{"gene":"POPDC1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2001,"finding":"BVES/POPDC1 is a membrane protein with three transmembrane helices, an extracellular N-terminus and an intracellular C-terminus, confined to the lateral membrane compartment of epithelial cells. It accumulates at points of cell-cell contact before E-cadherin appearance, and transfection into non-adherent L-cells confers adhesive behavior, establishing it as a novel cell adhesion molecule.","method":"Transfection into L-cells (adhesion assay), antibody inhibition of epicardial migration, subcellular localization by immunofluorescence","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (transfection adhesion assay, antibody inhibition, localization) replicated across multiple model systems","pmids":["11493530"],"is_preprint":false},{"year":2003,"finding":"The membrane topology of BVES/Pop1A consists of an extracellular N-terminus (glycosylated), three transmembrane domains, and a cytoplasmic C-terminus. This was established by glycosylation assays, topology-reversal constructs, and differential immunoreactivity with/without detergent permeabilization.","method":"Glycosylation assays, glycosylation-site insertion constructs, co-expression topology experiments, selective immunoreactivity assay on intact vs. permeabilized cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — three independent biochemical approaches in one study establishing membrane topology","pmids":["12815060"],"is_preprint":false},{"year":2005,"finding":"BVES localizes with tight junction markers ZO-1 and occludin in polarized epithelial cells. GST pull-down demonstrates a direct interaction between ZO-1 and the intracellular C-terminal tail of BVES. Knockdown of BVES causes loss of transepithelial resistance and junctional protein membrane localization, demonstrating BVES modulates tight junction integrity.","method":"GST pull-down, immunolocalization with TJ markers, Ca2+-chelation/TPA challenge, siRNA knockdown with transepithelial resistance measurement","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal localization, direct biochemical interaction (GST pull-down), and functional knockdown phenotype with multiple readouts","pmids":["16188940"],"is_preprint":false},{"year":2008,"finding":"BVES directly interacts with GEFT (a GEF for Rho-family GTPases), co-localizing in adult skeletal muscle. Exogenous BVES expression reduces Rac1 and Cdc42 activity levels without affecting RhoA activity, and produces corresponding changes in cell locomotion speed and cell roundness.","method":"Co-immunoprecipitation/pulldown interaction assay, co-localization, Rho GTPase activity assays, cell motility and morphology analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein interaction identified plus functional GTPase activity readouts and cellular phenotype, multiple orthogonal methods","pmids":["18541910"],"is_preprint":false},{"year":2008,"finding":"BVES interacts with itself through a specific intracellular homodimerization domain (amino acids 268-274, critical residues lysines 272 and 273). Mutation of these lysines abolishes homodimerization and cell adhesion, disrupts ZO-1 and E-cadherin membrane localization, reduces transepithelial resistance, and promotes epithelial-to-mesenchymal transition.","method":"GST pull-down, SPOTS analysis, site-directed mutagenesis, transepithelial resistance, immunofluorescence of junctional proteins","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — domain mapping with mutagenesis, multiple functional readouts in single rigorous study","pmids":["18493308"],"is_preprint":false},{"year":2010,"finding":"BVES directly interacts with VAMP3 (a SNARE protein), and disruption of BVES impairs recycling of transferrin and β1-integrin (consistent with VAMP3 dysfunction). Morpholino knockdown of BVES in Xenopus specifically inhibits transferrin receptor recycling, causing gastrulation defects; BVES-depleted cells show impaired spreading and adhesion on fibronectin.","method":"Co-immunoprecipitation, VAMP3 recycling assays (transferrin/integrin recycling), Xenopus morpholino knockdown, kymographic analysis of cell spreading","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction demonstrated, two independent recycling assays, in vivo Xenopus knockdown with specific phenotypic readouts","pmids":["20057356"],"is_preprint":false},{"year":2011,"finding":"BVES regulates epithelial-to-mesenchymal transition (EMT): re-expression of BVES in colorectal cancer cell lines promotes epithelial phenotype with decreased proliferation, migration, and invasion; a dominant-negative C-terminus-truncated BVES mutant in corneal epithelial cells induces mesenchymal features. These changes are associated with alterations in adherens junction and tight junction composition.","method":"Stable re-expression of BVES in CRC cell lines, dominant-negative mutant expression, orthotopic xenograft, migration/invasion assays, TJ/AJ protein localization","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function and dominant-negative loss-of-function, in vivo xenograft, multiple orthogonal cellular readouts","pmids":["21911938"],"is_preprint":false},{"year":2011,"finding":"BVES modulates RhoA signaling and ZONAB/DbpA transcriptional activity through tight junction regulation. C-terminus-truncated BVES disrupts membrane localization of endogenous BVES and ZO-1 interaction, increases RhoA activity (measured by FRET), increases ZONAB/DbpA transcriptional activity (luciferase reporter), and reduces membrane localization of GEF-H1.","method":"Stable transfection of truncated vs. wild-type BVES, FRET-based RhoA activity assay, luciferase reporter for ZONAB/DbpA, immunolocalization","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts (FRET, luciferase), single lab","pmids":["21283798"],"is_preprint":false},{"year":2012,"finding":"In zebrafish, loss of BVES disrupts the PAR junctional complex, particularly atypical PKC (aPKC). Knockdown causes impaired epidermal barrier function and osmotic stress sensitivity; rescue with ZO-2/par-3/par-6/aPKC mRNAs partially restores viability and barrier function, placing BVES upstream of the PAR complex and aPKC in tight junction assembly.","method":"Morpholino knockdown in zebrafish, mRNA rescue experiments, immunofluorescence of aPKC localization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via mRNA rescue in zebrafish with functional barrier readout, single lab","pmids":["23019331"],"is_preprint":false},{"year":2013,"finding":"BVES directly interacts with NDRG4, and this interaction is required for directional epicardial cell movement. BVES/NDRG4 interaction regulates trafficking of internalized fibronectin through the autocrine ECM deposition pathway. TIRF microscopy shows BVES/NDRG4 interaction is required for fusion of recycling endosomes with the basal cell surface.","method":"Protein-protein interaction assays, live TIRF microscopy of recycling endosome fusion, fibronectin recycling assay, directional migration analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction identified, specific recycling pathway assayed, TIRF microscopy providing molecular mechanism, multiple orthogonal methods","pmids":["24048452"],"is_preprint":false},{"year":2013,"finding":"POPDC1/BVES is a caveolae-associated protein: it co-localizes and co-immunoprecipitates with caveolin-3 in cardiomyocytes and co-sediments with caveolin-3 in equilibrium density gradients. Popdc1-null hearts show a 70% reduction in caveolae number, impaired Ca2+ transients, increased oxidative stress vulnerability, and loss of ischemic preconditioning.","method":"Co-immunoprecipitation with caveolin-3, equilibrium density gradient sedimentation, electron microscopy, Ca2+ transient measurement, Langendorff ischemia/reperfusion model in knockout mice","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple biochemical interaction methods (Co-IP, density gradients), ultrastructural evidence, knockout phenotype with functional readouts","pmids":["24066022"],"is_preprint":false},{"year":2015,"finding":"The disease-causing POPDC1(S201F) missense variant shows ~50% reduction in cAMP-binding affinity and causes impaired membrane trafficking of both POPDC1(S201F) and WT POPDC2 in patient skeletal muscle. Forced expression in HL-1 cardiomyocytes increases hyperpolarization and action potential upstroke velocity. The homologous zebrafish mutation recapitulates cardiac arrhythmia and skeletal muscle phenotypes.","method":"cAMP-binding affinity assay (S201F vs WT), immunohistochemistry of patient muscle for membrane trafficking, HL-1 cell electrophysiology, zebrafish knockin model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct biochemical cAMP binding assay, patient tissue analysis, cellular electrophysiology, and in vivo zebrafish model with multiple orthogonal methods","pmids":["26642364"],"is_preprint":false},{"year":2016,"finding":"BVES interacts with PR61α, a PP2A regulatory subunit, identified by yeast two-hybrid screen and validated mechanistically. This interaction mediates c-Myc protein destruction: loss of BVES leads to increased c-Myc levels and Wnt activation, promoting inflammatory tumourigenesis in vivo.","method":"Yeast two-hybrid screen, mechanistic studies in multiple cell lines, Bves-/- mouse AOM/DSS tumourigenesis model, molecular analysis of c-Myc and Wnt pathway","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid interaction plus in vivo knockout model, single lab, partial mechanistic follow-up in cell lines","pmids":["28389570"],"is_preprint":false},{"year":2016,"finding":"BVES loss in cardiomyocytes under serum deprivation upregulates the pro-apoptotic protein Bnip3 and reduces Rac1-GTPase activity and Akt phosphorylation. Combined Popdc1/Bves and Bnip3 silencing attenuates cell injury; chromatin immunoprecipitation shows increased FoxO3 binding to the Bnip3 promoter, while NFκB is excluded from nuclei and shows decreased Bnip3 promoter binding in BVES-deficient cells.","method":"siRNA-mediated gene silencing, Rac1 GTPase activity assay, Western blot for Akt phosphorylation, chromatin immunoprecipitation (ChIP) for FoxO3 and NFκB at Bnip3 promoter","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and functional rescue experiments, single lab, multiple mechanistic readouts","pmids":["27886395"],"is_preprint":false},{"year":2009,"finding":"Overexpression of BVES in trabecular meshwork cells increases tight junction formation (increased occludin, cingulin, ZO-1) and decreases RhoA activation (FRET assay) and myosin light chain phosphorylation (MLC-p), establishing a regulatory pathway upstream of RhoA in these cells.","method":"Stable transfection/overexpression, FRET-based RhoA activity assay, Western blot for MLC-p, transepithelial resistance, TJ protein expression","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET RhoA assay plus functional TJ readouts, single lab, single cell type","pmids":["19628742"],"is_preprint":false},{"year":2022,"finding":"POPDC1 scaffolds a complex of adenylyl cyclase 9 (AC9) and TREK-1 potassium channels in 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. AC9 activity is required for βAR-mediated reduction of TREK-1 complex formation and for reversing POPDC1 enhancement of TREK-1 currents. Adcy9 knockout mice show bradycardia and stress-induced heart rate variability.","method":"Co-immunoprecipitation, co-purification assays, electrophysiology (TREK-1 currents), Adcy9 knockout mouse model with heart rate recording, β-adrenergic receptor stimulation experiments","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional electrophysiology, in vivo knockout phenotype, multiple orthogonal methods in single study","pmids":["36254885"],"is_preprint":false},{"year":2020,"finding":"POPDC1 and POPDC2 interact with XIRP1 (Xin actin binding repeat-containing protein 1) and actin, identified by proteomic pull-down from human skeletal myotubes. The POPDC1-XIRP1 interaction was confirmed in adult rat heart extracts. Both POPDC1/2 and XIRP1 co-localize at intercalated discs and T-tubules in adult heart.","method":"Bead-based pulldown with proteomic analysis, co-immunoprecipitation from adult rat heart, immunolocalization with new monoclonal antibodies","journal":"BMC molecular and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic pulldown confirmed by Co-IP, single lab, localization data","pmids":["33261556"],"is_preprint":false},{"year":2021,"finding":"BVES is a novel interacting protein of ANO5: identified by proximity labeling (BioID2) mass spectrometry and confirmed by co-immunoprecipitation. The N-terminus of ANO5 mediates interaction with the C-terminus of BVES. ANO5 and BVES co-localize at the ER membrane in muscle cells. Genome editing-mediated disruption of either ANO5 or BVES significantly suppresses C2C12 myoblast differentiation.","method":"BioID2 proximity labeling, mass spectrometry, co-immunoprecipitation, co-localization, CRISPR/genome editing knockout with differentiation assay","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity labeling + Co-IP + domain mapping + knockout phenotype, single lab","pmids":["34963485"],"is_preprint":false},{"year":2023,"finding":"BVES functions as a negative feedback regulator of adenylyl cyclase 9 (ADCY9)-mediated cAMP signaling in skeletal muscle. BVES interacts with and negatively regulates ADCY9's activity. BVES deletion increases PKA signaling, promoting FoxO-mediated ubiquitin-proteasome degradation and autophagy. Viral BVES re-expression in Bves-deficient muscle reverses these defects.","method":"BVES knockout mice, co-immunoprecipitation of BVES-ADCY9, cAMP/PKA activity assays, AAV-mediated rescue, FoxO pathway analysis, autophagy markers","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct biochemical interaction, functional cAMP/PKA assays, genetic rescue with viral vector, multiple pathway readouts in single study","pmids":["36997581"],"is_preprint":false},{"year":2022,"finding":"In BVES-knockout mice, BVES maintains vascular smooth muscle cell (VSMC) contractile phenotype through Dusp1-dependent suppression of p38MAPK and ERK1/2. BVES knockdown reduces Dusp1 expression and enhances p38MAPK and ERK1/2 activation; VSMC-specific Bves and Dusp1 overexpression in aortic grafts attenuates neointimal lesion formation.","method":"RNA sequencing, in vitro knockdown/overexpression in VSMCs, in vivo rat aortic graft model with VSMC-specific Bves overexpression, p38MAPK/ERK1/2 phosphorylation Western blot","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway identified by RNA-seq + functional validation in vitro and in vivo, single lab","pmids":["36037759"],"is_preprint":false},{"year":2024,"finding":"POPDC1 dysfunction causes AV node dysfunction: popdc1 mutant and knockout zebrafish show reduced heart rate, altered AV delay, slower action potential upstroke, and abnormal calcium transient duration. In adult popdc1 mutant hearts, β-adrenergic receptor stimulation with isoproterenol worsens AV block and alters calcium handling, demonstrating SNS-dependent arrhythmogenesis.","method":"Functional fluorescent analysis (action potential and calcium transient imaging) in zebrafish larvae and adult isolated hearts, isoproterenol stimulation, popdc1 knockin and knockout zebrafish","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct electrophysiology and Ca2+ imaging in multiple zebrafish models, single lab","pmids":["38540339"],"is_preprint":false},{"year":2022,"finding":"Mice lacking POPDC1 show PKA-dependent enhancement in CA1 hippocampal long-term potentiation (LTP) in response to weaker stimulation paradigms and enhanced forskolin-induced potentiation, identifying POPDC1 as a negative regulator of hippocampal synaptic plasticity via cAMP-PKA-PDE signaling.","method":"Popdc1 knockout mice, acute hippocampal slice electrophysiology (LTP induction protocols), pharmacological PKA manipulation","journal":"Cerebral cortex (New York, N.Y. : 1991)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with direct electrophysiology and pharmacological validation, single lab","pmids":["34937090"],"is_preprint":false}],"current_model":"POPDC1/BVES is a plasma membrane-localized transmembrane protein (extracellular N-terminus, three TM domains, cytoplasmic C-terminus) that binds cAMP through its Popeye domain and functions as a scaffolding and signaling hub: it maintains tight junction integrity via direct interaction with ZO-1, suppresses Rac1/Cdc42 activity through interaction with GEFT, regulates vesicular recycling of integrins and transferrin via VAMP3, controls cardiac pacemaking and skeletal muscle mass by interacting with and negatively regulating adenylyl cyclase 9 (ADCY9)–cAMP–PKA signaling, scaffolds an AC9–TREK-1 potassium channel complex at the sarcolemma, and associates with caveolin-3 in caveolae to support ischemic preconditioning; loss-of-function mutations cause limb-girdle muscular dystrophy with cardiac arrhythmia (LGMDR25)."},"narrative":{"mechanistic_narrative":"POPDC1/BVES is a three-pass transmembrane protein with an extracellular, glycosylated N-terminus and a cytoplasmic C-terminus that functions as a membrane-localized scaffold coordinating cell adhesion, junctional integrity, vesicular recycling, and cAMP-dependent signaling [PMID:11493530, PMID:12815060]. It first localizes to lateral epithelial membranes at sites of cell-cell contact and confers adhesive behavior on non-adherent cells, acting through an intracellular homodimerization domain (K272/K273) required for adhesion and junction assembly [PMID:11493530, PMID:18493308]. Its cytoplasmic tail directly binds ZO-1 to maintain tight junction integrity and transepithelial resistance, places POPDC1 upstream of the PAR/aPKC complex, and restrains RhoA, Rac1, and Cdc42 signaling—both via direct interaction with the Rho-family GEF GEFT and through GEF-H1/ZONAB regulation—thereby suppressing epithelial-to-mesenchymal transition [PMID:16188940, PMID:18541910, PMID:21283798, PMID:23019331, PMID:21911938]. Through direct binding to the SNARE protein VAMP3 and to NDRG4, POPDC1 controls recycling-endosome fusion and trafficking of transferrin, β1-integrin, and fibronectin, supporting directional cell movement [PMID:20057356, PMID:24048452]. In striated muscle and heart, POPDC1 binds cAMP via its Popeye domain and functions as a negative-feedback regulator of adenylyl cyclase 9 (ADCY9): it scaffolds an AC9–TREK-1 potassium channel complex at the sarcolemma whose composition is tuned by β-adrenergic signaling, and it restrains AC9–cAMP–PKA signaling to limit FoxO-driven proteasomal degradation and autophagy, controlling cardiac pacemaking and muscle mass [PMID:36254885, PMID:36997581]. POPDC1 associates with caveolin-3 in cardiac caveolae to support ischemic preconditioning and Ca2+ handling [PMID:24066022]. The loss-of-function S201F variant reduces cAMP binding and impairs membrane trafficking of POPDC1 and POPDC2, causing limb-girdle muscular dystrophy with cardiac arrhythmia [PMID:26642364].","teleology":[{"year":2001,"claim":"Establishing what kind of molecule BVES is: it was identified as a novel membrane protein that confers cell adhesion and localizes to sites of cell-cell contact, defining it as a cell adhesion molecule.","evidence":"L-cell transfection adhesion assay, antibody inhibition of epicardial migration, immunofluorescence localization","pmids":["11493530"],"confidence":"High","gaps":["No binding partner identified for the adhesive activity","Mechanism of contact accumulation unresolved"]},{"year":2003,"claim":"Resolving the membrane topology was needed to interpret which terminus engages cytoplasmic partners; biochemistry established an extracellular glycosylated N-terminus, three TM domains, and a cytoplasmic C-terminus.","evidence":"Glycosylation assays, glycosylation-site insertion, topology-reversal constructs, permeabilization immunoreactivity","pmids":["12815060"],"confidence":"High","gaps":["No structural model of the cytoplasmic domain","Functional roles of N- vs C-terminus not yet assigned"]},{"year":2005,"claim":"Identifying the first direct binding partner connected BVES to junctional biology: its C-terminus binds ZO-1 and is required to maintain tight junction integrity.","evidence":"GST pull-down, TJ marker localization, siRNA knockdown with transepithelial resistance","pmids":["16188940"],"confidence":"High","gaps":["Binding interface on ZO-1 not mapped","Whether ZO-1 binding is direct in vivo not addressed"]},{"year":2008,"claim":"Two studies defined how BVES restrains Rho-family signaling and self-associates: it binds the GEF GEFT to suppress Rac1/Cdc42, and an intracellular homodimerization domain (K272/K273) is essential for adhesion and junction assembly.","evidence":"Co-IP/pulldown, Rho GTPase activity assays, GST pull-down, SPOTS, site-directed mutagenesis, transepithelial resistance","pmids":["18541910","18493308"],"confidence":"High","gaps":["RhoA-specific regulation mechanism distinct from GEFT not resolved","Stoichiometry of homodimer unknown"]},{"year":2010,"claim":"Linking BVES to membrane trafficking, it was shown to bind the SNARE VAMP3 and control recycling of transferrin and β1-integrin, with in vivo gastrulation consequences.","evidence":"Co-IP, transferrin/integrin recycling assays, Xenopus morpholino knockdown, kymography","pmids":["20057356"],"confidence":"High","gaps":["How BVES regulates VAMP3 fusion machinery mechanistically unclear","Cargo selectivity not fully defined"]},{"year":2011,"claim":"BVES was placed as a suppressor of EMT and RhoA/ZONAB signaling, connecting its junctional role to tumor-relevant phenotypes.","evidence":"Re-expression and dominant-negative constructs in cancer cells, xenograft, FRET RhoA assay, ZONAB luciferase reporter","pmids":["21911938","21283798"],"confidence":"High","gaps":["Direct mechanism linking ZO-1 loss to GEF-H1/RhoA activation incomplete","ZONAB regulation is correlative"]},{"year":2013,"claim":"Two studies extended trafficking and membrane-microdomain roles: BVES binds NDRG4 to drive recycling-endosome fusion for directional migration, and associates with caveolin-3 to support cardiac caveolae and ischemic preconditioning.","evidence":"Protein interaction assays, TIRF of endosome fusion, fibronectin recycling, Co-IP with caveolin-3, density gradients, EM, knockout ischemia/reperfusion model","pmids":["24048452","24066022"],"confidence":"High","gaps":["Whether NDRG4 and caveolin-3 functions are mechanistically linked unknown","Caveolae loss mechanism downstream of POPDC1 not defined"]},{"year":2015,"claim":"The S201F disease variant established cAMP binding as functionally critical: it reduces cAMP affinity and impairs membrane trafficking of POPDC1 and POPDC2, causing muscular dystrophy with arrhythmia.","evidence":"cAMP-binding affinity assay, patient muscle immunohistochemistry, HL-1 electrophysiology, zebrafish knockin","pmids":["26642364"],"confidence":"High","gaps":["How cAMP binding regulates downstream effectors not yet mechanistically defined here","POPDC1-POPDC2 heterodimer trafficking mechanism unresolved"]},{"year":2022,"claim":"Defining a cardiac signaling module, POPDC1 was shown to scaffold an AC9-TREK-1 potassium channel complex whose TREK-1 association is tuned by β-adrenergic input, providing a molecular basis for pacemaking control.","evidence":"Reciprocal Co-IP, co-purification, TREK-1 electrophysiology, Adcy9 knockout mice with heart rate recording, βAR stimulation","pmids":["36254885"],"confidence":"High","gaps":["How POPDC1 cAMP binding couples to TREK-1 gating not fully resolved","Whether AC9-POPDC1 scaffolding generalizes beyond heart untested here"]},{"year":2023,"claim":"The cAMP-effector logic in skeletal muscle was clarified: POPDC1 directly binds and negatively regulates ADCY9, restraining PKA-FoxO-driven proteolysis and autophagy to maintain muscle mass.","evidence":"Bves knockout mice, BVES-ADCY9 Co-IP, cAMP/PKA assays, AAV rescue, FoxO and autophagy readouts","pmids":["36997581"],"confidence":"High","gaps":["Structural basis of ADCY9 inhibition unknown","Role of cAMP binding by POPDC1 in this regulation not directly tested here"]},{"year":2022,"claim":"Additional partners and tissue roles broadened the scaffolding picture: POPDC1 engages XIRP1/actin at intercalated discs, PR61α-PP2A to control c-Myc/Wnt, Dusp1-MAPK in vascular smooth muscle, and restrains hippocampal LTP via cAMP-PKA.","evidence":"Proteomic pull-down and Co-IP (XIRP1), yeast two-hybrid and AOM/DSS model (PR61α), RNA-seq and aortic graft model (Dusp1), knockout slice electrophysiology (LTP)","pmids":["33261556","28389570","36037759","34937090"],"confidence":"Medium","gaps":["Several interactions rest on single-lab evidence","Mechanistic connections among these tissue-specific roles not integrated"]},{"year":2021,"claim":"POPDC1 was linked to ER-resident muscle biology through interaction with ANO5, with both required for myoblast differentiation.","evidence":"BioID2 proximity labeling, mass spectrometry, Co-IP, domain mapping, CRISPR knockout differentiation assay","pmids":["34963485"],"confidence":"Medium","gaps":["Functional consequence of ER co-localization unclear","Single-lab interaction without reciprocal in vivo validation"]},{"year":2024,"claim":"POPDC1 dysfunction was tied to AV node–specific conduction defects and sympathetic-dependent arrhythmogenesis.","evidence":"Action potential and calcium imaging in zebrafish mutants/knockouts, isoproterenol stimulation","pmids":["38540339"],"confidence":"Medium","gaps":["Which POPDC1 effector complex drives AV node phenotype not pinpointed","Single-lab zebrafish data"]},{"year":null,"claim":"How cAMP binding to the Popeye domain mechanistically toggles POPDC1's multiple effector interactions (AC9, TREK-1, trafficking partners) into a unified regulatory output remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of POPDC1 bound to effectors","Integration of junctional, trafficking, and cAMP-signaling roles in one tissue untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3,5,9,15]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[15,18]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2,10]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15,18,21]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[2,0]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[5,9]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[15,18]}],"complexes":["AC9-TREK-1-POPDC1 sarcolemmal complex"],"partners":["ZO-1","GEFT","VAMP3","NDRG4","CAV3","ADCY9","XIRP1","ANO5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NE79","full_name":"Popeye domain-containing protein 1","aliases":[],"length_aa":360,"mass_kda":41.5,"function":"Cell adhesion molecule involved in the establishment and/or maintenance of cell integrity. Involved in the formation and regulation of the tight junction (TJ) paracellular permeability barrier in epithelial cells (PubMed:16188940). Plays a role in VAMP3-mediated vesicular transport and recycling of different receptor molecules through its interaction with VAMP3. Plays a role in the regulation of cell shape and movement by modulating the Rho-family GTPase activity through its interaction with ARHGEF25/GEFT. Induces primordial adhesive contact and aggregation of epithelial cells in a Ca(2+)-independent manner. Also involved in striated muscle regeneration and repair and in the regulation of cell spreading (By similarity). Important for the maintenance of cardiac function. Plays a regulatory function in heart rate dynamics mediated, at least in part, through cAMP-binding and, probably, by increasing cell surface expression of the potassium channel KCNK2 and enhancing current density (PubMed:26642364). Is also a caveolae-associated protein important for the preservation of caveolae structural and functional integrity as well as for heart protection against ischemia injury","subcellular_location":"Lateral cell membrane; Cell junction, tight junction; Membrane; Cell membrane, sarcolemma; Membrane, caveola","url":"https://www.uniprot.org/uniprotkb/Q8NE79/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/POPDC1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/POPDC1","total_profiled":1310},"omim":[{"mim_id":"616812","title":"MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 25; LGMDR25","url":"https://www.omim.org/entry/616812"},{"mim_id":"605824","title":"POPEYE DOMAIN-CONTAINING PROTEIN 3; POPDC3","url":"https://www.omim.org/entry/605824"},{"mim_id":"605823","title":"POPEYE DOMAIN-CONTAINING PROTEIN 2; POPDC2","url":"https://www.omim.org/entry/605823"},{"mim_id":"604577","title":"POPEYE DOMAIN cAMP EFFECTOR 1; POPDC1","url":"https://www.omim.org/entry/604577"}],"hpa":{"profiled":true,"resolved_as":"BVES","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"heart muscle","ntpm":26.0},{"tissue":"skeletal muscle","ntpm":41.0},{"tissue":"tongue","ntpm":27.3}],"url":"https://www.proteinatlas.org/search/BVES"},"hgnc":{"alias_symbol":["POP1","HBVES"],"prev_symbol":["BVES"]},"alphafold":{"accession":"Q8NE79","domains":[{"cath_id":"-","chopping":"37-116","consensus_level":"high","plddt":91.3216,"start":37,"end":116},{"cath_id":"2.60.120.10","chopping":"126-267","consensus_level":"high","plddt":91.6265,"start":126,"end":267}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NE79","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NE79-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NE79-F1-predicted_aligned_error_v6.png","plddt_mean":75.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=POPDC1","jax_strain_url":"https://www.jax.org/strain/search?query=POPDC1"},"sequence":{"accession":"Q8NE79","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NE79.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NE79/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NE79"}},"corpus_meta":[{"pmid":"10208750","id":"PMC_10208750","title":"bves: 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It accumulates at points of cell-cell contact before E-cadherin appearance, and transfection into non-adherent L-cells confers adhesive behavior, establishing it as a novel cell adhesion molecule.\",\n      \"method\": \"Transfection into L-cells (adhesion assay), antibody inhibition of epicardial migration, subcellular localization by immunofluorescence\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (transfection adhesion assay, antibody inhibition, localization) replicated across multiple model systems\",\n      \"pmids\": [\"11493530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The membrane topology of BVES/Pop1A consists of an extracellular N-terminus (glycosylated), three transmembrane domains, and a cytoplasmic C-terminus. This was established by glycosylation assays, topology-reversal constructs, and differential immunoreactivity with/without detergent permeabilization.\",\n      \"method\": \"Glycosylation assays, glycosylation-site insertion constructs, co-expression topology experiments, selective immunoreactivity assay on intact vs. permeabilized cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — three independent biochemical approaches in one study establishing membrane topology\",\n      \"pmids\": [\"12815060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"BVES localizes with tight junction markers ZO-1 and occludin in polarized epithelial cells. GST pull-down demonstrates a direct interaction between ZO-1 and the intracellular C-terminal tail of BVES. Knockdown of BVES causes loss of transepithelial resistance and junctional protein membrane localization, demonstrating BVES modulates tight junction integrity.\",\n      \"method\": \"GST pull-down, immunolocalization with TJ markers, Ca2+-chelation/TPA challenge, siRNA knockdown with transepithelial resistance measurement\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal localization, direct biochemical interaction (GST pull-down), and functional knockdown phenotype with multiple readouts\",\n      \"pmids\": [\"16188940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"BVES directly interacts with GEFT (a GEF for Rho-family GTPases), co-localizing in adult skeletal muscle. Exogenous BVES expression reduces Rac1 and Cdc42 activity levels without affecting RhoA activity, and produces corresponding changes in cell locomotion speed and cell roundness.\",\n      \"method\": \"Co-immunoprecipitation/pulldown interaction assay, co-localization, Rho GTPase activity assays, cell motility and morphology analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein interaction identified plus functional GTPase activity readouts and cellular phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"18541910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"BVES interacts with itself through a specific intracellular homodimerization domain (amino acids 268-274, critical residues lysines 272 and 273). Mutation of these lysines abolishes homodimerization and cell adhesion, disrupts ZO-1 and E-cadherin membrane localization, reduces transepithelial resistance, and promotes epithelial-to-mesenchymal transition.\",\n      \"method\": \"GST pull-down, SPOTS analysis, site-directed mutagenesis, transepithelial resistance, immunofluorescence of junctional proteins\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — domain mapping with mutagenesis, multiple functional readouts in single rigorous study\",\n      \"pmids\": [\"18493308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BVES directly interacts with VAMP3 (a SNARE protein), and disruption of BVES impairs recycling of transferrin and β1-integrin (consistent with VAMP3 dysfunction). Morpholino knockdown of BVES in Xenopus specifically inhibits transferrin receptor recycling, causing gastrulation defects; BVES-depleted cells show impaired spreading and adhesion on fibronectin.\",\n      \"method\": \"Co-immunoprecipitation, VAMP3 recycling assays (transferrin/integrin recycling), Xenopus morpholino knockdown, kymographic analysis of cell spreading\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction demonstrated, two independent recycling assays, in vivo Xenopus knockdown with specific phenotypic readouts\",\n      \"pmids\": [\"20057356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BVES regulates epithelial-to-mesenchymal transition (EMT): re-expression of BVES in colorectal cancer cell lines promotes epithelial phenotype with decreased proliferation, migration, and invasion; a dominant-negative C-terminus-truncated BVES mutant in corneal epithelial cells induces mesenchymal features. These changes are associated with alterations in adherens junction and tight junction composition.\",\n      \"method\": \"Stable re-expression of BVES in CRC cell lines, dominant-negative mutant expression, orthotopic xenograft, migration/invasion assays, TJ/AJ protein localization\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function and dominant-negative loss-of-function, in vivo xenograft, multiple orthogonal cellular readouts\",\n      \"pmids\": [\"21911938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BVES modulates RhoA signaling and ZONAB/DbpA transcriptional activity through tight junction regulation. C-terminus-truncated BVES disrupts membrane localization of endogenous BVES and ZO-1 interaction, increases RhoA activity (measured by FRET), increases ZONAB/DbpA transcriptional activity (luciferase reporter), and reduces membrane localization of GEF-H1.\",\n      \"method\": \"Stable transfection of truncated vs. wild-type BVES, FRET-based RhoA activity assay, luciferase reporter for ZONAB/DbpA, immunolocalization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts (FRET, luciferase), single lab\",\n      \"pmids\": [\"21283798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In zebrafish, loss of BVES disrupts the PAR junctional complex, particularly atypical PKC (aPKC). Knockdown causes impaired epidermal barrier function and osmotic stress sensitivity; rescue with ZO-2/par-3/par-6/aPKC mRNAs partially restores viability and barrier function, placing BVES upstream of the PAR complex and aPKC in tight junction assembly.\",\n      \"method\": \"Morpholino knockdown in zebrafish, mRNA rescue experiments, immunofluorescence of aPKC localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via mRNA rescue in zebrafish with functional barrier readout, single lab\",\n      \"pmids\": [\"23019331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BVES directly interacts with NDRG4, and this interaction is required for directional epicardial cell movement. BVES/NDRG4 interaction regulates trafficking of internalized fibronectin through the autocrine ECM deposition pathway. TIRF microscopy shows BVES/NDRG4 interaction is required for fusion of recycling endosomes with the basal cell surface.\",\n      \"method\": \"Protein-protein interaction assays, live TIRF microscopy of recycling endosome fusion, fibronectin recycling assay, directional migration analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction identified, specific recycling pathway assayed, TIRF microscopy providing molecular mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"24048452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"POPDC1/BVES is a caveolae-associated protein: it co-localizes and co-immunoprecipitates with caveolin-3 in cardiomyocytes and co-sediments with caveolin-3 in equilibrium density gradients. Popdc1-null hearts show a 70% reduction in caveolae number, impaired Ca2+ transients, increased oxidative stress vulnerability, and loss of ischemic preconditioning.\",\n      \"method\": \"Co-immunoprecipitation with caveolin-3, equilibrium density gradient sedimentation, electron microscopy, Ca2+ transient measurement, Langendorff ischemia/reperfusion model in knockout mice\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple biochemical interaction methods (Co-IP, density gradients), ultrastructural evidence, knockout phenotype with functional readouts\",\n      \"pmids\": [\"24066022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The disease-causing POPDC1(S201F) missense variant shows ~50% reduction in cAMP-binding affinity and causes impaired membrane trafficking of both POPDC1(S201F) and WT POPDC2 in patient skeletal muscle. Forced expression in HL-1 cardiomyocytes increases hyperpolarization and action potential upstroke velocity. The homologous zebrafish mutation recapitulates cardiac arrhythmia and skeletal muscle phenotypes.\",\n      \"method\": \"cAMP-binding affinity assay (S201F vs WT), immunohistochemistry of patient muscle for membrane trafficking, HL-1 cell electrophysiology, zebrafish knockin model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct biochemical cAMP binding assay, patient tissue analysis, cellular electrophysiology, and in vivo zebrafish model with multiple orthogonal methods\",\n      \"pmids\": [\"26642364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BVES interacts with PR61α, a PP2A regulatory subunit, identified by yeast two-hybrid screen and validated mechanistically. This interaction mediates c-Myc protein destruction: loss of BVES leads to increased c-Myc levels and Wnt activation, promoting inflammatory tumourigenesis in vivo.\",\n      \"method\": \"Yeast two-hybrid screen, mechanistic studies in multiple cell lines, Bves-/- mouse AOM/DSS tumourigenesis model, molecular analysis of c-Myc and Wnt pathway\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid interaction plus in vivo knockout model, single lab, partial mechanistic follow-up in cell lines\",\n      \"pmids\": [\"28389570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BVES loss in cardiomyocytes under serum deprivation upregulates the pro-apoptotic protein Bnip3 and reduces Rac1-GTPase activity and Akt phosphorylation. Combined Popdc1/Bves and Bnip3 silencing attenuates cell injury; chromatin immunoprecipitation shows increased FoxO3 binding to the Bnip3 promoter, while NFκB is excluded from nuclei and shows decreased Bnip3 promoter binding in BVES-deficient cells.\",\n      \"method\": \"siRNA-mediated gene silencing, Rac1 GTPase activity assay, Western blot for Akt phosphorylation, chromatin immunoprecipitation (ChIP) for FoxO3 and NFκB at Bnip3 promoter\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and functional rescue experiments, single lab, multiple mechanistic readouts\",\n      \"pmids\": [\"27886395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Overexpression of BVES in trabecular meshwork cells increases tight junction formation (increased occludin, cingulin, ZO-1) and decreases RhoA activation (FRET assay) and myosin light chain phosphorylation (MLC-p), establishing a regulatory pathway upstream of RhoA in these cells.\",\n      \"method\": \"Stable transfection/overexpression, FRET-based RhoA activity assay, Western blot for MLC-p, transepithelial resistance, TJ protein expression\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET RhoA assay plus functional TJ readouts, single lab, single cell type\",\n      \"pmids\": [\"19628742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"POPDC1 scaffolds a complex of adenylyl cyclase 9 (AC9) and TREK-1 potassium channels in 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. AC9 activity is required for βAR-mediated reduction of TREK-1 complex formation and for reversing POPDC1 enhancement of TREK-1 currents. Adcy9 knockout mice show bradycardia and stress-induced heart rate variability.\",\n      \"method\": \"Co-immunoprecipitation, co-purification assays, electrophysiology (TREK-1 currents), Adcy9 knockout mouse model with heart rate recording, β-adrenergic receptor stimulation experiments\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional electrophysiology, in vivo knockout phenotype, multiple orthogonal methods in single study\",\n      \"pmids\": [\"36254885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"POPDC1 and POPDC2 interact with XIRP1 (Xin actin binding repeat-containing protein 1) and actin, identified by proteomic pull-down from human skeletal myotubes. The POPDC1-XIRP1 interaction was confirmed in adult rat heart extracts. Both POPDC1/2 and XIRP1 co-localize at intercalated discs and T-tubules in adult heart.\",\n      \"method\": \"Bead-based pulldown with proteomic analysis, co-immunoprecipitation from adult rat heart, immunolocalization with new monoclonal antibodies\",\n      \"journal\": \"BMC molecular and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic pulldown confirmed by Co-IP, single lab, localization data\",\n      \"pmids\": [\"33261556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BVES is a novel interacting protein of ANO5: identified by proximity labeling (BioID2) mass spectrometry and confirmed by co-immunoprecipitation. The N-terminus of ANO5 mediates interaction with the C-terminus of BVES. ANO5 and BVES co-localize at the ER membrane in muscle cells. Genome editing-mediated disruption of either ANO5 or BVES significantly suppresses C2C12 myoblast differentiation.\",\n      \"method\": \"BioID2 proximity labeling, mass spectrometry, co-immunoprecipitation, co-localization, CRISPR/genome editing knockout with differentiation assay\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling + Co-IP + domain mapping + knockout phenotype, single lab\",\n      \"pmids\": [\"34963485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BVES functions as a negative feedback regulator of adenylyl cyclase 9 (ADCY9)-mediated cAMP signaling in skeletal muscle. BVES interacts with and negatively regulates ADCY9's activity. BVES deletion increases PKA signaling, promoting FoxO-mediated ubiquitin-proteasome degradation and autophagy. Viral BVES re-expression in Bves-deficient muscle reverses these defects.\",\n      \"method\": \"BVES knockout mice, co-immunoprecipitation of BVES-ADCY9, cAMP/PKA activity assays, AAV-mediated rescue, FoxO pathway analysis, autophagy markers\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct biochemical interaction, functional cAMP/PKA assays, genetic rescue with viral vector, multiple pathway readouts in single study\",\n      \"pmids\": [\"36997581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In BVES-knockout mice, BVES maintains vascular smooth muscle cell (VSMC) contractile phenotype through Dusp1-dependent suppression of p38MAPK and ERK1/2. BVES knockdown reduces Dusp1 expression and enhances p38MAPK and ERK1/2 activation; VSMC-specific Bves and Dusp1 overexpression in aortic grafts attenuates neointimal lesion formation.\",\n      \"method\": \"RNA sequencing, in vitro knockdown/overexpression in VSMCs, in vivo rat aortic graft model with VSMC-specific Bves overexpression, p38MAPK/ERK1/2 phosphorylation Western blot\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway identified by RNA-seq + functional validation in vitro and in vivo, single lab\",\n      \"pmids\": [\"36037759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"POPDC1 dysfunction causes AV node dysfunction: popdc1 mutant and knockout zebrafish show reduced heart rate, altered AV delay, slower action potential upstroke, and abnormal calcium transient duration. In adult popdc1 mutant hearts, β-adrenergic receptor stimulation with isoproterenol worsens AV block and alters calcium handling, demonstrating SNS-dependent arrhythmogenesis.\",\n      \"method\": \"Functional fluorescent analysis (action potential and calcium transient imaging) in zebrafish larvae and adult isolated hearts, isoproterenol stimulation, popdc1 knockin and knockout zebrafish\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct electrophysiology and Ca2+ imaging in multiple zebrafish models, single lab\",\n      \"pmids\": [\"38540339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mice lacking POPDC1 show PKA-dependent enhancement in CA1 hippocampal long-term potentiation (LTP) in response to weaker stimulation paradigms and enhanced forskolin-induced potentiation, identifying POPDC1 as a negative regulator of hippocampal synaptic plasticity via cAMP-PKA-PDE signaling.\",\n      \"method\": \"Popdc1 knockout mice, acute hippocampal slice electrophysiology (LTP induction protocols), pharmacological PKA manipulation\",\n      \"journal\": \"Cerebral cortex (New York, N.Y. : 1991)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with direct electrophysiology and pharmacological validation, single lab\",\n      \"pmids\": [\"34937090\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"POPDC1/BVES is a plasma membrane-localized transmembrane protein (extracellular N-terminus, three TM domains, cytoplasmic C-terminus) that binds cAMP through its Popeye domain and functions as a scaffolding and signaling hub: it maintains tight junction integrity via direct interaction with ZO-1, suppresses Rac1/Cdc42 activity through interaction with GEFT, regulates vesicular recycling of integrins and transferrin via VAMP3, controls cardiac pacemaking and skeletal muscle mass by interacting with and negatively regulating adenylyl cyclase 9 (ADCY9)–cAMP–PKA signaling, scaffolds an AC9–TREK-1 potassium channel complex at the sarcolemma, and associates with caveolin-3 in caveolae to support ischemic preconditioning; loss-of-function mutations cause limb-girdle muscular dystrophy with cardiac arrhythmia (LGMDR25).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"POPDC1/BVES is a three-pass transmembrane protein with an extracellular, glycosylated N-terminus and a cytoplasmic C-terminus that functions as a membrane-localized scaffold coordinating cell adhesion, junctional integrity, vesicular recycling, and cAMP-dependent signaling [#0, #1]. It first localizes to lateral epithelial membranes at sites of cell-cell contact and confers adhesive behavior on non-adherent cells, acting through an intracellular homodimerization domain (K272/K273) required for adhesion and junction assembly [#0, #4]. Its cytoplasmic tail directly binds ZO-1 to maintain tight junction integrity and transepithelial resistance, places POPDC1 upstream of the PAR/aPKC complex, and restrains RhoA, Rac1, and Cdc42 signaling—both via direct interaction with the Rho-family GEF GEFT and through GEF-H1/ZONAB regulation—thereby suppressing epithelial-to-mesenchymal transition [#2, #3, #7, #8, #6]. Through direct binding to the SNARE protein VAMP3 and to NDRG4, POPDC1 controls recycling-endosome fusion and trafficking of transferrin, β1-integrin, and fibronectin, supporting directional cell movement [#5, #9]. In striated muscle and heart, POPDC1 binds cAMP via its Popeye domain and functions as a negative-feedback regulator of adenylyl cyclase 9 (ADCY9): it scaffolds an AC9–TREK-1 potassium channel complex at the sarcolemma whose composition is tuned by β-adrenergic signaling, and it restrains AC9–cAMP–PKA signaling to limit FoxO-driven proteasomal degradation and autophagy, controlling cardiac pacemaking and muscle mass [#15, #18]. POPDC1 associates with caveolin-3 in cardiac caveolae to support ischemic preconditioning and Ca2+ handling [#10]. The loss-of-function S201F variant reduces cAMP binding and impairs membrane trafficking of POPDC1 and POPDC2, causing limb-girdle muscular dystrophy with cardiac arrhythmia [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing what kind of molecule BVES is: it was identified as a novel membrane protein that confers cell adhesion and localizes to sites of cell-cell contact, defining it as a cell adhesion molecule.\",\n      \"evidence\": \"L-cell transfection adhesion assay, antibody inhibition of epicardial migration, immunofluorescence localization\",\n      \"pmids\": [\"11493530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No binding partner identified for the adhesive activity\", \"Mechanism of contact accumulation unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolving the membrane topology was needed to interpret which terminus engages cytoplasmic partners; biochemistry established an extracellular glycosylated N-terminus, three TM domains, and a cytoplasmic C-terminus.\",\n      \"evidence\": \"Glycosylation assays, glycosylation-site insertion, topology-reversal constructs, permeabilization immunoreactivity\",\n      \"pmids\": [\"12815060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the cytoplasmic domain\", \"Functional roles of N- vs C-terminus not yet assigned\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying the first direct binding partner connected BVES to junctional biology: its C-terminus binds ZO-1 and is required to maintain tight junction integrity.\",\n      \"evidence\": \"GST pull-down, TJ marker localization, siRNA knockdown with transepithelial resistance\",\n      \"pmids\": [\"16188940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface on ZO-1 not mapped\", \"Whether ZO-1 binding is direct in vivo not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Two studies defined how BVES restrains Rho-family signaling and self-associates: it binds the GEF GEFT to suppress Rac1/Cdc42, and an intracellular homodimerization domain (K272/K273) is essential for adhesion and junction assembly.\",\n      \"evidence\": \"Co-IP/pulldown, Rho GTPase activity assays, GST pull-down, SPOTS, site-directed mutagenesis, transepithelial resistance\",\n      \"pmids\": [\"18541910\", \"18493308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RhoA-specific regulation mechanism distinct from GEFT not resolved\", \"Stoichiometry of homodimer unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linking BVES to membrane trafficking, it was shown to bind the SNARE VAMP3 and control recycling of transferrin and β1-integrin, with in vivo gastrulation consequences.\",\n      \"evidence\": \"Co-IP, transferrin/integrin recycling assays, Xenopus morpholino knockdown, kymography\",\n      \"pmids\": [\"20057356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How BVES regulates VAMP3 fusion machinery mechanistically unclear\", \"Cargo selectivity not fully defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"BVES was placed as a suppressor of EMT and RhoA/ZONAB signaling, connecting its junctional role to tumor-relevant phenotypes.\",\n      \"evidence\": \"Re-expression and dominant-negative constructs in cancer cells, xenograft, FRET RhoA assay, ZONAB luciferase reporter\",\n      \"pmids\": [\"21911938\", \"21283798\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanism linking ZO-1 loss to GEF-H1/RhoA activation incomplete\", \"ZONAB regulation is correlative\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two studies extended trafficking and membrane-microdomain roles: BVES binds NDRG4 to drive recycling-endosome fusion for directional migration, and associates with caveolin-3 to support cardiac caveolae and ischemic preconditioning.\",\n      \"evidence\": \"Protein interaction assays, TIRF of endosome fusion, fibronectin recycling, Co-IP with caveolin-3, density gradients, EM, knockout ischemia/reperfusion model\",\n      \"pmids\": [\"24048452\", \"24066022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NDRG4 and caveolin-3 functions are mechanistically linked unknown\", \"Caveolae loss mechanism downstream of POPDC1 not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The S201F disease variant established cAMP binding as functionally critical: it reduces cAMP affinity and impairs membrane trafficking of POPDC1 and POPDC2, causing muscular dystrophy with arrhythmia.\",\n      \"evidence\": \"cAMP-binding affinity assay, patient muscle immunohistochemistry, HL-1 electrophysiology, zebrafish knockin\",\n      \"pmids\": [\"26642364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cAMP binding regulates downstream effectors not yet mechanistically defined here\", \"POPDC1-POPDC2 heterodimer trafficking mechanism unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defining a cardiac signaling module, POPDC1 was shown to scaffold an AC9-TREK-1 potassium channel complex whose TREK-1 association is tuned by β-adrenergic input, providing a molecular basis for pacemaking control.\",\n      \"evidence\": \"Reciprocal Co-IP, co-purification, TREK-1 electrophysiology, Adcy9 knockout mice with heart rate recording, βAR stimulation\",\n      \"pmids\": [\"36254885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How POPDC1 cAMP binding couples to TREK-1 gating not fully resolved\", \"Whether AC9-POPDC1 scaffolding generalizes beyond heart untested here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The cAMP-effector logic in skeletal muscle was clarified: POPDC1 directly binds and negatively regulates ADCY9, restraining PKA-FoxO-driven proteolysis and autophagy to maintain muscle mass.\",\n      \"evidence\": \"Bves knockout mice, BVES-ADCY9 Co-IP, cAMP/PKA assays, AAV rescue, FoxO and autophagy readouts\",\n      \"pmids\": [\"36997581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ADCY9 inhibition unknown\", \"Role of cAMP binding by POPDC1 in this regulation not directly tested here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Additional partners and tissue roles broadened the scaffolding picture: POPDC1 engages XIRP1/actin at intercalated discs, PR61α-PP2A to control c-Myc/Wnt, Dusp1-MAPK in vascular smooth muscle, and restrains hippocampal LTP via cAMP-PKA.\",\n      \"evidence\": \"Proteomic pull-down and Co-IP (XIRP1), yeast two-hybrid and AOM/DSS model (PR61α), RNA-seq and aortic graft model (Dusp1), knockout slice electrophysiology (LTP)\",\n      \"pmids\": [\"33261556\", \"28389570\", \"36037759\", \"34937090\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several interactions rest on single-lab evidence\", \"Mechanistic connections among these tissue-specific roles not integrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"POPDC1 was linked to ER-resident muscle biology through interaction with ANO5, with both required for myoblast differentiation.\",\n      \"evidence\": \"BioID2 proximity labeling, mass spectrometry, Co-IP, domain mapping, CRISPR knockout differentiation assay\",\n      \"pmids\": [\"34963485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of ER co-localization unclear\", \"Single-lab interaction without reciprocal in vivo validation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"POPDC1 dysfunction was tied to AV node–specific conduction defects and sympathetic-dependent arrhythmogenesis.\",\n      \"evidence\": \"Action potential and calcium imaging in zebrafish mutants/knockouts, isoproterenol stimulation\",\n      \"pmids\": [\"38540339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which POPDC1 effector complex drives AV node phenotype not pinpointed\", \"Single-lab zebrafish data\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How cAMP binding to the Popeye domain mechanistically toggles POPDC1's multiple effector interactions (AC9, TREK-1, trafficking partners) into a unified regulatory output remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of POPDC1 bound to effectors\", \"Integration of junctional, trafficking, and cAMP-signaling roles in one tissue untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3, 5, 9, 15]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15, 18]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2, 10]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15, 18, 21]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [2, 0]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [15, 18]}\n    ],\n    \"complexes\": [\"AC9-TREK-1-POPDC1 sarcolemmal complex\"],\n    \"partners\": [\"ZO-1\", \"GEFT\", \"VAMP3\", \"NDRG4\", \"CAV3\", \"ADCY9\", \"XIRP1\", \"ANO5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}