Affinage

ARVCF

Splicing regulator ARVCF · UniProt O00192

Length
962 aa
Mass
104.6 kDa
Annotated
2026-06-09
34 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1997 Medium

    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

    PMID:9126485

    Open questions at the time
    • Function entirely inferred from sequence homology
    • No direct binding partner demonstrated
    • No causative role in VCFS phenotype shown
  2. 2000 High

    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

    PMID:10725230 PMID:11058098

    Open questions at the time
    • 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
  3. 2004 High

    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

    PMID:11821434 PMID:15456900

    Open questions at the time
    • Signal triggering nuclear import upon adhesion loss not defined
    • Nuclear function still unknown at this stage
  4. 2004 High

    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)

    PMID:15067024

    Open questions at the time
    • Molecular link between ARVCF and RhoA/Rac not yet identified
    • Direct GTPase regulator partner unknown at this point
  5. 2011 High

    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

    PMID:21062899 PMID:22028074 PMID:22028109

    Open questions at the time
    • Whether ARVCF directly regulates p190B activity vs. acting through Kazrin unresolved
    • Relationship between junctional and developmental roles not dissected
  6. 2014 High

    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

    PMID:24644279

    Open questions at the time
    • Sequence/transcript determinants of ARVCF-dependent splicing not defined
    • Whether membrane and nuclear pools are functionally coupled unknown
  7. 2019 High

    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

    PMID:31827232

    Open questions at the time
    • Specific p53-dependent splicing targets mediating apoptosis not enumerated
    • Generality across cell types untested
  8. 2022 High

    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

    PMID:35476939 PMID:35874813

    Open questions at the time
    • Molecular mechanism converting ARVCF binding into pulsatile recruitment unknown
    • How ARVCF stabilizes nanoclusters at the structural level undefined
  9. 2025 Medium

    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

    PMID:40082601 PMID:41058879

    Open questions at the time
    • Mechanism by which ARVCF promotes dopamine synthesis/release not established
    • Whether neuronal role is junctional or nuclear unknown
    • RRAGA APA regulation mechanism single-lab
  10. 2026 High

    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

    PMID:42006337

    Open questions at the time
    • How the C-terminal disordered regions discriminate p120-free cadherin not structurally resolved
    • Relationship to RhoA regulation in endothelium untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 4 GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 2 GO:0003723 RNA binding 1
Localization
GO:0005886 plasma membrane 5 GO:0005634 nucleus 4
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-1500931 Cell-Cell communication 4 R-HSA-162582 Signal Transduction 3 R-HSA-8953854 Metabolism of RNA 3
Partners
CDH1CDH2DDX5ERBINKAZNSRSF1TJP1TJP2
Complex memberships
ARVCF–Kazrin–β2-spectrin complexVE-cadherin interactomecadherin-catenin complex

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 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. Gene isolation, sequence analysis, structural domain prediction Genomics Medium 9126485
2000 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. Immunoprecipitation, immunofluorescence, domain chimera analysis, monoclonal antibodies Journal of cell science High 10725230
2000 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. Yeast two-hybrid, MOM recruitment assay, immunoprecipitation, in vitro binding assay, domain truncation/deletion mutagenesis, EGFP-fusion localization Journal of cell science High 11058098
2002 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. Phage peptide library, in vitro binding with synthetic peptides, co-immunoprecipitation, co-localization, mutagenesis, peptide competition The Journal of biological chemistry High 11821434
2004 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. Co-immunoprecipitation, co-localization (immunofluorescence), cell-cell adhesion disruption assay, PDZ-binding motif mutagenesis, epithelial MDCK cell fractionation Molecular biology of the cell High 15456900
2004 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. Morpholino depletion, rescue with exogenous protein, dominant-negative/dominant-active RhoA and Rac epistasis, cell reaggregation assay The Journal of cell biology High 15067024
2010 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. Co-immunoprecipitation, direct binding assay, ternary complex pull-down, Xenopus morpholino knockdown with rescue, RhoA activity assay Journal of cell science High 21062899
2011 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. Morpholino knockdown, double depletion epistasis, craniofacial skeletal staining, molecular marker analysis Developmental dynamics Medium 22028109
2011 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. Morpholino knockdown, rescue with exogenous ARVCF, molecular marker analysis (neural crest), confocal microscopy Developmental dynamics Medium 22028074
2014 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. Co-immunoprecipitation (RNA-independent), domain analysis, splicing reporter assay, RNA-seq after ARVCF knockdown The Journal of biological chemistry High 24644279
2019 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. ChIP-sequencing, RT-PCR/Western blot, siRNA knockdown with apoptosis assay, co-immunoprecipitation (ARVCF–hnRNPH2), alternative splicing profiling Oncogene High 31827232
2022 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. Morpholino knockdown in intact embryos vs. isolated tissue explants, tissue force measurement, live imaging of protein dynamics at membranes Developmental cell High 35476939
2022 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. Arvcf conditional KO mice, immunofluorescence, super-resolution imaging, electron microscopy, lens compression biomechanical assay Frontiers in cell and developmental biology High 35874813
2025 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. Arvcf-KO mouse model, conditioned place preference, viral vector overexpression/knockdown in VTA, dopamine measurement (synthesis and release), snRNA-seq Communications biology Medium 40082601
2026 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. Mass spectrometry proteomics of VE-cadherin interactome, co-immunoprecipitation, co-localization, ARVCF depletion with barrier function assay and migration assay iScience High 42006337
2025 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. Loss-of-function experiments in hepatocytes, RhoA activity assay, co-localization, polarity and bile canaliculi formation assays bioRxivpreprint Low bio_10.1101_2025.10.06.680681
2025 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. VIM-KO cell lines, RNA-seq with APA analysis (DaPars), proteomic profiling, ARVCF overexpression rescue, CCK-8/EdU proliferation assays, Western blot Human mutation Medium 41058879

Source papers

Stage 0 corpus · 34 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 The Erbin PDZ domain binds with high affinity and specificity to the carboxyl termini of delta-catenin and ARVCF. The Journal of biological chemistry 130 11821434
1997 Identification of a new human catenin gene family member (ARVCF) from the region deleted in velo-cardio-facial syndrome. Genomics 99 9126485
2004 Vertebrate development requires ARVCF and p120 catenins and their interplay with RhoA and Rac. The Journal of cell biology 86 15067024
2004 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. Molecular biology of the cell 81 15456900
2000 ARVCF localizes to the nucleus and adherens junction and is mutually exclusive with p120(ctn) in E-cadherin complexes. Journal of cell science 77 10725230
2009 Over-expression of a human chromosome 22q11.2 segment including TXNRD2, COMT and ARVCF developmentally affects incentive learning and working memory in mice. Human molecular genetics 48 19617637
2000 The armadillo repeat region targets ARVCF to cadherin-based cellular junctions. Journal of cell science 48 11058098
2010 Xenopus Kazrin interacts with ARVCF-catenin, spectrin and p190B RhoGAP, and modulates RhoA activity and epithelial integrity. Journal of cell science 17 21062899
2009 ARVCF single marker and haplotypic association with schizophrenia. Progress in neuro-psychopharmacology & biological psychiatry 17 19508883
2008 Differential expression pattern of protein ARVCF in nephron segments of human and mouse kidney. Histochemistry and cell biology 16 18600340
2005 Haplotype analysis of the COMT-ARVCF gene region in Israeli anorexia nervosa family trios. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 16 16118784
2011 ARVCF genetic influences on neurocognitive and neuroanatomical intermediate phenotypes in Chinese patients with schizophrenia. The Journal of clinical psychiatry 14 22053977
2022 ARVCF catenin controls force production during vertebrate convergent extension. Developmental cell 13 35476939
2011 Kazrin, and its binding partners ARVCF- and delta-catenin, are required for Xenopus laevis craniofacial development. Developmental dynamics : an official publication of the American Association of Anatomists 13 22028074
2014 Nuclear ARVCF protein binds splicing factors and contributes to the regulation of alternative splicing. The Journal of biological chemistry 12 24644279
2011 ARVCF depletion cooperates with Tbx1 deficiency in the development of 22q11.2DS-like phenotypes in Xenopus. Developmental dynamics : an official publication of the American Association of Anatomists 12 22028109
2004 Expression of ARVCF in the human ganglionic eminence during fetal development. Developmental neuroscience 12 15509897
2012 Chemotherapy refractory testicular germ cell tumor is associated with a variant in Armadillo Repeat gene deleted in Velco-Cardio-Facial syndrome (ARVCF). Frontiers in endocrinology 11 23248619
2010 A functional variant provided further evidence for the association of ARVCF with schizophrenia. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 11 20333729
2018 Patients affected by a new variant of endemic pemphigus foliaceus have autoantibodies colocalizing with MYZAP, p0071, desmoplakins 1-2 and ARVCF, causing renal damage. Clinical and experimental dermatology 8 29768670
2019 p53-induced ARVCF modulates the splicing landscape and supports the tumor suppressive function of p53. Oncogene 7 31827232
1999 Production and characterization of monoclonal antibodies to ARVCF. Hybridoma 7 10571264
2023 Single nucleotide polymorphisms rs148582811 regulates its host gene ARVCF expression to affect nicotine-associated hippocampus-dependent memory. iScience 6 38025780
2022 Arvcf Dependent Adherens Junction Stability is Required to Prevent Age-Related Cortical Cataracts. Frontiers in cell and developmental biology 6 35874813
2017 Autoantibodies to full body vascular cell junctions colocalize with MYZAP, ARVCF, desmoplakins I and II and p0071 in endemic pemphigus in Colombia, South America. International journal of dermatology 6 29152726
2017 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. Clinical and experimental dermatology 5 29034528
2025 Investigating the effect of Arvcf reveals an essential role on regulating the mesolimbic dopamine signaling-mediated nicotine reward. Communications biology 4 40082601
2015 ARVCF expression is significantly correlated with the malignant phenotype of non-small cell lung cancer. Molecular carcinogenesis 4 25683624
2024 Identification and validation of a novel gene ARVCF associated with alcohol dependence among Chinese population. iScience 3 39429782
2022 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. The journal of applied laboratory medicine 2 35899599
2026 VE-cadherin interaction proteomics identifies ARVCF as stabilizer of endothelial adherens junctions. iScience 1 42006337
2025 Single-Cell Profiling Identifies Reward Behavior-Related Neurons and Alterations in the Ventral Tegmental Area Based on Arvcf-Knockout Mouse Model. Research (Washington, D.C.) 1 41395251
2026 Effects of Arvcf on anxiety- and depression-like behaviors in mice of different ages and sexes. Journal of affective disorders 0 42000070
2025 Vimentin Regulates Alternative Polyadenylation and mTOR Signaling via ARVCF to Promote B Cell Lymphoma Progression. Human mutation 0 41058879

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