{"gene":"VANGL2","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2001,"finding":"Vangl2 (Ltap) was identified as a mammalian homologue of Drosophila Strabismus/Van Gogh, a component of the frizzled/dishevelled tissue polarity pathway, and is altered in two independent Looptail (Lp) alleles that cause craniorachischisis (open neural tube defect).","method":"Positional cloning, sequence analysis of two independent Lp alleles","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — positional cloning with two independent mutant alleles, replicated across multiple labs subsequently","pmids":["11431695"],"is_preprint":false},{"year":2003,"finding":"Loss-of-function mutation in Vangl2 results in disruption of stereociliary bundle polarization in mouse cochlear hair cells, with genetic interaction between Vangl2 and Scrb1 (heterozygous double mutants phenocopy Vangl2 homozygotes), establishing both genes in mammalian PCP regulation.","method":"Mouse genetics, compound heterozygote epistasis analysis, scanning electron microscopy of cochlear hair cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with two independent mutant alleles, multiple orthogonal analyses, replicated","pmids":["12724779"],"is_preprint":false},{"year":2002,"finding":"Stbm/Vangl2 physically interacts with Dishevelled (Dsh) protein in vertebrate embryos, inhibits Wnt-mediated beta-catenin-dependent transcription, and promotes phosphorylation of c-Jun/AP-1-dependent transcription; both gain- and loss-of-function affect cell movements during zebrafish gastrulation.","method":"Co-immunoprecipitation, overexpression/morpholino loss-of-function in zebrafish, transcriptional reporter assays","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating Stbm-Dsh interaction, functional assays in zebrafish, single lab","pmids":["11780127"],"is_preprint":false},{"year":2004,"finding":"Both mouse Vangl1 and Vangl2 physically interact with all three Dishevelled (Dvl1, Dvl2, Dvl3) family members via the cytoplasmic C-terminal half of Vangl and the PDZ and DIX domains of Dvl. The two Looptail missense mutations (D255E and S464N) in Vangl2 impair binding to all three Dvl proteins.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation; loss-of-function Vangl2 Lp allele mutagenesis analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical methods (Y2H, GST pulldown, Co-IP), mutagenesis confirming disease-relevant residues, replicated by subsequent studies","pmids":["15456783"],"is_preprint":false},{"year":2005,"finding":"Vangl2 is required for polarized cell migration of myocardializing cells into outflow tract cushions, acting via the RhoA/ROCK1 signaling axis; RhoA expression is lost from the myocardial-cushion interface in Lp/Lp mutants.","method":"Mouse Lp mutant analysis, immunofluorescence for RhoA and ROCK1, actin cytoskeleton analysis in wild-type vs. Lp/Lp fetuses","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with cellular phenotype, pathway placement via RhoA/ROCK1 co-expression analysis, single lab","pmids":["15637299"],"is_preprint":false},{"year":2006,"finding":"Vangl2 becomes asymmetrically localized to specific cell-cell boundaries along the polarization axis in the mammalian cochlea; PDZ2, PDZ3, and PDZ4 domains of Scrb1/Scribble directly bind the C-terminal PDZ-binding domain of Vangl2; Frizzled3 asymmetric localization depends on Vangl2 and the two proteins physically interact.","method":"Immunofluorescence localization in cochlea, PDZ domain binding assays, Co-immunoprecipitation of Fz3 and Vangl2","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (localization, domain-binding assays, Co-IP), replicated across labs","pmids":["16687519"],"is_preprint":false},{"year":2006,"finding":"Scribble binds Vangl2 selectively through specific PDZ domains (Scrb PDZ domains 2, 3, and 4 interact with Vangl2 C-terminal PDZ-binding domain), and this interaction was demonstrated in polarized mammalian epithelial cells.","method":"Co-immunoprecipitation, domain mapping with EGFP-Scrib fusion proteins in polarized epithelial cells","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and domain mapping, single lab, consistent with independent findings in PMID 16687519","pmids":["16791850"],"is_preprint":false},{"year":2006,"finding":"Vangl2 protein subcellular localization is disrupted and overall expression is decreased in the neural tubes and cochleas of Lp/Lp mutant embryos, demonstrating that Lp missense mutations affect Vangl2 membrane targeting.","method":"Immunofluorescence with specific anti-Vangl2 antiserum on wild-type and Lp/Lp embryos","journal":"Gene expression patterns","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence (membrane mislocalization in mutants), single lab","pmids":["16962386"],"is_preprint":false},{"year":2008,"finding":"The extracellular domain (CRD) of Frizzled acts as a ligand for Van Gogh/Strabismus (Vang/Stbm) transmembrane protein, demonstrating a direct biochemical and physical interaction between FzECD and Vang/Stbm that mediates nonautonomous PCP signaling.","method":"In vivo Drosophila genetics, biochemical interaction assays between FzECD and Vang/Stbm","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and biochemical interaction demonstrated in Drosophila ortholog studies, single lab","pmids":["18804440"],"is_preprint":false},{"year":2009,"finding":"Sec24b, a cargo-sorting component of the COPII ER-to-Golgi transport vesicle complex, selectively sorts Vangl2 into COPII vesicles for ER-to-Golgi transport. Looptail Vangl2 point mutants (D255E and S464N) fail to sort into COPII vesicles and are trapped in the ER. Sec24b genetically interacts with Vangl2 loss-of-function to increase spina bifida prevalence.","method":"Forward genetic screen in mice, COPII vesicle sorting assays, ER retention assays with mutant Vangl2, genetic interaction analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro vesicle sorting reconstitution assay, mutagenesis of disease-relevant residues, confirmed by genetic epistasis, replicated in independent study (PMID 20215345)","pmids":["19966784"],"is_preprint":false},{"year":2009,"finding":"Dact1 forms a complex with Vangl2 at the primitive streak; in Dact1 mutants, Vangl2 protein levels are increased at the primitive streak; heterozygous Vangl2 mutation rescues recessive Dact1 phenotypes and loss of Dact1 rescues semidominant Vangl2 phenotypes, placing Dact1 as a regulator of Vangl2 upstream of cell adhesion and PCP.","method":"Co-immunoprecipitation, immunofluorescence on mutant embryos, reciprocal genetic rescue experiments in compound mutant mice","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, reciprocal genetic rescue, multiple orthogonal methods, independent confirmation","pmids":["19701191"],"is_preprint":false},{"year":2009,"finding":"Scribble interacts physically with Stbm/Vang through PDZ domain 3 and cooperates with Stbm/Vang in PCP establishment in Drosophila eye and wing; Scribble is part of the Stbm/Vang PCP complex and acts as an effector of Stbm/Vang.","method":"Drosophila genetic interaction analysis, physical interaction assays (PDZ domain binding), PCP phenotype analysis","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — physical interaction and genetic epistasis in Drosophila ortholog, single lab","pmids":["19563796"],"is_preprint":false},{"year":2010,"finding":"Sec24b deficiency specifically impairs transport of PCP core protein Vangl2 in mouse embryos and primary cultured cells, establishing a direct role for Sec24b in Vangl2 trafficking.","method":"Mouse genetic mutants, cell-based trafficking assays with primary cells and embryos","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with specific cargo-trafficking phenotype, independent confirmation of PMID 19966784","pmids":["20215345"],"is_preprint":false},{"year":2010,"finding":"Vangl2 controls the posterior tilting and asymmetric localization of motile primary cilia to the posterior apical membrane of neuroepithelial cells in zebrafish; Vangl2 is not required for ciliogenesis itself.","method":"Zebrafish vangl2 null mutant analysis, live imaging with Arl13b-GFP ciliary axoneme marker","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — live imaging with specific cilia marker in complete null mutant, clear phenotypic separation between ciliogenesis and cilia orientation, multiple orthogonal analyses","pmids":["20305649"],"is_preprint":false},{"year":2011,"finding":"Vangl2 forms a Wnt-induced receptor complex with Ror2 to sense Wnt dosages; Wnts dose-dependently induce phosphorylation of serine/threonine residues in Vangl2 through Ror2; Wnt5a signaling gradient controls PCP in chondrocytes and limb elongation via Vangl2 phosphorylation. Vangl2 activity depends on its phosphorylation level.","method":"Co-immunoprecipitation of Vangl2-Ror2 complex, phosphorylation assays with Wnt dose-response, limb bud in vivo analysis, genetic interaction","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of receptor complex, dose-dependent phosphorylation assays, in vivo functional validation, replicated by PMID 29056748","pmids":["21316585"],"is_preprint":false},{"year":2011,"finding":"Vangl2 antagonizes Dvl1-mediated hyperphosphorylation of Frizzled3 and promotes Frizzled3 internalization in commissural axon growth cones; Vangl2 is enriched on filopodial tips and emerging filopodial membrane patches in growth cones.","method":"Cell-based phosphorylation assays, internalization assays, immunofluorescence localization in growth cones, loss-of-function analysis","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional biochemical assays and localization in neurons, single lab","pmids":["21316586"],"is_preprint":false},{"year":2011,"finding":"Rack1 is an interacting protein of Vangl2; knockdown of Rack1 affects membrane localization of Vangl2 in zebrafish, and the Vangl2-interacting domain of Rack1 has a dominant-negative effect on Vangl2 localization and gastrulation.","method":"Protein interaction screen, co-immunoprecipitation, zebrafish knockdown, localization assays","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional localization assay, zebrafish loss-of-function, single lab","pmids":["21262816"],"is_preprint":false},{"year":2011,"finding":"Maternal Vangl2 in Xenopus oocytes interacts with the post-Golgi v-SNARE protein VAMP1 and acetylated microtubules; Vangl2 is required for VAMP1 stability and maintenance of stable microtubule architecture; Vangl2 also interacts with aPKC, and both are required for membrane asymmetry during oocyte maturation and asymmetric distribution of maternal transcripts (VegT, Wnt11).","method":"Co-immunoprecipitation, immunofluorescence, morpholino knockdown in Xenopus oocytes, transcript localization assays","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional knockdown, multiple binding partners identified, single lab","pmids":["21813572"],"is_preprint":false},{"year":2012,"finding":"VANGL2 regulates the endocytosis and cell-surface availability of MMP14 (MT1-MMP) in a focal adhesion kinase-dependent manner; vangl2 mutant zebrafish embryos show increased Mmp14 activity and decreased ECM; in vivo knockdown of Mmp14 partially rescues the Vangl2 loss-of-function convergence and extension phenotype, placing MMP14 as a downstream effector of VANGL2.","method":"Zebrafish trilobite/vangl2 mutant analysis, endocytosis assays, MMP14 activity assays, genetic rescue with mmp14 morpholino","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis rescue, activity assays, endocytosis assays, multiple orthogonal methods, functional consequence confirmed in vivo","pmids":["22357946"],"is_preprint":false},{"year":2012,"finding":"The Wnt coreceptor Ryk interacts with Vangl2 biochemically and genetically; interaction is potentiated by Wnt5a; Ryk regulates PCP by promoting Vangl2 protein stability (degradation of Vangl2 is increased when Ryk is absent); complete loss of both Ryk and Vangl2 produces phenotypes resembling Wnt5a null mutants.","method":"Co-immunoprecipitation, genetic interaction analysis in compound mutant mice, Vangl2 stability/degradation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, stability assay, genetic epistasis, single lab","pmids":["23144463"],"is_preprint":false},{"year":2012,"finding":"Vangl2 S464N (Looptail mutation) disrupts delivery of Vangl1 and Vangl2 to the cell surface through oligomer formation between Vangl2(S464N) and wild-type Vangl1 or Vangl2, causing intracellular retention. Vangl1 and Vangl2 form endogenous heterodimers/oligomers.","method":"Co-immunoprecipitation of Vangl1/Vangl2, cell surface localization assays, compound mutant mouse analysis","journal":"PLoS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct Co-IP, cell surface localization assay, in vivo validation in mutant mice, consistent with independent finding in PMID 23029439","pmids":["22363783"],"is_preprint":false},{"year":2012,"finding":"Endogenous Vangl2/Vangl1 heteromeric protein complexes exist; confirmed by specific monoclonal anti-Vangl2 antibody and proteomic analysis of Vangl2 immunoprecipitates from cell lysates.","method":"Monoclonal antibody generation validated by SPR, western blot, immunoprecipitation; mass spectrometry proteomic analysis of immunoprecipitates","journal":"PLoS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — SPR-validated antibody, proteomic identification of endogenous complex, multiple orthogonal methods","pmids":["23029439"],"is_preprint":false},{"year":2013,"finding":"Vangl2 transport from the trans-Golgi network (TGN) requires the GTP-binding protein Arfrp1 and clathrin adaptor complex AP-1; a YYXXF sorting signal in Vangl2's C-terminal cytosolic domain is required for TGN traffic and interaction with the AP-1 μ subunit. Vangl2 and Frizzled6 are sorted by different mechanisms from the TGN.","method":"siRNA knockdown of Arfrp1/AP-1, mutagenesis of YYXXF sorting signal, TGN transport assays, binding assays with AP-1 μ subunit","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro mutagenesis identifying sorting signal, AP-1 binding assays, siRNA functional validation, replicated by PMID 29666182","pmids":["23326640"],"is_preprint":false},{"year":2013,"finding":"Cofilin 1 (actin-severing protein) and Vangl2 cooperate to control PCP in the early mouse embryo; in Vangl2/Cfl1 double mutants, PCP protein complexes fail to traffic to the apical cell membrane, and F-actin remodeling is essential for initiation but not maintenance of PCP. Vangl2 and cofilin cooperate to target Rab11+ vesicles containing PCP proteins to the apical membrane.","method":"Compound mutant mouse genetics, vesicle trafficking assays, Rab11 immunofluorescence, pharmacological F-actin manipulation","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in double mutants, mechanistic vesicle trafficking assays, pharmacological confirmation, multiple orthogonal methods","pmids":["23406901"],"is_preprint":false},{"year":2013,"finding":"Syndecan 4 (Sdc4) and Vangl2 proteins colocalize; Vangl2 (particularly the Lp mutant form) diminishes Sdc4 protein levels, and Vangl2 knockdown enhances Sdc4 protein levels; genetic interaction between Sdc4 null and Vangl2(Lp) allele causes neural tube and cochlear defects, indicating HSPG levels are regulated downstream of Vangl2.","method":"Co-localization in HEK293 cells, protein level analysis after Vangl2 overexpression/knockdown, compound mutant mouse and Xenopus genetics","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic interaction and protein-level regulation, cell-based assays, two organism models","pmids":["23760952"],"is_preprint":false},{"year":2013,"finding":"Gipc1 (GAIP C-terminus interacting protein 1) is a novel interactor of Vangl2; a myosin VI-Gipc1 complex regulates Vangl2 trafficking in heterologous cells. In Myosin VI mutant mice, Vangl2 presence at the membrane is increased.","method":"Protein interaction screen, co-immunoprecipitation, heterologous cell trafficking assays, mouse mutant membrane localization analysis","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, trafficking assay, in vivo mouse validation, single lab","pmids":["22991442"],"is_preprint":false},{"year":2013,"finding":"Sestd1 is a novel binding partner of Vangl2 and Dact1; loss of Sestd1 phenocopies loss of Dact1 and exhibits reciprocal genetic rescue with Vangl2 semidominant mutation; Sestd1-Dact1 interaction can induce Rho GTPase activation in cell-based assays.","method":"Co-immunoprecipitation, compound mutant mouse genetics, cell-based Rho GTPase activity assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, genetic rescue, functional Rho assay, single lab","pmids":["23696638"],"is_preprint":false},{"year":2013,"finding":"Vangl2 is a postsynaptic factor that directly binds N-cadherin; enhances N-cadherin internalization in a Rab5-dependent manner; this interaction is suppressed by beta-catenin which competes for the same intracellular region of N-cadherin. Vangl2 knockdown impairs dendritic spine formation and synaptic marker clustering. Prickle2 inhibits N-cadherin-Vangl2 interaction and is required for normal spine formation.","method":"Co-immunoprecipitation from synapse-rich brain extracts, internalization assays, Rab5-dependence assay, neuronal knockdown, spine density analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP from endogenous brain tissue, multiple interaction partners, functional internalization assay with mechanistic competition experiment, loss-of-function phenotype","pmids":["24582966"],"is_preprint":false},{"year":2013,"finding":"Vangl2 is tightly associated with the postsynaptic density (PSD) fraction in adult rat neurons; Vangl2 forms a complex with PSD-95 through direct binding requiring its C-terminal PDZ-binding motif (TSV); Vangl2 PDZ-binding motif is required for localization to dendritic spines.","method":"Subcellular fractionation, co-immunoprecipitation, PDZ-binding motif deletion mutagenesis, spine localization assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation, Co-IP, mutagenesis of PDZ motif, single lab","pmids":["23567299"],"is_preprint":false},{"year":2014,"finding":"Vangl2 is required specifically within second heart field (SHF) cells to direct outflow tract lengthening; Vangl2 marks the proximal extent of a transition zone where SHF cells acquire epithelial phenotype; absence of Vangl2 causes abnormal polarization and disorganization of SHF-derived cells, leading to premature cardiomyocyte differentiation.","method":"Conditional knockout using floxed Vangl2 allele with tissue-specific Cre drivers, immunofluorescence, lineage tracing","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific conditional knockout with multiple markers and functional outcome, mechanistic connection to epithelial transition zone","pmids":["25521757"],"is_preprint":false},{"year":2014,"finding":"Vangl2 directly binds E-cadherin (co-immunoprecipitation from embryonic kidney extracts and transfected fibroblasts); Vangl2 overexpression enhances E-cadherin internalization; loss of Vangl2 (Lp mutant) increases surface E-cadherin; Vangl2 itself is internalized via Rab5- and Dynamin-dependent endocytosis.","method":"Co-immunoprecipitation, cell surface biotinylation assay, internalization assay, pharmacological inhibition of endocytosis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP from endogenous tissue, functional internalization assay, single lab","pmids":["25373475"],"is_preprint":false},{"year":2015,"finding":"Vangl2 protein is enriched at anterior cell edges in the Xenopus neural plate (anteroposterior planar cell polarity); this localization is directed by Prickle (a Vangl2-interacting protein); Vangl2 AP-PCP is established by Wnt-dependent phosphorylation; Myosin II activity provides feedback regulation of Vangl2 polarity.","method":"Immunofluorescence in Xenopus neural plate, morpholino knockdown of Prickle, pharmacological inhibition of Wnt signaling and Myosin II","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional perturbation, multiple pharmacological and genetic manipulations, single lab","pmids":["25910938"],"is_preprint":false},{"year":2015,"finding":"Vangl2 PDZ interaction links PSD-95 and Prickle2 in postsynaptic complexes; the PDZ interaction is dispensable for normal Vangl2 cluster formation but partially required for PSD-95-overlapping synaptic localization; Vangl2 PDZ interaction enhances protein interactions between PSD-95 and Prickle2.","method":"Co-immunoprecipitation, deletion mutagenesis of PDZ-binding motif, immunofluorescence in hippocampal neurons","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutagenesis, neuronal localization analysis, single lab","pmids":["26257100"],"is_preprint":false},{"year":2016,"finding":"p62/SQSTM1 is a novel VANGL2-binding partner; VANGL2-p62/SQSTM1-JNK forms an evolutionarily conserved signaling cascade that promotes cell proliferation in breast cancer; disruption of the VANGL2-p62/SQSTM1 interaction or JNK inhibition inactivates this cascade.","method":"Co-immunoprecipitation identifying p62/SQSTM1 as VANGL2 partner, JNK signaling assays, patient-derived xenograft cell inhibition experiments","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying novel binding partner, functional pathway analysis, in vivo xenograft validation, single lab","pmids":["26754771"],"is_preprint":false},{"year":2016,"finding":"Vangl2 is localized at ectoplasmic specialization (ES) in the testis and interacts structurally with actin, N-cadherin, and Scribble; Vangl2 knockdown in Sertoli cells tightens the blood-testis barrier while overexpression perturbs it; these effects are mediated through alteration of actin microfilament organization via EPS8, Arp3, and Scribble.","method":"Co-immunoprecipitation (Vangl2 with actin/N-cadherin/Scribble), RNAi knockdown, overexpression, barrier function assays, in vivo RNAi in testis","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with multiple partners, functional KD/OE with defined cellular phenotype, in vivo RNAi validation, single lab","pmids":["26990065"],"is_preprint":false},{"year":2017,"finding":"Wnt5a-induced Vangl2 phosphorylation requires CK1ε and CK1δ (redundantly) and Dvl family members (which enhance CK1-Vangl2 interaction); phospho-mutant Vangl2 exhibits dominant negative effects while reduced-phosphorylation Vangl2 is hypomorphic; Vangl2 phosphorylation is essential for its uniform polarization pattern in vivo.","method":"In vivo phosphorylation assays with CK1 inhibitors and Dvl knockouts, phospho-mutant knock-in mice, tissue polarity analysis","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo phospho-mutant knock-in, kinase identification with inhibitors and genetic knockouts, multiple tissues analyzed, replicates/extends PMID 21316585","pmids":["29056748"],"is_preprint":false},{"year":2017,"finding":"Vangl2 exerts dual (bimodal) regulation on Dvl during convergent extension: Vangl2 promotes efficient Dvl plasma membrane recruitment (positive regulation, required for PCP activation), while simultaneously inhibiting Dvl from interacting with downstream effector Daam1 (negative regulation).","method":"Co-immunoprecipitation of Vangl2-Dvl and Dvl-Daam1 complexes, morpholino/overexpression in Xenopus and mouse mutant analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP in two experimental systems (mouse and Xenopus), functional rescue assays, single lab","pmids":["28334810"],"is_preprint":false},{"year":2017,"finding":"Vangl2 regulates spermatid planar cell polarity through the microtubule-based cytoskeleton via downstream signaling proteins aPKCζ and MARK2; Vangl2 knockdown in rat testis disrupts microtubule organization and perturbs spermatid PCP.","method":"RNAi knockdown in vivo in rat testis, confocal microscopy with 3D reconstruction, immunofluorescence for MT markers and aPKCζ/MARK2","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo RNAi with specific phenotype and pathway placement, single lab","pmids":["29497043"],"is_preprint":false},{"year":2018,"finding":"Vangl2 and Frizzled6 exit the TGN in separate vesicle compartments sorted by different clathrin adaptors: AP-1 (with Arfrp1) sorts Vangl2 while epsinR sorts Frizzled6 through a conserved polybasic motif in the Fzd6 cytosolic domain. EpsinR-AP-1 binding is disrupted by Frizzled6 binding to epsinR.","method":"In vitro TGN vesicle reconstitution, siRNA knockdown, immunoblotting of released vesicles, protein interaction analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of TGN vesicle release, siRNA knockdowns, protein interaction assays, mechanistic separation of Vangl2 and Fzd6 sorting","pmids":["29666182"],"is_preprint":false},{"year":2018,"finding":"Vangl2 depletion inhibited RMS tumor propagating cell (TPC) self-renewal, proliferation, and induced differentiation; constitutively active RhoA rescues TPC maintenance in VANGL2-depleted cells, and dominant-negative RhoA phenocopies VANGL2 depletion, placing RhoA downstream of VANGL2 in TPC self-renewal.","method":"shRNA knockdown in human RMS cells and xenografts, zebrafish ERMS model, constitutively active/dominant-negative RhoA constructs","journal":"Cell stem cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined phenotype, epistasis via dominant-negative/constitutively-active constructs, multiple model systems","pmids":["29499154"],"is_preprint":false},{"year":2018,"finding":"VANGL2 interacts with integrin αvβ3; VANGL2 knockdown increases integrin αvβ3 cell surface expression, enhances MMP14/MMP2 proteolytic activity, and disrupts adhesion to fibronectin, laminin, and vitronectin; MMP14/MMP2 inhibition suppresses the cell adhesion defect in VANGL2 knockdown cells.","method":"Co-immunoprecipitation of VANGL2-integrin αvβ3, siRNA knockdown, integrin surface expression assays, MMP activity assays, cell adhesion assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying novel binding partner, functional loss-of-function with rescue, single lab","pmids":["29097183"],"is_preprint":false},{"year":2019,"finding":"Prickle2 protein levels are negatively regulated through physical interaction with Vangl2; Vangl2 interaction promotes Cullin-1-dependent polyubiquitination (K48-linked) of Prickle2, targeting it for proteasomal degradation.","method":"Co-immunoprecipitation, proteasome inhibitor treatment, ubiquitin K48 mutant co-expression, polyubiquitination assays in HEK293T cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay with mechanistic detail (K48 linkage, Cullin-1), proteasome inhibitor rescue, single lab","pmids":["30814664"],"is_preprint":false},{"year":2020,"finding":"Vangl2 controls growth cone velocity by regulating internal retrograde actin flow in an N-cadherin-dependent fashion; loss of Vangl2 decreases fast-diffusing N-cadherin membrane molecules, increases confined N-cadherin trajectories, and strengthens mechanical coupling of N-cadherin with the actin cytoskeleton ('molecular clutch'). Vangl2 distribution within growth cones is selectively affected by N-cadherin-coated substrate.","method":"Single molecule tracking of N-cadherin, optical manipulation (N-cadherin-coated microspheres), live imaging of growth cones, Vangl2 KO neurons","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — single molecule tracking combined with optical force measurements and genetic knockout, multiple orthogonal biophysical methods","pmids":["31909712"],"is_preprint":false},{"year":2020,"finding":"A Wnt5a-Ror2-Vangl2 cascade controls cytoskeletal organization, PDGF secretion from alveolar epithelial cells, cell shape changes of type I cells, and myofibroblast migration during alveologenesis; these cellular properties are conferred by changes in the actin cytoskeleton.","method":"Conditional knockout of Vangl2/Ror2/Wnt5a in specific lung cell types, cytoskeletal analysis, PDGF secretion assays, migration assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific conditional knockouts, multiple functional readouts, pathway placement, single lab","pmids":["32394892"],"is_preprint":false},{"year":2021,"finding":"Vangl2 directly binds LAMP-2A (lysosome-associated membrane protein 2A) and targets it for degradation, thereby limiting chaperone-mediated autophagy (CMA) lysosome activity in mesenchymal stem cells; MSC-specific Vangl2 ablation increases LAMP-2A and CMA-lysosome numbers, promoting osteogenesis while reducing adipogenesis.","method":"Co-immunoprecipitation of Vangl2-LAMP-2A, conditional knockout in MSCs, lysosome number/activity assays, differentiation assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP demonstrating direct binding to LAMP-2A, conditional knockout with defined molecular and cellular phenotype, multiple orthogonal assays","pmids":["34214490"],"is_preprint":false},{"year":2021,"finding":"Vangl2 promotes formation of long, branching cytonemes in zebrafish epiblast cells, mouse intestinal telocytes, and human gastric cancer cells; Vangl2 activation increases cytoneme length and branching, enhancing paracrine Wnt/β-catenin signaling to surrounding cells; Vangl2 inhibition causes fewer and shorter cytonemes.","method":"Live imaging of cytonemes in multiple cell types/organisms, Vangl2 gain/loss-of-function, mathematical modeling validated by in vivo neural plate patterning","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging with gain/loss-of-function in multiple systems, mathematical model predictions confirmed in vivo, single lab","pmids":["33824332"],"is_preprint":false},{"year":2021,"finding":"Vangl2-deleted neuroepithelial cells non-autonomously prevent apical constriction by an average of five neighboring Vangl2-replete cells; this involves diminished myosin-II localization on neighbor cell borders and shortening of basally-extending microtubule tails; Vangl2-deleted cells themselves preferentially recruit myosin-II to their apical cortex rather than apical cap.","method":"Mosaic conditional deletion of Vangl2 in mouse neuroepithelium, quantitative imaging of myosin-II localization, laser ablation and apical constriction analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — mosaic deletion with precise quantification of non-autonomous effects, multiple imaging modalities, mechanistic identification of myosin-II and microtubule involvement","pmids":["33608529"],"is_preprint":false},{"year":2023,"finding":"VANGL2 acts as an IFN-inducible negative feedback regulator of IFN-I signaling during viral infection: VANGL2 interacts with TBK1 and promotes its selective autophagic degradation via K48-linked polyubiquitination of TBK1 at Lys372 by E3 ligase TRIP, with recognition by cargo receptor OPTN; myeloid-specific deletion of VANGL2 enhances IFN-I production and improves survival against VSV.","method":"Co-immunoprecipitation of VANGL2-TBK1, ubiquitination mapping (K48, Lys372), E3 ligase identification (TRIP), cargo receptor identification (OPTN), myeloid-specific conditional knockout in mice, viral infection model","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, site-specific ubiquitination mapping, E3 ligase and cargo receptor identification, in vivo conditional knockout validation, multiple orthogonal methods","pmids":["37352355"],"is_preprint":false},{"year":2023,"finding":"HB-EGF binds ERBB2 and ERBB3 to recruit VANGL2 for tyrosine phosphorylation; uterine VANGL2 tyrosine phosphorylation is suppressed in Erbb2/Erbb3 double conditional knockout mice; uterine deletion of Vangl2 disrupts implantation crypt formation, linking HB-EGF-ERBB2/3-VANGL2 signaling to uterine epithelial polarity during implantation.","method":"Co-immunoprecipitation (VANGL2 with ERBB2/ERBB3), tyrosine phosphorylation assays, conditional knockout mouse models, implantation analysis","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying receptor complex, phosphorylation assays, conditional knockout validation, single lab","pmids":["37155852"],"is_preprint":false}],"current_model":"VANGL2 is a four-pass transmembrane core planar cell polarity (PCP) protein that is sorted from the ER via COPII/Sec24b and from the trans-Golgi network via an Arfrp1/AP-1/YYXXF-signal pathway to specific cell membranes, where it forms asymmetrically distributed complexes with Frizzled receptors, Scribble (via PDZ domains), Dishevelled (via its cytoplasmic C-terminal domain), Ror2, and Prickle; Wnt5a signals through Ror2 to induce CK1δ/ε-mediated serine/threonine phosphorylation of VANGL2 (potentiated by Dvl), which is required for its uniform polarization and PCP activity; VANGL2 regulates diverse downstream processes including actin cytoskeleton organization via RhoA/ROCK, endocytosis of membrane proteins such as MMP14, N-cadherin, and E-cadherin, microtubule-based cytoskeletal dynamics, Prickle2 ubiquitin-proteasomal degradation, LAMP-2A-dependent chaperone-mediated autophagy, and TBK1 autophagic degradation in innate immune signaling."},"narrative":{"mechanistic_narrative":"VANGL2 is a four-pass transmembrane core planar cell polarity (PCP) protein that establishes and propagates tissue-level polarity, and whose loss causes craniorachischisis through the Looptail (Lp) mutations D255E and S464N [PMID:11431695, PMID:12724779]. Reaching the cell surface is a tightly chaperoned process: VANGL2 is selectively sorted into COPII vesicles by Sec24b for ER exit—a step the Lp point mutants fail, trapping them in the ER [PMID:19966784, PMID:20215345]—and then exits the trans-Golgi network through a YYXXF signal in its cytosolic C-terminus that engages the Arfrp1/AP-1 clathrin-adaptor machinery, distinct from the epsinR pathway used by Frizzled6 [PMID:23326640, PMID:29666182]. At the membrane it assembles asymmetric PCP complexes, binding Frizzled directly, recruiting Scribble through specific PDZ domains and Dishevelled through its cytoplasmic C-terminal half; the Lp mutations disrupt Dvl binding [PMID:15456783, PMID:16687519, PMID:18804440]. VANGL2 forms endogenous Vangl1/Vangl2 heteromers, and the dominant S464N mutant poisons surface delivery of wild-type partners through oligomerization [PMID:22363783, PMID:23029439]. Wnt5a signaling through a VANGL2–Ror2 receptor complex drives CK1δ/ε-mediated serine/threonine phosphorylation of VANGL2, potentiated by Dvl, which is required for its uniform polarization and PCP output [PMID:21316585, PMID:29056748]. Downstream, VANGL2 organizes the actin cytoskeleton via RhoA/ROCK [PMID:15637299, PMID:29499154], governs endocytosis of membrane proteins including MMP14, E-cadherin and N-cadherin [PMID:22357946, PMID:25373475, PMID:24582966], and shapes cytoskeletal and morphogenetic behaviors in cardiac, neural, and ciliary contexts [PMID:20305649, PMID:25521757, PMID:33608529]. Beyond development, VANGL2 directly binds LAMP-2A to restrain chaperone-mediated autophagy [PMID:34214490] and interacts with TBK1 to promote its autophagic degradation as a negative-feedback brake on type I interferon signaling [PMID:37352355].","teleology":[{"year":2001,"claim":"Established that a mammalian Van Gogh/Strabismus homolog exists and that its mutation causes a severe neural tube defect, anchoring VANGL2 in the conserved tissue polarity pathway.","evidence":"Positional cloning and sequencing of two independent Looptail alleles in mouse","pmids":["11431695"],"confidence":"High","gaps":["Molecular function of the protein not yet defined","Direct partners unidentified"]},{"year":2002,"claim":"Linked VANGL2 biochemically to Dishevelled and functionally to non-canonical Wnt signaling and gastrulation cell movements, separating it from canonical β-catenin transcription.","evidence":"Co-IP and morpholino/overexpression with transcriptional reporters in zebrafish","pmids":["11780127"],"confidence":"Medium","gaps":["Interaction domains not mapped","Single-lab functional assays"]},{"year":2003,"claim":"Demonstrated VANGL2 governs mammalian PCP at single-cell resolution and genetically partners Scribble, establishing the core machinery.","evidence":"Mouse genetics, compound-heterozygote epistasis, SEM of cochlear hair cells","pmids":["12724779"],"confidence":"High","gaps":["Did not define the molecular Scribble–Vangl2 contact"]},{"year":2004,"claim":"Mapped the VANGL–Dishevelled interaction to specific domains and showed Looptail residues directly impair Dvl binding, connecting genotype to a molecular defect.","evidence":"Y2H, GST pulldown, Co-IP, Lp allele mutagenesis","pmids":["15456783"],"confidence":"High","gaps":["Functional consequence of lost Dvl binding in vivo not resolved here"]},{"year":2006,"claim":"Defined VANGL2 asymmetric membrane localization and its direct PDZ-mediated binding to Scribble and physical interaction with Frizzled3, building the asymmetric complex picture.","evidence":"Cochlear immunofluorescence, PDZ-domain binding assays, Co-IP","pmids":["16687519","16791850","16962386"],"confidence":"High","gaps":["How asymmetry is initiated mechanistically unresolved","Lp effect on trafficking only correlative at this stage"]},{"year":2008,"claim":"Showed the Frizzled extracellular CRD acts as a ligand for Vang/Stbm, providing a molecular basis for non-autonomous PCP signaling.","evidence":"Drosophila genetics and biochemical FzECD–Vang interaction assays","pmids":["18804440"],"confidence":"Medium","gaps":["Demonstrated in Drosophila ortholog only","Affinity/stoichiometry not quantified"]},{"year":2009,"claim":"Identified the ER-export step as Sec24b/COPII-dependent and explained why Looptail mutants fail to traffic, unifying disease alleles with a trafficking checkpoint; concurrently placed Dact1 as an upstream regulator of VANGL2 levels.","evidence":"Forward genetic screen, COPII sorting and ER-retention assays, reciprocal genetic rescue","pmids":["19966784","19701191"],"confidence":"High","gaps":["Cargo recognition motif for Sec24b not defined","How Dact1 controls Vangl2 abundance unclear"]},{"year":2010,"claim":"Independently confirmed Sec24b specificity for VANGL2 cargo and revealed that VANGL2 orients posterior tilting of motile cilia without controlling ciliogenesis.","evidence":"Mouse mutants/primary cell trafficking; zebrafish null live imaging with Arl13b-GFP","pmids":["20215345","20305649"],"confidence":"High","gaps":["Mechanism coupling Vangl2 polarity to cilium positioning not detailed"]},{"year":2011,"claim":"Established Wnt5a–Ror2-driven, dose-dependent phosphorylation of VANGL2 as the input that tunes PCP activity, and identified trafficking regulators (Rack1) and microtubule/SNARE associations.","evidence":"Vangl2–Ror2 Co-IP, Wnt dose-response phosphorylation, limb-bud genetics; zebrafish Rack1 knockdown; Xenopus oocyte Co-IP","pmids":["21316585","21316586","21262816","21813572"],"confidence":"High","gaps":["Specific phosphosites and kinase identity not yet pinned down","Some interactions single-lab"]},{"year":2012,"claim":"Showed VANGL2 controls cell-surface availability of effectors by regulating endocytosis (MMP14) and forms endogenous Vangl1/Vangl2 heteromers whose surface delivery is poisoned by the dominant S464N mutant.","evidence":"Zebrafish vangl2 mutant epistasis and endocytosis assays; Co-IP, surface-localization assays, proteomics; Ryk stability assays","pmids":["22357946","22363783","23029439","23144463"],"confidence":"High","gaps":["Mechanism by which Vangl2 directs cargo into endocytic routes not fully defined","Ryk stabilization mechanism single-lab"]},{"year":2013,"claim":"Defined the TGN export route (Arfrp1/AP-1 via a YYXXF signal) and elaborated the cytoskeletal/vesicular delivery machinery (cofilin, Rab11), plus regulators Gipc1/myosin-VI, Sestd1, and downstream HSPG (Sdc4) control.","evidence":"siRNA, YYXXF mutagenesis and AP-1 binding; compound-mutant genetics with Rab11 imaging and F-actin pharmacology; Co-IP and Rho assays","pmids":["23326640","23406901","22991442","23696638","23760952"],"confidence":"High","gaps":["Coordination between ER, TGN, and apical delivery steps not integrated","Several effector links single-lab"]},{"year":2013,"claim":"Revealed a neuronal/postsynaptic role: VANGL2 binds N-cadherin and PSD-95 and drives Rab5-dependent N-cadherin internalization, with Prickle2 and β-catenin acting as competing modulators of spine formation.","evidence":"Co-IP from brain extracts, internalization assays, neuronal knockdown, spine-density analysis","pmids":["24582966","23567299"],"confidence":"High","gaps":["How synaptic VANGL2 connects to canonical PCP signaling unresolved"]},{"year":2014,"claim":"Demonstrated tissue-autonomous developmental requirements (second heart field outflow tract elongation) and direct E-cadherin binding/internalization, extending VANGL2's cadherin-trafficking role to epithelial morphogenesis.","evidence":"Conditional knockout with lineage tracing; Co-IP, surface biotinylation, endocytosis inhibition","pmids":["25521757","25373475"],"confidence":"High","gaps":["Cadherin-internalization mechanism single-lab","Link between cadherin trafficking and PCP output not formalized"]},{"year":2015,"claim":"Showed Prickle directs anterior VANGL2 enrichment and that Wnt-dependent phosphorylation plus Myosin-II feedback establish anteroposterior planar polarity, and resolved PDZ-mediated assembly of PSD-95/Prickle2 synaptic complexes.","evidence":"Xenopus neural-plate immunofluorescence with Prickle knockdown and Wnt/Myosin-II inhibition; Co-IP with PDZ-motif mutagenesis","pmids":["25910938","26257100"],"confidence":"Medium","gaps":["Feedback circuitry not mechanistically dissected","Single-lab assays"]},{"year":2016,"claim":"Extended VANGL2 to disease/effector contexts: a VANGL2–p62/SQSTM1–JNK cascade promoting breast cancer proliferation, and an ectoplasmic-specialization role organizing actin via EPS8/Arp3/Scribble in the testis.","evidence":"Co-IP identifying p62/SQSTM1, JNK assays, PDX experiments; Co-IP with actin/N-cadherin/Scribble, RNAi/overexpression barrier assays","pmids":["26754771","26990065"],"confidence":"Medium","gaps":["Generality of the p62-JNK cascade beyond tested cells unclear","Single-lab"]},{"year":2017,"claim":"Identified CK1δ/ε as the kinases (with Dvl enhancing recruitment) for Wnt5a-induced VANGL2 phosphorylation and proved phosphorylation is essential for uniform polarization in vivo, and dissected VANGL2's bimodal regulation of Dvl.","evidence":"Phospho-mutant knock-in mice, CK1 inhibitors, Dvl knockouts; Co-IP of Vangl2-Dvl and Dvl-Daam1 in mouse/Xenopus; microtubule PCP analysis in testis","pmids":["29056748","28334810","29497043"],"confidence":"High","gaps":["Exact phosphosite map and structural consequences not resolved","Dvl bimodal regulation single-lab"]},{"year":2018,"claim":"Resolved that VANGL2 and Frizzled6 use distinct clathrin adaptors at the TGN (AP-1/Arfrp1 vs epsinR), and connected VANGL2 to cancer stem-cell self-renewal through RhoA and to integrin/MMP-mediated adhesion control.","evidence":"In vitro TGN vesicle reconstitution and siRNA; shRNA in RMS cells/xenografts with RhoA epistasis; Co-IP with integrin αvβ3 and MMP/adhesion assays","pmids":["29666182","29499154","29097183"],"confidence":"High","gaps":["How sorting choice is regulated physiologically unclear","Integrin link single-lab"]},{"year":2019,"claim":"Defined a degradative output: VANGL2 promotes Cullin-1-dependent K48 polyubiquitination and proteasomal turnover of Prickle2, showing VANGL2 actively shapes the abundance of a core PCP partner.","evidence":"Co-IP, proteasome inhibition, K48 ubiquitin assays in HEK293T","pmids":["30814664"],"confidence":"Medium","gaps":["The E3 ligase complex composition not fully defined","In vivo relevance not tested here"]},{"year":2020,"claim":"Provided biophysical mechanism—VANGL2 strengthens the N-cadherin–actin 'molecular clutch' to control growth cone velocity—and placed VANGL2 in a Wnt5a-Ror2 actin program governing alveologenesis.","evidence":"Single-molecule tracking, optical force measurements in Vangl2 KO neurons; conditional lung knockouts with cytoskeletal/secretion/migration readouts","pmids":["31909712","32394892"],"confidence":"High","gaps":["Molecular link from VANGL2 to clutch engagement not fully resolved"]},{"year":2021,"claim":"Expanded VANGL2 function to non-autonomous morphogenesis (regulating neighbor apical constriction via myosin-II and microtubules), cytoneme-based paracrine Wnt signaling, and a direct LAMP-2A–binding brake on chaperone-mediated autophagy controlling MSC fate.","evidence":"Mosaic conditional deletion with quantitative imaging; multi-organism cytoneme live imaging; Co-IP and MSC conditional knockout with lysosome/differentiation assays","pmids":["33608529","33824332","34214490"],"confidence":"High","gaps":["Mechanistic basis of non-autonomous myosin recruitment unclear","Cytoneme regulation single-lab"]},{"year":2023,"claim":"Established two new VANGL2 axes: a TBK1-targeting negative-feedback brake on type I interferon signaling, and an HB-EGF–ERBB2/3–driven tyrosine phosphorylation event required for uterine epithelial polarity at implantation.","evidence":"Co-IP, site-specific ubiquitination mapping (TBK1 Lys372/TRIP/OPTN), myeloid conditional KO and VSV challenge; Co-IP with ERBB2/3, phosphorylation assays, uterine conditional KO","pmids":["37352355","37155852"],"confidence":"High","gaps":["Tyrosine-phosphorylation sites and their effect on VANGL2 PCP activity undefined","Integration of immune role with developmental PCP unclear"]},{"year":null,"claim":"How VANGL2's phosphorylation state, trafficking itinerary, and the choice between its many effector outputs (cadherin/MMP endocytosis, autophagy, TBK1 degradation, RhoA activation) are coordinated within one cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of full-length VANGL2 with its partners","Mechanism selecting among competing effector pathways unknown","Phosphosite map (Ser/Thr vs Tyr) incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,5,27,36]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[14,36,41,47]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[18,30,27]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,7,20,30]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[9,12]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[22,38]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[23,30]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[14,35,2]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1,29,13]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[9,22,38]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[47]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[44,47]}],"complexes":["VANGL1/VANGL2 heteromer","VANGL2-Ror2 Wnt receptor complex","core PCP complex (with Frizzled, Scribble, Dishevelled, Prickle)","postsynaptic density complex (with PSD-95)"],"partners":["DVL1/DVL2/DVL3","SCRIB","FZD3","ROR2","PRICKLE2","N-CADHERIN","TBK1","LAMP-2A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9ULK5","full_name":"Vang-like protein 2","aliases":["Loop-tail protein 1 homolog","Strabismus 1","Van Gogh-like protein 2"],"length_aa":521,"mass_kda":59.7,"function":"Involved in the control of early morphogenesis and patterning of both axial midline structures and the development of neural plate. Plays a role in the regulation of planar cell polarity, particularly in the orientation of stereociliary bundles in the cochlea. Required for polarization and movement of myocardializing cells in the outflow tract and seems to act via RHOA signaling to regulate this process. Required for cell surface localization of FZD3 and FZD6 in the inner ear (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9ULK5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VANGL2","classification":"Not Classified","n_dependent_lines":10,"n_total_lines":1208,"dependency_fraction":0.008278145695364239},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/VANGL2","total_profiled":1310},"omim":[{"mim_id":"621011","title":"SEC14 AND SPECTRIN DOMAINS-CONTAINING PROTEIN 1; SESTD1","url":"https://www.omim.org/entry/621011"},{"mim_id":"615943","title":"MEMBRANE-ASSOCIATED GUANYLATE KINASE, WW AND PDZ DOMAINS-CONTAINING, 3; MAGI3","url":"https://www.omim.org/entry/615943"},{"mim_id":"612411","title":"FAT ATYPICAL CADHERIN 4; FAT4","url":"https://www.omim.org/entry/612411"},{"mim_id":"610635","title":"COLLAGEN TRIPLE-HELIX REPEAT-CONTAINING PROTEIN 1; CTHRC1","url":"https://www.omim.org/entry/610635"},{"mim_id":"610622","title":"FUZZY PLANAR CELL POLARITY PROTEIN; FUZ","url":"https://www.omim.org/entry/610622"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skin 1","ntpm":35.5}],"url":"https://www.proteinatlas.org/search/VANGL2"},"hgnc":{"alias_symbol":["KIAA1215","LTAP","LPP1","STBM","STB1","STBM1","MGC119403","MGC119404"],"prev_symbol":[]},"alphafold":{"accession":"Q9ULK5","domains":[{"cath_id":"-","chopping":"102-240","consensus_level":"high","plddt":84.7372,"start":102,"end":240},{"cath_id":"3.10.20","chopping":"245-287_453-492","consensus_level":"high","plddt":86.0523,"start":245,"end":492},{"cath_id":"1.20.1280","chopping":"352-443","consensus_level":"medium","plddt":86.1224,"start":352,"end":443}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULK5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULK5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULK5-F1-predicted_aligned_error_v6.png","plddt_mean":73.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VANGL2","jax_strain_url":"https://www.jax.org/strain/search?query=VANGL2"},"sequence":{"accession":"Q9ULK5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULK5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULK5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULK5"}},"corpus_meta":[{"pmid":"12724779","id":"PMC_12724779","title":"Identification of Vangl2 and Scrb1 as planar polarity genes in mammals.","date":"2003","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12724779","citation_count":581,"is_preprint":false},{"pmid":"11431695","id":"PMC_11431695","title":"Ltap, a mammalian homolog of Drosophila Strabismus/Van Gogh, is altered in the mouse neural tube mutant Loop-tail.","date":"2001","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11431695","citation_count":414,"is_preprint":false},{"pmid":"21316585","id":"PMC_21316585","title":"Wnt signaling gradients establish planar cell polarity by inducing Vangl2 phosphorylation through Ror2.","date":"2011","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/21316585","citation_count":398,"is_preprint":false},{"pmid":"11780127","id":"PMC_11780127","title":"The planar cell-polarity gene stbm regulates cell behaviour and cell fate in vertebrate embryos.","date":"2002","source":"Nature cell 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\"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — positional cloning with two independent mutant alleles, replicated across multiple labs subsequently\",\n      \"pmids\": [\"11431695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Loss-of-function mutation in Vangl2 results in disruption of stereociliary bundle polarization in mouse cochlear hair cells, with genetic interaction between Vangl2 and Scrb1 (heterozygous double mutants phenocopy Vangl2 homozygotes), establishing both genes in mammalian PCP regulation.\",\n      \"method\": \"Mouse genetics, compound heterozygote epistasis analysis, scanning electron microscopy of cochlear hair cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with two independent mutant alleles, multiple orthogonal analyses, replicated\",\n      \"pmids\": [\"12724779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Stbm/Vangl2 physically interacts with Dishevelled (Dsh) protein in vertebrate embryos, inhibits Wnt-mediated beta-catenin-dependent transcription, and promotes phosphorylation of c-Jun/AP-1-dependent transcription; both gain- and loss-of-function affect cell movements during zebrafish gastrulation.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/morpholino loss-of-function in zebrafish, transcriptional reporter assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating Stbm-Dsh interaction, functional assays in zebrafish, single lab\",\n      \"pmids\": [\"11780127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Both mouse Vangl1 and Vangl2 physically interact with all three Dishevelled (Dvl1, Dvl2, Dvl3) family members via the cytoplasmic C-terminal half of Vangl and the PDZ and DIX domains of Dvl. The two Looptail missense mutations (D255E and S464N) in Vangl2 impair binding to all three Dvl proteins.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation; loss-of-function Vangl2 Lp allele mutagenesis analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical methods (Y2H, GST pulldown, Co-IP), mutagenesis confirming disease-relevant residues, replicated by subsequent studies\",\n      \"pmids\": [\"15456783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Vangl2 is required for polarized cell migration of myocardializing cells into outflow tract cushions, acting via the RhoA/ROCK1 signaling axis; RhoA expression is lost from the myocardial-cushion interface in Lp/Lp mutants.\",\n      \"method\": \"Mouse Lp mutant analysis, immunofluorescence for RhoA and ROCK1, actin cytoskeleton analysis in wild-type vs. Lp/Lp fetuses\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with cellular phenotype, pathway placement via RhoA/ROCK1 co-expression analysis, single lab\",\n      \"pmids\": [\"15637299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Vangl2 becomes asymmetrically localized to specific cell-cell boundaries along the polarization axis in the mammalian cochlea; PDZ2, PDZ3, and PDZ4 domains of Scrb1/Scribble directly bind the C-terminal PDZ-binding domain of Vangl2; Frizzled3 asymmetric localization depends on Vangl2 and the two proteins physically interact.\",\n      \"method\": \"Immunofluorescence localization in cochlea, PDZ domain binding assays, Co-immunoprecipitation of Fz3 and Vangl2\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (localization, domain-binding assays, Co-IP), replicated across labs\",\n      \"pmids\": [\"16687519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Scribble binds Vangl2 selectively through specific PDZ domains (Scrb PDZ domains 2, 3, and 4 interact with Vangl2 C-terminal PDZ-binding domain), and this interaction was demonstrated in polarized mammalian epithelial cells.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping with EGFP-Scrib fusion proteins in polarized epithelial cells\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and domain mapping, single lab, consistent with independent findings in PMID 16687519\",\n      \"pmids\": [\"16791850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Vangl2 protein subcellular localization is disrupted and overall expression is decreased in the neural tubes and cochleas of Lp/Lp mutant embryos, demonstrating that Lp missense mutations affect Vangl2 membrane targeting.\",\n      \"method\": \"Immunofluorescence with specific anti-Vangl2 antiserum on wild-type and Lp/Lp embryos\",\n      \"journal\": \"Gene expression patterns\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence (membrane mislocalization in mutants), single lab\",\n      \"pmids\": [\"16962386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The extracellular domain (CRD) of Frizzled acts as a ligand for Van Gogh/Strabismus (Vang/Stbm) transmembrane protein, demonstrating a direct biochemical and physical interaction between FzECD and Vang/Stbm that mediates nonautonomous PCP signaling.\",\n      \"method\": \"In vivo Drosophila genetics, biochemical interaction assays between FzECD and Vang/Stbm\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and biochemical interaction demonstrated in Drosophila ortholog studies, single lab\",\n      \"pmids\": [\"18804440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sec24b, a cargo-sorting component of the COPII ER-to-Golgi transport vesicle complex, selectively sorts Vangl2 into COPII vesicles for ER-to-Golgi transport. Looptail Vangl2 point mutants (D255E and S464N) fail to sort into COPII vesicles and are trapped in the ER. Sec24b genetically interacts with Vangl2 loss-of-function to increase spina bifida prevalence.\",\n      \"method\": \"Forward genetic screen in mice, COPII vesicle sorting assays, ER retention assays with mutant Vangl2, genetic interaction analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro vesicle sorting reconstitution assay, mutagenesis of disease-relevant residues, confirmed by genetic epistasis, replicated in independent study (PMID 20215345)\",\n      \"pmids\": [\"19966784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Dact1 forms a complex with Vangl2 at the primitive streak; in Dact1 mutants, Vangl2 protein levels are increased at the primitive streak; heterozygous Vangl2 mutation rescues recessive Dact1 phenotypes and loss of Dact1 rescues semidominant Vangl2 phenotypes, placing Dact1 as a regulator of Vangl2 upstream of cell adhesion and PCP.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence on mutant embryos, reciprocal genetic rescue experiments in compound mutant mice\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, reciprocal genetic rescue, multiple orthogonal methods, independent confirmation\",\n      \"pmids\": [\"19701191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Scribble interacts physically with Stbm/Vang through PDZ domain 3 and cooperates with Stbm/Vang in PCP establishment in Drosophila eye and wing; Scribble is part of the Stbm/Vang PCP complex and acts as an effector of Stbm/Vang.\",\n      \"method\": \"Drosophila genetic interaction analysis, physical interaction assays (PDZ domain binding), PCP phenotype analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — physical interaction and genetic epistasis in Drosophila ortholog, single lab\",\n      \"pmids\": [\"19563796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Sec24b deficiency specifically impairs transport of PCP core protein Vangl2 in mouse embryos and primary cultured cells, establishing a direct role for Sec24b in Vangl2 trafficking.\",\n      \"method\": \"Mouse genetic mutants, cell-based trafficking assays with primary cells and embryos\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with specific cargo-trafficking phenotype, independent confirmation of PMID 19966784\",\n      \"pmids\": [\"20215345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Vangl2 controls the posterior tilting and asymmetric localization of motile primary cilia to the posterior apical membrane of neuroepithelial cells in zebrafish; Vangl2 is not required for ciliogenesis itself.\",\n      \"method\": \"Zebrafish vangl2 null mutant analysis, live imaging with Arl13b-GFP ciliary axoneme marker\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live imaging with specific cilia marker in complete null mutant, clear phenotypic separation between ciliogenesis and cilia orientation, multiple orthogonal analyses\",\n      \"pmids\": [\"20305649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Vangl2 forms a Wnt-induced receptor complex with Ror2 to sense Wnt dosages; Wnts dose-dependently induce phosphorylation of serine/threonine residues in Vangl2 through Ror2; Wnt5a signaling gradient controls PCP in chondrocytes and limb elongation via Vangl2 phosphorylation. Vangl2 activity depends on its phosphorylation level.\",\n      \"method\": \"Co-immunoprecipitation of Vangl2-Ror2 complex, phosphorylation assays with Wnt dose-response, limb bud in vivo analysis, genetic interaction\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of receptor complex, dose-dependent phosphorylation assays, in vivo functional validation, replicated by PMID 29056748\",\n      \"pmids\": [\"21316585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Vangl2 antagonizes Dvl1-mediated hyperphosphorylation of Frizzled3 and promotes Frizzled3 internalization in commissural axon growth cones; Vangl2 is enriched on filopodial tips and emerging filopodial membrane patches in growth cones.\",\n      \"method\": \"Cell-based phosphorylation assays, internalization assays, immunofluorescence localization in growth cones, loss-of-function analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional biochemical assays and localization in neurons, single lab\",\n      \"pmids\": [\"21316586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Rack1 is an interacting protein of Vangl2; knockdown of Rack1 affects membrane localization of Vangl2 in zebrafish, and the Vangl2-interacting domain of Rack1 has a dominant-negative effect on Vangl2 localization and gastrulation.\",\n      \"method\": \"Protein interaction screen, co-immunoprecipitation, zebrafish knockdown, localization assays\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional localization assay, zebrafish loss-of-function, single lab\",\n      \"pmids\": [\"21262816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Maternal Vangl2 in Xenopus oocytes interacts with the post-Golgi v-SNARE protein VAMP1 and acetylated microtubules; Vangl2 is required for VAMP1 stability and maintenance of stable microtubule architecture; Vangl2 also interacts with aPKC, and both are required for membrane asymmetry during oocyte maturation and asymmetric distribution of maternal transcripts (VegT, Wnt11).\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, morpholino knockdown in Xenopus oocytes, transcript localization assays\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional knockdown, multiple binding partners identified, single lab\",\n      \"pmids\": [\"21813572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"VANGL2 regulates the endocytosis and cell-surface availability of MMP14 (MT1-MMP) in a focal adhesion kinase-dependent manner; vangl2 mutant zebrafish embryos show increased Mmp14 activity and decreased ECM; in vivo knockdown of Mmp14 partially rescues the Vangl2 loss-of-function convergence and extension phenotype, placing MMP14 as a downstream effector of VANGL2.\",\n      \"method\": \"Zebrafish trilobite/vangl2 mutant analysis, endocytosis assays, MMP14 activity assays, genetic rescue with mmp14 morpholino\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis rescue, activity assays, endocytosis assays, multiple orthogonal methods, functional consequence confirmed in vivo\",\n      \"pmids\": [\"22357946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The Wnt coreceptor Ryk interacts with Vangl2 biochemically and genetically; interaction is potentiated by Wnt5a; Ryk regulates PCP by promoting Vangl2 protein stability (degradation of Vangl2 is increased when Ryk is absent); complete loss of both Ryk and Vangl2 produces phenotypes resembling Wnt5a null mutants.\",\n      \"method\": \"Co-immunoprecipitation, genetic interaction analysis in compound mutant mice, Vangl2 stability/degradation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, stability assay, genetic epistasis, single lab\",\n      \"pmids\": [\"23144463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Vangl2 S464N (Looptail mutation) disrupts delivery of Vangl1 and Vangl2 to the cell surface through oligomer formation between Vangl2(S464N) and wild-type Vangl1 or Vangl2, causing intracellular retention. Vangl1 and Vangl2 form endogenous heterodimers/oligomers.\",\n      \"method\": \"Co-immunoprecipitation of Vangl1/Vangl2, cell surface localization assays, compound mutant mouse analysis\",\n      \"journal\": \"PLoS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct Co-IP, cell surface localization assay, in vivo validation in mutant mice, consistent with independent finding in PMID 23029439\",\n      \"pmids\": [\"22363783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Endogenous Vangl2/Vangl1 heteromeric protein complexes exist; confirmed by specific monoclonal anti-Vangl2 antibody and proteomic analysis of Vangl2 immunoprecipitates from cell lysates.\",\n      \"method\": \"Monoclonal antibody generation validated by SPR, western blot, immunoprecipitation; mass spectrometry proteomic analysis of immunoprecipitates\",\n      \"journal\": \"PLoS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — SPR-validated antibody, proteomic identification of endogenous complex, multiple orthogonal methods\",\n      \"pmids\": [\"23029439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Vangl2 transport from the trans-Golgi network (TGN) requires the GTP-binding protein Arfrp1 and clathrin adaptor complex AP-1; a YYXXF sorting signal in Vangl2's C-terminal cytosolic domain is required for TGN traffic and interaction with the AP-1 μ subunit. Vangl2 and Frizzled6 are sorted by different mechanisms from the TGN.\",\n      \"method\": \"siRNA knockdown of Arfrp1/AP-1, mutagenesis of YYXXF sorting signal, TGN transport assays, binding assays with AP-1 μ subunit\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro mutagenesis identifying sorting signal, AP-1 binding assays, siRNA functional validation, replicated by PMID 29666182\",\n      \"pmids\": [\"23326640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cofilin 1 (actin-severing protein) and Vangl2 cooperate to control PCP in the early mouse embryo; in Vangl2/Cfl1 double mutants, PCP protein complexes fail to traffic to the apical cell membrane, and F-actin remodeling is essential for initiation but not maintenance of PCP. Vangl2 and cofilin cooperate to target Rab11+ vesicles containing PCP proteins to the apical membrane.\",\n      \"method\": \"Compound mutant mouse genetics, vesicle trafficking assays, Rab11 immunofluorescence, pharmacological F-actin manipulation\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in double mutants, mechanistic vesicle trafficking assays, pharmacological confirmation, multiple orthogonal methods\",\n      \"pmids\": [\"23406901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Syndecan 4 (Sdc4) and Vangl2 proteins colocalize; Vangl2 (particularly the Lp mutant form) diminishes Sdc4 protein levels, and Vangl2 knockdown enhances Sdc4 protein levels; genetic interaction between Sdc4 null and Vangl2(Lp) allele causes neural tube and cochlear defects, indicating HSPG levels are regulated downstream of Vangl2.\",\n      \"method\": \"Co-localization in HEK293 cells, protein level analysis after Vangl2 overexpression/knockdown, compound mutant mouse and Xenopus genetics\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic interaction and protein-level regulation, cell-based assays, two organism models\",\n      \"pmids\": [\"23760952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Gipc1 (GAIP C-terminus interacting protein 1) is a novel interactor of Vangl2; a myosin VI-Gipc1 complex regulates Vangl2 trafficking in heterologous cells. In Myosin VI mutant mice, Vangl2 presence at the membrane is increased.\",\n      \"method\": \"Protein interaction screen, co-immunoprecipitation, heterologous cell trafficking assays, mouse mutant membrane localization analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, trafficking assay, in vivo mouse validation, single lab\",\n      \"pmids\": [\"22991442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Sestd1 is a novel binding partner of Vangl2 and Dact1; loss of Sestd1 phenocopies loss of Dact1 and exhibits reciprocal genetic rescue with Vangl2 semidominant mutation; Sestd1-Dact1 interaction can induce Rho GTPase activation in cell-based assays.\",\n      \"method\": \"Co-immunoprecipitation, compound mutant mouse genetics, cell-based Rho GTPase activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, genetic rescue, functional Rho assay, single lab\",\n      \"pmids\": [\"23696638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Vangl2 is a postsynaptic factor that directly binds N-cadherin; enhances N-cadherin internalization in a Rab5-dependent manner; this interaction is suppressed by beta-catenin which competes for the same intracellular region of N-cadherin. Vangl2 knockdown impairs dendritic spine formation and synaptic marker clustering. Prickle2 inhibits N-cadherin-Vangl2 interaction and is required for normal spine formation.\",\n      \"method\": \"Co-immunoprecipitation from synapse-rich brain extracts, internalization assays, Rab5-dependence assay, neuronal knockdown, spine density analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP from endogenous brain tissue, multiple interaction partners, functional internalization assay with mechanistic competition experiment, loss-of-function phenotype\",\n      \"pmids\": [\"24582966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Vangl2 is tightly associated with the postsynaptic density (PSD) fraction in adult rat neurons; Vangl2 forms a complex with PSD-95 through direct binding requiring its C-terminal PDZ-binding motif (TSV); Vangl2 PDZ-binding motif is required for localization to dendritic spines.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation, PDZ-binding motif deletion mutagenesis, spine localization assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation, Co-IP, mutagenesis of PDZ motif, single lab\",\n      \"pmids\": [\"23567299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Vangl2 is required specifically within second heart field (SHF) cells to direct outflow tract lengthening; Vangl2 marks the proximal extent of a transition zone where SHF cells acquire epithelial phenotype; absence of Vangl2 causes abnormal polarization and disorganization of SHF-derived cells, leading to premature cardiomyocyte differentiation.\",\n      \"method\": \"Conditional knockout using floxed Vangl2 allele with tissue-specific Cre drivers, immunofluorescence, lineage tracing\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific conditional knockout with multiple markers and functional outcome, mechanistic connection to epithelial transition zone\",\n      \"pmids\": [\"25521757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Vangl2 directly binds E-cadherin (co-immunoprecipitation from embryonic kidney extracts and transfected fibroblasts); Vangl2 overexpression enhances E-cadherin internalization; loss of Vangl2 (Lp mutant) increases surface E-cadherin; Vangl2 itself is internalized via Rab5- and Dynamin-dependent endocytosis.\",\n      \"method\": \"Co-immunoprecipitation, cell surface biotinylation assay, internalization assay, pharmacological inhibition of endocytosis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP from endogenous tissue, functional internalization assay, single lab\",\n      \"pmids\": [\"25373475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Vangl2 protein is enriched at anterior cell edges in the Xenopus neural plate (anteroposterior planar cell polarity); this localization is directed by Prickle (a Vangl2-interacting protein); Vangl2 AP-PCP is established by Wnt-dependent phosphorylation; Myosin II activity provides feedback regulation of Vangl2 polarity.\",\n      \"method\": \"Immunofluorescence in Xenopus neural plate, morpholino knockdown of Prickle, pharmacological inhibition of Wnt signaling and Myosin II\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional perturbation, multiple pharmacological and genetic manipulations, single lab\",\n      \"pmids\": [\"25910938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Vangl2 PDZ interaction links PSD-95 and Prickle2 in postsynaptic complexes; the PDZ interaction is dispensable for normal Vangl2 cluster formation but partially required for PSD-95-overlapping synaptic localization; Vangl2 PDZ interaction enhances protein interactions between PSD-95 and Prickle2.\",\n      \"method\": \"Co-immunoprecipitation, deletion mutagenesis of PDZ-binding motif, immunofluorescence in hippocampal neurons\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutagenesis, neuronal localization analysis, single lab\",\n      \"pmids\": [\"26257100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"p62/SQSTM1 is a novel VANGL2-binding partner; VANGL2-p62/SQSTM1-JNK forms an evolutionarily conserved signaling cascade that promotes cell proliferation in breast cancer; disruption of the VANGL2-p62/SQSTM1 interaction or JNK inhibition inactivates this cascade.\",\n      \"method\": \"Co-immunoprecipitation identifying p62/SQSTM1 as VANGL2 partner, JNK signaling assays, patient-derived xenograft cell inhibition experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying novel binding partner, functional pathway analysis, in vivo xenograft validation, single lab\",\n      \"pmids\": [\"26754771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Vangl2 is localized at ectoplasmic specialization (ES) in the testis and interacts structurally with actin, N-cadherin, and Scribble; Vangl2 knockdown in Sertoli cells tightens the blood-testis barrier while overexpression perturbs it; these effects are mediated through alteration of actin microfilament organization via EPS8, Arp3, and Scribble.\",\n      \"method\": \"Co-immunoprecipitation (Vangl2 with actin/N-cadherin/Scribble), RNAi knockdown, overexpression, barrier function assays, in vivo RNAi in testis\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with multiple partners, functional KD/OE with defined cellular phenotype, in vivo RNAi validation, single lab\",\n      \"pmids\": [\"26990065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Wnt5a-induced Vangl2 phosphorylation requires CK1ε and CK1δ (redundantly) and Dvl family members (which enhance CK1-Vangl2 interaction); phospho-mutant Vangl2 exhibits dominant negative effects while reduced-phosphorylation Vangl2 is hypomorphic; Vangl2 phosphorylation is essential for its uniform polarization pattern in vivo.\",\n      \"method\": \"In vivo phosphorylation assays with CK1 inhibitors and Dvl knockouts, phospho-mutant knock-in mice, tissue polarity analysis\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo phospho-mutant knock-in, kinase identification with inhibitors and genetic knockouts, multiple tissues analyzed, replicates/extends PMID 21316585\",\n      \"pmids\": [\"29056748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Vangl2 exerts dual (bimodal) regulation on Dvl during convergent extension: Vangl2 promotes efficient Dvl plasma membrane recruitment (positive regulation, required for PCP activation), while simultaneously inhibiting Dvl from interacting with downstream effector Daam1 (negative regulation).\",\n      \"method\": \"Co-immunoprecipitation of Vangl2-Dvl and Dvl-Daam1 complexes, morpholino/overexpression in Xenopus and mouse mutant analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP in two experimental systems (mouse and Xenopus), functional rescue assays, single lab\",\n      \"pmids\": [\"28334810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Vangl2 regulates spermatid planar cell polarity through the microtubule-based cytoskeleton via downstream signaling proteins aPKCζ and MARK2; Vangl2 knockdown in rat testis disrupts microtubule organization and perturbs spermatid PCP.\",\n      \"method\": \"RNAi knockdown in vivo in rat testis, confocal microscopy with 3D reconstruction, immunofluorescence for MT markers and aPKCζ/MARK2\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo RNAi with specific phenotype and pathway placement, single lab\",\n      \"pmids\": [\"29497043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Vangl2 and Frizzled6 exit the TGN in separate vesicle compartments sorted by different clathrin adaptors: AP-1 (with Arfrp1) sorts Vangl2 while epsinR sorts Frizzled6 through a conserved polybasic motif in the Fzd6 cytosolic domain. EpsinR-AP-1 binding is disrupted by Frizzled6 binding to epsinR.\",\n      \"method\": \"In vitro TGN vesicle reconstitution, siRNA knockdown, immunoblotting of released vesicles, protein interaction analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of TGN vesicle release, siRNA knockdowns, protein interaction assays, mechanistic separation of Vangl2 and Fzd6 sorting\",\n      \"pmids\": [\"29666182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Vangl2 depletion inhibited RMS tumor propagating cell (TPC) self-renewal, proliferation, and induced differentiation; constitutively active RhoA rescues TPC maintenance in VANGL2-depleted cells, and dominant-negative RhoA phenocopies VANGL2 depletion, placing RhoA downstream of VANGL2 in TPC self-renewal.\",\n      \"method\": \"shRNA knockdown in human RMS cells and xenografts, zebrafish ERMS model, constitutively active/dominant-negative RhoA constructs\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined phenotype, epistasis via dominant-negative/constitutively-active constructs, multiple model systems\",\n      \"pmids\": [\"29499154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"VANGL2 interacts with integrin αvβ3; VANGL2 knockdown increases integrin αvβ3 cell surface expression, enhances MMP14/MMP2 proteolytic activity, and disrupts adhesion to fibronectin, laminin, and vitronectin; MMP14/MMP2 inhibition suppresses the cell adhesion defect in VANGL2 knockdown cells.\",\n      \"method\": \"Co-immunoprecipitation of VANGL2-integrin αvβ3, siRNA knockdown, integrin surface expression assays, MMP activity assays, cell adhesion assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying novel binding partner, functional loss-of-function with rescue, single lab\",\n      \"pmids\": [\"29097183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Prickle2 protein levels are negatively regulated through physical interaction with Vangl2; Vangl2 interaction promotes Cullin-1-dependent polyubiquitination (K48-linked) of Prickle2, targeting it for proteasomal degradation.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor treatment, ubiquitin K48 mutant co-expression, polyubiquitination assays in HEK293T cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay with mechanistic detail (K48 linkage, Cullin-1), proteasome inhibitor rescue, single lab\",\n      \"pmids\": [\"30814664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Vangl2 controls growth cone velocity by regulating internal retrograde actin flow in an N-cadherin-dependent fashion; loss of Vangl2 decreases fast-diffusing N-cadherin membrane molecules, increases confined N-cadherin trajectories, and strengthens mechanical coupling of N-cadherin with the actin cytoskeleton ('molecular clutch'). Vangl2 distribution within growth cones is selectively affected by N-cadherin-coated substrate.\",\n      \"method\": \"Single molecule tracking of N-cadherin, optical manipulation (N-cadherin-coated microspheres), live imaging of growth cones, Vangl2 KO neurons\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — single molecule tracking combined with optical force measurements and genetic knockout, multiple orthogonal biophysical methods\",\n      \"pmids\": [\"31909712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A Wnt5a-Ror2-Vangl2 cascade controls cytoskeletal organization, PDGF secretion from alveolar epithelial cells, cell shape changes of type I cells, and myofibroblast migration during alveologenesis; these cellular properties are conferred by changes in the actin cytoskeleton.\",\n      \"method\": \"Conditional knockout of Vangl2/Ror2/Wnt5a in specific lung cell types, cytoskeletal analysis, PDGF secretion assays, migration assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific conditional knockouts, multiple functional readouts, pathway placement, single lab\",\n      \"pmids\": [\"32394892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Vangl2 directly binds LAMP-2A (lysosome-associated membrane protein 2A) and targets it for degradation, thereby limiting chaperone-mediated autophagy (CMA) lysosome activity in mesenchymal stem cells; MSC-specific Vangl2 ablation increases LAMP-2A and CMA-lysosome numbers, promoting osteogenesis while reducing adipogenesis.\",\n      \"method\": \"Co-immunoprecipitation of Vangl2-LAMP-2A, conditional knockout in MSCs, lysosome number/activity assays, differentiation assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP demonstrating direct binding to LAMP-2A, conditional knockout with defined molecular and cellular phenotype, multiple orthogonal assays\",\n      \"pmids\": [\"34214490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Vangl2 promotes formation of long, branching cytonemes in zebrafish epiblast cells, mouse intestinal telocytes, and human gastric cancer cells; Vangl2 activation increases cytoneme length and branching, enhancing paracrine Wnt/β-catenin signaling to surrounding cells; Vangl2 inhibition causes fewer and shorter cytonemes.\",\n      \"method\": \"Live imaging of cytonemes in multiple cell types/organisms, Vangl2 gain/loss-of-function, mathematical modeling validated by in vivo neural plate patterning\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging with gain/loss-of-function in multiple systems, mathematical model predictions confirmed in vivo, single lab\",\n      \"pmids\": [\"33824332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Vangl2-deleted neuroepithelial cells non-autonomously prevent apical constriction by an average of five neighboring Vangl2-replete cells; this involves diminished myosin-II localization on neighbor cell borders and shortening of basally-extending microtubule tails; Vangl2-deleted cells themselves preferentially recruit myosin-II to their apical cortex rather than apical cap.\",\n      \"method\": \"Mosaic conditional deletion of Vangl2 in mouse neuroepithelium, quantitative imaging of myosin-II localization, laser ablation and apical constriction analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mosaic deletion with precise quantification of non-autonomous effects, multiple imaging modalities, mechanistic identification of myosin-II and microtubule involvement\",\n      \"pmids\": [\"33608529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VANGL2 acts as an IFN-inducible negative feedback regulator of IFN-I signaling during viral infection: VANGL2 interacts with TBK1 and promotes its selective autophagic degradation via K48-linked polyubiquitination of TBK1 at Lys372 by E3 ligase TRIP, with recognition by cargo receptor OPTN; myeloid-specific deletion of VANGL2 enhances IFN-I production and improves survival against VSV.\",\n      \"method\": \"Co-immunoprecipitation of VANGL2-TBK1, ubiquitination mapping (K48, Lys372), E3 ligase identification (TRIP), cargo receptor identification (OPTN), myeloid-specific conditional knockout in mice, viral infection model\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, site-specific ubiquitination mapping, E3 ligase and cargo receptor identification, in vivo conditional knockout validation, multiple orthogonal methods\",\n      \"pmids\": [\"37352355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HB-EGF binds ERBB2 and ERBB3 to recruit VANGL2 for tyrosine phosphorylation; uterine VANGL2 tyrosine phosphorylation is suppressed in Erbb2/Erbb3 double conditional knockout mice; uterine deletion of Vangl2 disrupts implantation crypt formation, linking HB-EGF-ERBB2/3-VANGL2 signaling to uterine epithelial polarity during implantation.\",\n      \"method\": \"Co-immunoprecipitation (VANGL2 with ERBB2/ERBB3), tyrosine phosphorylation assays, conditional knockout mouse models, implantation analysis\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying receptor complex, phosphorylation assays, conditional knockout validation, single lab\",\n      \"pmids\": [\"37155852\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VANGL2 is a four-pass transmembrane core planar cell polarity (PCP) protein that is sorted from the ER via COPII/Sec24b and from the trans-Golgi network via an Arfrp1/AP-1/YYXXF-signal pathway to specific cell membranes, where it forms asymmetrically distributed complexes with Frizzled receptors, Scribble (via PDZ domains), Dishevelled (via its cytoplasmic C-terminal domain), Ror2, and Prickle; Wnt5a signals through Ror2 to induce CK1δ/ε-mediated serine/threonine phosphorylation of VANGL2 (potentiated by Dvl), which is required for its uniform polarization and PCP activity; VANGL2 regulates diverse downstream processes including actin cytoskeleton organization via RhoA/ROCK, endocytosis of membrane proteins such as MMP14, N-cadherin, and E-cadherin, microtubule-based cytoskeletal dynamics, Prickle2 ubiquitin-proteasomal degradation, LAMP-2A-dependent chaperone-mediated autophagy, and TBK1 autophagic degradation in innate immune signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VANGL2 is a four-pass transmembrane core planar cell polarity (PCP) protein that establishes and propagates tissue-level polarity, and whose loss causes craniorachischisis through the Looptail (Lp) mutations D255E and S464N [#0, #1]. Reaching the cell surface is a tightly chaperoned process: VANGL2 is selectively sorted into COPII vesicles by Sec24b for ER exit—a step the Lp point mutants fail, trapping them in the ER [#9, #12]—and then exits the trans-Golgi network through a YYXXF signal in its cytosolic C-terminus that engages the Arfrp1/AP-1 clathrin-adaptor machinery, distinct from the epsinR pathway used by Frizzled6 [#22, #38]. At the membrane it assembles asymmetric PCP complexes, binding Frizzled directly, recruiting Scribble through specific PDZ domains and Dishevelled through its cytoplasmic C-terminal half; the Lp mutations disrupt Dvl binding [#3, #5, #8]. VANGL2 forms endogenous Vangl1/Vangl2 heteromers, and the dominant S464N mutant poisons surface delivery of wild-type partners through oligomerization [#20, #21]. Wnt5a signaling through a VANGL2–Ror2 receptor complex drives CK1δ/ε-mediated serine/threonine phosphorylation of VANGL2, potentiated by Dvl, which is required for its uniform polarization and PCP output [#14, #35]. Downstream, VANGL2 organizes the actin cytoskeleton via RhoA/ROCK [#4, #39], governs endocytosis of membrane proteins including MMP14, E-cadherin and N-cadherin [#18, #30, #27], and shapes cytoskeletal and morphogenetic behaviors in cardiac, neural, and ciliary contexts [#13, #29, #46]. Beyond development, VANGL2 directly binds LAMP-2A to restrain chaperone-mediated autophagy [#44] and interacts with TBK1 to promote its autophagic degradation as a negative-feedback brake on type I interferon signaling [#47].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that a mammalian Van Gogh/Strabismus homolog exists and that its mutation causes a severe neural tube defect, anchoring VANGL2 in the conserved tissue polarity pathway.\",\n      \"evidence\": \"Positional cloning and sequencing of two independent Looptail alleles in mouse\",\n      \"pmids\": [\"11431695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular function of the protein not yet defined\", \"Direct partners unidentified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linked VANGL2 biochemically to Dishevelled and functionally to non-canonical Wnt signaling and gastrulation cell movements, separating it from canonical β-catenin transcription.\",\n      \"evidence\": \"Co-IP and morpholino/overexpression with transcriptional reporters in zebrafish\",\n      \"pmids\": [\"11780127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction domains not mapped\", \"Single-lab functional assays\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated VANGL2 governs mammalian PCP at single-cell resolution and genetically partners Scribble, establishing the core machinery.\",\n      \"evidence\": \"Mouse genetics, compound-heterozygote epistasis, SEM of cochlear hair cells\",\n      \"pmids\": [\"12724779\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular Scribble–Vangl2 contact\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapped the VANGL–Dishevelled interaction to specific domains and showed Looptail residues directly impair Dvl binding, connecting genotype to a molecular defect.\",\n      \"evidence\": \"Y2H, GST pulldown, Co-IP, Lp allele mutagenesis\",\n      \"pmids\": [\"15456783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of lost Dvl binding in vivo not resolved here\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined VANGL2 asymmetric membrane localization and its direct PDZ-mediated binding to Scribble and physical interaction with Frizzled3, building the asymmetric complex picture.\",\n      \"evidence\": \"Cochlear immunofluorescence, PDZ-domain binding assays, Co-IP\",\n      \"pmids\": [\"16687519\", \"16791850\", \"16962386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How asymmetry is initiated mechanistically unresolved\", \"Lp effect on trafficking only correlative at this stage\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed the Frizzled extracellular CRD acts as a ligand for Vang/Stbm, providing a molecular basis for non-autonomous PCP signaling.\",\n      \"evidence\": \"Drosophila genetics and biochemical FzECD–Vang interaction assays\",\n      \"pmids\": [\"18804440\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Demonstrated in Drosophila ortholog only\", \"Affinity/stoichiometry not quantified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified the ER-export step as Sec24b/COPII-dependent and explained why Looptail mutants fail to traffic, unifying disease alleles with a trafficking checkpoint; concurrently placed Dact1 as an upstream regulator of VANGL2 levels.\",\n      \"evidence\": \"Forward genetic screen, COPII sorting and ER-retention assays, reciprocal genetic rescue\",\n      \"pmids\": [\"19966784\", \"19701191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo recognition motif for Sec24b not defined\", \"How Dact1 controls Vangl2 abundance unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Independently confirmed Sec24b specificity for VANGL2 cargo and revealed that VANGL2 orients posterior tilting of motile cilia without controlling ciliogenesis.\",\n      \"evidence\": \"Mouse mutants/primary cell trafficking; zebrafish null live imaging with Arl13b-GFP\",\n      \"pmids\": [\"20215345\", \"20305649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling Vangl2 polarity to cilium positioning not detailed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established Wnt5a–Ror2-driven, dose-dependent phosphorylation of VANGL2 as the input that tunes PCP activity, and identified trafficking regulators (Rack1) and microtubule/SNARE associations.\",\n      \"evidence\": \"Vangl2–Ror2 Co-IP, Wnt dose-response phosphorylation, limb-bud genetics; zebrafish Rack1 knockdown; Xenopus oocyte Co-IP\",\n      \"pmids\": [\"21316585\", \"21316586\", \"21262816\", \"21813572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phosphosites and kinase identity not yet pinned down\", \"Some interactions single-lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed VANGL2 controls cell-surface availability of effectors by regulating endocytosis (MMP14) and forms endogenous Vangl1/Vangl2 heteromers whose surface delivery is poisoned by the dominant S464N mutant.\",\n      \"evidence\": \"Zebrafish vangl2 mutant epistasis and endocytosis assays; Co-IP, surface-localization assays, proteomics; Ryk stability assays\",\n      \"pmids\": [\"22357946\", \"22363783\", \"23029439\", \"23144463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Vangl2 directs cargo into endocytic routes not fully defined\", \"Ryk stabilization mechanism single-lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the TGN export route (Arfrp1/AP-1 via a YYXXF signal) and elaborated the cytoskeletal/vesicular delivery machinery (cofilin, Rab11), plus regulators Gipc1/myosin-VI, Sestd1, and downstream HSPG (Sdc4) control.\",\n      \"evidence\": \"siRNA, YYXXF mutagenesis and AP-1 binding; compound-mutant genetics with Rab11 imaging and F-actin pharmacology; Co-IP and Rho assays\",\n      \"pmids\": [\"23326640\", \"23406901\", \"22991442\", \"23696638\", \"23760952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coordination between ER, TGN, and apical delivery steps not integrated\", \"Several effector links single-lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a neuronal/postsynaptic role: VANGL2 binds N-cadherin and PSD-95 and drives Rab5-dependent N-cadherin internalization, with Prickle2 and β-catenin acting as competing modulators of spine formation.\",\n      \"evidence\": \"Co-IP from brain extracts, internalization assays, neuronal knockdown, spine-density analysis\",\n      \"pmids\": [\"24582966\", \"23567299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How synaptic VANGL2 connects to canonical PCP signaling unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated tissue-autonomous developmental requirements (second heart field outflow tract elongation) and direct E-cadherin binding/internalization, extending VANGL2's cadherin-trafficking role to epithelial morphogenesis.\",\n      \"evidence\": \"Conditional knockout with lineage tracing; Co-IP, surface biotinylation, endocytosis inhibition\",\n      \"pmids\": [\"25521757\", \"25373475\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cadherin-internalization mechanism single-lab\", \"Link between cadherin trafficking and PCP output not formalized\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed Prickle directs anterior VANGL2 enrichment and that Wnt-dependent phosphorylation plus Myosin-II feedback establish anteroposterior planar polarity, and resolved PDZ-mediated assembly of PSD-95/Prickle2 synaptic complexes.\",\n      \"evidence\": \"Xenopus neural-plate immunofluorescence with Prickle knockdown and Wnt/Myosin-II inhibition; Co-IP with PDZ-motif mutagenesis\",\n      \"pmids\": [\"25910938\", \"26257100\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Feedback circuitry not mechanistically dissected\", \"Single-lab assays\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended VANGL2 to disease/effector contexts: a VANGL2–p62/SQSTM1–JNK cascade promoting breast cancer proliferation, and an ectoplasmic-specialization role organizing actin via EPS8/Arp3/Scribble in the testis.\",\n      \"evidence\": \"Co-IP identifying p62/SQSTM1, JNK assays, PDX experiments; Co-IP with actin/N-cadherin/Scribble, RNAi/overexpression barrier assays\",\n      \"pmids\": [\"26754771\", \"26990065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of the p62-JNK cascade beyond tested cells unclear\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified CK1δ/ε as the kinases (with Dvl enhancing recruitment) for Wnt5a-induced VANGL2 phosphorylation and proved phosphorylation is essential for uniform polarization in vivo, and dissected VANGL2's bimodal regulation of Dvl.\",\n      \"evidence\": \"Phospho-mutant knock-in mice, CK1 inhibitors, Dvl knockouts; Co-IP of Vangl2-Dvl and Dvl-Daam1 in mouse/Xenopus; microtubule PCP analysis in testis\",\n      \"pmids\": [\"29056748\", \"28334810\", \"29497043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact phosphosite map and structural consequences not resolved\", \"Dvl bimodal regulation single-lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved that VANGL2 and Frizzled6 use distinct clathrin adaptors at the TGN (AP-1/Arfrp1 vs epsinR), and connected VANGL2 to cancer stem-cell self-renewal through RhoA and to integrin/MMP-mediated adhesion control.\",\n      \"evidence\": \"In vitro TGN vesicle reconstitution and siRNA; shRNA in RMS cells/xenografts with RhoA epistasis; Co-IP with integrin αvβ3 and MMP/adhesion assays\",\n      \"pmids\": [\"29666182\", \"29499154\", \"29097183\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How sorting choice is regulated physiologically unclear\", \"Integrin link single-lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a degradative output: VANGL2 promotes Cullin-1-dependent K48 polyubiquitination and proteasomal turnover of Prickle2, showing VANGL2 actively shapes the abundance of a core PCP partner.\",\n      \"evidence\": \"Co-IP, proteasome inhibition, K48 ubiquitin assays in HEK293T\",\n      \"pmids\": [\"30814664\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The E3 ligase complex composition not fully defined\", \"In vivo relevance not tested here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided biophysical mechanism—VANGL2 strengthens the N-cadherin–actin 'molecular clutch' to control growth cone velocity—and placed VANGL2 in a Wnt5a-Ror2 actin program governing alveologenesis.\",\n      \"evidence\": \"Single-molecule tracking, optical force measurements in Vangl2 KO neurons; conditional lung knockouts with cytoskeletal/secretion/migration readouts\",\n      \"pmids\": [\"31909712\", \"32394892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link from VANGL2 to clutch engagement not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded VANGL2 function to non-autonomous morphogenesis (regulating neighbor apical constriction via myosin-II and microtubules), cytoneme-based paracrine Wnt signaling, and a direct LAMP-2A–binding brake on chaperone-mediated autophagy controlling MSC fate.\",\n      \"evidence\": \"Mosaic conditional deletion with quantitative imaging; multi-organism cytoneme live imaging; Co-IP and MSC conditional knockout with lysosome/differentiation assays\",\n      \"pmids\": [\"33608529\", \"33824332\", \"34214490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic basis of non-autonomous myosin recruitment unclear\", \"Cytoneme regulation single-lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established two new VANGL2 axes: a TBK1-targeting negative-feedback brake on type I interferon signaling, and an HB-EGF–ERBB2/3–driven tyrosine phosphorylation event required for uterine epithelial polarity at implantation.\",\n      \"evidence\": \"Co-IP, site-specific ubiquitination mapping (TBK1 Lys372/TRIP/OPTN), myeloid conditional KO and VSV challenge; Co-IP with ERBB2/3, phosphorylation assays, uterine conditional KO\",\n      \"pmids\": [\"37352355\", \"37155852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tyrosine-phosphorylation sites and their effect on VANGL2 PCP activity undefined\", \"Integration of immune role with developmental PCP unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How VANGL2's phosphorylation state, trafficking itinerary, and the choice between its many effector outputs (cadherin/MMP endocytosis, autophagy, TBK1 degradation, RhoA activation) are coordinated within one cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of full-length VANGL2 with its partners\", \"Mechanism selecting among competing effector pathways unknown\", \"Phosphosite map (Ser/Thr vs Tyr) incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 5, 27, 36]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [14, 36, 41, 47]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [18, 30, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 7, 20, 30]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [9, 12]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [22, 38]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [23, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [14, 35, 2]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1, 29, 13]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [9, 22, 38]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [47]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [44, 47]}\n    ],\n    \"complexes\": [\n      \"VANGL1/VANGL2 heteromer\",\n      \"VANGL2-Ror2 Wnt receptor complex\",\n      \"core PCP complex (with Frizzled, Scribble, Dishevelled, Prickle)\",\n      \"postsynaptic density complex (with PSD-95)\"\n    ],\n    \"partners\": [\n      \"DVL1/DVL2/DVL3\",\n      \"SCRIB\",\n      \"FZD3\",\n      \"ROR2\",\n      \"PRICKLE2\",\n      \"N-cadherin\",\n      \"TBK1\",\n      \"LAMP-2A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}