Affinage

VCL

Vinculin · UniProt P18206

Length
1134 aa
Mass
123.8 kDa
Annotated
2026-06-11
31 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Vinculin (VCL) is a mechanosensitive cytoskeletal adaptor that couples filamentous actin to both cell-matrix (integrin) and cell-cell (cadherin) adhesions and translates mechanical force into adhesion and cytoskeletal remodeling [PMID:31495694, PMID:bio_10.1101_2024.10.28.620745]. In cardiomyocytes, mechanical force from contractility controls VCL localization and activation, and VCL recruits the SSH1 phosphatase together with cofilin to drive F-actin rearrangement and myofilament maturation through the VCL-SSH1-CFL axis (PMID:31495694). The balance between cadherin- and integrin-based adhesion is set by VCL phosphorylation at tyrosine 822: loss of this phosphorylation reduces junctional VCL and adherens-junction proteins while increasing α5/β1 integrin and fibronectin at lateral borders, with cardiac dysfunction as the in vivo consequence [PMID:bio_10.1101_2024.10.28.620745]. VCL function at adherens junctions is further regulated by covalent poly-ADP-ribosylation by tankyrase via conserved tankyrase-binding motifs, a modification linked to cell shape maintenance (PMID:34123588). Beyond adhesion, VCL participates in planar cell polarity signaling and cell migration—where human loss- and gain-of-function variants are associated with neural tube defects (PMID:33491343)—and its abundance and isoform usage are tightly controlled post-transcriptionally, by miRNAs targeting the muscle-specific meta-VCL isoform (PMID:39296643) and epithelial VCL (PMID:37262956) and by RBM10-dependent splicing that links an exon-inclusion isoform to cell motility [PMID:bio_10.1101_2024.07.09.602730].

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1992 High

    Establishing the chromosomal location of VCL provided the genomic anchor needed to connect the gene to human phenotypes and to distinguish it from neighboring loci.

    Evidence Somatic hybrid panel hybridization, FISH to flow-sorted chromosomes, and genetic recombination mapping in MEN2 families

    PMID:1505973

    Open questions at the time
    • Mapping alone does not address protein function
    • No isoform or splice structure resolved
  2. 2019 High

    It was unknown how mechanical force is converted into cytoskeletal maturation in heart muscle; this work showed VCL is a force-responsive node that recruits SSH1 and cofilin to remodel F-actin and mature myofilaments.

    Evidence Zebrafish contracting vs. non-contracting cardiomyocyte model with VCL interactome and loss-of-function myofilament readout

    PMID:31495694

    Open questions at the time
    • Direct vs. bridged nature of the VCL-SSH1 interaction not resolved
    • Generality beyond cardiomyocytes untested in this study
  3. 2021 Medium

    How VCL is covalently regulated at junctions was unclear; this established that a membrane pool of VCL is PARylated by tankyrase through conserved binding motifs, linking the modification to adherens-junction and cell-shape control.

    Evidence PAR-binding affinity precipitation, tankyrase inhibition, and TBM point-mutant overexpression with morphological readout in epithelial cells

    PMID:34123588

    Open questions at the time
    • Functional readout relies on overexpression of a mutant
    • Endogenous consequences of blocking PARylation not measured
  4. 2021 Medium

    Whether VCL contributes to human developmental disease was open; identification of loss- and gain-of-function variants in neural tube defect patients tied VCL to PCP signaling and migration during neural tube closure.

    Evidence Targeted sequencing of an NTD cohort with PCP-activity and cell-migration assays

    PMID:33491343

    Open questions at the time
    • Causality at the organismal level not demonstrated
    • Mechanistic link from VCL to PCP components undefined
  5. 2023 Medium

    The post-transcriptional control of VCL in epithelial barriers was unknown; miR-29a-3p was shown to directly repress VCL and disrupt junctional integrity, with antagomir rescue restoring barrier function.

    Evidence Dual-luciferase 3'-UTR assay, miRNA mimic/inhibitor transfection, and in vivo antagomir allergic-rhinitis mouse model

    PMID:37262956

    Open questions at the time
    • Effects shared with co-target CTNNB1 not fully separated
    • Single epithelial context
  6. 2024 Medium

    How phosphorylation tunes VCL between adhesion systems was unresolved; a Y822F knock-in showed pY822 sets the cadherin-versus-integrin adhesion balance with late-onset cardiac dysfunction.

    Evidence Mouse Y822F knock-in with immunofluorescence and cardiac function assessment (preprint)

    PMID:bio_10.1101_2024.10.28.620745

    Open questions at the time
    • Preprint, single lab
    • Upstream kinase and signal triggering Y822 phosphorylation not identified
  7. 2024 Medium

    Isoform-specific regulation of VCL was clarified by showing miR-6721-5p directly represses the muscle-specific meta-VCL isoform, coupling it to inflammatory cytokine changes.

    Evidence Dual-luciferase reporter assay, ectopic expression, and qPCR

    PMID:39296643

    Open questions at the time
    • Mechanism linking meta-VCL loss to cytokine changes unresolved
    • In vivo relevance limited
  8. 2024 Medium

    It was unclear how RBM10 loss promotes motility; aberrant VCL exon inclusion was placed in the pathway, with isoform-specific knockdown reducing cell velocity and contributing to metastatic fitness.

    Evidence RNA-seq, isoform-specific knockdown with velocity readout, and Hras/Rbm10 KO mouse with combined-knockdown rescue (preprint)

    PMID:bio_10.1101_2024.07.09.602730

    Open questions at the time
    • Preprint, single lab
    • Molecular difference of the exon-inclusion isoform not characterized
  9. 2025 Medium

    Whether VCL participates in vascular barrier failure was open; anti-VCL intervention reduced alveolar edema and restored barrier integrity, implicating a VCL/ICAM-1 axis in endothelial dysfunction.

    Evidence Rat lung injury model with anti-VCL treatment, histology, electron microscopy, and plasma multi-omics

    PMID:40268929

    Open questions at the time
    • Mechanism of plasma VCL action on endothelium undefined
    • VCL/ICAM-1 relationship correlative

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the distinct VCL regulatory layers—force sensing, Y822 phosphorylation, tankyrase PARylation, and splicing/miRNA control—are integrated to set adhesion identity in a given cell type remains unresolved.
  • No unified model connecting modifications and isoforms
  • Upstream regulators of each modification largely unknown
  • Cross-tissue generality untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005886 plasma membrane 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1500931 Cell-Cell communication 2 R-HSA-1474244 Extracellular matrix organization 1
Partners
CFLSSH1TNKS
Complex memberships
adherens junction

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 Mechanical forces from cardiac contractility regulate the localization and activation of vinculin (VCL) in cardiomyocytes; VCL recruits the phosphatase SSH1 and its effector cofilin (CFL) to regulate F-actin rearrangement and promote myofilament maturation via the VCL-SSH1-CFL axis. Zebrafish genetic model (contracting vs. non-contracting cardiomyocytes), VCL interactome analysis (proteomics/co-IP), loss-of-function with myofilament maturation readout Developmental Cell High 31495694
2024 Vinculin phosphorylation at tyrosine residue 822 (pY822) regulates the balance between cadherin-based cell-cell adhesion and integrin-based cell-matrix adhesion in cardiomyocytes; Y822F knock-in mice show reduced vinculin and adherens junction proteins at junctions and increased α5/β1 integrin and fibronectin at lateral borders, with cardiac dysfunction emerging at 28 weeks. Mouse knock-in (Y822F point mutation), immunofluorescence, cardiac function assessment bioRxiv (preprint)preprint Medium bio_10.1101_2024.10.28.620745
2021 A pool of vinculin (VCL) is covalently PARylated (poly-ADP-ribosylated) by tankyrase (TNKS) at the plasma membrane in epithelial cells; VCL contains conserved tankyrase-binding motifs (TBMs), and overexpression of a TBM-II point mutant (GgVCL/*TBM) induced mesenchymal-like cell shape changes, implicating this modification in adherens junction regulation and cell shape maintenance. Affinity precipitation with PAR-binding reagent followed by western blot, TNKS inhibitor experiments, transfection of TBM point-mutant VCL with morphological readout PeerJ Medium 34123588
2021 Loss-of-function (p.D256fs) and gain-of-function (p.L555V, conferring enhanced protein stability) VCL variants identified in human neural tube defect patients affect planar cell polarity (PCP) pathway regulation and cell migration, consistent with VCL's role in cell skeleton remodeling during neural tube closure. Targeted next-generation sequencing of human NTD cohort, functional assays for PCP pathway activity and cell migration Molecular Genetics & Genomic Medicine Medium 33491343
2024 miR-6721-5p directly targets the 3'-UTR of meta-VCL (the muscle-specific splice isoform of VCL) and suppresses its expression, as validated by dual-luciferase reporter assay; meta-VCL downregulation was associated with reduced anti-inflammatory cytokine levels (IL-10, TNF-α). Dual-luciferase reporter assay, cell-based ectopic expression, qPCR Non-coding RNA Research Medium 39296643
2023 miR-29a-3p directly targets VCL (and CTNNB1) 3'-UTR in nasal epithelial cells, suppressing VCL expression and disrupting adherens and tight junction integrity; miR-29a-3p antagomir treatment in OVA-induced allergic rhinitis mice restored VCL/Ctnnb1 expression and improved epithelial barrier function. Dual-luciferase reporter assay, miRNA mimic/inhibitor transfection, in vivo antagomir mouse model with barrier function readout International Immunopharmacology Medium 37262956
2024 RBM10 loss causes aberrant exon inclusion in VCL transcripts; knockdown of the VCL exon-inclusion isoform in RBM10-null cells reduced cell velocity, placing this VCL isoform in the pathway linking RBM10 loss to increased cell motility and metastatic fitness. RNA-seq, isoform-specific knockdown with cell velocity readout, mouse Hras/Rbm10 KO model with combined VCL/CD44/TNC knockdown rescue bioRxiv (preprint)preprint Medium bio_10.1101_2024.07.09.602730
2025 In a rat model of lung injury, anti-VCL intervention reduced plasma VCL levels, mitigated alveolar edema, and restored alveolar-capillary barrier integrity, demonstrating that VCL modulation affects vascular leakage and extravasation; multi-omics analysis identified VCL's involvement in the VCL/ICAM-1 signaling pathway associated with Omicron-induced endothelial dysfunction. Rat lung injury model with anti-VCL treatment, histological staining, electron microscopy, plasma proteomics and metabolomics Nature Communications Medium 40268929
1992 The vinculin gene (VCL) was mapped to human chromosome 10q22.1-q23 by physical (somatic hybrid panel hybridization, flow-sorted translocation chromosome hybridization) and genetic recombination mapping. Human-rodent somatic hybrid panel hybridization, fluorescence in situ hybridization to flow-sorted chromosomes, genetic recombination mapping in MEN2 families Genomics High 1505973

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Renal cell carcinoma with novel VCL-ALK fusion: new representative of ALK-associated tumor spectrum. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 178 21076462
2014 VCL-ALK renal cell carcinoma in children with sickle-cell trait: the eighth sickle-cell nephropathy? The American journal of surgical pathology 81 24698962
1994 Abolition of cyclic flow variations in stenosed, endothelium-injured coronary arteries in nonhuman primates with a peptide fragment (VCL) derived from human plasma von Willebrand factor-glycoprotein Ib binding domain. Circulation 62 7994845
2019 Mechanical Forces Regulate Cardiomyocyte Myofilament Maturation via the VCL-SSH1-CFL Axis. Developmental cell 44 31495694
1995 VCL, an antagonist of the platelet GP1b receptor, markedly inhibits platelet adhesion and intimal thickening after balloon injury in the rat. Circulation 39 7648675
1995 Antithrombotic effect of a recombinant von Willebrand factor, VCL, on nitrogen laser-induced thrombus formation in guinea pig mesenteric arteries. Thrombosis and haemostasis 26 7792749
2013 Polymorphisms in FGF12, VCL, CX43 and VAX1 in Brazilian patients with nonsyndromic cleft lip with or without cleft palate. BMC medical genetics 24 23679094
2021 ALK-rearranged Renal Cell Carcinoma (RCC): A Report of 2 Cases and Review of the Literature Emphasizing the Distinction Between VCL-ALK and Non-VCL-ALK RCC. International journal of surgical pathology 22 33729862
1996 Adhesion of blood platelets is inhibited by VCL, a recombinant fragment (leucine504 to lysine728) of von Willebrand factor. Arteriosclerosis, thrombosis, and vascular biology 21 8548428
2021 Epithelioid inflammatory myofibroblastic sarcoma with VCL-ALK fusion of central nervous system: case report and brief review of the literature. Brain tumor pathology 18 34743247
2020 Promotive effect of Talin-1 protein on gastric cancer progression through PTK2-PXN-VCL-E-Cadherin-CAPN2-MAPK1 signaling axis. Journal of clinical laboratory analysis 17 32951272
2009 VCL-CB01, an injectable bivalent plasmid DNA vaccine for potential protection against CMV disease and infection. Current opinion in molecular therapeutics 17 19806506
2019 Targeted next-generation sequencing revealed distinct clinicopathologic and molecular features of VCL-ALK RCC: A unique case from an older patient without clinical evidence of sickle cell trait. Pathology, research and practice 13 31563285
2011 Familial dilated cardiomyopathy associated with congenital defects in the setting of a novel VCL mutation (Lys815Arg) in conjunction with a known MYPBC3 variant. Cardiogenetics 13 24062880
1992 Complementary physical and genetic techniques map the vinculin (VCL) gene on chromosome 10q. Genomics 11 1505973
2008 Thermochemistry of the gaseous vanadium chlorides VCl, VCl2, VCl3, and VCl4. The journal of physical chemistry. A 10 18774788
2024 MiR-6721-5p as a natural regulator of Meta-VCL is upregulated in the serum of patients with coronary artery disease. Non-coding RNA research 6 39296643
2008 Cationic poly(VCL-AETA) hydrogels and ovalbumin (OVA) release in vitro. Journal of materials science. Materials in medicine 6 18642060
2023 Cutaneous VCL::ALK fusion ovoid-spindle cell neoplasm. Journal of cutaneous pathology 5 36843055
2015 Sex-specific association of rs4746172 of VCL gene with hypertension in two Han populations from Southern China. Scientific reports 5 26487440
2025 VCL/ICAM-1 pathway is associated with lung inflammatory damage in SARS-CoV-2 Omicron infection. Nature communications 4 40268929
2024 Osteoblastic Cell Sheet Engineering Using P(VCL-HEMA)-Based Thermosensitive Hydrogels Doped with pVCL@Icariin Nanoparticles Obtained with Supercritical CO2-SAS. Pharmaceutics 4 39204408
2023 MiR-29a-3p promotes nasal epithelial barrier dysfunction via direct targeting of CTNNB1-VCL module in allergic rhinitis. International immunopharmacology 4 37262956
2022 MicroRNA-21-5p Regulates CD3+T Lymphocytes Through VCL and LTF in Patients with Immune Thrombocytopenia. Clinical laboratory 3 35975534
2024 Identification of a hub gene VCL for atherosclerotic plaques and discovery of potential therapeutic targets by molecular docking. BMC medical genomics 2 38287421
2021 Loss-of-function or gain-of-function variations in VINCULIN (VCL) are risk factors of human neural tube defects. Molecular genetics & genomic medicine 2 33491343
2021 First body of evidence suggesting a role of a tankyrase-binding motif (TBM) of vinculin (VCL) in epithelial cells. PeerJ 2 34123588
2024 VCL::ROS1: A Novel ROS1 Oncogenic Fusion Detected on Next Generation Sequencing. Clinical pathology (Thousand Oaks, Ventura County, Calif.) 1 39139859
2023 [No Effect of the p.Arg230His Variant Of The VCL Protein on the Course of the Hypertrophic Cardiomyopathy In Russian Family Carrying The p.Gln1233Ter Pathogenic Variant In The MYBPC3 Gene]. Kardiologiia 1 37061858
2026 Development of venus-fused Cypridina luciferase (VCL) and specific nanobody-tethering assay to model kleptoprotein uptake. Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology 0 42118211
2026 Epithelioid Fibrous Histiocytoma With Giant Cells and VCL-Anaplastic Lymphoma Kinase Fusion: A Diagnostic Challenge. The American Journal of dermatopathology 0 42160676

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