helix interface at the C-terminus of the Popeye domain. Ultra-conserved hydrophobic residues at this interface are required for membrane trafficking of the POPDC1-POPDC2 complex; mutations impairing complex formation cause greater trafficking defects than mutations that preserve interaction. Co-precipitation, proximity ligation assay, bioluminescence resonance energy transfer (BRET), bimolecular fluorescence complementation (BiFC), site-directed mutagenesis of conserved hydrophobic residues, immunostaining of patient biopsies Acta neuropathologica communications High 36624536
2023 BVES/POPDC1 functions as a negative feedback regulator of adenylyl cyclase 9 (ADCY9)-mediated cAMP signaling in skeletal muscle. BVES interacts with and negatively regulates ADCY9 activity. BVES deletion increases PKA signaling, promoting FoxO-mediated ubiquitin-proteasome degradation and autophagy initiation, leading to reduced muscle mass and impaired performance. Viral re-expression of BVES in Bves-deficient muscle reverses these defects. BVES KO mice, AAV-mediated BVES re-expression, co-immunoprecipitation with ADCY9, cAMP/PKA activity assays, proteolysis and autophagy pathway Western blots, muscle mass/strength/exercise performance measures Nature communications High 36997581
2022 BVES/POPDC1 co-localizes with ZO-1 and GEFT in HCC cells, regulates ZO-1 expression and localization and GEFT distribution, and thereby modulates RhoA activity. BVES overexpression decreases HCC cell extrusion in vitro and in vivo (orthotopic xenograft), and BVES suppression enhances tumor cell extrusion, promoting HCC metastasis. Co-immunoprecipitation, RhoA activity assay, silicone chamber and 3D cell culture extrusion models, orthotopic xenograft mouse model, immunofluorescence Cell communication and signaling Medium 36123685
2022 Systemic AAV9-mediated delivery of human BVES to BVES-KO mice restores POPDC1 in cardiac and skeletal muscle and rescues body weight, muscle mass, muscle strength, exercise performance, and stress-induced heart rate abnormality. Intravenous delivery to adult KO mice after disease onset also provides substantial improvement, establishing BVES gene replacement as a viable therapeutic approach for LGMDR25. AAV9 vector systemic delivery in neonatal and adult KO mice, grip strength, treadmill exercise, histopathology, ECG under stress Molecular therapy Medium 36433649
2022 Bves/POPDC1 maintains the VSMC contractile phenotype through Dusp1 (dual-specificity protein phosphatase 1)-dependent suppression of p38MAPK and ERK1/2 signaling. Bves knockdown reduces Dusp1 expression and enhances p38MAPK and ERK1/2 activation; in vivo, VSMC-specific Bves and Dusp1 overexpression attenuates neointimal lesion formation in a rat graft arteriosclerosis model. In vivo rat graft arteriosclerosis model, RNA sequencing identifying Dusp1 correlation, siRNA knockdown and overexpression, p38MAPK/ERK1/2 phosphorylation Western blot, VSMC phenotypic marker analysis Atherosclerosis Medium 36037759
2024 POPDC1 dysfunction in popdc1(S201F) and popdc1 KO zebrafish alters cardiac electrophysiology including heart rate, AV delay, action potential and calcium transient upstroke speed and duration. SNS stress by β-adrenergic stimulation increases AV delay and leads to AV block in popdc1 mutant adult hearts, while reducing AP and CaT duration; arrhythmogenic effects are present from early development. Homozygous popdc1 and KO zebrafish larvae and adult isolated hearts, functional fluorescent analysis (AP and Ca2+ transient imaging), isoproterenol (β-AR) stimulation Genes Medium 38540339
2020 BVES knockdown in zebrafish decreases expression of second heart field (SHF) regulatory genes NKX2.5, GATA4, and HAND2, and causes ventricular outflow tract stenosis and looping defects, partially rescued by bves mRNA and partially by nkx2.5 mRNA. Dual-fluorescence reporter assays show BVES positively regulates transcriptional activity of GATA4, NKX2.5, and HAND2 promoters. Zebrafish morpholino knockdown and mRNA rescue, reporter assay for transcription factor promoters, qPCR for SHF gene expression, cardiac morphology imaging Scientific reports Medium 32843646

Source papers

Stage 0 corpus · 118 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Many sequence variants affecting diversity of adult human height. Nature genetics 520 18391951
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2017 Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proceedings of the National Academy of Sciences of the United States of America 282 28611215
1995 pop-1 encodes an HMG box protein required for the specification of a mesoderm precursor in early C. elegans embryos. Cell 265 7585963
1998 POP-1 and anterior-posterior fate decisions in C. elegans embryos. Cell 235 9458047
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
1994 The POP1 gene encodes a protein component common to the RNase MRP and RNase P ribonucleoproteins. Genes & development 202 7926742
2009 Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche. Nature genetics 165 19448622
2003 The PAAD/PYRIN-only protein POP1/ASC2 is a modulator of ASC-mediated nuclear-factor-kappa B and pro-caspase-1 regulation. The Biochemical journal 150 12656673
1997 Fission yeast WD-repeat protein pop1 regulates genome ploidy through ubiquitin-proteasome-mediated degradation of the CDK inhibitor Rum1 and the S-phase initiator Cdc18. Genes & development 147 9203581
2008 DNA methylation in tumor and matched normal tissues from non-small cell lung cancer patients. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 140 18349282
2012 Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice. The Journal of clinical investigation 126 22354168
2002 POP-1 controls axis formation during early gonadogenesis in C. elegans. Development (Cambridge, England) 113 11807036
2015 The PYRIN Domain-only Protein POP1 Inhibits Inflammasome Assembly and Ameliorates Inflammatory Disease. Immunity 112 26275995
2000 Isolation and characterization of the novel popeye gene family expressed in skeletal muscle and heart. Developmental biology 107 10882522
1998 Two F-box/WD-repeat proteins Pop1 and Pop2 form hetero- and homo-complexes together with cullin-1 in the fission yeast SCF (Skp1-Cullin-1-F-box) ubiquitin ligase. Genes to cells : devoted to molecular & cellular mechanisms 93 9990507
2005 C. elegans TCF protein, POP-1, converts from repressor to activator as a result of Wnt-induced lowering of nuclear levels. Developmental biology 91 16112103
1999 bves: A novel gene expressed during coronary blood vessel development. Developmental biology 86 10208750
2002 Dynamics of a developmental switch: recursive intracellular and intranuclear redistribution of Caenorhabditis elegans POP-1 parallels Wnt-inhibited transcriptional repression. Developmental biology 85 12142026
2001 Bves: prototype of a new class of cell adhesion molecules expressed during coronary artery development. Development (Cambridge, England) 85 11493530
2007 Binary cell fate specification during C. elegans embryogenesis driven by reiterated reciprocal asymmetry of TCF POP-1 and its coactivator beta-catenin SYS-1. Development (Cambridge, England) 82 17567664
2005 The Wnt effector POP-1 and the PAL-1/Caudal homeoprotein collaborate with SKN-1 to activate C. elegans endoderm development. Developmental biology 80 16084508
2001 A POP-1 repressor complex restricts inappropriate cell type-specific gene transcription during Caenorhabditis elegans embryogenesis. The EMBO journal 75 11742996
2015 POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking. The Journal of clinical investigation 72 26642364
2005 Bves modulates epithelial integrity through an interaction at the tight junction. Journal of cell science 72 16188940
2024 POP1 Facilitates Proliferation in Triple-Negative Breast Cancer via m6A-Dependent Degradation of CDKN1A mRNA. Research (Washington, D.C.) 67 39268503
2002 Mouse Pop1 is required for muscle regeneration in adult skeletal muscle. Molecular and cellular biology 66 11839816
2011 BVES regulates EMT in human corneal and colon cancer cells and is silenced via promoter methylation in human colorectal carcinoma. The Journal of clinical investigation 64 21911938
2011 Whole-exome re-sequencing in a family quartet identifies POP1 mutations as the cause of a novel skeletal dysplasia. PLoS genetics 62 21455487
2008 Bves directly interacts with GEFT, and controls cell shape and movement through regulation of Rac1/Cdc42 activity. Proceedings of the National Academy of Sciences of the United States of America 57 18541910
2017 New kids on the block: The Popeye domain containing (POPDC) protein family acting as a novel class of cAMP effector proteins in striated muscle. Cellular signalling 56 28939104
2003 Establishment of POP-1 asymmetry in early C. elegans embryos. Development (Cambridge, England) 56 12810601
2010 The role of height-associated loci identified in genome wide association studies in the determination of pediatric stature. BMC medical genetics 54 20546612
2003 Membrane topology of Bves/Pop1A, a cell adhesion molecule that displays dynamic changes in cellular distribution during development. The Journal of biological chemistry 50 12815060
2010 Frequent silencing of popeye domain-containing genes, BVES and POPDC3, is associated with promoter hypermethylation in gastric cancer. Carcinogenesis 48 20627872
2021 lncRNA lnc-POP1-1 upregulated by VN1R5 promotes cisplatin resistance in head and neck squamous cell carcinoma through interaction with MCM5. Molecular therapy : the journal of the American Society of Gene Therapy 47 34111560
2016 BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis. Gut 44 28389570
2010 Identification of a novel Bves function: regulation of vesicular transport. The EMBO journal 43 20057356
2015 Netrin-1 promotes cell migration and invasion by down-regulation of BVES expression in human hepatocellular carcinoma. American journal of cancer research 42 26101705
2008 Mapping of POP1-binding site on pyrin domain of ASC. The Journal of biological chemistry 42 18362139
2013 Popeye domain containing 1 (Popdc1/Bves) is a caveolae-associated protein involved in ischemia tolerance. PloS one 41 24066022
2014 The functional landscape of Hsp27 reveals new cellular processes such as DNA repair and alternative splicing and proposes novel anticancer targets. Molecular & cellular proteomics : MCP 40 25277244
2013 Bves and NDRG4 regulate directional epicardial cell migration through autocrine extracellular matrix deposition. Molecular biology of the cell 40 24048452
2003 Acetylation regulates subcellular localization of the Wnt signaling nuclear effector POP-1. Genes & development 40 12651889
2004 Developmental expression of Pop1/Bves. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 39 14966204
2011 Bves modulates tight junction associated signaling. PloS one 35 21283798
2004 Bves is expressed in the epithelial components of the retina, lens, and cornea. Investigative ophthalmology & visual science 31 15277466
2009 Inhibition of RhoA signaling with increased Bves in trabecular meshwork cells. Investigative ophthalmology & visual science 30 19628742
2023 Peptide encoded by lncRNA BVES-AS1 promotes cell viability, migration, and invasion in colorectal cancer cells via the SRC/mTOR signaling pathway. PloS one 29 37347740
2009 Bves: ten years after. Histology and histopathology 29 19337975
2008 Identification of a novel intracellular interaction domain essential for Bves function. PloS one 29 18493308
2014 BVES inhibition triggers epithelial-mesenchymal transition in human hepatocellular carcinoma. Digestive diseases and sciences 28 24442236
1999 Cloning and expression of hbves, a novel and highly conserved mRNA expressed in the developing and adult heart and skeletal muscle in the human. Mammalian genome : official journal of the International Mammalian Genome Society 28 10441744
2006 Characterization of Bves expression during mouse development using newly generated immunoreagents. Developmental dynamics : an official publication of the American Association of Anatomists 27 16538658
2019 Muscular dystrophy with arrhythmia caused by loss-of-function mutations in BVES. Neurology. Genetics 26 31119192
2010 Popeye domain-containing 1 is down-regulated in failing human hearts. International journal of molecular medicine 26 21069264
2007 Blood vessel/epicardial substance (bves) expression, essential for embryonic development, is down regulated by Grk/EFGR signalling. The International journal of developmental biology 26 17183463
2006 Bves, a member of the Popeye domain-containing gene family. Developmental dynamics : an official publication of the American Association of Anatomists 26 16444674
2016 BVES Regulates Intestinal Stem Cell Programs and Intestinal Crypt Viability after Radiation. Stem cells (Dayton, Ohio) 24 26891025
2004 Bves expression during avian embryogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 22 14991721
2024 Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of α-synuclein inclusions. Neuron 20 39079530
2017 Broadening the phenotypic spectrum of POP1-skeletal dysplasias: identification of POP1 mutations in a mild and severe skeletal dysplasia. Clinical genetics 20 28067412
2012 Blood vessel epicardial substance (Bves) regulates epidermal tight junction integrity through atypical protein kinase C. The Journal of biological chemistry 20 23019331
2018 BVES is required for maintenance of colonic epithelial integrity in experimental colitis by modifying intestinal permeability. Mucosal immunology 19 29907869
2017 A Human Tyrosine Phosphatase Interactome Mapped by Proteomic Profiling. Journal of proteome research 19 28675297
2001 Production of monoclonal antibodies against chicken Pop1 (BVES). Hybridoma and hybridomics 19 11839256
2022 Proteomic and morphological insights and clinical presentation of two young patients with novel mutations of BVES (POPDC1). Molecular genetics and metabolism 18 35660068
2016 Further evidence of POP1 mutations as the cause of anauxetic dysplasia. American journal of medical genetics. Part A 18 27380734
2015 Footprinting analysis of interactions between the largest eukaryotic RNase P/MRP protein Pop1 and RNase P/MRP RNA components. RNA (New York, N.Y.) 18 26135751
2022 POP1 inhibits MSU-induced inflammasome activation and ameliorates gout. Frontiers in immunology 17 36225929
2019 Ten years of research on the role of BVES/ POPDC1 in human disease: a review. OncoTargets and therapy 16 30863095
2017 POPDC1 is suppressed in human breast cancer tissues and is negatively regulated by EGFR in breast cancer cell lines. Cancer letters 16 28807821
2017 Dysregulation of POPDC1 promotes breast cancer cell migration and proliferation. Bioscience reports 15 28954821
2022 POPDC1 scaffolds a complex of adenylyl cyclase 9 and the potassium channel TREK-1 in heart. EMBO reports 14 36254885
2020 MKRN2 Physically Interacts with GLE1 to Regulate mRNA Export and Zebrafish Retinal Development. Cell reports 14 32460013
2020 Two Japanese LGMDR25 patients with a biallelic recurrent nonsense variant of BVES. Neuromuscular disorders : NMD 14 32684383
2017 POP1 might be recruiting its type-Ia interface for NLRP3-mediated PYD-PYD interaction: Insights from MD simulation. Journal of molecular recognition : JMR 13 28370480
2016 Popdc1/Bves Functions in the Preservation of Cardiomyocyte Viability While Affecting Rac1 Activity and Bnip3 Expression. Journal of cellular biochemistry 13 27886395
2013 Mutational and functional analysis of the BVES gene coding region in Chinese patients with non-syndromic tetralogy of Fallot. International journal of molecular medicine 13 23403794
2019 C. elegans Runx/CBFβ suppresses POP-1 TCF to convert asymmetric to proliferative division of stem cell-like seam cells. Development (Cambridge, England) 12 31740621
2022 A novel biallelic variant in the Popeye domain-containing protein 1 (POPDC1) underlies limb girdle muscle dystrophy type 25. Clinical genetics 11 36155908
2018 Blood Vessel Epicardial Substance (BVES) in junctional signaling and cancer. Tissue barriers 11 30307367
2021 The Transition from Gastric Intestinal Metaplasia to Gastric Cancer Involves POPDC1 and POPDC3 Downregulation. International journal of molecular sciences 10 34069715
2020 An interaction of heart disease-associated proteins POPDC1/2 with XIRP1 in transverse tubules and intercalated discs. BMC molecular and cell biology 10 33261556
2025 The solute carrier superfamily interactome. Molecular systems biology 9 40355756
2022 Cell adhesion molecule BVES functions as a suppressor of tumor cells extrusion in hepatocellular carcinoma metastasis. Cell communication and signaling : CCS 9 36123685
2021 BVES is a novel interactor of ANO5 and regulates myoblast differentiation. Cell & bioscience 9 34963485
2023 Differential effects of mutations of POPDC proteins on heteromeric interaction and membrane trafficking. Acta neuropathologica communications 8 36624536
2022 Mice Lacking the cAMP Effector Protein POPDC1 Show Enhanced Hippocampal Synaptic Plasticity. Cerebral cortex (New York, N.Y. : 1991) 8 34937090
2022 Bves maintains vascular smooth muscle cell contractile phenotype and protects against transplant vasculopathy via Dusp1-dependent p38MAPK and ERK1/2 signaling. Atherosclerosis 7 36037759
2015 Crystal structure of human POP1 and its distinct structural feature for PYD domain. Biochemical and biophysical research communications 7 25839653
2025 EndoMAP.v1 charts the structural landscape of human early endosome complexes. Nature 6 40437099
2022 Systemic AAV9.BVES delivery ameliorates muscular dystrophy in a mouse model of LGMDR25. Molecular therapy : the journal of the American Society of Gene Therapy 6 36433649
2021 The role of Popeye domain-containing protein 1 (POPDC1) in the progression of the malignant phenotype. British journal of pharmacology 6 33533478
2021 BVES-AS1 inhibits the malignant behaviors of colon adenocarcinoma cells via regulating BVES. Cell biology international 6 34003551
2023 Defective BVES-mediated feedback control of cAMP in muscular dystrophy. Nature communications 5 36997581
2023 POP1 promotes the progression of breast cancer through maintaining telomere integrity. Carcinogenesis 5 37010429
2020 The novel R211Q POP1 homozygous mutation causes different pathogenesis and skeletal changes from those of previously reported POP1-associated anauxetic dysplasia. American journal of medical genetics. Part A 5 32134183
2011 Abnormal expression of adhesion protein Bves is associated with gastric cancer progression and poor survival. Pathology oncology research : POR 5 22109561
2024 BVES-AS1 suppresses the colorectal cancer progression via the miR-1269a/b-SVEP1-PI3K/AKT axis. Advances in clinical and experimental medicine : official organ Wroclaw Medical University 4 38239081
2023 MBNL1‑AS1 attenuates tumor cell proliferation by regulating the miR‑29c‑3p/BVES signal in colorectal cancer. Oncology reports 4 37711058
2020 BVES downregulation in non-syndromic tetralogy of fallot is associated with ventricular outflow tract stenosis. Scientific reports 4 32843646
2022 Modulation of POPDC1 Expression by Phenothiazine and Trifluoperazine Suppress Colon Cancer Growth and Migration. Asian Pacific journal of cancer prevention : APJCP 3 36037145
2019 The Functional Polymorphism R129W in the BVES Gene Is Associated with Sporadic Tetralogy of Fallot in the Han Chinese Population. Genetic testing and molecular biomarkers 3 31386585
2024 miR-665-Mediated Regulation of AHCYL2 and BVES Genes in Recurrent Implantation Failure. Genes 2 38397233
2005 Advocating asymmetry and the POP-1 paradox: noncanonical Wnt signaling in C. elegans. Cell 2 15935751
2024 POPDC1 Variants Cause Atrioventricular Node Dysfunction and Arrhythmogenic Changes in Cardiac Electrophysiology and Intracellular Calcium Handling in Zebrafish. Genes 1 38540339
2024 PGC-1α inhibits NLRP3 signaling through transcriptional activation of POP1 to alleviate inflammation and strengthen osteogenic differentiation of lipopolysaccharide-induced human periodontal stem cells. Prostaglandins & other lipid mediators 1 38763227
2025 The BVES Gene Regulates the Homeostasis of Deer Antler Mesenchymal Stem Cells Through Wnt Signaling. Biology 0 41007355
2024 Novel phenotype associated with homozygous likely pathogenic variant in the POP1 gene. Clinical genetics 0 38351533
2024 Dysregulated expression of IGSF11-AS1 and BVES-AS in azoospermia and its correlation with serum hormone levels. Biomarkers in medicine 0 38881522
2024 LncRNA GAS5 regulates the inflammatory response in inflammatory bowel disease via targeting the miR-23a-3p/BVES axis. Central-European journal of immunology 0 39944256