{"gene":"VANGL1","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2025,"finding":"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.","method":"Cryo-EM structure determination combined with biochemical oligomerization assays and in vitro binding assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with biochemical validation of oligomerization and Prickle1 binding in a single rigorous study","pmids":["39753546"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Protein-protein interaction assay (co-immunoprecipitation/yeast two-hybrid)","journal":"The New England Journal of Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction assay with disease-linked mutant, single lab but replicated across three DVL paralogs","pmids":["17409324"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Reciprocal co-immunoprecipitation with a monospecific antibody validated by SPR, western blot, and proteomic analysis; confocal co-localization","journal":"PLoS One","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — antibody validated by SPR, endogenous proteins immunoprecipitated and identified by mass spectrometry, colocalization confirmed; multiple orthogonal methods in one study","pmids":["23029439"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Mass spectrometry of SCRIB immunoprecipitates, confocal microscopy co-localization, shRNA knockdown with migration and polarity assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry-identified complex confirmed by confocal co-localization and functional knockdown, single lab","pmids":["22179838"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Epitope (HA) tag insertion at six positions, immunofluorescence in intact vs. permeabilized cells, surface labeling in polarized MDCK cells","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic epitope-tag topology mapping with multiple insertion sites and orthogonal surface-labeling controls in a single rigorous study","pmids":["21291170"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Immunoprecipitation of phosphorylated proteins followed by mass spectrometry; confocal microscopy; siRNA knockdown and overexpression with wound closure assays","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation identified by MS, functional role confirmed by both KD and OE with specific migration readout, single lab","pmids":["16410243"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Confocal microscopy with anti-Vangl1 antibody; co-localization with E-cadherin; Western blot fractionation","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by confocal microscopy with functional correlation to phosphorylation state, single lab","pmids":["16410243"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Antisense morpholino knockdown rescue assay and overexpression in zebrafish embryos with body axis and somite phenotype readout","journal":"Mechanisms of Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two complementary in vivo assays (rescue and overexpression) in zebrafish, single lab","pmids":["20043994"],"is_preprint":false},{"year":2017,"finding":"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.","method":"shRNA knockdown of Scrib1 and Par-3 in MDCK II cells; immunofluorescence localization; rescue experiments with Par-3","journal":"Human Molecular Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by rescue experiment, two proteins manipulated, single lab","pmids":["28369449"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Transfection of mutant recombinant VANGL1 in MDCK cells; immunofluorescence microscopy","journal":"Spine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (immunofluorescence), single lab, no functional rescue","pmids":["27755493"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation; shRNA knockdown with proliferation, migration, and invasion assays; Rho GTPase activity assays; intracranial xenograft mouse model","journal":"Cancer Letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with functional KD phenotype across multiple readouts including in vivo, single lab","pmids":["37336284"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Conditional knockout mice for Wnt5a and Vangl1/2; lung explant assays; cytoskeletal and focal adhesion imaging","journal":"PLoS Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in conditional KO mice combined with cellular mechanistic readouts, single lab","pmids":["36026468"],"is_preprint":false},{"year":2024,"finding":"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).","method":"Tissue-specific knockout mice (epithelial and mesenchymal); phenotypic analysis of branching morphogenesis","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific conditional KO with specific morphogenetic phenotype, genetic dissection from Celsr1, single lab","pmids":["39225402"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Cre-mediated conditional double knockout (Emx2-Cre); hair cell bundle orientation analysis; immunofluorescence for core PCP protein distribution","journal":"Developmental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis/conditional KO with defined cellular polarity phenotype and protein localization analysis, single lab","pmids":["29510119"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation; VANGL1 knockdown/overexpression with Western blot for BRAF and downstream targets; DNA damage assays","journal":"Journal of Experimental & Clinical Cancer Research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP, mechanism of BRAF stabilization inferred rather than directly demonstrated, single lab","pmids":["33228740"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Luciferase reporter assay for 3'-UTR targeting; RT-qPCR and Western blot; EdU proliferation assay; ChIP-PCR for upstream transcription factor","journal":"Biochimica et Biophysica Acta. Gene Regulatory Mechanisms","confidence":"Low","confidence_rationale":"Tier 3 / Weak — luciferase validation of miRNA targeting and proliferation phenotype, but pathway placement based on β-catenin level changes without direct mechanistic reconstitution, single lab","pmids":["36288764"],"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 decreasing ubiquitination and increasing VANGL1/2 stability; PRICKLE1 does not show comparable activity.","method":"miniTurboID proximity biotinylation combined with mass spectrometry; inducible expression system; Western blot for phosphorylation and ubiquitination; co-immunoprecipitation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity proteomics plus co-IP plus phosphorylation and ubiquitination assays, multiple orthogonal methods, single lab, preprint","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; 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.","method":"Live cell imaging; subcellular fractionation; siRNA/morpholino knockdown of Vangl1 and Coronin1C; endocytosis/exocytosis assays; in vivo zebrafish vessel sprouting analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (live imaging, fractionation, KD, in vivo), single lab, preprint","pmids":["bio_10.1101_2024.06.25.600357"],"is_preprint":true},{"year":2015,"finding":"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.","method":"Stable siRNA transfection; Transwell invasion and motility assays","journal":"Genetic Testing and Molecular Biomarkers","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method KD with invasion assay, single lab, no pathway placement","pmids":["25874746"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Morpholino knockdown; mRNA overexpression; epistasis experiments; neural crest marker gene expression analysis in Xenopus","journal":"Genesis","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — epistasis established in Xenopus with multiple manipulations, but limited mechanistic detail on molecular mechanism, single lab","pmids":["26259516"],"is_preprint":false}],"current_model":"VANGL1 is a four-transmembrane-domain planar cell polarity (PCP) scaffold protein that oligomerizes as dimers of trimers (cryo-EM structure), localizes to the plasma membrane where it binds Dishevelled-1/2/3, Prickle1, Fzd7, and forms heterodimers with VANGL2; its membrane stability is regulated by PRICKLE3-mediated protection from Casein kinase 1ε phosphorylation and RNF43-mediated ubiquitination, while its membrane trafficking is controlled by Coronin1C-dependent endo/exocytosis in response to shear stress; in intestinal epithelia it is phosphorylated downstream of ITF/TFF3 to promote wound healing migration, and across multiple developmental and cellular contexts it transmits non-canonical Wnt/PCP signals to regulate convergent extension, airway branching morphogenesis, inner ear hair cell polarity, vascular cell alignment, and invasive cell migration."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2006,"claim":"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","pmids":["16410243"],"confidence":"Medium","gaps":["Kinase responsible for ITF-induced phosphorylation not identified","Phosphosites not mapped","Link to canonical PCP signaling not established"]},{"year":2007,"claim":"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","pmids":["17409324"],"confidence":"Medium","gaps":["Single interaction assay without reciprocal endogenous validation","Functional consequence of lost DVL binding not directly tested here"]},{"year":2010,"claim":"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","pmids":["20043994"],"confidence":"Medium","gaps":["Molecular basis of loss of function not resolved","Cross-species ortholog complementation may not capture human-specific behavior"]},{"year":2011,"claim":"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","pmids":["21291170","23029439","22179838"],"confidence":"High","gaps":["Stoichiometry of VANGL1/VANGL2 heterodimer not quantified","How SCRIB/NOS1AP complex couples to PCP signaling unclear"]},{"year":2018,"claim":"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","pmids":["29510119"],"confidence":"Medium","gaps":["Molecular signal transmitted across the boundary not identified","Redundancy with Vangl2 obscures Vangl1-specific contribution"]},{"year":2023,"claim":"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","pmids":["37336284"],"confidence":"Medium","gaps":["Direct vs indirect Fzd7 binding not resolved","Which Rho GTPase effectors are engaged not defined"]},{"year":2024,"claim":"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","pmids":["39225402"],"confidence":"Medium","gaps":["Mechanism of Celsr1-independent action unknown","Vangl1-specific role not separated from Vangl2"]},{"year":2025,"claim":"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)","pmids":["39753546","bio_10.1101_2025.03.24.644882"],"confidence":"Medium","gaps":["Whether oligomerization state is regulated in vivo unknown","PRICKLE3 stabilization data from a single-lab preprint awaiting peer review"]},{"year":null,"claim":"How VANGL1 oligomerization, post-translational stability control, and partner selection are integrated to specify directional polarity across distinct tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,11,17]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,4,9,17]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[6,17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,11,17]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[11,12,13]}],"complexes":[],"partners":["VANGL2","DVL1","DVL2","DVL3","PRICKLE1","SCRIB","FZD7","PRICKLE3"],"other_free_text":[]}},"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":236,"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 oncology","url":"https://pubmed.ncbi.nlm.nih.gov/11956595","citation_count":67,"is_preprint":false},{"pmid":"33228740","id":"PMC_33228740","title":"Up-regulation of VANGL1 by IGF2BPs and miR-29b-3p attenuates the detrimental effect of irradiation on lung adenocarcinoma.","date":"2020","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/33228740","citation_count":60,"is_preprint":false},{"pmid":"24981109","id":"PMC_24981109","title":"Vangl1 and Vangl2: planar cell polarity components with a developing role in cancer.","date":"2014","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24981109","citation_count":59,"is_preprint":false},{"pmid":"30146736","id":"PMC_30146736","title":"Circular RNA circ-VANGL1 as a competing endogenous RNA contributes to bladder cancer progression by regulating miR-605-3p/VANGL1 pathway.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30146736","citation_count":57,"is_preprint":false},{"pmid":"23029439","id":"PMC_23029439","title":"Molecular characterisation of endogenous Vangl2/Vangl1 heteromeric protein complexes.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23029439","citation_count":46,"is_preprint":false},{"pmid":"20043994","id":"PMC_20043994","title":"VANGL1 rare variants associated with neural tube defects affect convergent extension in zebrafish.","date":"2010","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/20043994","citation_count":41,"is_preprint":false},{"pmid":"16410243","id":"PMC_16410243","title":"Vangl1 protein acts as a downstream effector of intestinal trefoil factor (ITF)/TFF3 signaling and regulates wound healing of intestinal epithelium.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16410243","citation_count":39,"is_preprint":false},{"pmid":"30779060","id":"PMC_30779060","title":"Circ-VANGL1 promotes the progression of osteoporosis by absorbing miRNA-217 to regulate RUNX2 expression.","date":"2019","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30779060","citation_count":33,"is_preprint":false},{"pmid":"12011995","id":"PMC_12011995","title":"Isolation and characterization of a novel human gene, VANGL1, as a therapeutic target for hepatocellular carcinoma.","date":"2002","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/12011995","citation_count":31,"is_preprint":false},{"pmid":"31076544","id":"PMC_31076544","title":"Up-regulated circular RNA VANGL1 contributes to progression of non-small cell lung cancer through inhibition of miR-195 and activation of Bcl-2.","date":"2019","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/31076544","citation_count":31,"is_preprint":false},{"pmid":"25208524","id":"PMC_25208524","title":"Expanding the mutational spectrum associated to neural tube defects: literature revision and description of novel VANGL1 mutations.","date":"2014","source":"Birth defects research. Part A, Clinical and molecular teratology","url":"https://pubmed.ncbi.nlm.nih.gov/25208524","citation_count":30,"is_preprint":false},{"pmid":"15809738","id":"PMC_15809738","title":"Comparative genomics on Vangl1 and Vangl2 genes.","date":"2005","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/15809738","citation_count":28,"is_preprint":false},{"pmid":"31758655","id":"PMC_31758655","title":"Silencing circular RNA VANGL1 inhibits progression of bladder cancer by regulating miR-1184/IGFBP2 axis.","date":"2019","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31758655","citation_count":27,"is_preprint":false},{"pmid":"23326252","id":"PMC_23326252","title":"Novel VANGL1 Gene Mutations in 144 Slovakian, Romanian and German Patients with Neural Tube Defects.","date":"2012","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/23326252","citation_count":27,"is_preprint":false},{"pmid":"28369449","id":"PMC_28369449","title":"Scribble1 plays an important role in the pathogenesis of neural tube defects through its mediating effect of Par-3 and Vangl1/2 localization.","date":"2017","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28369449","citation_count":23,"is_preprint":false},{"pmid":"26914375","id":"PMC_26914375","title":"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.","date":"2016","source":"Biosensors & bioelectronics","url":"https://pubmed.ncbi.nlm.nih.gov/26914375","citation_count":20,"is_preprint":false},{"pmid":"26735870","id":"PMC_26735870","title":"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.","date":"2015","source":"Biosensors & bioelectronics","url":"https://pubmed.ncbi.nlm.nih.gov/26735870","citation_count":20,"is_preprint":false},{"pmid":"29510119","id":"PMC_29510119","title":"Domineering non-autonomy in Vangl1;Vangl2 double mutants demonstrates intercellular PCP signaling in the vertebrate inner ear.","date":"2018","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/29510119","citation_count":18,"is_preprint":false},{"pmid":"27755493","id":"PMC_27755493","title":"Mutation of the Planar Cell Polarity Gene VANGL1 in Adolescent Idiopathic Scoliosis.","date":"2017","source":"Spine","url":"https://pubmed.ncbi.nlm.nih.gov/27755493","citation_count":17,"is_preprint":false},{"pmid":"21291170","id":"PMC_21291170","title":"Transmembrane topology of mammalian planar cell polarity protein Vangl1.","date":"2011","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21291170","citation_count":14,"is_preprint":false},{"pmid":"34258391","id":"PMC_34258391","title":"Circular RNA VANGL1 knockdown suppressed viability, promoted apoptosis, and increased doxorubicin sensitivity through targeting miR-145-5p to regulate SOX4 in bladder cancer cells.","date":"2021","source":"Open medicine (Warsaw, Poland)","url":"https://pubmed.ncbi.nlm.nih.gov/34258391","citation_count":14,"is_preprint":false},{"pmid":"24407469","id":"PMC_24407469","title":"Association between VANGL1 gene polymorphisms and neural tube defects.","date":"2014","source":"Neuropediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/24407469","citation_count":13,"is_preprint":false},{"pmid":"34750955","id":"PMC_34750955","title":"Knockdown of circular RNA VANGL1 inhibits TGF-β-induced epithelial-mesenchymal transition in melanoma cells by sponging miR-150-5p.","date":"2021","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34750955","citation_count":11,"is_preprint":false},{"pmid":"39225402","id":"PMC_39225402","title":"Mesenchymal Vangl1 and Vangl2 facilitate airway elongation and widening independently of the planar cell polarity complex.","date":"2024","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/39225402","citation_count":10,"is_preprint":false},{"pmid":"36026468","id":"PMC_36026468","title":"Wnt5a-Vangl1/2 signaling regulates the position and direction of lung branching through the cytoskeleton and focal adhesions.","date":"2022","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/36026468","citation_count":10,"is_preprint":false},{"pmid":"37336284","id":"PMC_37336284","title":"A complex of Wnt/planar cell polarity signaling components Vangl1 and Fzd7 drives glioblastoma multiforme malignant properties.","date":"2023","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/37336284","citation_count":10,"is_preprint":false},{"pmid":"25445275","id":"PMC_25445275","title":"The homologous genes Vangl1 and Vangl2 are required for embryo implantation in the uterus of mice during early pregnancy.","date":"2014","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/25445275","citation_count":9,"is_preprint":false},{"pmid":"39753546","id":"PMC_39753546","title":"Cryo-EM structure and oligomerization of the human planar cell polarity core protein Vangl1.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39753546","citation_count":8,"is_preprint":false},{"pmid":"29189642","id":"PMC_29189642","title":"VANGL1 Is Not Associated With the Susceptibility of Adolescent Idiopathic Scoliosis in the Chinese Population.","date":"2018","source":"Spine","url":"https://pubmed.ncbi.nlm.nih.gov/29189642","citation_count":8,"is_preprint":false},{"pmid":"35300347","id":"PMC_35300347","title":"Circular RNA VANGL1 Facilitates Migration and Invasion of Papillary Thyroid Cancer by Modulating the miR-194/ZEB1/EMT Axis.","date":"2022","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35300347","citation_count":8,"is_preprint":false},{"pmid":"38669183","id":"PMC_38669183","title":"Core planar cell polarity genes VANGL1 and VANGL2 in predisposition to congenital vertebral malformations.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/38669183","citation_count":7,"is_preprint":false},{"pmid":"25874746","id":"PMC_25874746","title":"Downregulation of VANGL1 inhibits cellular invasion rather than cell motility in hepatocellular carcinoma cells without stimulation.","date":"2015","source":"Genetic testing and molecular biomarkers","url":"https://pubmed.ncbi.nlm.nih.gov/25874746","citation_count":7,"is_preprint":false},{"pmid":"35028616","id":"PMC_35028616","title":"Deletions in VANGL1 are a risk factor for antibody-mediated kidney disease.","date":"2021","source":"Cell reports. Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35028616","citation_count":7,"is_preprint":false},{"pmid":"19012162","id":"PMC_19012162","title":"Effects of retinoic acid on the expressions of Vangl1 and vangl2 in mouse fetuses.","date":"2008","source":"Journal of neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/19012162","citation_count":6,"is_preprint":false},{"pmid":"36288764","id":"PMC_36288764","title":"MicroRNA-27a-3p targeting Vangl1 and Vangl2 inhibits cell proliferation in mouse granulosa cells.","date":"2022","source":"Biochimica et biophysica acta. Gene regulatory mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/36288764","citation_count":5,"is_preprint":false},{"pmid":"26259516","id":"PMC_26259516","title":"Neural crest specification by Prohibitin1 depends on transcriptional regulation of prl3 and vangl1.","date":"2015","source":"Genesis (New York, N.Y. : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/26259516","citation_count":3,"is_preprint":false},{"pmid":"34014041","id":"PMC_34014041","title":"The VANGL1 P384R variant cause both neural tube defect and Klippel-Feil syndrome.","date":"2021","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34014041","citation_count":2,"is_preprint":false},{"pmid":"38929291","id":"PMC_38929291","title":"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?","date":"2024","source":"Children (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/38929291","citation_count":0,"is_preprint":false},{"pmid":"40852977","id":"PMC_40852977","title":"RETRACTION: Silencing Circular RNA VANGL1 Inhibits Progression of Bladder Cancer by Regulating miR-1184/IGFBP2 Axis.","date":"2025","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40852977","citation_count":0,"is_preprint":false},{"pmid":"23301910","id":"PMC_23301910","title":"Recurrent anencephaly: a case report and examination of the VANGL1 and FOXN1 genes.","date":"2013","source":"Fetal and pediatric pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23301910","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.24.644882","title":"Armed with PRICKLE(3)s: Stabilizing WNT/PCP complexes against RNF43-mediated ubiquitination","date":"2025-03-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.24.644882","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.06.25.600357","title":"Mechanical Strain Activates Planar Cell Polarity Signaling to Coordinate Vascular Cell Dynamics","date":"2024-06-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.25.600357","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23984,"output_tokens":4608,"usd":0.070536,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12718,"output_tokens":3104,"usd":0.070595,"stage2_stop_reason":"end_turn"},"total_usd":0.141131,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-EM structure determination combined with biochemical oligomerization assays and in vitro binding assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with biochemical validation of oligomerization and Prickle1 binding in a single rigorous study\",\n      \"pmids\": [\"39753546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Protein-protein interaction assay (co-immunoprecipitation/yeast two-hybrid)\",\n      \"journal\": \"The New England Journal of Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction assay with disease-linked mutant, single lab but replicated across three DVL paralogs\",\n      \"pmids\": [\"17409324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Reciprocal co-immunoprecipitation with a monospecific antibody validated by SPR, western blot, and proteomic analysis; confocal co-localization\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — antibody validated by SPR, endogenous proteins immunoprecipitated and identified by mass spectrometry, colocalization confirmed; multiple orthogonal methods in one study\",\n      \"pmids\": [\"23029439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry of SCRIB immunoprecipitates, confocal microscopy co-localization, shRNA knockdown with migration and polarity assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry-identified complex confirmed by confocal co-localization and functional knockdown, single lab\",\n      \"pmids\": [\"22179838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Epitope (HA) tag insertion at six positions, immunofluorescence in intact vs. permeabilized cells, surface labeling in polarized MDCK cells\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic epitope-tag topology mapping with multiple insertion sites and orthogonal surface-labeling controls in a single rigorous study\",\n      \"pmids\": [\"21291170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Immunoprecipitation of phosphorylated proteins followed by mass spectrometry; confocal microscopy; siRNA knockdown and overexpression with wound closure assays\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation identified by MS, functional role confirmed by both KD and OE with specific migration readout, single lab\",\n      \"pmids\": [\"16410243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Confocal microscopy with anti-Vangl1 antibody; co-localization with E-cadherin; Western blot fractionation\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by confocal microscopy with functional correlation to phosphorylation state, single lab\",\n      \"pmids\": [\"16410243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Antisense morpholino knockdown rescue assay and overexpression in zebrafish embryos with body axis and somite phenotype readout\",\n      \"journal\": \"Mechanisms of Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two complementary in vivo assays (rescue and overexpression) in zebrafish, single lab\",\n      \"pmids\": [\"20043994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"shRNA knockdown of Scrib1 and Par-3 in MDCK II cells; immunofluorescence localization; rescue experiments with Par-3\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by rescue experiment, two proteins manipulated, single lab\",\n      \"pmids\": [\"28369449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Transfection of mutant recombinant VANGL1 in MDCK cells; immunofluorescence microscopy\",\n      \"journal\": \"Spine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (immunofluorescence), single lab, no functional rescue\",\n      \"pmids\": [\"27755493\"],\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 cellular proliferation, migration, invasiveness, and engages Rho GTPases to drive cytoskeletal rearrangements and actin dynamics.\",\n      \"method\": \"Co-immunoprecipitation; shRNA knockdown with proliferation, migration, and invasion assays; Rho GTPase activity assays; intracranial xenograft mouse model\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with functional KD phenotype across multiple readouts including in vivo, single lab\",\n      \"pmids\": [\"37336284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout mice for Wnt5a and Vangl1/2; lung explant assays; cytoskeletal and focal adhesion imaging\",\n      \"journal\": \"PLoS Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in conditional KO mice combined with cellular mechanistic readouts, single lab\",\n      \"pmids\": [\"36026468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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).\",\n      \"method\": \"Tissue-specific knockout mice (epithelial and mesenchymal); phenotypic analysis of branching morphogenesis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific conditional KO with specific morphogenetic phenotype, genetic dissection from Celsr1, single lab\",\n      \"pmids\": [\"39225402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Cre-mediated conditional double knockout (Emx2-Cre); hair cell bundle orientation analysis; immunofluorescence for core PCP protein distribution\",\n      \"journal\": \"Developmental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis/conditional KO with defined cellular polarity phenotype and protein localization analysis, single lab\",\n      \"pmids\": [\"29510119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; VANGL1 knockdown/overexpression with Western blot for BRAF and downstream targets; DNA damage assays\",\n      \"journal\": \"Journal of Experimental & Clinical Cancer Research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP, mechanism of BRAF stabilization inferred rather than directly demonstrated, single lab\",\n      \"pmids\": [\"33228740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Luciferase reporter assay for 3'-UTR targeting; RT-qPCR and Western blot; EdU proliferation assay; ChIP-PCR for upstream transcription factor\",\n      \"journal\": \"Biochimica et Biophysica Acta. Gene Regulatory Mechanisms\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — luciferase validation of miRNA targeting and proliferation phenotype, but pathway placement based on β-catenin level changes without direct mechanistic reconstitution, single lab\",\n      \"pmids\": [\"36288764\"],\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 decreasing ubiquitination and increasing VANGL1/2 stability; PRICKLE1 does not show comparable activity.\",\n      \"method\": \"miniTurboID proximity biotinylation combined with mass spectrometry; inducible expression system; Western blot for phosphorylation and ubiquitination; co-immunoprecipitation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity proteomics plus co-IP plus phosphorylation and ubiquitination assays, multiple orthogonal methods, single lab, preprint\",\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; 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.\",\n      \"method\": \"Live cell imaging; subcellular fractionation; siRNA/morpholino knockdown of Vangl1 and Coronin1C; endocytosis/exocytosis assays; in vivo zebrafish vessel sprouting analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (live imaging, fractionation, KD, in vivo), single lab, preprint\",\n      \"pmids\": [\"bio_10.1101_2024.06.25.600357\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Stable siRNA transfection; Transwell invasion and motility assays\",\n      \"journal\": \"Genetic Testing and Molecular Biomarkers\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method KD with invasion assay, single lab, no pathway placement\",\n      \"pmids\": [\"25874746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Morpholino knockdown; mRNA overexpression; epistasis experiments; neural crest marker gene expression analysis in Xenopus\",\n      \"journal\": \"Genesis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — epistasis established in Xenopus with multiple manipulations, but limited mechanistic detail on molecular mechanism, single lab\",\n      \"pmids\": [\"26259516\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VANGL1 is a four-transmembrane-domain planar cell polarity (PCP) scaffold protein that oligomerizes as dimers of trimers (cryo-EM structure), localizes to the plasma membrane where it binds Dishevelled-1/2/3, Prickle1, Fzd7, and forms heterodimers with VANGL2; its membrane stability is regulated by PRICKLE3-mediated protection from Casein kinase 1ε phosphorylation and RNF43-mediated ubiquitination, while its membrane trafficking is controlled by Coronin1C-dependent endo/exocytosis in response to shear stress; in intestinal epithelia it is phosphorylated downstream of ITF/TFF3 to promote wound healing migration, and across multiple developmental and cellular contexts it transmits non-canonical Wnt/PCP signals to regulate convergent extension, airway branching morphogenesis, inner ear hair cell polarity, vascular cell alignment, and invasive cell migration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#4, #11]. It adopts a four-TMD topology with intracellular N- and C-terminal domains [#4] and oligomerizes as dimers of trimers, with this higher-order assembly promoting binding to the PCP effector Prickle1 [#0]. At the plasma membrane VANGL1 forms heterodimeric complexes with VANGL2 [#2] and engages the cytoplasmic transducers Dishevelled-1/2/3, an interaction abolished by the neural-tube-defect-associated V239I substitution [#1]. Its membrane residence is dynamically controlled: PRICKLE3 stabilizes VANGL1/2 at the membrane by shielding them from Casein kinase 1\\u03b5 phosphorylation and limiting RNF43-mediated ubiquitination [#16], 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 [#17]. Through these activities VANGL1, acting together with VANGL2, governs convergent extension [#7], inner ear hair cell polarity via intercellular (domineering non-autonomous) PCP signaling [#13], and lung airway branching downstream of Wnt5a, independent of the core PCP protein Celsr1 [#11, #12]. In migrating and invasive cells VANGL1 assembles with SCRIB/NOS1AP at cellular protrusions to establish leading-trailing polarity [#3] and complexes with Fzd7 to engage Rho GTPases driving actin dynamics and invasion [#10]. Loss-of-function VANGL1 variants are linked to neural tube defects, where disease alleles fail to rescue convergent extension and disrupt membrane trafficking [#7, #1].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"evidence\": \"Phospho-protein immunoprecipitation/MS, confocal microscopy, and siRNA/overexpression with wound closure assays in intestinal epithelial cells\",\n      \"pmids\": [\"16410243\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for ITF-induced phosphorylation not identified\", \"Phosphosites not mapped\", \"Link to canonical PCP signaling not established\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Connected VANGL1 to human neural tube defects and to the PCP transducers Dishevelled by showing a disease-associated mutation disrupts DVL binding.\",\n      \"evidence\": \"Protein-protein interaction assay with disease-linked V239I mutant against DVL1/2/3\",\n      \"pmids\": [\"17409324\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single interaction assay without reciprocal endogenous validation\", \"Functional consequence of lost DVL binding not directly tested here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated that human NTD-associated VANGL1 variants are genuine loss-of-function alleles in a vertebrate PCP assay, supporting causality.\",\n      \"evidence\": \"Morpholino knockdown rescue and overexpression in zebrafish with convergent extension/somite readouts\",\n      \"pmids\": [\"20043994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of loss of function not resolved\", \"Cross-species ortholog complementation may not capture human-specific behavior\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"Epitope-tag topology mapping in MDCK cells; reciprocal endogenous co-IP with SPR-validated antibody; MS of SCRIB immunoprecipitates with knockdown migration assays\",\n      \"pmids\": [\"21291170\", \"23029439\", \"22179838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of VANGL1/VANGL2 heterodimer not quantified\", \"How SCRIB/NOS1AP complex couples to PCP signaling unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed VANGL1 mediates intercellular PCP communication in vertebrate sensory epithelium, formalizing its non-autonomous signaling role.\",\n      \"evidence\": \"Vangl1/Vangl2 conditional double knockout in mouse inner ear with hair bundle orientation and PCP protein localization analysis\",\n      \"pmids\": [\"29510119\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular signal transmitted across the boundary not identified\", \"Redundancy with Vangl2 obscures Vangl1-specific contribution\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended VANGL1 function to invasive cancer by linking a Fzd7 complex at the leading edge to Rho GTPase-driven cytoskeletal dynamics.\",\n      \"evidence\": \"Co-IP, shRNA knockdown with proliferation/migration/invasion assays, Rho GTPase activity assays, and intracranial xenografts in GBM cells\",\n      \"pmids\": [\"37336284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect Fzd7 binding not resolved\", \"Which Rho GTPase effectors are engaged not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Distinguished VANGL1/2 function in lung branching from the core PCP module, showing a mesenchymal, Celsr1-independent requirement.\",\n      \"evidence\": \"Tissue-specific conditional knockout mice with branching morphogenesis phenotyping\",\n      \"pmids\": [\"39225402\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Celsr1-independent action unknown\", \"Vangl1-specific role not separated from Vangl2\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the oligomeric architecture of VANGL1 and the post-translational control of its membrane stability, defining how assembly state and PRICKLE3/CK1\\u03b5/RNF43 regulate effector engagement.\",\n      \"evidence\": \"Cryo-EM with biochemical oligomerization and Prickle1 binding assays; miniTurboID proximity proteomics with phosphorylation/ubiquitination and co-IP assays (preprint)\",\n      \"pmids\": [\"39753546\", \"bio_10.1101_2025.03.24.644882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether oligomerization state is regulated in vivo unknown\", \"PRICKLE3 stabilization data from a single-lab preprint awaiting peer review\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How VANGL1 oligomerization, post-translational stability control, and partner selection are integrated to specify directional polarity across distinct tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 11, 17]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 4, 9, 17]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [6, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 11, 17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [11, 12, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VANGL2\", \"DVL1\", \"DVL2\", \"DVL3\", \"PRICKLE1\", \"SCRIB\", \"FZD7\", \"PRICKLE3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}