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VANGL1

Vang-like protein 1 · UniProt Q8TAA9

Length
524 aa
Mass
60.0 kDa
Annotated
2026-06-11
43 papers in source corpus 19 papers cited in narrative 20 extracted findings
Cross-family judge faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VANGL1 is a four-transmembrane planar cell polarity (PCP) core protein that transmits non-canonical Wnt/PCP signals to coordinate cell polarity, directed migration, and tissue morphogenesis (PMID:21291170, PMID:36026468). It adopts a four-TMD topology with intracellular N- and C-terminal domains (PMID:21291170) and oligomerizes as dimers of trimers, with this higher-order assembly promoting binding to the PCP effector Prickle1 (PMID:39753546). At the plasma membrane VANGL1 forms heterodimeric complexes with VANGL2 (PMID:23029439) and engages the cytoplasmic transducers Dishevelled-1/2/3, an interaction abolished by the neural-tube-defect-associated V239I substitution (PMID:17409324). Its membrane residence is dynamically controlled: PRICKLE3 stabilizes VANGL1/2 at the membrane by shielding them from Casein kinase 1ε phosphorylation and limiting RNF43-mediated ubiquitination [PMID:bio_10.1101_2025.03.24.644882], while shear stress drives Coronin1C-dependent relocation of VANGL1 from an internal reservoir to the membrane, where it spatially segregates from Frizzled6 along the flow axis [PMID:bio_10.1101_2024.06.25.600357]. Through these activities VANGL1, acting together with VANGL2, governs convergent extension (PMID:20043994), inner ear hair cell polarity via intercellular (domineering non-autonomous) PCP signaling (PMID:29510119), and lung airway branching downstream of Wnt5a, independent of the core PCP protein Celsr1 (PMID:36026468, PMID:39225402). In migrating and invasive cells VANGL1 assembles with SCRIB/NOS1AP at cellular protrusions to establish leading-trailing polarity (PMID:22179838) and complexes with Fzd7 to engage Rho GTPases driving actin dynamics and invasion (PMID:37336284). Loss-of-function VANGL1 variants are linked to neural tube defects, where disease alleles fail to rescue convergent extension and disrupt membrane trafficking (PMID:20043994, PMID:17409324).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2006 Medium

    Established that VANGL1 is a phosphorylation-responsive effector of epithelial migration, linking it to a signaling input (ITF/TFF3) and a functional output (wound healing) for the first time.

    Evidence Phospho-protein immunoprecipitation/MS, confocal microscopy, and siRNA/overexpression with wound closure assays in intestinal epithelial cells

    PMID:16410243

    Open questions at the time
    • Kinase responsible for ITF-induced phosphorylation not identified
    • Phosphosites not mapped
    • Link to canonical PCP signaling not established
  2. 2007 Medium

    Connected VANGL1 to human neural tube defects and to the PCP transducers Dishevelled by showing a disease-associated mutation disrupts DVL binding.

    Evidence Protein-protein interaction assay with disease-linked V239I mutant against DVL1/2/3

    PMID:17409324

    Open questions at the time
    • Single interaction assay without reciprocal endogenous validation
    • Functional consequence of lost DVL binding not directly tested here
  3. 2010 Medium

    Demonstrated that human NTD-associated VANGL1 variants are genuine loss-of-function alleles in a vertebrate PCP assay, supporting causality.

    Evidence Morpholino knockdown rescue and overexpression in zebrafish with convergent extension/somite readouts

    PMID:20043994

    Open questions at the time
    • Molecular basis of loss of function not resolved
    • Cross-species ortholog complementation may not capture human-specific behavior
  4. 2011 High

    Defined the membrane topology and key membrane partnerships of VANGL1, establishing it as a four-TMD protein that heterodimerizes with VANGL2 and assembles a migration-associated SCRIB/NOS1AP complex.

    Evidence Epitope-tag topology mapping in MDCK cells; reciprocal endogenous co-IP with SPR-validated antibody; MS of SCRIB immunoprecipitates with knockdown migration assays

    PMID:21291170 PMID:22179838 PMID:23029439

    Open questions at the time
    • Stoichiometry of VANGL1/VANGL2 heterodimer not quantified
    • How SCRIB/NOS1AP complex couples to PCP signaling unclear
  5. 2018 Medium

    Showed VANGL1 mediates intercellular PCP communication in vertebrate sensory epithelium, formalizing its non-autonomous signaling role.

    Evidence Vangl1/Vangl2 conditional double knockout in mouse inner ear with hair bundle orientation and PCP protein localization analysis

    PMID:29510119

    Open questions at the time
    • Molecular signal transmitted across the boundary not identified
    • Redundancy with Vangl2 obscures Vangl1-specific contribution
  6. 2023 Medium

    Extended VANGL1 function to invasive cancer by linking a Fzd7 complex at the leading edge to Rho GTPase-driven cytoskeletal dynamics.

    Evidence Co-IP, shRNA knockdown with proliferation/migration/invasion assays, Rho GTPase activity assays, and intracranial xenografts in GBM cells

    PMID:37336284

    Open questions at the time
    • Direct vs indirect Fzd7 binding not resolved
    • Which Rho GTPase effectors are engaged not defined
  7. 2024 Medium

    Distinguished VANGL1/2 function in lung branching from the core PCP module, showing a mesenchymal, Celsr1-independent requirement.

    Evidence Tissue-specific conditional knockout mice with branching morphogenesis phenotyping

    PMID:39225402

    Open questions at the time
    • Mechanism of Celsr1-independent action unknown
    • Vangl1-specific role not separated from Vangl2
  8. 2025 Medium

    Resolved the oligomeric architecture of VANGL1 and the post-translational control of its membrane stability, defining how assembly state and PRICKLE3/CK1ε/RNF43 regulate effector engagement.

    Evidence Cryo-EM with biochemical oligomerization and Prickle1 binding assays; miniTurboID proximity proteomics with phosphorylation/ubiquitination and co-IP assays (preprint)

    PMID:39753546 PMID:bio_10.1101_2025.03.24.644882

    Open questions at the time
    • Whether oligomerization state is regulated in vivo unknown
    • PRICKLE3 stabilization data from a single-lab preprint awaiting peer review

Open questions

Synthesis pass · forward-looking unresolved questions
  • How VANGL1 oligomerization, post-translational stability control, and partner selection are integrated to specify directional polarity across distinct tissues remains unresolved.
  • No unified model linking trimer-of-dimers assembly to in vivo PCP output
  • Vangl1-specific versus Vangl2-redundant functions not systematically dissected
  • Identity of physiological kinases/ligases acting on VANGL1 in each tissue incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3
Partners
DVL1DVL2DVL3FZD7PRICKLE1PRICKLE3SCRIBVANGL2

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2025 Cryo-EM structure of human Vangl1 reveals it oligomerizes as dimers of trimers, and that dimerization of trimers promotes binding to the PCP effector Prickle1 (Pk1) in vitro. Cryo-EM structure determination combined with biochemical oligomerization assays and in vitro binding assays Nature Communications High 39753546
2007 The NTD-associated VANGL1 missense mutation V239I abolishes interaction of VANGL1 protein with its binding partners Dishevelled-1, -2, and -3 in a protein-protein interaction assay. Protein-protein interaction assay (co-immunoprecipitation/yeast two-hybrid) The New England Journal of Medicine Medium 17409324
2011 Endogenous Vangl1 and Vangl2 form heterodimeric complexes at the plasma membrane, as established by co-immunoprecipitation using a highly specific monoclonal anti-Vangl2 antibody validated by surface plasmon resonance. Reciprocal co-immunoprecipitation with a monospecific antibody validated by SPR, western blot, and proteomic analysis; confocal co-localization PLoS One High 23029439
2011 VANGL1 forms a protein complex with SCRIB and NOS1AP; this complex co-localizes along cellular protrusions in metastatic breast cancer cells, and knockdown of NOS1AP or SCRIB slows breast cancer cell migration and prevents establishment of leading-trailing polarity. Mass spectrometry of SCRIB immunoprecipitates, confocal microscopy co-localization, shRNA knockdown with migration and polarity assays Oncogene Medium 22179838
2011 Vangl1 has a four-transmembrane domain topology with both the N-terminal and large C-terminal portions intracellular, and loops between TMD1-2 and TMD3-4 are extracellular while the TMD2-3 linker is intracellular, as determined by epitope-tag insertion and immunofluorescence in polarized MDCK cells. Epitope (HA) tag insertion at six positions, immunofluorescence in intact vs. permeabilized cells, surface labeling in polarized MDCK cells Biochemistry High 21291170
2006 Vangl1 is Ser/Thr phosphorylated in response to ITF/TFF3 stimulation in intestinal epithelial cells; overexpression of Vangl1 enhances ITF-stimulated wound closure, while siRNA knockdown inhibits the migratory response to ITF. Immunoprecipitation of phosphorylated proteins followed by mass spectrometry; confocal microscopy; siRNA knockdown and overexpression with wound closure assays The Journal of Biological Chemistry Medium 16410243
2006 Vangl1 is predominantly intracellular in cytoplasmic vesicular structures in undifferentiated intestinal epithelial cells, and membrane association with E-cadherin increases upon differentiation; ITF-induced phosphorylation of Vangl1 corresponds to decreased membrane association with E-cadherin. Confocal microscopy with anti-Vangl1 antibody; co-localization with E-cadherin; Western blot fractionation The Journal of Biological Chemistry Medium 16410243
2010 The VANGL1 NTD-associated variants p.Val239Ile and p.Met328Thr are loss-of-function alleles: they fail to rescue the convergent extension defect caused by knockdown of zebrafish trilobite (Vangl2 ortholog), and fail to induce a convergent extension phenotype when overexpressed at high doses, unlike wild-type VANGL1. Antisense morpholino knockdown rescue assay and overexpression in zebrafish embryos with body axis and somite phenotype readout Mechanisms of Development Medium 20043994
2017 Scrib1 regulates Vangl1 subcellular localization indirectly through Par-3: partial knockdown of Scrib1 causes mislocalization of Vangl1, and Par-3 overexpression rescues this localization defect; partial knockdown of Par-3 alone causes apical enrichment of Vangl1. shRNA knockdown of Scrib1 and Par-3 in MDCK II cells; immunofluorescence localization; rescue experiments with Par-3 Human Molecular Genetics Medium 28369449
2017 NTD-associated VANGL1 missense mutations p.I136N and p.F440V abolish normal translocation of VANGL1 to the cell membrane in MDCK cells, as demonstrated by immunofluorescence analysis of transfected recombinant protein. Transfection of mutant recombinant VANGL1 in MDCK cells; immunofluorescence microscopy Spine Low 27755493
2023 Vangl1 forms a complex with Fzd7 at the leading edge of migrating GBM cells; this complex promotes cellular proliferation, migration, invasiveness, and engages Rho GTPases to drive cytoskeletal rearrangements and actin dynamics. Co-immunoprecipitation; shRNA knockdown with proliferation, migration, and invasion assays; Rho GTPase activity assays; intracranial xenograft mouse model Cancer Letters Medium 37336284
2022 Wnt5a signals through Vangl1/2 to control position and direction of lung branching; in response, lung cells undergo cytoskeletal reorganization and altered focal adhesions, and perturbation of focal adhesions associates with defective branching. Conditional knockout mice for Wnt5a and Vangl1/2; lung explant assays; cytoskeletal and focal adhesion imaging PLoS Biology Medium 36026468
2024 Mesenchymal Vangl1 and Vangl2 are required for airway branch initiation, elongation, and widening during lung branching morphogenesis, acting independently of the core PCP complex (Celsr1-independent). Tissue-specific knockout mice (epithelial and mesenchymal); phenotypic analysis of branching morphogenesis Development Medium 39225402
2018 Vangl1 and Vangl2 double conditional knockouts in the mouse inner ear demonstrate domineering non-autonomy at the mutant boundary in the utricle, establishing intercellular PCP signaling in vertebrate sensory epithelium. Cre-mediated conditional double knockout (Emx2-Cre); hair cell bundle orientation analysis; immunofluorescence for core PCP protein distribution Developmental Biology Medium 29510119
2020 VANGL1 interacts with BRAF (co-immunoprecipitation) and increases BRAF protein levels, likely by suppressing BRAF protein degradation, leading to upregulation of downstream DNA repair effectors TP53BP1 and RAD51 in lung adenocarcinoma cells. Co-immunoprecipitation; VANGL1 knockdown/overexpression with Western blot for BRAF and downstream targets; DNA damage assays Journal of Experimental & Clinical Cancer Research Low 33228740
2022 miR-27a-3p directly targets the 3'-UTR of Vangl1 to suppress its expression in mouse granulosa cells; Vangl1 (and Vangl2) promote granulosa cell proliferation and suppress the Wnt pathway by reducing β-catenin and Bcl-2 expression. Luciferase reporter assay for 3'-UTR targeting; RT-qPCR and Western blot; EdU proliferation assay; ChIP-PCR for upstream transcription factor Biochimica et Biophysica Acta. Gene Regulatory Mechanisms Low 36288764
2025 PRICKLE3 stabilizes VANGL1 and VANGL2 at the plasma membrane by shielding them from Casein kinase 1ε-mediated phosphorylation and by negatively regulating the interaction between Casein kinase 1ε and ubiquitin ligase RNF43, thereby decreasing ubiquitination and increasing VANGL1/2 stability; PRICKLE1 does not show comparable activity. miniTurboID proximity biotinylation combined with mass spectrometry; inducible expression system; Western blot for phosphorylation and ubiquitination; co-immunoprecipitation bioRxivpreprint Medium bio_10.1101_2025.03.24.644882
2024 Shear stress triggers relocation of Vangl1 from an internal reservoir to the plasma membrane at the initiation of vascular cell remodeling; membrane enrichment is mediated by a Coronin1C-dependent shift in endo/exocytosis equilibrium and results in spatial reorganization of Frizzled6, driving mutual exclusion of Fzd6 and Vangl1 along the flow axis to augment differential junctional and cytoskeletal dynamics. Live cell imaging; subcellular fractionation; siRNA/morpholino knockdown of Vangl1 and Coronin1C; endocytosis/exocytosis assays; in vivo zebrafish vessel sprouting analysis bioRxivpreprint Medium bio_10.1101_2024.06.25.600357
2015 Stable siRNA-mediated knockdown of VANGL1 in HepG2 hepatocellular carcinoma cells significantly suppresses invasive capacity without substantially affecting cellular motility, indicating a specific role for VANGL1 in invasion rather than general motility. Stable siRNA transfection; Transwell invasion and motility assays Genetic Testing and Molecular Biomarkers Low 25874746
2015 In Xenopus, Vangl1 acts downstream of Prohibitin1 (Phb1) and upstream of twist in neural crest specification, as established by gain-of-function, loss-of-function, and epistasis experiments in Xenopus embryos. Morpholino knockdown; mRNA overexpression; epistasis experiments; neural crest marker gene expression analysis in Xenopus Genesis Low 26259516

Source papers

Stage 0 corpus · 43 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Mutations in VANGL1 associated with neural-tube defects. The New England journal of medicine 236 17409324
2011 A protein complex of SCRIB, NOS1AP and VANGL1 regulates cell polarity and migration, and is associated with breast cancer progression. Oncogene 101 22179838
2009 Novel mutations in VANGL1 in neural tube defects. Human mutation 85 19319979
2002 Molecular cloning and characterization of Strabismus 2 (STB2). International journal of oncology 67 11956595
2020 Up-regulation of VANGL1 by IGF2BPs and miR-29b-3p attenuates the detrimental effect of irradiation on lung adenocarcinoma. Journal of experimental & clinical cancer research : CR 60 33228740
2014 Vangl1 and Vangl2: planar cell polarity components with a developing role in cancer. Endocrine-related cancer 59 24981109
2018 Circular RNA circ-VANGL1 as a competing endogenous RNA contributes to bladder cancer progression by regulating miR-605-3p/VANGL1 pathway. Journal of cellular physiology 57 30146736
2012 Molecular characterisation of endogenous Vangl2/Vangl1 heteromeric protein complexes. PloS one 46 23029439
2010 VANGL1 rare variants associated with neural tube defects affect convergent extension in zebrafish. Mechanisms of development 41 20043994
2006 Vangl1 protein acts as a downstream effector of intestinal trefoil factor (ITF)/TFF3 signaling and regulates wound healing of intestinal epithelium. The Journal of biological chemistry 39 16410243
2019 Circ-VANGL1 promotes the progression of osteoporosis by absorbing miRNA-217 to regulate RUNX2 expression. European review for medical and pharmacological sciences 33 30779060
2019 Up-regulated circular RNA VANGL1 contributes to progression of non-small cell lung cancer through inhibition of miR-195 and activation of Bcl-2. Bioscience reports 31 31076544
2002 Isolation and characterization of a novel human gene, VANGL1, as a therapeutic target for hepatocellular carcinoma. International journal of oncology 31 12011995
2014 Expanding the mutational spectrum associated to neural tube defects: literature revision and description of novel VANGL1 mutations. Birth defects research. Part A, Clinical and molecular teratology 30 25208524
2005 Comparative genomics on Vangl1 and Vangl2 genes. International journal of oncology 28 15809738
2019 Silencing circular RNA VANGL1 inhibits progression of bladder cancer by regulating miR-1184/IGFBP2 axis. Cancer medicine 27 31758655
2012 Novel VANGL1 Gene Mutations in 144 Slovakian, Romanian and German Patients with Neural Tube Defects. Molecular syndromology 27 23326252
2017 Scribble1 plays an important role in the pathogenesis of neural tube defects through its mediating effect of Par-3 and Vangl1/2 localization. Human molecular genetics 23 28369449
2016 A novel DNA biosensor integrated with Polypyrrole/streptavidin and Au-PAMAM-CP bionanocomposite probes to detect the rs4839469 locus of the vangl1 gene for dysontogenesis prediction. Biosensors & bioelectronics 20 26914375
2015 A novel electrochemical immunosensor based on the rGO-TEPA-PTC-NH₂ and AuPt modified C₆₀ bimetallic nanoclusters for the detection of Vangl1, a potential biomarker for dysontogenesis. Biosensors & bioelectronics 20 26735870
2018 Domineering non-autonomy in Vangl1;Vangl2 double mutants demonstrates intercellular PCP signaling in the vertebrate inner ear. Developmental biology 18 29510119
2017 Mutation of the Planar Cell Polarity Gene VANGL1 in Adolescent Idiopathic Scoliosis. Spine 17 27755493
2021 Circular RNA VANGL1 knockdown suppressed viability, promoted apoptosis, and increased doxorubicin sensitivity through targeting miR-145-5p to regulate SOX4 in bladder cancer cells. Open medicine (Warsaw, Poland) 14 34258391
2011 Transmembrane topology of mammalian planar cell polarity protein Vangl1. Biochemistry 14 21291170
2014 Association between VANGL1 gene polymorphisms and neural tube defects. Neuropediatrics 13 24407469
2021 Knockdown of circular RNA VANGL1 inhibits TGF-β-induced epithelial-mesenchymal transition in melanoma cells by sponging miR-150-5p. Journal of cellular and molecular medicine 11 34750955
2024 Mesenchymal Vangl1 and Vangl2 facilitate airway elongation and widening independently of the planar cell polarity complex. Development (Cambridge, England) 10 39225402
2023 A complex of Wnt/planar cell polarity signaling components Vangl1 and Fzd7 drives glioblastoma multiforme malignant properties. Cancer letters 10 37336284
2022 Wnt5a-Vangl1/2 signaling regulates the position and direction of lung branching through the cytoskeleton and focal adhesions. PLoS biology 10 36026468
2014 The homologous genes Vangl1 and Vangl2 are required for embryo implantation in the uterus of mice during early pregnancy. Gene 9 25445275
2025 Cryo-EM structure and oligomerization of the human planar cell polarity core protein Vangl1. Nature communications 8 39753546
2022 Circular RNA VANGL1 Facilitates Migration and Invasion of Papillary Thyroid Cancer by Modulating the miR-194/ZEB1/EMT Axis. Journal of oncology 8 35300347
2018 VANGL1 Is Not Associated With the Susceptibility of Adolescent Idiopathic Scoliosis in the Chinese Population. Spine 8 29189642
2024 Core planar cell polarity genes VANGL1 and VANGL2 in predisposition to congenital vertebral malformations. Proceedings of the National Academy of Sciences of the United States of America 7 38669183
2021 Deletions in VANGL1 are a risk factor for antibody-mediated kidney disease. Cell reports. Medicine 7 35028616
2015 Downregulation of VANGL1 inhibits cellular invasion rather than cell motility in hepatocellular carcinoma cells without stimulation. Genetic testing and molecular biomarkers 7 25874746
2008 Effects of retinoic acid on the expressions of Vangl1 and vangl2 in mouse fetuses. Journal of neurogenetics 6 19012162
2022 MicroRNA-27a-3p targeting Vangl1 and Vangl2 inhibits cell proliferation in mouse granulosa cells. Biochimica et biophysica acta. Gene regulatory mechanisms 5 36288764
2015 Neural crest specification by Prohibitin1 depends on transcriptional regulation of prl3 and vangl1. Genesis (New York, N.Y. : 2000) 3 26259516
2021 The VANGL1 P384R variant cause both neural tube defect and Klippel-Feil syndrome. Molecular genetics & genomic medicine 2 34014041
2025 RETRACTION: Silencing Circular RNA VANGL1 Inhibits Progression of Bladder Cancer by Regulating miR-1184/IGFBP2 Axis. Cancer medicine 0 40852977
2024 Does the esv3587290 Copy Number Variation in the VANGL1 Gene Differ as a Genetic Factor for Developing Nephritis in Mexican Childhood-Onset Systemic Lupus Erythematosus Patients? Children (Basel, Switzerland) 0 38929291
2013 Recurrent anencephaly: a case report and examination of the VANGL1 and FOXN1 genes. Fetal and pediatric pathology 0 23301910

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