{"gene":"ARVCF","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":1997,"finding":"ARVCF encodes a 962-amino-acid protein containing a coiled-coil domain and 10 tandem armadillo repeats, with primary structure most closely related to p120-catenin, suggesting a role in protein-protein interactions at adherens junctions. It is hemizygous in VCFS patients with interstitial deletions.","method":"Gene isolation, sequence analysis, structural domain prediction","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — original identification with structural characterization, but functional role inferred from sequence homology","pmids":["9126485"],"is_preprint":false},{"year":2000,"finding":"ARVCF associates with E-cadherin and competes with p120-catenin for interaction with the E-cadherin juxtamembrane domain. ARVCF also localizes to the nucleus, and this nuclear localization requires sequences in the amino-terminal end of ARVCF (distinct from the predicted bipartite NLS between repeats 6 and 7). ARVCF completely lacked the ability to induce the cell-branching phenotype of p120-catenin, and branching activity maps to the Armadillo repeat domain.","method":"Immunoprecipitation, immunofluorescence, domain chimera analysis, monoclonal antibodies","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, domain-mapping chimeras, and localization experiments with functional readout, multiple orthogonal methods","pmids":["10725230"],"is_preprint":false},{"year":2000,"finding":"The armadillo repeat region of ARVCF is both sufficient and necessary for interaction with the 55 membrane-proximal amino acids of the M-cadherin cytoplasmic tail. The N-terminus of ARVCF is not required for junctional localization, but deletion of the four N-terminal armadillo repeats abolishes targeting to cadherin-based junctions in cardiomyocytes.","method":"Yeast two-hybrid, MOM recruitment assay, immunoprecipitation, in vitro binding assay, domain truncation/deletion mutagenesis, EGFP-fusion localization","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding assay plus multiple orthogonal in-cell methods and systematic mutagenesis within a single study","pmids":["11058098"],"is_preprint":false},{"year":2002,"finding":"The Erbin PDZ domain binds with high affinity and specificity to the C-terminal PDZ-binding motif (DSWV-COOH) of ARVCF. Erbin co-localizes and co-precipitates with ARVCF complexed with beta-catenin and E/N-cadherin. Mutagenesis and peptide competition confirmed that the PDZ domain of Erbin mediates association with the cadherin-catenin complex through the ARVCF C-terminus.","method":"Phage peptide library, in vitro binding with synthetic peptides, co-immunoprecipitation, co-localization, mutagenesis, peptide competition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with peptides, mutagenesis, and in vivo co-IP; multiple orthogonal methods","pmids":["11821434"],"is_preprint":false},{"year":2004,"finding":"ARVCF interacts via its C-terminal PDZ-binding motif with ZO-1 and ZO-2. ARVCF, ZO-1, and E-cadherin form a trimeric complex recruited to sites of initial cell-cell contact. Disruption of cell-cell adhesion releases ARVCF from the plasma membrane and increases nuclear localization. E-cadherin binding and plasma membrane localization of ARVCF require the PDZ-binding motif; nuclear localization can be mediated by ZO-2 PDZ domains.","method":"Co-immunoprecipitation, co-localization (immunofluorescence), cell-cell adhesion disruption assay, PDZ-binding motif mutagenesis, epithelial MDCK cell fractionation","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, mutagenesis of the binding motif, functional consequence on localization, multiple orthogonal methods","pmids":["15456900"],"is_preprint":false},{"year":2004,"finding":"xARVCF and Xp120-catenin are each required for vertebrate (Xenopus) gastrulation and axial elongation. Depletion of either can be cross-rescued by exogenous xARVCF or Xp120, and each depletion is rescued by dominant-negative RhoA or dominant-active Rac, placing ARVCF functionally upstream of RhoA/Rac signaling in development.","method":"Morpholino depletion, rescue with exogenous protein, dominant-negative/dominant-active RhoA and Rac epistasis, cell reaggregation assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with dominant-negative/active GTPases, depletion-rescue strategy, multiple orthogonal assays","pmids":["15067024"],"is_preprint":false},{"year":2010,"finding":"Xenopus ARVCF (xARVCF) binds directly to Xenopus KazrinA (xKazrinA), and a ternary biochemical complex of xARVCF–xKazrinA–xβ2-spectrin was resolved. KazrinA also binds p190B RhoGAP. Loss of Kazrin leads to RhoA activation, altered actin organization, and ectodermal cell shedding, which is partially rescued by exogenous xARVCF. xKazrinA associates with delta-catenin and p0071-catenin but not p120-catenin.","method":"Co-immunoprecipitation, direct binding assay, ternary complex pull-down, Xenopus morpholino knockdown with rescue, RhoA activity assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding established, ternary complex resolved, knockdown-rescue epistasis with RhoA activity measurements","pmids":["21062899"],"is_preprint":false},{"year":2011,"finding":"Depletion of ARVCF in Xenopus results in delayed migration of cranial neural crest cells and defects in craniofacial skeleton and aortic arches, phenotypes that cooperate with Tbx1 depletion, indicating ARVCF and Tbx1 act in the same developmental pathway for 22q11.2DS phenotypes.","method":"Morpholino knockdown, double depletion epistasis, craniofacial skeletal staining, molecular marker analysis","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by double knockdown, single lab, defined phenotypic readout","pmids":["22028109"],"is_preprint":false},{"year":2011,"finding":"Kazrin, ARVCF-catenin, and delta-catenin are all required for Xenopus craniofacial development; knockdown of Kazrin or ARVCF in the anterior neural region reduces cartilaginous head structures and eyes and impairs neural crest cell establishment and migration. Exogenous ARVCF partially rescues Kazrin knockdown, supporting a Kazrin:ARVCF functional relationship.","method":"Morpholino knockdown, rescue with exogenous ARVCF, molecular marker analysis (neural crest), confocal microscopy","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown-rescue epistasis, defined phenotypic readout, single lab","pmids":["22028074"],"is_preprint":false},{"year":2014,"finding":"Nuclear ARVCF interacts with splicing factors SRSF1 (SF2/ASF), RNA helicase p68 (DDX5), and hnRNP H2 in an RNA-independent manner. These interactions occur via the ARVCF C-terminus. ARVCF occurs in large RNA-containing complexes with spliced and unspliced mRNAs. Overexpression of ARVCF increases splicing activity of a reporter mRNA, and ARVCF depletion followed by RNA-seq reveals significant changes in alternatively spliced transcripts.","method":"Co-immunoprecipitation (RNA-independent), domain analysis, splicing reporter assay, RNA-seq after ARVCF knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP with RNA-independence control, domain mapping, functional splicing reporter assay, and transcriptome-wide validation","pmids":["24644279"],"is_preprint":false},{"year":2019,"finding":"ARVCF is a direct transcriptional target of p53; activated p53 binds two distinct sites in the ARVCF gene (by ChIP-seq), inducing ARVCF expression at mRNA and protein levels. ARVCF knockdown inhibits p53-induced apoptosis. ARVCF interacts with hnRNPH2 and its knockdown causes dynamic changes in alternative splicing, indicating ARVCF indirectly regulates p53 target selectivity through splicing alterations.","method":"ChIP-sequencing, RT-PCR/Western blot, siRNA knockdown with apoptosis assay, co-immunoprecipitation (ARVCF–hnRNPH2), alternative splicing profiling","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq establishes direct p53 binding, functional rescue confirms pathway position, co-IP confirms binding partner, multiple orthogonal methods","pmids":["31827232"],"is_preprint":false},{"year":2022,"finding":"Arvcf is required for Xenopus convergent extension (head-to-tail axis elongation) at the organismal but not isolated-tissue scale. The defect results from impaired tissue-scale force production, which arises from dampened pulsatile recruitment of cell adhesion and cytoskeletal proteins to cell membranes.","method":"Morpholino knockdown in intact embryos vs. isolated tissue explants, tissue force measurement, live imaging of protein dynamics at membranes","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined organism-scale vs. tissue-scale phenotype dissection, mechanical force measurement, live imaging of membrane dynamics","pmids":["35476939"],"is_preprint":false},{"year":2022,"finding":"Arvcf is required for N-cadherin complex stability in lens fiber cells. Arvcf-deficient mice develop cortical cataracts by >6 months of age with fiber cell separation and hexagonal lattice disorganization. Loss of Arvcf reduces membrane localization of N-cadherin, β-catenin, and αN-catenin, and shrinks cadherin nanoclusters (by super-resolution imaging). Arvcf KO also alters lens biomechanical properties.","method":"Arvcf conditional KO mice, immunofluorescence, super-resolution imaging, electron microscopy, lens compression biomechanical assay","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model with defined phenotypic readout, super-resolution imaging of cadherin nanoclusters, biomechanical assay, multiple orthogonal methods","pmids":["35874813"],"is_preprint":false},{"year":2025,"finding":"ARVCF is expressed in VTA dopaminergic neurons and its expression is upregulated by nicotine. Arvcf-KO mice show reduced dopamine synthesis and release in the nucleus accumbens upon nicotine stimulation and impaired nicotine-induced conditioned place preference. Inhibition of Arvcf in VTA dopaminergic neurons (via viral vector) decreased dopamine release within the VTA-NAc circuit and suppressed nicotine reward-related behavior; overexpression had the opposite effect.","method":"Arvcf-KO mouse model, conditioned place preference, viral vector overexpression/knockdown in VTA, dopamine measurement (synthesis and release), snRNA-seq","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO and viral rescue in defined circuit, dopamine measurement, single lab","pmids":["40082601"],"is_preprint":false},{"year":2026,"finding":"ARVCF is a component of the VE-cadherin interactome in endothelial cells; it selectively binds a pool of VE-cadherin that is unbound from p120-catenin, through a mechanism involving its C-terminal intrinsically disordered regions. ARVCF depletion results in unstable junctions, loss of endothelial barrier function, and impaired collective cell migration.","method":"Mass spectrometry proteomics of VE-cadherin interactome, co-immunoprecipitation, co-localization, ARVCF depletion with barrier function assay and migration assay","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-based interactome, reciprocal co-IP, domain mechanism identified, functional KD with defined cellular phenotypes, multiple orthogonal methods","pmids":["42006337"],"is_preprint":false},{"year":2025,"finding":"In hepatocytes, N-cadherin maintains hepatic polarity by facilitating RhoA inactivation through the p120-catenin family member ARVCF and its partner p190B RhoGAP (ARHGAP5), placing ARVCF as a component of the N-cadherin–RhoA inactivation axis opposing E-cadherin–driven RhoA activation.","method":"Loss-of-function experiments in hepatocytes, RhoA activity assay, co-localization, polarity and bile canaliculi formation assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, ARVCF mechanistic role inferred from co-localization and functional context, full methods not detailed in abstract","pmids":["bio_10.1101_2025.10.06.680681"],"is_preprint":true},{"year":2025,"finding":"In B cell lymphoma cells, ARVCF maintains RRAGA 3'UTR length via alternative polyadenylation regulation and suppresses mTOR-EIF4G1 signaling, thereby inhibiting lymphoma proliferation. VIM (vimentin) deletion downregulates ARVCF protein, linking cytoskeletal disruption to APA-mediated mTOR activation via ARVCF.","method":"VIM-KO cell lines, RNA-seq with APA analysis (DaPars), proteomic profiling, ARVCF overexpression rescue, CCK-8/EdU proliferation assays, Western blot","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue with ARVCF OE, APA and proliferation readouts, single lab","pmids":["41058879"],"is_preprint":false}],"current_model":"ARVCF is an armadillo-repeat catenin (p120-catenin subfamily) that binds the juxtamembrane domain of classical cadherins (E-, N-, M-, VE-cadherin) via its armadillo repeats, competing with p120-catenin; at the plasma membrane it stabilizes cadherin nanoclusters and adherens junctions, regulates pulsatile cytoskeletal recruitment, and suppresses RhoA activity (in part through interactions with Kazrin and p190B RhoGAP); in the nucleus it binds splicing factors (SRSF1, p68/DDX5, hnRNP H2) via its C-terminus and modulates alternative splicing of pre-mRNAs, a function induced downstream of p53; its C-terminal PDZ-binding motif (DSWV) recruits PDZ proteins including Erbin, ZO-1, and ZO-2, with ZO-1/2 controlling its membrane vs. nuclear distribution in response to cell-cell adhesion cues; and in dopaminergic neurons it promotes dopamine synthesis and release to support reward-related behavior."},"narrative":{"mechanistic_narrative":"ARVCF is an armadillo-repeat protein of the p120-catenin subfamily that functions both as a junctional regulator of classical cadherins and as a nuclear modulator of pre-mRNA processing [PMID:9126485, PMID:10725230, PMID:24644279]. Through its armadillo repeat domain it binds the membrane-proximal cytoplasmic (juxtamembrane) tail of classical cadherins—E-, M-, N-, and VE-cadherin—competing with p120-catenin for this site, and at the plasma membrane it stabilizes cadherin-catenin complexes and cadherin nanoclusters required for adherens junction integrity [PMID:10725230, PMID:11058098, PMID:35874813, PMID:42006337]. Its C-terminal PDZ-binding motif (DSWV) recruits PDZ-domain proteins including Erbin, ZO-1, and ZO-2, and the ZO proteins govern the balance between its membrane and nuclear pools in response to cell-cell adhesion cues [PMID:11821434, PMID:15456900]. ARVCF acts upstream of Rho-family GTPase signaling, suppressing RhoA activity in part through the Kazrin–p190B RhoGAP axis, and this activity underlies its requirement in vertebrate gastrulation, convergent extension, and neural crest-dependent craniofacial development [PMID:15067024, PMID:21062899, PMID:35476939]. In the nucleus, ARVCF binds the splicing factors SRSF1, p68/DDX5, and hnRNP H2 via its C-terminus to promote alternative splicing and alternative polyadenylation; this function is induced downstream of p53, where ARVCF shapes p53 target selectivity and apoptotic output [PMID:24644279, PMID:31827232, PMID:41058879]. Physiologically, loss of Arvcf causes cortical cataracts through N-cadherin complex destabilization in lens fiber cells and modulates dopamine synthesis and release in VTA dopaminergic neurons to support nicotine reward behavior [PMID:35874813, PMID:40082601].","teleology":[{"year":1997,"claim":"Established ARVCF as a p120-catenin-related armadillo-repeat protein and a candidate gene in the 22q11.2 deletion (velocardiofacial) interval, framing it as a likely adherens-junction protein.","evidence":"Gene isolation, sequence and structural domain analysis in VCFS deletion patients","pmids":["9126485"],"confidence":"Medium","gaps":["Function entirely inferred from sequence homology","No direct binding partner demonstrated","No causative role in VCFS phenotype shown"]},{"year":2000,"claim":"Showed ARVCF physically engages the cadherin-catenin system and competes with p120-catenin, while also occupying the nucleus, defining its dual-compartment behavior.","evidence":"Reciprocal co-IP with E-cadherin, p120 competition, domain chimera analysis and immunofluorescence; yeast two-hybrid and in vitro binding mapping to M-cadherin juxtamembrane tail","pmids":["10725230","11058098"],"confidence":"High","gaps":["Functional consequence of p120 competition unresolved","ARVCF lacks the cell-branching activity of p120, leaving its distinct junctional output undefined","Nuclear function not yet characterized"]},{"year":2004,"claim":"Identified the C-terminal PDZ-binding motif as the hub linking ARVCF to ZO-1/ZO-2 and showed that adhesion state controls its membrane-versus-nuclear partitioning, establishing a regulated shuttling mechanism.","evidence":"Co-IP, co-localization, adhesion-disruption assays and PDZ-motif mutagenesis in MDCK cells; Erbin PDZ binding via phage peptide library and peptide competition","pmids":["15456900","11821434"],"confidence":"High","gaps":["Signal triggering nuclear import upon adhesion loss not defined","Nuclear function still unknown at this stage"]},{"year":2004,"claim":"Placed ARVCF upstream of RhoA/Rac signaling in vertebrate morphogenesis, demonstrating it is functionally required for gastrulation and axis elongation.","evidence":"Xenopus morpholino depletion with cross-rescue by p120 and GTPase epistasis (dominant-negative RhoA, dominant-active Rac)","pmids":["15067024"],"confidence":"High","gaps":["Molecular link between ARVCF and RhoA/Rac not yet identified","Direct GTPase regulator partner unknown at this point"]},{"year":2011,"claim":"Connected ARVCF to RhoA control through a Kazrin–p190B RhoGAP complex and linked it genetically to Tbx1 in neural crest and craniofacial development, providing a mechanistic route to 22q11.2DS phenotypes.","evidence":"Direct binding and ternary complex pulldowns (xARVCF–Kazrin–β2-spectrin), RhoA activity assays, and double-knockdown epistasis with Tbx1 in Xenopus","pmids":["21062899","22028109","22028074"],"confidence":"High","gaps":["Whether ARVCF directly regulates p190B activity vs. acting through Kazrin unresolved","Relationship between junctional and developmental roles not dissected"]},{"year":2014,"claim":"Defined the nuclear function of ARVCF as a splicing regulator, showing it binds splicing machinery and shapes the alternatively spliced transcriptome.","evidence":"RNA-independent co-IP with SRSF1, DDX5, hnRNP H2, C-terminal domain mapping, splicing reporter assay, and RNA-seq after knockdown","pmids":["24644279"],"confidence":"High","gaps":["Sequence/transcript determinants of ARVCF-dependent splicing not defined","Whether membrane and nuclear pools are functionally coupled unknown"]},{"year":2019,"claim":"Positioned ARVCF within the p53 pathway as a direct transcriptional target that feeds back through splicing to influence p53 target selectivity and apoptosis.","evidence":"ChIP-seq mapping of p53 binding sites, expression induction, siRNA knockdown apoptosis assays, and ARVCF–hnRNPH2 co-IP","pmids":["31827232"],"confidence":"High","gaps":["Specific p53-dependent splicing targets mediating apoptosis not enumerated","Generality across cell types untested"]},{"year":2022,"claim":"Resolved how ARVCF contributes to tissue mechanics and junction stability in vivo, showing scale-dependent force production and a requirement for cadherin nanocluster integrity.","evidence":"Xenopus knockdown with tissue-scale force measurement and live membrane imaging; Arvcf KO mouse lens with super-resolution nanocluster imaging and biomechanical assays","pmids":["35476939","35874813"],"confidence":"High","gaps":["Molecular mechanism converting ARVCF binding into pulsatile recruitment unknown","How ARVCF stabilizes nanoclusters at the structural level undefined"]},{"year":2025,"claim":"Extended ARVCF function to neuronal physiology, demonstrating a role in dopaminergic signaling and reward behavior, and to APA-mediated control of mTOR signaling in lymphoma.","evidence":"Arvcf-KO mice and viral circuit manipulation with dopamine measurement and conditioned place preference; VIM-KO lymphoma cells with APA profiling, proteomics, and ARVCF overexpression rescue","pmids":["40082601","41058879"],"confidence":"Medium","gaps":["Mechanism by which ARVCF promotes dopamine synthesis/release not established","Whether neuronal role is junctional or nuclear unknown","RRAGA APA regulation mechanism single-lab"]},{"year":2026,"claim":"Defined an endothelial role for ARVCF in selectively binding p120-free VE-cadherin to maintain barrier function, refining the model of how ARVCF and p120 partition cadherin pools.","evidence":"Mass-spectrometry VE-cadherin interactome, co-IP, co-localization, and depletion with barrier and migration assays in endothelial cells","pmids":["42006337"],"confidence":"High","gaps":["How the C-terminal disordered regions discriminate p120-free cadherin not structurally resolved","Relationship to RhoA regulation in endothelium untested"]},{"year":null,"claim":"It remains unknown how ARVCF integrates its junctional, RhoA-regulatory, and nuclear splicing functions, and whether shuttling between these compartments is coordinately regulated by a single signal.","evidence":"No study in the corpus directly couples membrane and nuclear pools mechanistically","pmids":[],"confidence":"Low","gaps":["No structural model of ARVCF in any complex","Signal coupling adhesion state to splicing output undefined","Causal contribution to human 22q11.2DS pathology not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,2,12,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,6,9,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,4,12,14]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,4,9,10]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[3,4,12,14]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[9,10,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,7,8,11]}],"complexes":["cadherin-catenin complex","ARVCF–Kazrin–β2-spectrin complex","VE-cadherin interactome"],"partners":["CDH1","CDH2","ERBIN","TJP1","TJP2","KAZN","SRSF1","DDX5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00192","full_name":"Splicing regulator ARVCF","aliases":["Armadillo repeat protein deleted in velo-cardio-facial syndrome"],"length_aa":962,"mass_kda":104.6,"function":"Contributes to the regulation of alternative splicing of pre-mRNAs","subcellular_location":"Cell junction, adherens junction; Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O00192/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ARVCF","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CDH2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ARVCF","total_profiled":1310},"omim":[{"mim_id":"613323","title":"FERM AND PDZ DOMAINS-CONTAINING PROTEIN 2; FRMPD2","url":"https://www.omim.org/entry/613323"},{"mim_id":"608363","title":"CHROMOSOME 22q11.2 DUPLICATION SYNDROME","url":"https://www.omim.org/entry/608363"},{"mim_id":"606788","title":"ANOREXIA NERVOSA, SUSCEPTIBILITY TO; ANON","url":"https://www.omim.org/entry/606788"},{"mim_id":"606448","title":"THIOREDOXIN REDUCTASE 2; TXNRD2","url":"https://www.omim.org/entry/606448"},{"mim_id":"604276","title":"PLAKOPHILIN 4; PKP4","url":"https://www.omim.org/entry/604276"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Plasma membrane","reliability":"Enhanced"},{"location":"Cell Junctions","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":52.5}],"url":"https://www.proteinatlas.org/search/ARVCF"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O00192","domains":[{"cath_id":"1.25.10.10","chopping":"358-474","consensus_level":"medium","plddt":96.5803,"start":358,"end":474},{"cath_id":"1.25.10.10","chopping":"486-503_513-592_652-692","consensus_level":"medium","plddt":95.4436,"start":486,"end":692}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00192","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00192-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00192-F1-predicted_aligned_error_v6.png","plddt_mean":64.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ARVCF","jax_strain_url":"https://www.jax.org/strain/search?query=ARVCF"},"sequence":{"accession":"O00192","fasta_url":"https://rest.uniprot.org/uniprotkb/O00192.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00192/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00192"}},"corpus_meta":[{"pmid":"11821434","id":"PMC_11821434","title":"The Erbin PDZ domain binds with high affinity and specificity to the carboxyl termini of delta-catenin and ARVCF.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11821434","citation_count":130,"is_preprint":false},{"pmid":"9126485","id":"PMC_9126485","title":"Identification of a new human catenin gene family member (ARVCF) from the region deleted in velo-cardio-facial syndrome.","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9126485","citation_count":99,"is_preprint":false},{"pmid":"15067024","id":"PMC_15067024","title":"Vertebrate development requires ARVCF and p120 catenins and their interplay with RhoA and Rac.","date":"2004","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15067024","citation_count":86,"is_preprint":false},{"pmid":"15456900","id":"PMC_15456900","title":"Association of ARVCF with zonula occludens (ZO)-1 and ZO-2: binding to PDZ-domain proteins and cell-cell adhesion regulate plasma membrane and nuclear localization of ARVCF.","date":"2004","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/15456900","citation_count":81,"is_preprint":false},{"pmid":"10725230","id":"PMC_10725230","title":"ARVCF localizes to the nucleus and adherens junction and is mutually exclusive with p120(ctn) in E-cadherin complexes.","date":"2000","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/10725230","citation_count":77,"is_preprint":false},{"pmid":"11058098","id":"PMC_11058098","title":"The armadillo repeat region targets ARVCF to cadherin-based cellular junctions.","date":"2000","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/11058098","citation_count":48,"is_preprint":false},{"pmid":"19617637","id":"PMC_19617637","title":"Over-expression of a human chromosome 22q11.2 segment including TXNRD2, COMT and ARVCF developmentally affects incentive learning and working memory in mice.","date":"2009","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19617637","citation_count":48,"is_preprint":false},{"pmid":"19508883","id":"PMC_19508883","title":"ARVCF single marker and haplotypic association with schizophrenia.","date":"2009","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/19508883","citation_count":17,"is_preprint":false},{"pmid":"21062899","id":"PMC_21062899","title":"Xenopus Kazrin interacts with ARVCF-catenin, spectrin and p190B RhoGAP, and modulates RhoA activity and epithelial integrity.","date":"2010","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/21062899","citation_count":17,"is_preprint":false},{"pmid":"18600340","id":"PMC_18600340","title":"Differential expression pattern of protein ARVCF in nephron segments of human and mouse kidney.","date":"2008","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18600340","citation_count":16,"is_preprint":false},{"pmid":"16118784","id":"PMC_16118784","title":"Haplotype analysis of the COMT-ARVCF gene region in Israeli anorexia nervosa family trios.","date":"2005","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16118784","citation_count":16,"is_preprint":false},{"pmid":"22053977","id":"PMC_22053977","title":"ARVCF genetic influences on neurocognitive and neuroanatomical intermediate phenotypes in Chinese patients with schizophrenia.","date":"2011","source":"The Journal of clinical psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/22053977","citation_count":14,"is_preprint":false},{"pmid":"22028074","id":"PMC_22028074","title":"Kazrin, and its binding partners ARVCF- and delta-catenin, are required for Xenopus laevis craniofacial development.","date":"2011","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/22028074","citation_count":13,"is_preprint":false},{"pmid":"35476939","id":"PMC_35476939","title":"ARVCF catenin controls force production during vertebrate convergent extension.","date":"2022","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/35476939","citation_count":13,"is_preprint":false},{"pmid":"24644279","id":"PMC_24644279","title":"Nuclear ARVCF protein binds splicing factors and contributes to the regulation of alternative splicing.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24644279","citation_count":12,"is_preprint":false},{"pmid":"22028109","id":"PMC_22028109","title":"ARVCF depletion cooperates with Tbx1 deficiency in the development of 22q11.2DS-like phenotypes in Xenopus.","date":"2011","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/22028109","citation_count":12,"is_preprint":false},{"pmid":"15509897","id":"PMC_15509897","title":"Expression of ARVCF in the human ganglionic eminence during fetal development.","date":"2004","source":"Developmental neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/15509897","citation_count":12,"is_preprint":false},{"pmid":"23248619","id":"PMC_23248619","title":"Chemotherapy refractory testicular germ cell tumor is associated with a variant in Armadillo Repeat gene deleted in Velco-Cardio-Facial syndrome (ARVCF).","date":"2012","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/23248619","citation_count":11,"is_preprint":false},{"pmid":"20333729","id":"PMC_20333729","title":"A functional variant provided further evidence for the association of ARVCF with schizophrenia.","date":"2010","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20333729","citation_count":11,"is_preprint":false},{"pmid":"29768670","id":"PMC_29768670","title":"Patients affected by a new variant of endemic pemphigus foliaceus have autoantibodies colocalizing with MYZAP, p0071, desmoplakins 1-2 and ARVCF, causing renal damage.","date":"2018","source":"Clinical and experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/29768670","citation_count":8,"is_preprint":false},{"pmid":"31827232","id":"PMC_31827232","title":"p53-induced ARVCF modulates the splicing landscape and supports the tumor suppressive function of p53.","date":"2019","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/31827232","citation_count":7,"is_preprint":false},{"pmid":"10571264","id":"PMC_10571264","title":"Production and characterization of monoclonal antibodies to ARVCF.","date":"1999","source":"Hybridoma","url":"https://pubmed.ncbi.nlm.nih.gov/10571264","citation_count":7,"is_preprint":false},{"pmid":"38025780","id":"PMC_38025780","title":"Single nucleotide polymorphisms rs148582811 regulates its host gene ARVCF expression to affect nicotine-associated hippocampus-dependent memory.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38025780","citation_count":6,"is_preprint":false},{"pmid":"35874813","id":"PMC_35874813","title":"Arvcf Dependent Adherens Junction Stability is Required to Prevent Age-Related Cortical Cataracts.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35874813","citation_count":6,"is_preprint":false},{"pmid":"29152726","id":"PMC_29152726","title":"Autoantibodies to full body vascular cell junctions colocalize with MYZAP, ARVCF, desmoplakins I and II and p0071 in endemic pemphigus in Colombia, South America.","date":"2017","source":"International journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/29152726","citation_count":6,"is_preprint":false},{"pmid":"29034528","id":"PMC_29034528","title":"Patients with a new variant of endemic pemphigus foliaceus have autoantibodies against arrector pili muscle, colocalizing with MYZAP, p0071, desmoplakins 1 and 2 and ARVCF.","date":"2017","source":"Clinical and experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/29034528","citation_count":5,"is_preprint":false},{"pmid":"25683624","id":"PMC_25683624","title":"ARVCF expression is significantly correlated with the malignant phenotype of non-small cell lung cancer.","date":"2015","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/25683624","citation_count":4,"is_preprint":false},{"pmid":"40082601","id":"PMC_40082601","title":"Investigating the effect of Arvcf reveals an essential role on regulating the mesolimbic dopamine signaling-mediated nicotine reward.","date":"2025","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/40082601","citation_count":4,"is_preprint":false},{"pmid":"39429782","id":"PMC_39429782","title":"Identification and validation of a novel gene ARVCF associated with alcohol dependence among Chinese population.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/39429782","citation_count":3,"is_preprint":false},{"pmid":"35899599","id":"PMC_35899599","title":"Patterns of Antinuclear Antibodies in a New Variant of Endemic Pemphigus in El Bagre, Colombia, Colocalizing with Antigens against MIZAP, ARVCF, p0071, and Desmoplakins I and II.","date":"2022","source":"The journal of applied laboratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35899599","citation_count":2,"is_preprint":false},{"pmid":"41395251","id":"PMC_41395251","title":"Single-Cell Profiling Identifies Reward Behavior-Related Neurons and Alterations in the Ventral Tegmental Area Based on Arvcf-Knockout Mouse Model.","date":"2025","source":"Research (Washington, D.C.)","url":"https://pubmed.ncbi.nlm.nih.gov/41395251","citation_count":1,"is_preprint":false},{"pmid":"42006337","id":"PMC_42006337","title":"VE-cadherin interaction proteomics identifies ARVCF as stabilizer of endothelial adherens junctions.","date":"2026","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/42006337","citation_count":1,"is_preprint":false},{"pmid":"41058879","id":"PMC_41058879","title":"Vimentin Regulates Alternative Polyadenylation and mTOR Signaling via ARVCF to Promote B Cell Lymphoma Progression.","date":"2025","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/41058879","citation_count":0,"is_preprint":false},{"pmid":"42000070","id":"PMC_42000070","title":"Effects of Arvcf on anxiety- and depression-like behaviors in mice of different ages and sexes.","date":"2026","source":"Journal of affective disorders","url":"https://pubmed.ncbi.nlm.nih.gov/42000070","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.06.680681","title":"E- and N-cadherin drive hepatic polarity and lumen elongation via opposing effects on RhoA activity","date":"2025-10-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.06.680681","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18905,"output_tokens":4622,"usd":0.063022,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12682,"output_tokens":4002,"usd":0.08173,"stage2_stop_reason":"end_turn"},"total_usd":0.144752,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"ARVCF encodes a 962-amino-acid protein containing a coiled-coil domain and 10 tandem armadillo repeats, with primary structure most closely related to p120-catenin, suggesting a role in protein-protein interactions at adherens junctions. It is hemizygous in VCFS patients with interstitial deletions.\",\n      \"method\": \"Gene isolation, sequence analysis, structural domain prediction\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — original identification with structural characterization, but functional role inferred from sequence homology\",\n      \"pmids\": [\"9126485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ARVCF associates with E-cadherin and competes with p120-catenin for interaction with the E-cadherin juxtamembrane domain. ARVCF also localizes to the nucleus, and this nuclear localization requires sequences in the amino-terminal end of ARVCF (distinct from the predicted bipartite NLS between repeats 6 and 7). ARVCF completely lacked the ability to induce the cell-branching phenotype of p120-catenin, and branching activity maps to the Armadillo repeat domain.\",\n      \"method\": \"Immunoprecipitation, immunofluorescence, domain chimera analysis, monoclonal antibodies\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, domain-mapping chimeras, and localization experiments with functional readout, multiple orthogonal methods\",\n      \"pmids\": [\"10725230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The armadillo repeat region of ARVCF is both sufficient and necessary for interaction with the 55 membrane-proximal amino acids of the M-cadherin cytoplasmic tail. The N-terminus of ARVCF is not required for junctional localization, but deletion of the four N-terminal armadillo repeats abolishes targeting to cadherin-based junctions in cardiomyocytes.\",\n      \"method\": \"Yeast two-hybrid, MOM recruitment assay, immunoprecipitation, in vitro binding assay, domain truncation/deletion mutagenesis, EGFP-fusion localization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding assay plus multiple orthogonal in-cell methods and systematic mutagenesis within a single study\",\n      \"pmids\": [\"11058098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The Erbin PDZ domain binds with high affinity and specificity to the C-terminal PDZ-binding motif (DSWV-COOH) of ARVCF. Erbin co-localizes and co-precipitates with ARVCF complexed with beta-catenin and E/N-cadherin. Mutagenesis and peptide competition confirmed that the PDZ domain of Erbin mediates association with the cadherin-catenin complex through the ARVCF C-terminus.\",\n      \"method\": \"Phage peptide library, in vitro binding with synthetic peptides, co-immunoprecipitation, co-localization, mutagenesis, peptide competition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with peptides, mutagenesis, and in vivo co-IP; multiple orthogonal methods\",\n      \"pmids\": [\"11821434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ARVCF interacts via its C-terminal PDZ-binding motif with ZO-1 and ZO-2. ARVCF, ZO-1, and E-cadherin form a trimeric complex recruited to sites of initial cell-cell contact. Disruption of cell-cell adhesion releases ARVCF from the plasma membrane and increases nuclear localization. E-cadherin binding and plasma membrane localization of ARVCF require the PDZ-binding motif; nuclear localization can be mediated by ZO-2 PDZ domains.\",\n      \"method\": \"Co-immunoprecipitation, co-localization (immunofluorescence), cell-cell adhesion disruption assay, PDZ-binding motif mutagenesis, epithelial MDCK cell fractionation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, mutagenesis of the binding motif, functional consequence on localization, multiple orthogonal methods\",\n      \"pmids\": [\"15456900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"xARVCF and Xp120-catenin are each required for vertebrate (Xenopus) gastrulation and axial elongation. Depletion of either can be cross-rescued by exogenous xARVCF or Xp120, and each depletion is rescued by dominant-negative RhoA or dominant-active Rac, placing ARVCF functionally upstream of RhoA/Rac signaling in development.\",\n      \"method\": \"Morpholino depletion, rescue with exogenous protein, dominant-negative/dominant-active RhoA and Rac epistasis, cell reaggregation assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with dominant-negative/active GTPases, depletion-rescue strategy, multiple orthogonal assays\",\n      \"pmids\": [\"15067024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Xenopus ARVCF (xARVCF) binds directly to Xenopus KazrinA (xKazrinA), and a ternary biochemical complex of xARVCF–xKazrinA–xβ2-spectrin was resolved. KazrinA also binds p190B RhoGAP. Loss of Kazrin leads to RhoA activation, altered actin organization, and ectodermal cell shedding, which is partially rescued by exogenous xARVCF. xKazrinA associates with delta-catenin and p0071-catenin but not p120-catenin.\",\n      \"method\": \"Co-immunoprecipitation, direct binding assay, ternary complex pull-down, Xenopus morpholino knockdown with rescue, RhoA activity assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding established, ternary complex resolved, knockdown-rescue epistasis with RhoA activity measurements\",\n      \"pmids\": [\"21062899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Depletion of ARVCF in Xenopus results in delayed migration of cranial neural crest cells and defects in craniofacial skeleton and aortic arches, phenotypes that cooperate with Tbx1 depletion, indicating ARVCF and Tbx1 act in the same developmental pathway for 22q11.2DS phenotypes.\",\n      \"method\": \"Morpholino knockdown, double depletion epistasis, craniofacial skeletal staining, molecular marker analysis\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by double knockdown, single lab, defined phenotypic readout\",\n      \"pmids\": [\"22028109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Kazrin, ARVCF-catenin, and delta-catenin are all required for Xenopus craniofacial development; knockdown of Kazrin or ARVCF in the anterior neural region reduces cartilaginous head structures and eyes and impairs neural crest cell establishment and migration. Exogenous ARVCF partially rescues Kazrin knockdown, supporting a Kazrin:ARVCF functional relationship.\",\n      \"method\": \"Morpholino knockdown, rescue with exogenous ARVCF, molecular marker analysis (neural crest), confocal microscopy\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown-rescue epistasis, defined phenotypic readout, single lab\",\n      \"pmids\": [\"22028074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Nuclear ARVCF interacts with splicing factors SRSF1 (SF2/ASF), RNA helicase p68 (DDX5), and hnRNP H2 in an RNA-independent manner. These interactions occur via the ARVCF C-terminus. ARVCF occurs in large RNA-containing complexes with spliced and unspliced mRNAs. Overexpression of ARVCF increases splicing activity of a reporter mRNA, and ARVCF depletion followed by RNA-seq reveals significant changes in alternatively spliced transcripts.\",\n      \"method\": \"Co-immunoprecipitation (RNA-independent), domain analysis, splicing reporter assay, RNA-seq after ARVCF knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP with RNA-independence control, domain mapping, functional splicing reporter assay, and transcriptome-wide validation\",\n      \"pmids\": [\"24644279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ARVCF is a direct transcriptional target of p53; activated p53 binds two distinct sites in the ARVCF gene (by ChIP-seq), inducing ARVCF expression at mRNA and protein levels. ARVCF knockdown inhibits p53-induced apoptosis. ARVCF interacts with hnRNPH2 and its knockdown causes dynamic changes in alternative splicing, indicating ARVCF indirectly regulates p53 target selectivity through splicing alterations.\",\n      \"method\": \"ChIP-sequencing, RT-PCR/Western blot, siRNA knockdown with apoptosis assay, co-immunoprecipitation (ARVCF–hnRNPH2), alternative splicing profiling\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq establishes direct p53 binding, functional rescue confirms pathway position, co-IP confirms binding partner, multiple orthogonal methods\",\n      \"pmids\": [\"31827232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Arvcf is required for Xenopus convergent extension (head-to-tail axis elongation) at the organismal but not isolated-tissue scale. The defect results from impaired tissue-scale force production, which arises from dampened pulsatile recruitment of cell adhesion and cytoskeletal proteins to cell membranes.\",\n      \"method\": \"Morpholino knockdown in intact embryos vs. isolated tissue explants, tissue force measurement, live imaging of protein dynamics at membranes\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined organism-scale vs. tissue-scale phenotype dissection, mechanical force measurement, live imaging of membrane dynamics\",\n      \"pmids\": [\"35476939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Arvcf is required for N-cadherin complex stability in lens fiber cells. Arvcf-deficient mice develop cortical cataracts by >6 months of age with fiber cell separation and hexagonal lattice disorganization. Loss of Arvcf reduces membrane localization of N-cadherin, β-catenin, and αN-catenin, and shrinks cadherin nanoclusters (by super-resolution imaging). Arvcf KO also alters lens biomechanical properties.\",\n      \"method\": \"Arvcf conditional KO mice, immunofluorescence, super-resolution imaging, electron microscopy, lens compression biomechanical assay\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model with defined phenotypic readout, super-resolution imaging of cadherin nanoclusters, biomechanical assay, multiple orthogonal methods\",\n      \"pmids\": [\"35874813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ARVCF is expressed in VTA dopaminergic neurons and its expression is upregulated by nicotine. Arvcf-KO mice show reduced dopamine synthesis and release in the nucleus accumbens upon nicotine stimulation and impaired nicotine-induced conditioned place preference. Inhibition of Arvcf in VTA dopaminergic neurons (via viral vector) decreased dopamine release within the VTA-NAc circuit and suppressed nicotine reward-related behavior; overexpression had the opposite effect.\",\n      \"method\": \"Arvcf-KO mouse model, conditioned place preference, viral vector overexpression/knockdown in VTA, dopamine measurement (synthesis and release), snRNA-seq\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO and viral rescue in defined circuit, dopamine measurement, single lab\",\n      \"pmids\": [\"40082601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ARVCF is a component of the VE-cadherin interactome in endothelial cells; it selectively binds a pool of VE-cadherin that is unbound from p120-catenin, through a mechanism involving its C-terminal intrinsically disordered regions. ARVCF depletion results in unstable junctions, loss of endothelial barrier function, and impaired collective cell migration.\",\n      \"method\": \"Mass spectrometry proteomics of VE-cadherin interactome, co-immunoprecipitation, co-localization, ARVCF depletion with barrier function assay and migration assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-based interactome, reciprocal co-IP, domain mechanism identified, functional KD with defined cellular phenotypes, multiple orthogonal methods\",\n      \"pmids\": [\"42006337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In hepatocytes, N-cadherin maintains hepatic polarity by facilitating RhoA inactivation through the p120-catenin family member ARVCF and its partner p190B RhoGAP (ARHGAP5), placing ARVCF as a component of the N-cadherin–RhoA inactivation axis opposing E-cadherin–driven RhoA activation.\",\n      \"method\": \"Loss-of-function experiments in hepatocytes, RhoA activity assay, co-localization, polarity and bile canaliculi formation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, ARVCF mechanistic role inferred from co-localization and functional context, full methods not detailed in abstract\",\n      \"pmids\": [\"bio_10.1101_2025.10.06.680681\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In B cell lymphoma cells, ARVCF maintains RRAGA 3'UTR length via alternative polyadenylation regulation and suppresses mTOR-EIF4G1 signaling, thereby inhibiting lymphoma proliferation. VIM (vimentin) deletion downregulates ARVCF protein, linking cytoskeletal disruption to APA-mediated mTOR activation via ARVCF.\",\n      \"method\": \"VIM-KO cell lines, RNA-seq with APA analysis (DaPars), proteomic profiling, ARVCF overexpression rescue, CCK-8/EdU proliferation assays, Western blot\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue with ARVCF OE, APA and proliferation readouts, single lab\",\n      \"pmids\": [\"41058879\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARVCF is an armadillo-repeat catenin (p120-catenin subfamily) that binds the juxtamembrane domain of classical cadherins (E-, N-, M-, VE-cadherin) via its armadillo repeats, competing with p120-catenin; at the plasma membrane it stabilizes cadherin nanoclusters and adherens junctions, regulates pulsatile cytoskeletal recruitment, and suppresses RhoA activity (in part through interactions with Kazrin and p190B RhoGAP); in the nucleus it binds splicing factors (SRSF1, p68/DDX5, hnRNP H2) via its C-terminus and modulates alternative splicing of pre-mRNAs, a function induced downstream of p53; its C-terminal PDZ-binding motif (DSWV) recruits PDZ proteins including Erbin, ZO-1, and ZO-2, with ZO-1/2 controlling its membrane vs. nuclear distribution in response to cell-cell adhesion cues; and in dopaminergic neurons it promotes dopamine synthesis and release to support reward-related behavior.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ARVCF is an armadillo-repeat protein of the p120-catenin subfamily that functions both as a junctional regulator of classical cadherins and as a nuclear modulator of pre-mRNA processing [#0, #1, #9]. Through its armadillo repeat domain it binds the membrane-proximal cytoplasmic (juxtamembrane) tail of classical cadherins\\u2014E-, M-, N-, and VE-cadherin\\u2014competing with p120-catenin for this site, and at the plasma membrane it stabilizes cadherin-catenin complexes and cadherin nanoclusters required for adherens junction integrity [#1, #2, #12, #14]. Its C-terminal PDZ-binding motif (DSWV) recruits PDZ-domain proteins including Erbin, ZO-1, and ZO-2, and the ZO proteins govern the balance between its membrane and nuclear pools in response to cell-cell adhesion cues [#3, #4]. ARVCF acts upstream of Rho-family GTPase signaling, suppressing RhoA activity in part through the Kazrin\\u2013p190B RhoGAP axis, and this activity underlies its requirement in vertebrate gastrulation, convergent extension, and neural crest-dependent craniofacial development [#5, #6, #11]. In the nucleus, ARVCF binds the splicing factors SRSF1, p68/DDX5, and hnRNP H2 via its C-terminus to promote alternative splicing and alternative polyadenylation; this function is induced downstream of p53, where ARVCF shapes p53 target selectivity and apoptotic output [#9, #10, #16]. Physiologically, loss of Arvcf causes cortical cataracts through N-cadherin complex destabilization in lens fiber cells and modulates dopamine synthesis and release in VTA dopaminergic neurons to support nicotine reward behavior [#12, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established ARVCF as a p120-catenin-related armadillo-repeat protein and a candidate gene in the 22q11.2 deletion (velocardiofacial) interval, framing it as a likely adherens-junction protein.\",\n      \"evidence\": \"Gene isolation, sequence and structural domain analysis in VCFS deletion patients\",\n      \"pmids\": [\"9126485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function entirely inferred from sequence homology\", \"No direct binding partner demonstrated\", \"No causative role in VCFS phenotype shown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed ARVCF physically engages the cadherin-catenin system and competes with p120-catenin, while also occupying the nucleus, defining its dual-compartment behavior.\",\n      \"evidence\": \"Reciprocal co-IP with E-cadherin, p120 competition, domain chimera analysis and immunofluorescence; yeast two-hybrid and in vitro binding mapping to M-cadherin juxtamembrane tail\",\n      \"pmids\": [\"10725230\", \"11058098\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of p120 competition unresolved\", \"ARVCF lacks the cell-branching activity of p120, leaving its distinct junctional output undefined\", \"Nuclear function not yet characterized\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified the C-terminal PDZ-binding motif as the hub linking ARVCF to ZO-1/ZO-2 and showed that adhesion state controls its membrane-versus-nuclear partitioning, establishing a regulated shuttling mechanism.\",\n      \"evidence\": \"Co-IP, co-localization, adhesion-disruption assays and PDZ-motif mutagenesis in MDCK cells; Erbin PDZ binding via phage peptide library and peptide competition\",\n      \"pmids\": [\"15456900\", \"11821434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal triggering nuclear import upon adhesion loss not defined\", \"Nuclear function still unknown at this stage\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Placed ARVCF upstream of RhoA/Rac signaling in vertebrate morphogenesis, demonstrating it is functionally required for gastrulation and axis elongation.\",\n      \"evidence\": \"Xenopus morpholino depletion with cross-rescue by p120 and GTPase epistasis (dominant-negative RhoA, dominant-active Rac)\",\n      \"pmids\": [\"15067024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between ARVCF and RhoA/Rac not yet identified\", \"Direct GTPase regulator partner unknown at this point\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected ARVCF to RhoA control through a Kazrin\\u2013p190B RhoGAP complex and linked it genetically to Tbx1 in neural crest and craniofacial development, providing a mechanistic route to 22q11.2DS phenotypes.\",\n      \"evidence\": \"Direct binding and ternary complex pulldowns (xARVCF\\u2013Kazrin\\u2013\\u03b22-spectrin), RhoA activity assays, and double-knockdown epistasis with Tbx1 in Xenopus\",\n      \"pmids\": [\"21062899\", \"22028109\", \"22028074\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ARVCF directly regulates p190B activity vs. acting through Kazrin unresolved\", \"Relationship between junctional and developmental roles not dissected\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the nuclear function of ARVCF as a splicing regulator, showing it binds splicing machinery and shapes the alternatively spliced transcriptome.\",\n      \"evidence\": \"RNA-independent co-IP with SRSF1, DDX5, hnRNP H2, C-terminal domain mapping, splicing reporter assay, and RNA-seq after knockdown\",\n      \"pmids\": [\"24644279\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sequence/transcript determinants of ARVCF-dependent splicing not defined\", \"Whether membrane and nuclear pools are functionally coupled unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Positioned ARVCF within the p53 pathway as a direct transcriptional target that feeds back through splicing to influence p53 target selectivity and apoptosis.\",\n      \"evidence\": \"ChIP-seq mapping of p53 binding sites, expression induction, siRNA knockdown apoptosis assays, and ARVCF\\u2013hnRNPH2 co-IP\",\n      \"pmids\": [\"31827232\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific p53-dependent splicing targets mediating apoptosis not enumerated\", \"Generality across cell types untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved how ARVCF contributes to tissue mechanics and junction stability in vivo, showing scale-dependent force production and a requirement for cadherin nanocluster integrity.\",\n      \"evidence\": \"Xenopus knockdown with tissue-scale force measurement and live membrane imaging; Arvcf KO mouse lens with super-resolution nanocluster imaging and biomechanical assays\",\n      \"pmids\": [\"35476939\", \"35874813\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism converting ARVCF binding into pulsatile recruitment unknown\", \"How ARVCF stabilizes nanoclusters at the structural level undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended ARVCF function to neuronal physiology, demonstrating a role in dopaminergic signaling and reward behavior, and to APA-mediated control of mTOR signaling in lymphoma.\",\n      \"evidence\": \"Arvcf-KO mice and viral circuit manipulation with dopamine measurement and conditioned place preference; VIM-KO lymphoma cells with APA profiling, proteomics, and ARVCF overexpression rescue\",\n      \"pmids\": [\"40082601\", \"41058879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ARVCF promotes dopamine synthesis/release not established\", \"Whether neuronal role is junctional or nuclear unknown\", \"RRAGA APA regulation mechanism single-lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined an endothelial role for ARVCF in selectively binding p120-free VE-cadherin to maintain barrier function, refining the model of how ARVCF and p120 partition cadherin pools.\",\n      \"evidence\": \"Mass-spectrometry VE-cadherin interactome, co-IP, co-localization, and depletion with barrier and migration assays in endothelial cells\",\n      \"pmids\": [\"42006337\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the C-terminal disordered regions discriminate p120-free cadherin not structurally resolved\", \"Relationship to RhoA regulation in endothelium untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how ARVCF integrates its junctional, RhoA-regulatory, and nuclear splicing functions, and whether shuttling between these compartments is coordinately regulated by a single signal.\",\n      \"evidence\": \"No study in the corpus directly couples membrane and nuclear pools mechanistically\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of ARVCF in any complex\", \"Signal coupling adhesion state to splicing output undefined\", \"Causal contribution to human 22q11.2DS pathology not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 2, 12, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 6, 9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 4, 12, 14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 4, 9, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [3, 4, 12, 14]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [9, 10, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 7, 8, 11]}\n    ],\n    \"complexes\": [\n      \"cadherin-catenin complex\",\n      \"ARVCF\\u2013Kazrin\\u2013\\u03b22-spectrin complex\",\n      \"VE-cadherin interactome\"\n    ],\n    \"partners\": [\n      \"CDH1\",\n      \"CDH2\",\n      \"Erbin\",\n      \"TJP1\",\n      \"TJP2\",\n      \"KAZN\",\n      \"SRSF1\",\n      \"DDX5\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}