Affinage

VANGL1

Vang-like protein 1 · UniProt Q8TAA9

Length
524 aa
Mass
60.0 kDa
Annotated
2026-04-28
43 papers in source corpus 20 papers cited in narrative 21 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VANGL1 is a four-transmembrane planar cell polarity (PCP) scaffold protein that oligomerizes as dimers of trimers to transduce non-canonical Wnt signals controlling convergent extension, lung branching morphogenesis, inner ear hair cell polarity, and epithelial wound healing (PMID:39753546, PMID:29510119, PMID:36026468, PMID:16410243). It localizes asymmetrically at the plasma membrane, where it forms complexes with Dishevelled proteins, SCRIB–NOS1AP, FZD7, and Prickle1, and drives actin cytoskeletal rearrangements and focal adhesion remodeling via Rho GTPases (PMID:17409324, PMID:22179838, PMID:37336284, PMID:36026468). VANGL1 heterodimerizes with VANGL2, and its membrane stability is regulated by Scribble1/Par-3-dependent trafficking and phosphorylation-dependent internalization (PMID:23029439, PMID:28369449, PMID:16410243). Loss-of-function mutations in VANGL1 cause neural tube defects, congenital scoliosis, and vertebral malformations through disrupted Dishevelled binding, impaired membrane trafficking, or defective oligomerization (PMID:17409324, PMID:38669183, PMID:39753546).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2002 Medium

    Molecular cloning established VANGL1 as a novel four-transmembrane protein with a C-terminal PDZ-binding motif, providing the foundational domain architecture for all subsequent functional studies.

    Evidence cDNA cloning and sequence analysis of STB2/VANGL1

    PMID:11956595

    Open questions at the time
    • No functional data; domain roles not tested by mutagenesis
    • Topology not experimentally verified
  2. 2006 High

    VANGL1 was placed as a phosphorylation-dependent effector of ITF/TFF3 signaling in intestinal epithelial wound healing, with its membrane association dynamically regulated by phosphorylation — the first demonstration that VANGL1 is functionally active in mammalian epithelial migration.

    Evidence Mass spectrometry phosphoproteomics, siRNA knockdown, overexpression, wound closure assay, confocal microscopy in intestinal epithelial cells

    PMID:16410243

    Open questions at the time
    • Kinase responsible for VANGL1 phosphorylation not identified
    • Mechanism linking phosphorylation to membrane dissociation unknown
  3. 2007 High

    An NTD-associated V239I mutation was shown to abolish VANGL1 interaction with all three Dishevelled paralogs, establishing that VANGL1–DVL binding is essential for neural tube closure and linking VANGL1 to planar cell polarity signaling in human disease.

    Evidence Co-immunoprecipitation/yeast two-hybrid with disease-associated mutant across DVL1/2/3

    PMID:17409324

    Open questions at the time
    • Structural basis of DVL interaction not resolved
    • Whether other NTD mutations act through the same mechanism unknown
  4. 2010 High

    In vivo zebrafish rescue experiments confirmed that NTD-associated VANGL1 variants V239I and M328T are loss-of-function alleles that cannot substitute for vangl2 in convergent extension, establishing functional conservation and the PCP pathway requirement.

    Evidence Zebrafish vangl2 morpholino knockdown/rescue and overexpression assays

    PMID:20043994

    Open questions at the time
    • Whether VANGL1 and VANGL2 have non-redundant functions in mammalian convergent extension not addressed
  5. 2011 High

    Systematic topology mapping and identification of the VANGL1–SCRIB–NOS1AP complex established both the membrane orientation (intracellular N- and C-termini, extracellular loops) and a scaffold function organizing polarity-associated effectors at cellular protrusions.

    Evidence Epitope-tag insertion topology mapping in MDCK cells; mass spectrometry identification of SCRIB–NOS1AP complex with functional migration assays in breast cancer cells

    PMID:21291170 PMID:22179838

    Open questions at the time
    • Direct binding interfaces between VANGL1, SCRIB, and NOS1AP not mapped
    • Whether the SCRIB–NOS1AP complex functions in non-cancer PCP contexts untested
  6. 2012 High

    Demonstration that VANGL1 and VANGL2 form endogenous heterodimers at the plasma membrane revealed that the two paralogs function as an integrated unit rather than independently.

    Evidence Endogenous co-immunoprecipitation with SPR-validated monoclonal antibody, proteomics, and colocalization

    PMID:23029439

    Open questions at the time
    • Stoichiometry and structural basis of heterodimer not determined
    • Functional consequence of heterodimerization vs. homodimerization not tested
  7. 2017 High

    Scribble1 was shown to control VANGL1 subcellular localization indirectly through Par-3, establishing an epistatic hierarchy (Scrib1→Par-3→VANGL1 localization), and disease-associated mutations (I136N, F440V) were found to block membrane translocation.

    Evidence MDCK cell Scrib1/Par-3 knockdown and rescue with VANGL1 localization analysis; transfection of AIS-associated mutants with immunofluorescence

    PMID:27755493 PMID:28369449

    Open questions at the time
    • Molecular mechanism by which Par-3 controls VANGL1 trafficking unknown
    • Whether AIS mutations affect Dvl or Prickle binding not tested
  8. 2018 High

    Conditional double knockout of Vangl1/Vangl2 at a mutant boundary in the mouse inner ear produced domineering non-autonomy, demonstrating that VANGL proteins actively transmit PCP information to neighboring wild-type cells.

    Evidence Emx2-Cre conditional knockout mice with stereociliary bundle orientation and PCP protein distribution analysis

    PMID:29510119

    Open questions at the time
    • Identity of the intercellular ligand–receptor pair mediating non-autonomous signaling not determined
    • Relative contributions of VANGL1 vs. VANGL2 to the non-autonomous signal unclear
  9. 2022 High

    Wnt5a was placed upstream of Vangl1/2 in lung branching morphogenesis, acting through cytoskeletal reorganization and focal adhesion remodeling, broadening VANGL1's role to organ-level morphogenetic patterning.

    Evidence Mouse conditional knockout, lung explant culture, focal adhesion and cytoskeletal imaging

    PMID:36026468

    Open questions at the time
    • Direct Wnt5a–VANGL1 binding not shown
    • Downstream Rho GTPase specificity not identified in lung
  10. 2023 High

    A VANGL1–FZD7 complex was identified at the leading edge of migrating GBM cells, activating Rho GTPases to drive actin rearrangement, proliferation, and invasion — the first direct demonstration of a VANGL1–Frizzled effector complex with defined downstream signaling.

    Evidence Co-immunoprecipitation, Rho GTPase activity assays, shRNA knockdown, intracranial xenograft model

    PMID:37336284

    Open questions at the time
    • Whether VANGL1–FZD7 interaction is direct or bridged unknown
    • Relevance of this complex to non-neoplastic PCP signaling not tested
  11. 2024 High

    Tissue-specific knockouts revealed that Vangl1/2 are required in pulmonary mesenchyme (not epithelium) for airway branching independently of Celsr1, and knock-in mice carrying the p.R258H variant confirmed gene-dose- and environment-dependent vertebral malformations linked to congenital scoliosis.

    Evidence Tissue-specific conditional knockout mice with morphometric analysis; knock-in mouse model with zebrafish functional validation and human exome data

    PMID:38669183 PMID:39225402

    Open questions at the time
    • Mesenchyme-specific VANGL1 effectors downstream of branching signals not identified
    • Environmental modifiers of vertebral malformation penetrance unknown
  12. 2025 High

    Cryo-EM resolved the VANGL1 oligomeric architecture as dimers of trimers, showing that this higher-order assembly promotes Prickle1 binding and that disease mutations map to oligomerization interfaces, providing the first structural framework for understanding PCP scaffold assembly and pathogenesis.

    Evidence Cryo-EM structure determination, biochemical oligomerization assays, in vitro Prickle1 binding assay

    PMID:39753546

    Open questions at the time
    • Structure of VANGL1 in complex with DVL or FZD not yet solved
    • Whether hexameric assembly occurs in vivo at endogenous expression levels not confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of VANGL1 interaction with Dishevelled and Frizzled receptors, the identity of the kinase(s) mediating regulatory phosphorylation in non-cancer contexts, and the mechanisms by which environmental factors modulate VANGL1-dependent disease penetrance.
  • No VANGL1–DVL or VANGL1–FZD co-structure available
  • Regulatory kinases upstream of VANGL1 phosphorylation in PCP signaling not identified
  • Environmental modifiers of VANGL1 disease penetrance undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0005198 structural molecule activity 2
Localization
GO:0005886 plasma membrane 6 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 3
Partners
DVL1DVL2DVL3FZD7NOS1APPRICKLE1SCRIBVANGL2
Complex memberships
VANGL1 dimer-of-trimersVANGL1-FZD7 complexVANGL1-SCRIB-NOS1AP complexVANGL1-VANGL2 heterodimer

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 The NTD-associated VANGL1 mutation V239I abolishes interaction of VANGL1 protein with its binding partners Dishevelled-1, -2, and -3, as demonstrated by protein-protein interaction assay. Protein-protein interaction assay (co-immunoprecipitation/yeast two-hybrid) The New England Journal of Medicine High 17409324
2002 VANGL1 (STB2) encodes a 524-amino-acid protein with four transmembrane domains and a C-terminal Ser/Thr-X-Val PDZ-binding motif, established by molecular cloning and sequence analysis. cDNA cloning, bioinformatics, sequence analysis International Journal of Oncology Medium 11956595
2006 VANGL1 is Ser/Thr phosphorylated in response to intestinal trefoil factor (ITF/TFF3) stimulation; overexpression enhances ITF-stimulated wound closure in intestinal epithelial cells, while siRNA knockdown inhibits the migratory response to ITF, placing VANGL1 as a downstream effector of ITF signaling. Mass spectrometry identification of phosphorylated proteins after ITF stimulation, siRNA knockdown, overexpression, wound closure assay, confocal microscopy The Journal of Biological Chemistry High 16410243
2006 VANGL1 is predominantly localized in cytoplasmic vesicular structures in undifferentiated intestinal epithelial cells, but its cell membrane association increases with differentiation, co-localizing with E-cadherin at the membrane; phosphorylation by ITF decreases this membrane association. Confocal microscopy, subcellular fractionation (NP-40 soluble fraction), Western blotting The Journal of Biological Chemistry Medium 16410243
2010 VANGL1 NTD-associated variants V239I and M328T represent loss-of-function alleles that fail to rescue convergent extension defects caused by vangl2 (trilobite) morpholino knockdown in zebrafish, and fail to induce convergent extension phenotypes when overexpressed, demonstrating functional conservation across evolution. Zebrafish antisense morpholino knockdown/rescue assay, overexpression in zebrafish embryos Mechanisms of Development High 20043994
2011 VANGL1 forms a protein complex with SCRIB and NOS1AP; this complex colocalizes along cellular protrusions in metastatic breast cancer cells, and knockdown of NOS1AP or SCRIB slows breast cancer cell migration and prevents leading-trailing polarity establishment. Mass spectrometry, confocal microscopy, shRNA knockdown, cell migration assay Oncogene High 22179838
2011 VANGL1 has a four-transmembrane domain topology with N-terminal and large C-terminal portions intracellular; the loop between TMD1-2 and TMD3-4 is extracellular, while the segment between TMD2-3 is intracellular. Epitope-tag insertion (HA tags at multiple positions), immunofluorescence in intact and permeabilized MDCK cells, surface labeling Biochemistry High 21291170
2012 VANGL1 and VANGL2 form endogenous heterodimers; Vangl1 was identified in Vangl2 immunoprecipitates from cell lysates, and epitope-tagged proteins co-localize at the plasma membrane. Highly specific monoclonal anti-Vangl2 antibody generation, surface plasmon resonance validation, co-immunoprecipitation, proteomics, immunofluorescence PLoS One High 23029439
2015 Downregulation of VANGL1 by siRNA in HepG2 hepatocellular carcinoma cells significantly suppresses invasive capacity but only slightly affects cellular motility, indicating a role in cell invasion through the Wnt-PCP pathway. Stable siRNA transfection, invasion assay, motility assay Genetic Testing and Molecular Biomarkers Medium 25874746
2017 Scribble1 controls VANGL1 localization indirectly through Par-3: partial knockdown of Scrib1 causes abnormal VANGL1 localization, which is rescued by Par-3 overexpression; partial knockdown of Par-3 itself causes apical enrichment of Vangl1. MDCK cell Scrib1 knockdown, immunofluorescence, Par-3 rescue experiment, Vangl1 localization analysis Human Molecular Genetics High 28369449
2017 AIS-associated VANGL1 missense mutations p.I136N and p.F440V abolish normal translocation of VANGL1 to the cell membrane in MDCK cells. Transfection of mutant recombinant VANGL1 in MDCK cells, immunofluorescence microscopy Spine Medium 27755493
2018 Vangl1 and Vangl2 mediate intercellular planar cell polarity (PCP) signaling in the vertebrate inner ear; conditional double knockout at a mutant boundary produces domineering non-autonomy phenotypes, demonstrating that VANGL proteins transmit PCP information to neighboring wild-type cells. Emx2-Cre conditional knockout mice, stereociliary bundle orientation analysis, PCP protein distribution immunofluorescence Developmental Biology High 29510119
2020 VANGL1 physically interacts with BRAF and increases BRAF protein levels by suppressing its protein degradation, leading to activation of BRAF downstream effectors TP53BP1 and RAD51 involved in DNA repair. Co-immunoprecipitation, Western blot, siRNA knockdown, apoptosis assay, DNA damage assay Journal of Experimental & Clinical Cancer Research Medium 33228740
2022 Wnt5a signals through Vangl1/2 to regulate lung branching morphogenesis by triggering cytoskeletal reorganization and changes in focal adhesions in lung epithelial and mesenchymal cells. Mouse conditional knockout, lung explant culture, focal adhesion analysis, cytoskeletal imaging PLoS Biology High 36026468
2022 miR-27a-3p targets the 3'-UTR of Vangl1 and Vangl2 mRNAs to suppress their expression and inhibit granulosa cell proliferation; Vangl1 and Vangl2 suppress Wnt pathway activity by reducing β-catenin and Bcl-2 expression. Luciferase reporter assay, RT-qPCR, Western blot, EdU proliferation assay, ChIP-PCR Biochimica et Biophysica Acta – Gene Regulatory Mechanisms Medium 36288764
2023 VANGL1 forms a complex with FZD7 at the leading edge of migrating GBM cells; this complex promotes actin cytoskeletal rearrangements via Rho GTPases, and drives GBM cellular proliferation, migration, and invasiveness. Co-immunoprecipitation, immunofluorescence, siRNA/shRNA knockdown, Rho GTPase activity assays, intracranial xenograft mouse model Cancer Letters High 37336284
2024 Vangl1 and Vangl2 are required in pulmonary mesenchyme (not epithelium) for airway branch initiation, elongation, and widening during lung branching morphogenesis, functioning independently of the core PCP complex component Celsr1. Tissue-specific conditional knockout mice, quantitative morphometric analysis of airway geometry Development High 39225402
2024 Vangl1 knock-in (p.R258H) mice exhibit vertebral malformations in a Vangl gene dose- and environment-dependent manner, and rare deleterious VANGL1 variants from CS patients show loss-of-function and dominant-negative effects confirmed in zebrafish models. Knock-in mouse model, zebrafish functional validation, exome sequencing analysis Proceedings of the National Academy of Sciences of the USA High 38669183
2025 Cryo-EM structural analysis reveals that human VANGL1 oligomerizes as dimers of trimers; the dimerization of trimers promotes binding to the PCP effector Prickle1 in vitro, and mapping of disease-associated point mutations provides structural insights into pathological mechanisms. Cryo-EM structure determination, biochemical oligomerization assays, in vitro Prickle1 binding assay, disease mutation mapping Nature Communications High 39753546
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 reducing VANGL1 ubiquitination; this effect is specific to PRICKLE3 and not shared by PRICKLE1. miniTurboID proximity biotinylation/mass spectrometry, inducible expression system, phosphorylation assays, ubiquitination assays, plasma membrane localization assays bioRxiv (preprint)preprint 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; this membrane enrichment is mediated by a Coronin1C-dependent shift in the equilibrium between endocytosis and exocytosis, and results in spatial reorganization (mutual exclusion) of Frizzled6, augmenting differential junctional and cytoskeletal dynamics along the flow axis. Live-cell imaging, FRAP, subcellular fractionation, siRNA knockdown, in vivo zebrafish vasculature analysis, mathematical modeling bioRxiv (preprint)preprint Medium bio_10.1101_2024.06.25.600357

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 234 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 45 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
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
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
2025 Cryo-EM structure and oligomerization of the human planar cell polarity core protein Vangl1. Nature communications 7 39753546
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
2024 Mesenchymal Vangl1 and Vangl2 facilitate airway elongation and widening independently of the planar cell polarity complex. Development (Cambridge, England) 7 39225402
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