{"gene":"VANGL1","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2007,"finding":"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.","method":"Protein-protein interaction assay (co-immunoprecipitation/yeast two-hybrid)","journal":"The New England Journal of Medicine","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction assay with disease-associated mutant, replicated across three DVL paralogs, high-citation foundational paper","pmids":["17409324"],"is_preprint":false},{"year":2002,"finding":"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.","method":"cDNA cloning, bioinformatics, sequence analysis","journal":"International Journal of Oncology","confidence":"Medium","confidence_rationale":"Tier 3 — molecular cloning and domain characterization without functional mutagenesis, but foundational structural description","pmids":["11956595"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Mass spectrometry identification of phosphorylated proteins after ITF stimulation, siRNA knockdown, overexpression, wound closure assay, confocal microscopy","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (MS, KD, OE, functional assay) in a single study establishing pathway position and functional consequence","pmids":["16410243"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Confocal microscopy, subcellular fractionation (NP-40 soluble fraction), Western blotting","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with functional consequence (phosphorylation-dependent membrane dissociation)","pmids":["16410243"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Zebrafish antisense morpholino knockdown/rescue assay, overexpression in zebrafish embryos","journal":"Mechanisms of Development","confidence":"High","confidence_rationale":"Tier 2 — in vivo functional epistasis with two orthogonal assays (rescue and overexpression) confirming loss-of-function","pmids":["20043994"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Mass spectrometry, confocal microscopy, shRNA knockdown, cell migration assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — mass spectrometry identification of complex confirmed by co-localization, with functional consequence of KD established by multiple assays","pmids":["22179838"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Epitope-tag insertion (HA tags at multiple positions), immunofluorescence in intact and permeabilized MDCK cells, surface labeling","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — systematic topology mapping with six epitope insertions and multiple detection methods","pmids":["21291170"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Highly specific monoclonal anti-Vangl2 antibody generation, surface plasmon resonance validation, co-immunoprecipitation, proteomics, immunofluorescence","journal":"PLoS One","confidence":"High","confidence_rationale":"Tier 1-2 — endogenous-level co-IP validated by SPR, proteomics, and colocalization, with rigorous antibody characterization","pmids":["23029439"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Stable siRNA transfection, invasion assay, motility assay","journal":"Genetic Testing and Molecular Biomarkers","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype, but single lab single method","pmids":["25874746"],"is_preprint":false},{"year":2017,"finding":"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.","method":"MDCK cell Scrib1 knockdown, immunofluorescence, Par-3 rescue experiment, Vangl1 localization analysis","journal":"Human Molecular Genetics","confidence":"High","confidence_rationale":"Tier 2 — epistasis established by KD and rescue experiments with defined localization phenotype, multiple orthogonal approaches","pmids":["28369449"],"is_preprint":false},{"year":2017,"finding":"AIS-associated VANGL1 missense mutations p.I136N and p.F440V abolish normal translocation of VANGL1 to the cell membrane in MDCK cells.","method":"Transfection of mutant recombinant VANGL1 in MDCK cells, immunofluorescence microscopy","journal":"Spine","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with disease-associated mutations, single lab","pmids":["27755493"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Emx2-Cre conditional knockout mice, stereociliary bundle orientation analysis, PCP protein distribution immunofluorescence","journal":"Developmental Biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis via conditional KO with defined intercellular signaling phenotype","pmids":["29510119"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation, Western blot, siRNA knockdown, apoptosis assay, DNA damage assay","journal":"Journal of Experimental & Clinical Cancer Research","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP with functional follow-up, single lab","pmids":["33228740"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Mouse conditional knockout, lung explant culture, focal adhesion analysis, cytoskeletal imaging","journal":"PLoS Biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in mouse KO with defined cellular mechanism (cytoskeleton/focal adhesion), multiple complementary approaches","pmids":["36026468"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Luciferase reporter assay, RT-qPCR, Western blot, EdU proliferation assay, ChIP-PCR","journal":"Biochimica et Biophysica Acta – Gene Regulatory Mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 — direct 3'-UTR targeting confirmed by luciferase assay plus functional proliferation assay, single lab","pmids":["36288764"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation, immunofluorescence, siRNA/shRNA knockdown, Rho GTPase activity assays, intracranial xenograft mouse model","journal":"Cancer Letters","confidence":"High","confidence_rationale":"Tier 2 — complex identified by Co-IP, localized by IF, functional consequence confirmed by multiple in vitro and in vivo assays","pmids":["37336284"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Tissue-specific conditional knockout mice, quantitative morphometric analysis of airway geometry","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific conditional KO with defined morphogenetic phenotype and genetic dissection from Celsr1","pmids":["39225402"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Knock-in mouse model, zebrafish functional validation, exome sequencing analysis","journal":"Proceedings of the National Academy of Sciences of the USA","confidence":"High","confidence_rationale":"Tier 2 — in vivo knock-in model combined with zebrafish functional validation and human genetic data","pmids":["38669183"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Cryo-EM structure determination, biochemical oligomerization assays, in vitro Prickle1 binding assay, disease mutation mapping","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with biochemical reconstitution and functional binding assay, rigorous structural validation","pmids":["39753546"],"is_preprint":false},{"year":2025,"finding":"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.","method":"miniTurboID proximity biotinylation/mass spectrometry, inducible expression system, phosphorylation assays, ubiquitination assays, plasma membrane localization assays","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (proximity proteomics, phosphorylation, ubiquitination, localization assays) but preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.03.24.644882"],"is_preprint":true},{"year":2024,"finding":"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.","method":"Live-cell imaging, FRAP, subcellular fractionation, siRNA knockdown, in vivo zebrafish vasculature analysis, mathematical modeling","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods with in vivo validation, but preprint not yet peer-reviewed","pmids":["bio_10.1101_2024.06.25.600357"],"is_preprint":true}],"current_model":"VANGL1 is a four-transmembrane planar cell polarity (PCP) scaffold protein that oligomerizes as dimers of trimers, localizes asymmetrically to the plasma membrane where its stability is regulated by PRICKLE3-mediated protection from Casein kinase 1ε phosphorylation and RNF43 ubiquitination; it interacts with Dishevelled-1/2/3, FZD7, SCRIB, NOS1AP, and Prickle1 to mediate non-canonical Wnt/PCP signaling, controls convergent extension, lung branching, inner ear hair cell polarity, and vascular remodeling by reorganizing the actin cytoskeleton and focal adhesions, and acts downstream of ITF/TFF3 as a phosphorylation-dependent regulator of intestinal epithelial wound healing, with disease-causing mutations disrupting membrane trafficking, Dishevelled binding, or oligomerization."},"narrative":{"teleology":[{"year":2002,"claim":"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","pmids":["11956595"],"confidence":"Medium","gaps":["No functional data; domain roles not tested by mutagenesis","Topology not experimentally verified"]},{"year":2006,"claim":"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","pmids":["16410243"],"confidence":"High","gaps":["Kinase responsible for VANGL1 phosphorylation not identified","Mechanism linking phosphorylation to membrane dissociation unknown"]},{"year":2007,"claim":"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","pmids":["17409324"],"confidence":"High","gaps":["Structural basis of DVL interaction not resolved","Whether other NTD mutations act through the same mechanism unknown"]},{"year":2010,"claim":"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","pmids":["20043994"],"confidence":"High","gaps":["Whether VANGL1 and VANGL2 have non-redundant functions in mammalian convergent extension not addressed"]},{"year":2011,"claim":"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","pmids":["21291170","22179838"],"confidence":"High","gaps":["Direct binding interfaces between VANGL1, SCRIB, and NOS1AP not mapped","Whether the SCRIB–NOS1AP complex functions in non-cancer PCP contexts untested"]},{"year":2012,"claim":"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","pmids":["23029439"],"confidence":"High","gaps":["Stoichiometry and structural basis of heterodimer not determined","Functional consequence of heterodimerization vs. homodimerization not tested"]},{"year":2017,"claim":"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","pmids":["28369449","27755493"],"confidence":"High","gaps":["Molecular mechanism by which Par-3 controls VANGL1 trafficking unknown","Whether AIS mutations affect Dvl or Prickle binding not tested"]},{"year":2018,"claim":"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","pmids":["29510119"],"confidence":"High","gaps":["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"]},{"year":2022,"claim":"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","pmids":["36026468"],"confidence":"High","gaps":["Direct Wnt5a–VANGL1 binding not shown","Downstream Rho GTPase specificity not identified in lung"]},{"year":2023,"claim":"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","pmids":["37336284"],"confidence":"High","gaps":["Whether VANGL1–FZD7 interaction is direct or bridged unknown","Relevance of this complex to non-neoplastic PCP signaling not tested"]},{"year":2024,"claim":"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","pmids":["39225402","38669183"],"confidence":"High","gaps":["Mesenchyme-specific VANGL1 effectors downstream of branching signals not identified","Environmental modifiers of vertebral malformation penetrance unknown"]},{"year":2025,"claim":"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","pmids":["39753546"],"confidence":"High","gaps":["Structure of VANGL1 in complex with DVL or FZD not yet solved","Whether hexameric assembly occurs in vivo at endogenous expression levels not confirmed"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,15,18]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[6,18]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,6,7,10,15,18]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,4,13,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,11,13,16,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,10,17]}],"complexes":["VANGL1-VANGL2 heterodimer","VANGL1 dimer-of-trimers","VANGL1-SCRIB-NOS1AP complex","VANGL1-FZD7 complex"],"partners":["DVL1","DVL2","DVL3","VANGL2","SCRIB","NOS1AP","FZD7","PRICKLE1"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"Q8TAA9","full_name":"Vang-like protein 1","aliases":["Loop-tail protein 2 homolog","LPP2","Strabismus 2","Van Gogh-like protein 1"],"length_aa":524,"mass_kda":60.0,"function":"","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8TAA9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VANGL1","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/VANGL1","total_profiled":1310},"omim":[{"mim_id":"610622","title":"FUZZY PLANAR CELL POLARITY PROTEIN; FUZ","url":"https://www.omim.org/entry/610622"},{"mim_id":"610132","title":"VANGL PLANAR CELL POLARITY PROTEIN 1; VANGL1","url":"https://www.omim.org/entry/610132"},{"mim_id":"600533","title":"VANGL PLANAR CELL POLARITY PROTEIN 2; VANGL2","url":"https://www.omim.org/entry/600533"},{"mim_id":"600145","title":"SACRAL DEFECT WITH ANTERIOR MENINGOCELE","url":"https://www.omim.org/entry/600145"},{"mim_id":"182940","title":"NEURAL TUBE DEFECTS, SUSCEPTIBILITY TO; NTD","url":"https://www.omim.org/entry/182940"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/VANGL1"},"hgnc":{"alias_symbol":["STB2"],"prev_symbol":[]},"alphafold":{"accession":"Q8TAA9","domains":[{"cath_id":"-","chopping":"337-446","consensus_level":"high","plddt":88.9685,"start":337,"end":446},{"cath_id":"1.20.1260","chopping":"107-244","consensus_level":"high","plddt":86.8696,"start":107,"end":244}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TAA9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TAA9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TAA9-F1-predicted_aligned_error_v6.png","plddt_mean":75.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VANGL1","jax_strain_url":"https://www.jax.org/strain/search?query=VANGL1"},"sequence":{"accession":"Q8TAA9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TAA9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TAA9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TAA9"}},"corpus_meta":[{"pmid":"17409324","id":"PMC_17409324","title":"Mutations in VANGL1 associated with neural-tube defects.","date":"2007","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17409324","citation_count":234,"is_preprint":false},{"pmid":"22179838","id":"PMC_22179838","title":"A protein complex of SCRIB, NOS1AP and VANGL1 regulates cell polarity and migration, and is associated with breast cancer progression.","date":"2011","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/22179838","citation_count":101,"is_preprint":false},{"pmid":"19319979","id":"PMC_19319979","title":"Novel mutations in VANGL1 in neural tube defects.","date":"2009","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/19319979","citation_count":85,"is_preprint":false},{"pmid":"11956595","id":"PMC_11956595","title":"Molecular cloning and characterization of Strabismus 2 (STB2).","date":"2002","source":"International journal of 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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.\",\n      \"method\": \"Mass spectrometry identification of phosphorylated proteins after ITF stimulation, siRNA knockdown, overexpression, wound closure assay, confocal microscopy\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (MS, KD, OE, functional assay) in a single study establishing pathway position and functional consequence\",\n      \"pmids\": [\"16410243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Confocal microscopy, subcellular fractionation (NP-40 soluble fraction), Western blotting\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional consequence (phosphorylation-dependent membrane dissociation)\",\n      \"pmids\": [\"16410243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Zebrafish antisense morpholino knockdown/rescue assay, overexpression in zebrafish embryos\",\n      \"journal\": \"Mechanisms of Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo functional epistasis with two orthogonal assays (rescue and overexpression) confirming loss-of-function\",\n      \"pmids\": [\"20043994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry, confocal microscopy, shRNA knockdown, cell migration assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mass spectrometry identification of complex confirmed by co-localization, with functional consequence of KD established by multiple assays\",\n      \"pmids\": [\"22179838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Epitope-tag insertion (HA tags at multiple positions), immunofluorescence in intact and permeabilized MDCK cells, surface labeling\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic topology mapping with six epitope insertions and multiple detection methods\",\n      \"pmids\": [\"21291170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Highly specific monoclonal anti-Vangl2 antibody generation, surface plasmon resonance validation, co-immunoprecipitation, proteomics, immunofluorescence\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — endogenous-level co-IP validated by SPR, proteomics, and colocalization, with rigorous antibody characterization\",\n      \"pmids\": [\"23029439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Stable siRNA transfection, invasion assay, motility assay\",\n      \"journal\": \"Genetic Testing and Molecular Biomarkers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype, but single lab single method\",\n      \"pmids\": [\"25874746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"MDCK cell Scrib1 knockdown, immunofluorescence, Par-3 rescue experiment, Vangl1 localization analysis\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established by KD and rescue experiments with defined localization phenotype, multiple orthogonal approaches\",\n      \"pmids\": [\"28369449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AIS-associated VANGL1 missense mutations p.I136N and p.F440V abolish normal translocation of VANGL1 to the cell membrane in MDCK cells.\",\n      \"method\": \"Transfection of mutant recombinant VANGL1 in MDCK cells, immunofluorescence microscopy\",\n      \"journal\": \"Spine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with disease-associated mutations, single lab\",\n      \"pmids\": [\"27755493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Emx2-Cre conditional knockout mice, stereociliary bundle orientation analysis, PCP protein distribution immunofluorescence\",\n      \"journal\": \"Developmental Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via conditional KO with defined intercellular signaling phenotype\",\n      \"pmids\": [\"29510119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, siRNA knockdown, apoptosis assay, DNA damage assay\",\n      \"journal\": \"Journal of Experimental & Clinical Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with functional follow-up, single lab\",\n      \"pmids\": [\"33228740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Mouse conditional knockout, lung explant culture, focal adhesion analysis, cytoskeletal imaging\",\n      \"journal\": \"PLoS Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in mouse KO with defined cellular mechanism (cytoskeleton/focal adhesion), multiple complementary approaches\",\n      \"pmids\": [\"36026468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Luciferase reporter assay, RT-qPCR, Western blot, EdU proliferation assay, ChIP-PCR\",\n      \"journal\": \"Biochimica et Biophysica Acta – Gene Regulatory Mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3'-UTR targeting confirmed by luciferase assay plus functional proliferation assay, single lab\",\n      \"pmids\": [\"36288764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, siRNA/shRNA knockdown, Rho GTPase activity assays, intracranial xenograft mouse model\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — complex identified by Co-IP, localized by IF, functional consequence confirmed by multiple in vitro and in vivo assays\",\n      \"pmids\": [\"37336284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Tissue-specific conditional knockout mice, quantitative morphometric analysis of airway geometry\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific conditional KO with defined morphogenetic phenotype and genetic dissection from Celsr1\",\n      \"pmids\": [\"39225402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Knock-in mouse model, zebrafish functional validation, exome sequencing analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the USA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo knock-in model combined with zebrafish functional validation and human genetic data\",\n      \"pmids\": [\"38669183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-EM structure determination, biochemical oligomerization assays, in vitro Prickle1 binding assay, disease mutation mapping\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with biochemical reconstitution and functional binding assay, rigorous structural validation\",\n      \"pmids\": [\"39753546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"miniTurboID proximity biotinylation/mass spectrometry, inducible expression system, phosphorylation assays, ubiquitination assays, plasma membrane localization assays\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (proximity proteomics, phosphorylation, ubiquitination, localization assays) but preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.03.24.644882\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Live-cell imaging, FRAP, subcellular fractionation, siRNA knockdown, in vivo zebrafish vasculature analysis, mathematical modeling\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods with in vivo validation, but preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.06.25.600357\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"VANGL1 is a four-transmembrane planar cell polarity (PCP) scaffold protein that oligomerizes as dimers of trimers, localizes asymmetrically to the plasma membrane where its stability is regulated by PRICKLE3-mediated protection from Casein kinase 1ε phosphorylation and RNF43 ubiquitination; it interacts with Dishevelled-1/2/3, FZD7, SCRIB, NOS1AP, and Prickle1 to mediate non-canonical Wnt/PCP signaling, controls convergent extension, lung branching, inner ear hair cell polarity, and vascular remodeling by reorganizing the actin cytoskeleton and focal adhesions, and acts downstream of ITF/TFF3 as a phosphorylation-dependent regulator of intestinal epithelial wound healing, with disease-causing mutations disrupting membrane trafficking, Dishevelled binding, or oligomerization.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"evidence\": \"cDNA cloning and sequence analysis of STB2/VANGL1\",\n      \"pmids\": [\"11956595\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional data; domain roles not tested by mutagenesis\", \"Topology not experimentally verified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"evidence\": \"Mass spectrometry phosphoproteomics, siRNA knockdown, overexpression, wound closure assay, confocal microscopy in intestinal epithelial cells\",\n      \"pmids\": [\"16410243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for VANGL1 phosphorylation not identified\", \"Mechanism linking phosphorylation to membrane dissociation unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-immunoprecipitation/yeast two-hybrid with disease-associated mutant across DVL1/2/3\",\n      \"pmids\": [\"17409324\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of DVL interaction not resolved\", \"Whether other NTD mutations act through the same mechanism unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"Zebrafish vangl2 morpholino knockdown/rescue and overexpression assays\",\n      \"pmids\": [\"20043994\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether VANGL1 and VANGL2 have non-redundant functions in mammalian convergent extension not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"Epitope-tag insertion topology mapping in MDCK cells; mass spectrometry identification of SCRIB–NOS1AP complex with functional migration assays in breast cancer cells\",\n      \"pmids\": [\"21291170\", \"22179838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interfaces between VANGL1, SCRIB, and NOS1AP not mapped\", \"Whether the SCRIB–NOS1AP complex functions in non-cancer PCP contexts untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Endogenous co-immunoprecipitation with SPR-validated monoclonal antibody, proteomics, and colocalization\",\n      \"pmids\": [\"23029439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of heterodimer not determined\", \"Functional consequence of heterodimerization vs. homodimerization not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"MDCK cell Scrib1/Par-3 knockdown and rescue with VANGL1 localization analysis; transfection of AIS-associated mutants with immunofluorescence\",\n      \"pmids\": [\"28369449\", \"27755493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which Par-3 controls VANGL1 trafficking unknown\", \"Whether AIS mutations affect Dvl or Prickle binding not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Emx2-Cre conditional knockout mice with stereociliary bundle orientation and PCP protein distribution analysis\",\n      \"pmids\": [\"29510119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Mouse conditional knockout, lung explant culture, focal adhesion and cytoskeletal imaging\",\n      \"pmids\": [\"36026468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Wnt5a–VANGL1 binding not shown\", \"Downstream Rho GTPase specificity not identified in lung\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-immunoprecipitation, Rho GTPase activity assays, shRNA knockdown, intracranial xenograft model\",\n      \"pmids\": [\"37336284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether VANGL1–FZD7 interaction is direct or bridged unknown\", \"Relevance of this complex to non-neoplastic PCP signaling not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Tissue-specific conditional knockout mice with morphometric analysis; knock-in mouse model with zebrafish functional validation and human exome data\",\n      \"pmids\": [\"39225402\", \"38669183\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mesenchyme-specific VANGL1 effectors downstream of branching signals not identified\", \"Environmental modifiers of vertebral malformation penetrance unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cryo-EM structure determination, biochemical oligomerization assays, in vitro Prickle1 binding assay\",\n      \"pmids\": [\"39753546\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of VANGL1 in complex with DVL or FZD not yet solved\", \"Whether hexameric assembly occurs in vivo at endogenous expression levels not confirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 15, 18]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [6, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 6, 7, 10, 15, 18]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 4, 13, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 11, 13, 16, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 10, 17]}\n    ],\n    \"complexes\": [\n      \"VANGL1-VANGL2 heterodimer\",\n      \"VANGL1 dimer-of-trimers\",\n      \"VANGL1-SCRIB-NOS1AP complex\",\n      \"VANGL1-FZD7 complex\"\n    ],\n    \"partners\": [\n      \"DVL1\",\n      \"DVL2\",\n      \"DVL3\",\n      \"VANGL2\",\n      \"SCRIB\",\n      \"NOS1AP\",\n      \"FZD7\",\n      \"PRICKLE1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}