Affinage

VANGL2

Vang-like protein 2 · UniProt Q9ULK5

Length
521 aa
Mass
59.7 kDa
Annotated
2026-04-28
100 papers in source corpus 43 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VANGL2 is a core planar cell polarity (PCP) transmembrane protein that functions as a signaling scaffold to coordinate asymmetric cell behaviors during convergent extension, neural tube closure, cilia positioning, axon guidance, and other morphogenetic processes. It is sorted from the ER by COPII/Sec24b and from the trans-Golgi network via an Arfrp1/AP-1-dependent YYXXF sorting signal, then delivered to specific plasma membrane domains where it becomes asymmetrically localized; its activity is controlled by Wnt5a-Ror2-induced phosphorylation mediated by CK1δ/ε and Dishevelled family members (PMID:19966784, PMID:23326640, PMID:21316585, PMID:29056748). At the membrane, VANGL2 physically interacts with Dishevelled (Dvl1/2/3), Frizzled3/6, Scribble, N-cadherin, and integrin αvβ3 to antagonize Dvl1-mediated Frizzled hyperphosphorylation, promote cadherin and MMP14 endocytosis, and activate RhoA/ROCK-dependent actin remodeling (PMID:15456783, PMID:16687519, PMID:21316586, PMID:22357946, PMID:15637299, PMID:24582966). Beyond classical PCP, VANGL2 limits chaperone-mediated autophagy by targeting LAMP-2A for degradation, promotes cytoneme-based paracrine Wnt distribution, and negatively regulates TBK1-dependent type I interferon signaling by recruiting the E3 ligase TRIP to drive TBK1 autophagic degradation (PMID:34214490, PMID:33824332, PMID:37352355).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2001 High

    Positional cloning of two independent Loop-tail alleles established that VANGL2 is the mammalian homolog of Drosophila Strabismus/Van Gogh and that its loss causes craniorachischisis, linking it to the conserved tissue polarity pathway.

    Evidence Positional cloning and sequencing of two Lp alleles in mouse

    PMID:11431695

    Open questions at the time
    • Mechanism by which Vangl2 loss causes neural tube defect was unknown
    • Direct molecular partners unidentified
  2. 2002 High

    Demonstration that Vangl2 physically interacts with Dishevelled and modulates Wnt signaling — suppressing β-catenin-dependent transcription while promoting JNK/AP-1 activation — established its role as a PCP-specific Wnt pathway component.

    Evidence Co-immunoprecipitation of Stbm/Vangl2 with Dsh plus reporter assays in zebrafish

    PMID:11780127

    Open questions at the time
    • Which Dvl domains mediate the interaction was unknown
    • Endogenous interaction not yet confirmed in mammals
  3. 2003 High

    Vangl2 was shown to control stereociliary bundle polarization in the cochlea and to cooperate genetically with Scribble (Scrb1), establishing a functional PCP signaling module in mammals.

    Evidence Mouse genetics with Vangl2 and Scrb1 single and double heterozygote cochlear analysis

    PMID:12724779

    Open questions at the time
    • Biochemical nature of Vangl2-Scribble interaction not yet mapped
    • How Vangl2 controls kinocilium positioning was unclear
  4. 2004 High

    Mapping of Vangl2 interactions with all three mammalian Dishevelled proteins via its C-terminal cytoplasmic domain, and demonstration that Looptail mutations abrogate these interactions, provided the first molecular explanation for loss-of-function pathogenesis.

    Evidence Yeast two-hybrid, GST pull-down, co-immunoprecipitation with mutagenesis of Lp alleles

    PMID:15456783

    Open questions at the time
    • Structural basis of Vangl2-Dvl interaction unresolved
    • Whether Dvl interaction is sufficient for PCP signaling untested
  5. 2005 Medium

    Vangl2 was placed upstream of RhoA/ROCK1 signaling in controlling polarized cell movements and actin dynamics, identifying the major downstream effector pathway.

    Evidence Analysis of RhoA and ROCK1 expression/activation in Lp/Lp mouse outflow tract

    PMID:15637299

    Open questions at the time
    • Direct biochemical link between Vangl2 and RhoA activation not demonstrated
    • Intermediate signaling steps unknown
  6. 2006 High

    Vangl2 was shown to be asymmetrically localized at specific cell boundaries in the cochlea and to physically interact with both Scribble (via PDZ domains) and Frizzled3 (required for Fz3 membrane anchoring), establishing the core PCP complex architecture at the plasma membrane.

    Evidence Immunofluorescence, PDZ domain binding assays, and co-immunoprecipitation in cochlear epithelium and polarized cells

    PMID:16687519 PMID:16791850

    Open questions at the time
    • How Vangl2 asymmetric localization is initially established was unknown
    • Frizzled3-Vangl2 interaction stoichiometry and structural details unresolved
  7. 2009 High

    Discovery that Sec24b selectively sorts Vangl2 into COPII vesicles for ER-to-Golgi transport — and that Looptail mutants fail this sorting step — revealed that trafficking defects, not just signaling defects, underlie Vangl2 loss-of-function pathology.

    Evidence Forward genetic screen, COPII vesicle cargo sorting assay, ER retention of Lp mutants, genetic interaction with Sec24b

    PMID:19966784

    Open questions at the time
    • Structural features of Vangl2 recognized by Sec24b unidentified
    • Whether other PCP proteins share this sorting requirement unknown
  8. 2011 High

    Wnt5a-Ror2 signaling was shown to induce Vangl2 phosphorylation on serine/threonine residues, establishing that a graded signaling input directly modifies Vangl2 to create an activity gradient controlling limb PCP; CK1δ/ε were later identified as the kinases, with Dvl enhancing the CK1-Vangl2 interaction.

    Evidence Biochemical phosphorylation assays, Ror2 co-immunoprecipitation, in vivo phospho-mutant analysis, kinase assays

    PMID:21316585 PMID:29056748

    Open questions at the time
    • Full complement of phosphorylation sites and their individual contributions not mapped
    • How phosphorylation gradient is read by downstream effectors unclear
  9. 2011 High

    Vangl2 was found to antagonize Dvl1-mediated Frizzled3 hyperphosphorylation and promote Fz3 internalization in commissural axon growth cones, revealing a mechanism by which Vangl2 sharpens directional Wnt sensing in axon guidance.

    Evidence Genetic knockdown, Fz3 phosphorylation assays, subcellular localization in growth cones

    PMID:21316586

    Open questions at the time
    • Whether this antagonism operates in all PCP-dependent tissues unclear
    • Phosphatase counterbalancing Dvl-mediated Fz3 phosphorylation unidentified
  10. 2010 High

    Vangl2 was shown to control posterior tilting and asymmetric positioning of motile primary cilia without affecting ciliogenesis itself, dissecting its PCP role from general ciliary biogenesis.

    Evidence Zebrafish vangl2 null with live Arl13b-GFP ciliary imaging

    PMID:20305649

    Open questions at the time
    • Molecular mechanism linking Vangl2 to basal body positioning unresolved
    • Whether Vangl2 acts directly at the basal body or indirectly via actin unclear
  11. 2013 High

    Arfrp1 and AP-1 were identified as required for Vangl2 export from the trans-Golgi network via a YYXXF sorting signal, and this was shown to be a distinct pathway from Frizzled6 TGN export, establishing that PCP core components take separate trafficking routes.

    Evidence Mutagenesis of YYXXF sorting signal, co-immunoprecipitation with AP-1 μ subunit, in vitro TGN transport, and reconstituted vesicle assays

    PMID:23326640 PMID:29666182

    Open questions at the time
    • Adaptor proteins linking AP-1-sorted vesicles to motor proteins unknown
    • Whether this sorting signal is conserved in Vangl1 untested
  12. 2013 High

    Vangl2 was shown to directly bind N-cadherin and enhance its Rab5-dependent internalization (competitively regulated by β-catenin), revealing a direct role in cadherin trafficking beyond classical PCP signaling, with implications for synaptogenesis.

    Evidence Co-immunoprecipitation from brain extracts, internalization assays, Rab5 dependence, competitive binding with β-catenin

    PMID:24582966

    Open questions at the time
    • Whether Vangl2-cadherin regulation is PCP-dependent or independent unclear
    • Structural basis of competitive Vangl2/β-catenin binding to N-cadherin unknown
  13. 2012 High

    Vangl2 was found to regulate endocytosis of MMP14 in a FAK-dependent manner, with Vangl2 loss causing increased MMP14 surface activity and ECM degradation — partial rescue by MMP14 knockdown linked this to convergent extension defects.

    Evidence Zebrafish genetics, MMP activity and endocytosis assays, morpholino rescue

    PMID:22357946

    Open questions at the time
    • Direct physical interaction between Vangl2 and MMP14 not demonstrated
    • How FAK integrates with PCP signaling at this step unclear
  14. 2020 High

    Single-molecule biophysical analysis revealed that Vangl2 controls growth cone velocity by regulating the molecular clutch between N-cadherin and retrograde actin flow, acting as a negative regulator of axonal outgrowth.

    Evidence Single molecule tracking of N-cadherin, optical manipulation, FRAP in growth cones

    PMID:31909712

    Open questions at the time
    • Which domain of Vangl2 mediates N-cadherin clutch regulation unknown
    • Whether this mechanism applies to non-neuronal cell migration untested
  15. 2021 High

    Vangl2 was discovered to directly bind LAMP-2A and target it for degradation, thereby limiting chaperone-mediated autophagy and controlling mesenchymal stem cell fate — a function independent of classical PCP.

    Evidence Co-immunoprecipitation, MSC-specific conditional knockout, LAMP-2A protein level and bone/fat phenotype analysis

    PMID:34214490

    Open questions at the time
    • Mechanism by which Vangl2 targets LAMP-2A for degradation (proteasomal vs. lysosomal) not fully defined
    • Whether CMA regulation extends to other Vangl2-expressing tissues unknown
  16. 2021 High

    Vangl2 was shown to generate branching cytonemes that deliver Wnt protein to neighboring cells, establishing a role in controlling the geometry of paracrine Wnt signaling distribution.

    Evidence Live imaging in zebrafish, mouse telocytes, and human gastric cancer cells; mathematical modeling validated in vivo

    PMID:33824332

    Open questions at the time
    • Which Vangl2-dependent actin regulators drive cytoneme formation unknown
    • Whether cytoneme-mediated Wnt delivery is PCP-dependent or a parallel function unclear
  17. 2023 High

    VANGL2 was identified as an IFN-inducible negative regulator of innate antiviral signaling: it recruits the E3 ligase TRIP to ubiquitinate TBK1 at K372 via K48-linked chains, directing TBK1 for OPTN-mediated selective autophagic degradation — a role validated by enhanced IFN-I production in myeloid-specific Vangl2 knockout mice.

    Evidence Co-immunoprecipitation, ubiquitination assays, autophagy assays, myeloid-specific conditional knockout with VSV infection

    PMID:37352355

    Open questions at the time
    • Whether other PCP components participate in TBK1 regulation unknown
    • How IFN induction of VANGL2 is transcriptionally regulated not addressed
    • Whether VANGL2-TBK1 axis operates in non-myeloid cells untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for VANGL2's multi-partner scaffold function, how VANGL2 asymmetric localization is initially established and maintained, and how its PCP-dependent and PCP-independent functions (CMA regulation, innate immune signaling, cytoneme formation) are coordinated or segregated in different cell types.
  • No high-resolution structure of full-length VANGL2 or any VANGL2 complex
  • Mechanism establishing initial VANGL2 asymmetric localization unclear
  • Integration of PCP-independent functions with canonical PCP signaling not understood

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 7 GO:0005856 cytoskeleton 3 GO:0005794 Golgi apparatus 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1500931 Cell-Cell communication 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-9612973 Autophagy 2 R-HSA-168256 Immune System 1
Partners
DVL1DVL2DVL3FZD3LAMP2ROR2SCRIBTBK1
Complex memberships
Core PCP complex (Vangl2-Fz3/6-Dvl-Scribble)Vangl1/Vangl2 heteromeric complex

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Vangl2 mutation causes significant disruptions in the polarization of stereociliary bundles in mouse cochlea due to defects in kinocilium movement/anchoring; genetic interaction between Vangl2 and Scrb1 (heterozygotes for both show comparable defects to Vangl2 homozygotes) demonstrates these genes cooperate in mammalian planar cell polarity. Mouse genetics (loss-of-function mutations, double heterozygote analysis), morphological analysis of cochlear hair cells Nature High 12724779
2001 Ltap/Vangl2 is a mammalian homolog of Drosophila Strabismus/Van Gogh; mutations in Vangl2 cause craniorachischisis (open neural tube) in the Loop-tail mouse, identifying it as a component of the frizzled/dishevelled tissue polarity pathway expressed broadly in neuroectoderm. Positional cloning, sequencing of two independent Lp alleles, expression analysis Nature genetics High 11431695
2002 Stbm/Vangl2 inhibits Wnt-mediated activation of beta-catenin-dependent transcription while promoting phosphorylation of c-Jun- and AP-1-dependent transcription; Stbm physically interacts with the Dishevelled (Dsh) protein. Gain- and loss-of-function assays in zebrafish, Co-immunoprecipitation of Stbm with Dsh, reporter assays Nature cell biology High 11780127
2004 Mouse Vangl2 physically interacts with all three members of the Dishevelled (Dvl1, Dvl2, Dvl3) family via its cytoplasmic C-terminal half and a Dvl region containing PDZ and DIX domains; the two Looptail loss-of-function mutations (D255E and S464N) impair binding to Dvl1, Dvl2, and Dvl3. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, mutagenesis The Journal of biological chemistry High 15456783
2006 Vangl2 becomes asymmetrically localized to specific cell-cell boundaries along the polarization axis in the mammalian cochlea; PDZ2, PDZ3, and PDZ4 domains of Scribble (Scrb1) bind the C-terminal PDZ-binding domain of Vangl2; Vangl2 physically interacts with Frizzled3 and is required for Fz3 membrane targeting/anchoring. Immunofluorescence localization, PDZ domain binding assays, co-immunoprecipitation, analysis of PCP mutants The Journal of neuroscience High 16687519
2006 Scribble binds selectively to specific PDZ domains of Vangl2 at the basolateral plasma membrane and forms a multimeric complex with Vangl2; the Scrib LRR domain independently associates with the plasma membrane while PDZ domains bind Vangl2. Co-immunoprecipitation, EGFP-tagged fusion protein localization in polarized epithelial cells, biochemical fractionation Journal of cellular biochemistry Medium 16791850
2005 Vangl2 acts via RhoA signaling to regulate polarized cell movements (lamellipodia/filopodia formation and actin stress fiber formation) of myocardializing cells into outflow tract cushions; RhoA and its downstream mediator ROCK1 are disrupted in Vangl2 Lp/Lp mice, placing RhoA/ROCK1 downstream of Vangl2 in the PCP pathway. Mouse genetics (Lp/Lp analysis), immunohistochemistry, actin cytoskeleton analysis, RhoA expression assays Circulation research Medium 15637299
2008 The extracellular domain (ECD/CRD) of Frizzled directly interacts biochemically and physically with the transmembrane protein Van Gogh/Strabismus (Vangl2 ortholog), allowing cells to sense Fz activity of their neighbors during PCP establishment. In vivo Drosophila genetics, biochemical interaction assays between FzECD and Vang/Stbm Developmental cell Medium 18804440
2009 Sec24b, a COPII cargo-sorting protein, selectively sorts Vangl2 into ER-to-Golgi transport vesicles; Vangl2 Looptail 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 allele causing increased spina bifida. Forward genetic screen, COPII vesicle cargo sorting assay, ER localization studies, genetic interaction analysis Nature cell biology High 19966784
2009 Dact1 forms a complex with Vangl2; in Dact1 mutants, Vangl2 is increased at the primitive streak and associated with abnormal E-cadherin distribution; heterozygous Vangl2 mutation rescues recessive Dact1 phenotypes, placing Dact1 upstream of Vangl2 as a regulator of Vangl2 levels at the primitive streak. Genetic epistasis (double mutant rescue), co-immunoprecipitation (complex formation), protein localization analysis Nature genetics High 19701191
2010 Vangl2 controls the posterior tilting and asymmetric localization of motile primary cilia to the posterior apical membrane of neuroepithelial cells; Vangl2 is not required for ciliogenesis itself. Zebrafish loss-of-function (vangl2 null), live imaging with Arl13b-GFP ciliary marker Nature cell biology High 20305649
2011 Wnt5a signaling gradient induces phosphorylation of Vangl2 serine/threonine residues through a receptor complex containing Ror2; Vangl2 activity depends on its phosphorylation levels; this controls limb PCP and elongation. Biochemical phosphorylation assays, receptor complex co-immunoprecipitation, mouse genetics, mutagenesis of phosphorylation sites Developmental cell High 21316585
2011 Vangl2 antagonizes Dvl1-mediated hyperphosphorylation of Frizzled3 and promotes Fz3 internalization in commissural axon growth cones; Vangl2 is enriched at filopodial tips and emerging filopodia membranes; the antagonistic functions of Vangl2 and Dvl1 sharpen PCP signaling for directional Wnt sensing. Genetic knockdown/knockout, phosphorylation assays, subcellular localization imaging, axon guidance assays Developmental cell High 21316586
2011 Rack1 physically interacts with Vangl2 and is required for Vangl2 membrane localization; Rack1 knockdown affects membrane localization of Vangl2; the Vangl2-interacting domain of Rack1 has a dominant-negative effect on Vangl2 localization; Rack1 also antagonizes canonical Wnt signaling. Co-immunoprecipitation, zebrafish knockdown, membrane localization assays, dominant-negative constructs Proceedings of the National Academy of Sciences of the United States of America Medium 21262816
2012 The Wnt coreceptor Ryk interacts with Vangl2 biochemically and genetically; this interaction is potentiated by Wnt5a; Ryk forms a complex with Vangl2 and promotes Vangl2 protein stability/reduces its degradation. Co-immunoprecipitation, genetic interaction analysis (double mutants), protein stability assays The Journal of biological chemistry Medium 23144463
2012 VANGL2 regulates endocytosis and cell-surface availability of MMP14 (MT1-MMP) in a focal adhesion kinase-dependent manner; vangl2 mutant zebrafish exhibit increased Mmp14 activity and decreased ECM; in vivo knockdown of Mmp14 partially rescues the Vangl2 loss-of-function convergent extension phenotype. Zebrafish genetics, endocytosis assays, MMP activity assays, morpholino rescue experiments Journal of cell science High 22357946
2012 The Looptail mutant Vangl2(S464N) disrupts delivery of Vangl1 and Vangl2 proteins to the cell surface by forming oligomers with wild-type Vangl1 and Vangl2, causing intracellular retention; direct physical interaction between Vangl1 and Vangl2 demonstrated. Heterologous cell system, cell surface biotinylation, co-immunoprecipitation, in vivo hair cell analysis PloS one Medium 22363783
2012 Endogenous Vangl1/Vangl2 heteromeric protein complexes exist; biochemically confirmed using specific monoclonal anti-Vangl2 antibody and proteomic analysis of immunoprecipitates; both proteins colocalize at the plasma membrane. Immunoprecipitation with specific monoclonal antibody, proteomics/mass spectrometry, surface plasmon resonance, co-IP of tagged proteins PloS one High 23029439
2013 Arfrp1 (GTP-binding protein) and the clathrin adaptor complex AP-1 are required for Vangl2 transport from the trans-Golgi network (TGN); a YYXXF sorting signal in the C-terminal cytosolic domain of Vangl2 is required for interaction with the μ subunit of AP-1 and for Vangl2 trafficking; this sorting is distinct from Frizzled6 TGN export. siRNA knockdown, mutagenesis of sorting signal, co-immunoprecipitation with AP-1 subunit, in vitro TGN transport assays eLife High 23326640
2013 Cofilin1 (actin-severing protein) and Vangl2 cooperate genetically to control PCP in the early mouse embryo; in Vangl2/Cfl1 double mutants, PCP protein complexes fail to traffic to the apical cell membrane, revealing that F-actin remodeling is essential for the initiation of PCP; Vangl2 and cofilin cooperate to target Rab11+ vesicles containing PCP proteins to the apical membrane. Double mutant genetic epistasis, immunofluorescence localization, pharmacological actin disruption Development (Cambridge, England) High 23406901
2013 Scribble binds Stbm/Vang (Drosophila Vangl2 ortholog) through its PDZ domain 3; Scribble cooperates with Stbm/Vang in PCP establishment; Scribble is part of the Stbm/Vang PCP complex and acts as an effector. Drosophila genetics, genetic interaction, physical interaction assays, identification of PCP-specific scribble allele Developmental biology Medium 19563796
2013 Vangl2 directly binds N-cadherin and enhances N-cadherin internalization in a Rab5-dependent manner; this interaction is suppressed by β-catenin which binds the same intracellular region of N-cadherin; Prickle2 inhibits the N-cadherin-Vangl2 interaction; Vangl2 co-precipitates with N-cadherin and PSD-95 from brain extracts. Co-immunoprecipitation from brain extracts, internalization assays, Rab5 dependence assays, siRNA knockdown Cell reports High 24582966
2013 Vangl2 is complexed with postsynaptic density protein PSD-95 through direct binding requiring the C-terminal TSV PDZ-binding motif; Vangl1 and Vangl2 are tightly associated with the PSD fraction in adult rat neurons; the C-terminal PDZ-binding motif is required for dendritic spine localization. Biochemical fractionation (PSD fraction), co-immunoprecipitation, mutagenesis of PDZ-binding motif, immunostaining FEBS letters Medium 23567299
2014 Gipc1 (GAIP C-terminus interacting protein 1) is a novel interactor of Vangl2; a myosin VI-Gipc1 protein complex regulates Vangl2 trafficking; in MyoVI mutant mice, Vangl2 presence at the membrane is increased, indicating myosin VI-Gipc1 promotes Vangl2 internalization/trafficking. Co-immunoprecipitation, siRNA knockdown, mouse mutant analysis, STED microscopy, GFP-Vangl2 overexpression Development (Cambridge, England) Medium 22991442
2014 Vangl2 enhances internalization of E-cadherin via Rab5- and dynamin-dependent endocytosis; E-cadherin co-immunoprecipitates with Vangl2 from embryonic kidney extracts; Vangl2(Lp+) mutant cells show increased cell-surface E-cadherin ratio. Co-immunoprecipitation, overexpression, cell surface quantification, Rab5/dynamin dependence assays Scientific reports Medium 25373475
2004 MAGI-3 interacts with both Frizzled-4/7 and Ltap/Vangl2 and forms a ternary complex; MAGI-3, frizzled-4, and Ltap colocalize at cell contact sites; MAGI-3 strongly activates JNK in conjunction with frizzled-4 and Ltap in a Rac-dependent manner, functioning as a scaffold for this signaling cascade. Co-immunoprecipitation, colocalization immunostaining, JNK activation assay Oncogene Medium 15195140
2016 p62/SQSTM1 is a novel VANGL2-binding partner; VANGL2-p62/SQSTM1-JNK forms a proliferative signaling cascade in breast cancer; disruption of the VANGL2-p62/SQSTM1 interaction inactivates this cascade. Co-immunoprecipitation, siRNA knockdown, patient-derived xenograft experiments, JNK inhibition Nature communications Medium 26754771
2017 Vangl2 phosphorylation (induced by Wnt5a) is required for Vangl2 function in PCP in multiple tissues in vivo; phospho-mutant Vangl2 acts as a dominant negative; CK1ε and CK1δ are redundantly required for Wnt5a-induced Vangl2 phosphorylation; Dvl family members are required for this phosphorylation by enhancing CK1-Vangl2 interaction. In vivo mutagenesis of phosphorylation sites, mouse genetics, kinase assays, co-immunoprecipitation of CK1-Vangl2 complex Cell research High 29056748
2017 Vangl2 exerts dual regulation on Dvl during convergent extension: it cell-autonomously promotes Dvl plasma membrane recruitment, while simultaneously inhibiting Dvl from interacting with its downstream effector Daam1; this bimodal regulation underlies the logic of PCP signaling during morphogenesis. Mouse and Xenopus genetics, co-immunoprecipitation, membrane recruitment assays, epistasis Human molecular genetics Medium 28334810
2014 Vangl2 regulates Vangl2-JNK signaling and is required solely within the second heart field (SHF) for outflow tract lengthening via polarized epithelial organization of SHF cells; membrane-bound Vangl2 marks the transition zone of SHF differentiation. Conditional knockout (Cre/lox), marker analysis, cell polarity assays PLoS genetics Medium 25521757
2015 Vangl2 protein is enriched at anterior cell edges in the Xenopus neural plate (AP-PCP); 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. Immunofluorescence localization in Xenopus neural plate, inhibition of Myosin II, morpholino knockdown, analysis of Wnt signaling Biology open Medium 25910938
2014 Vangl2 cooperates with Rab11 and Myosin V to regulate apical constriction during Xenopus gastrulation; Vangl2 is required for apical accumulation of Rab11 recycling endosomes at the blastopore lip; overexpression of Rab11 RNA partially rescues blastopore formation in Vangl2-deficient embryos. Morpholino knockdown, Rab11 localization, rescue experiments, dominant-negative constructs Development (Cambridge, England) Medium 25480917
2018 Vangl2/RhoA signaling acts in rhabdomyosarcoma: RHOA acts downstream of VANGL2 to regulate proliferation and maintenance of tumor propagating cells, as shown with constitutively active and dominant-negative RhoA isoforms. siRNA knockdown, xenograft assays, constitutively active/dominant-negative RhoA constructs, zebrafish model Cell stem cell Medium 29499154
2018 Vangl2 directly interacts with integrin αvβ3; VANGL2 negatively regulates cell-surface integrin αvβ3 expression and MMP14/MMP2 activity; inhibition of MMP14/MMP2 activity suppresses the cell adhesion defect in VANGL2 knockdown cells. Co-immunoprecipitation, cell surface integrin assays, MMP activity assays, siRNA knockdown Experimental cell research Medium 29097183
2018 Vangl2 in the trans-Golgi network is reconstituted into vesicles in vitro; Vangl2 and Frizzled6 exit the TGN in separate compartments; epsinR regulates TGN export of Frizzled6 (but not Vangl2) via a polybasic motif in the Frizzled6 cytosolic domain, separating AP-1 (Vangl2) and epsinR (Fzd6) cargo-sorting functions. In vitro TGN vesicle reconstitution, siRNA knockdown, protein interaction analysis, immunoblotting of vesicle fractions The Journal of biological chemistry High 29666182
2021 Vangl2 directly binds to lysosome-associated membrane protein 2A (LAMP-2A) and targets it for degradation, thereby limiting chaperone-mediated autophagy (CMA) and controlling osteogenic vs. adipogenic differentiation of mesenchymal stem cells. Co-immunoprecipitation, MSC-specific conditional knockout, LAMP-2A protein level assays, bone/fat phenotype analysis Developmental cell High 34214490
2021 Vangl2 activation generates long branching cytonemes in zebrafish epiblast, mouse intestinal telocytes, and human gastric cancer cells that deliver Wnt protein to multiple cells and increase Wnt/β-catenin signaling in surrounding cells; Vangl2 inhibition causes fewer and shorter cytonemes and reduces paracrine Wnt signaling. Live imaging, morpholino knockdown, mouse and human cell culture, mathematical modeling confirmed by in vivo prediction Nature communications High 33824332
2023 VANGL2 acts as an IFN-inducible negative feedback regulator of type I IFN signaling; VANGL2 interacts with TBK1 and promotes its selective autophagic degradation via K48-linked polyubiquitination at Lys372 by E3 ligase TRIP, which creates a recognition signal for cargo receptor OPTN; myeloid-specific VANGL2 deletion enhances IFN-I production against VSV. Co-immunoprecipitation, ubiquitination assays, autophagy assays, myeloid-specific conditional knockout mice, viral infection model Science advances High 37352355
2011 Maternal Vangl2 interacts with the post-Golgi v-SNARE protein VAMP1 and with acetylated microtubules in Xenopus oocyte; Vangl2 is required for the stability of VAMP1 and for maintenance of stable microtubule architecture; Vangl2 also interacts with atypical PKC (aPKC), and both are required for cell membrane asymmetry during oocyte maturation. Co-immunoprecipitation, morpholino knockdown, immunostaining, microtubule stability assays Development (Cambridge, England) Medium 21813572
2016 Vangl2 is localized at the testis-specific ectoplasmic specialization (ES) and structurally interacts with actin, N-cadherin, and Scribble; Vangl2 knockdown by RNAi in Sertoli cells tightens the blood-testis barrier while overexpression perturbs it; these changes are mediated through actin microfilament organization involving Eps8, Arp3, and Scribble. RNAi knockdown, overexpression, tight junction permeability assay, co-immunoprecipitation, in vivo RNAi Endocrinology Medium 26990065
2020 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 and increases confined N-cadherin trajectories (stronger mechanical coupling of N-cadherin to actin cytoskeleton); Vangl2 acts as a negative regulator of axonal outgrowth by regulating the molecular clutch between N-cadherin and actin. Single molecule tracking, optical manipulation of N-cadherin-coated microspheres, FRAP, live imaging in growth cones eLife High 31909712
2016 Vangl2 EGFP shows polarized localization in the mouse oviduct enriched at specific cellular edges; FRAP analysis reveals Vangl2 forms stable complexes at the enriched cellular edge; Vangl2 asymmetry is maintained independently of microtubule formation (nocodazole treatment does not disrupt asymmetry), suggesting a different maintenance mechanism from the microtubule-dependent polarized transport model. FRAP analysis, nocodazole treatment, electroporation of GFP-tagged constructs, R26-Vangl2-EGFP transgenic mice Mechanisms of development Medium 27155041
2021 Vangl2-deleted neuroepithelial cells non-autonomously prevent apical constriction of 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. Mosaic conditional deletion in mouse neuroepithelium, live imaging, myosin-II localization, laser ablation Nature communications High 33608529

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Identification of Vangl2 and Scrb1 as planar polarity genes in mammals. Nature 580 12724779
2001 Ltap, a mammalian homolog of Drosophila Strabismus/Van Gogh, is altered in the mouse neural tube mutant Loop-tail. Nature genetics 412 11431695
2011 Wnt signaling gradients establish planar cell polarity by inducing Vangl2 phosphorylation through Ror2. Developmental cell 394 21316585
2002 The planar cell-polarity gene stbm regulates cell behaviour and cell fate in vertebrate embryos. Nature cell biology 310 11780127
2010 Vangl2 directs the posterior tilting and asymmetric localization of motile primary cilia. Nature cell biology 283 20305649
2001 Severe neural tube defects in the loop-tail mouse result from mutation of Lpp1, a novel gene involved in floor plate specification. Human molecular genetics 272 11709546
2006 Asymmetric localization of Vangl2 and Fz3 indicate novel mechanisms for planar cell polarity in mammals. The Journal of neuroscience : the official journal of the Society for Neuroscience 260 16687519
2009 Sec24b selectively sorts Vangl2 to regulate planar cell polarity during neural tube closure. Nature cell biology 178 19966784
2011 Vangl2 promotes Wnt/planar cell polarity-like signaling by antagonizing Dvl1-mediated feedback inhibition in growth cone guidance. Developmental cell 163 21316586
2005 Vangl2 acts via RhoA signaling to regulate polarized cell movements during development of the proximal outflow tract. Circulation research 143 15637299
2004 Independent mutations in mouse Vangl2 that cause neural tube defects in looptail mice impair interaction with members of the Dishevelled family. The Journal of biological chemistry 143 15456783
2010 The PCP genes Celsr1 and Vangl2 are required for normal lung branching morphogenesis. Human molecular genetics 128 20223754
2008 The frizzled extracellular domain is a ligand for Van Gogh/Stbm during nonautonomous planar cell polarity signaling. Developmental cell 123 18804440
2006 Scribble associates with two polarity proteins, Lgl2 and Vangl2, via distinct molecular domains. Journal of cellular biochemistry 119 16791850
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