{"gene":"DVL3","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2026,"finding":"Wnt stimulation triggers CK1-mediated multiphosphorylation of DVL3 that induces an intramolecular conformational switch between the DEP domain and the adjacent disordered region (phospho-switch), which is mutually exclusive with Frizzled receptor association. Charge accumulation proximal to the DEP domain is required (but not sufficient) for Wnt/β-catenin signaling. Proximity interactomics confirmed FZD receptors as prominent effectors of this phospho-switch.","method":"DVL3 phospho-switch mutant panel, proximity interactomics (BioID), in vitro phosphorylation assays, electrostatic/structural analysis","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (mutant panel, proximity interactomics, structural analysis) in a single rigorous study, with mechanistic detail at molecular level","pmids":["42127203"],"is_preprint":false},{"year":2025,"finding":"Pathogenic DVL3 frameshifting variants (novel basic C-terminus replacing ≥82 amino acids) fail to redistribute from cytoplasmic puncta to membrane upon WNT stimulation and fail to activate canonical WNT/β-catenin signaling (TOPFlash assay). The mutant C-terminal tail interferes with CSNK1E-induced phosphorylation of DVL3, providing a mechanism for impaired WNT response.","method":"Immunocytochemistry (localization), TOPFlash reporter assay (canonical WNT activation), transfection of WT vs. frameshift vs. truncated DVL1-3 constructs, in vitro phosphorylation assay","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (reporter assay, immunocytochemistry, phosphorylation assay) in single study with defined molecular mechanism","pmids":["bio_10.1101_2025.08.02.668297"],"is_preprint":true},{"year":2012,"finding":"DVL3 translocates IPMK (inositol polyphosphate multikinase) to the cell membrane upon Wnt3a stimulation. This requires the PDZ domain and the C-terminal proline-rich tail of DVL3. Membrane translocation of IPMK is obligate for its function in Wnt signaling, and a deletion mutant of IPMK lacking the NH2-terminal variable region fails to translocate and cannot propagate canonical Wnt signaling.","method":"Co-immunoprecipitation, domain deletion mutants, cellular fractionation/imaging, Wnt3a stimulation assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional evidence with domain mutants and localization, single lab with multiple methods","pmids":["22940627"],"is_preprint":false},{"year":2024,"finding":"WNT5B binding to FZD3 recruits DVL3 to the plasma membrane for phosphorylation in a WNT5B-dependent manner, and the DEP domain of DVL3 is required for this recruitment. DVL3 then activates RAC1 and downstream JNK signaling (non-canonical WNT/PCP pathway) in non-small cell lung cancer cells. Deletion of the DEP domain of DVL3 abrogated these effects.","method":"Co-immunoprecipitation (WNT5B-FZD3-DVL3 complex), domain deletion mutants (DEP domain), knockdown/overexpression, membrane fractionation, JNK/RAC1 activation assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and domain mutagenesis with defined signaling readout, single lab","pmids":["39094673"],"is_preprint":false},{"year":2016,"finding":"ALFY (an autophagy scaffold protein) specifically removes aggregates of DVL3, but not DVL1 or DVL2, via autophagy-dependent degradation, thereby attenuating canonical Wnt signaling. Loss of ALFY function leads to DVL3 aggregate accumulation and increased Wnt signaling, contributing to brain size determination.","method":"Genetic linkage/exome sequencing (human microcephaly), Drosophila transgenic model, molecular biology (autophagy inhibition, aggregate analysis), isoform-specific knockdowns","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics + Drosophila model + molecular mechanism, replicated across model systems with DVL isoform specificity demonstrated","pmids":["27008544"],"is_preprint":false},{"year":2014,"finding":"DVL3 is present in an adaptor complex that links IGFIR to RAS signaling, including Shc, Grb2, SOS, and the tumor suppressor DAB2. DVL3 blockade (genetic or pharmacologic) enhances MEK-ERK activation and sensitizes cells to IGFIR inhibition. Dual DVL3 and DAB2 blockade synergizes in activating ERKs, indicating a non-redundant role for DVL3 in the Shc-Grb2-SOS complex.","method":"Genetic screen, Co-immunoprecipitation (DVL3-Shc-Grb2-SOS-DAB2 complex), siRNA knockdown, in vivo xenograft, MEK-ERK activation assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP demonstrating complex, genetic validation in vitro and in vivo, multiple orthogonal methods, mechanistic pathway placement","pmids":["25168481"],"is_preprint":false},{"year":2011,"finding":"Dvl-3 regulates both GSK-3 phosphorylation state and β-catenin levels downstream of the dopamine D2 receptor (D2DR) in rat brain. Altering Dvl-3 levels in SH-SY5Y cells changes Akt activity and the Wnt pathway similar to D2DR manipulation. Co-immunoprecipitation revealed association between GSK-3 and the D2DR complex that was altered by D2DR agonist/antagonist treatment.","method":"Co-immunoprecipitation (GSK-3/D2DR complex), Western blotting, in vitro manipulation of Dvl-3 in SH-SY5Y cells, pharmacological (raclopride, quinpirole) treatment","journal":"The international journal of neuropsychopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional cell-based assays, multiple signaling readouts, single lab","pmids":["21777508"],"is_preprint":false},{"year":2019,"finding":"DVL3 knockdown in rat Sertoli cells disrupts actin- and microtubule-based cytoskeleton organization, impairing tight junction-permeability barrier function. In vivo Dvl1/2/3 triple knockdown caused spermatid polarity defects, defective spermatid adhesion and transport, and disruptive spatial expression of actin- and MT-regulatory proteins.","method":"RNAi knockdown (individual Dvl1, Dvl2, Dvl3 and triple knockdown), physiological/biochemical assays (TJ-permeability barrier), morphological analysis, in vivo testis knockdown","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro RNAi with defined cytoskeletal and functional phenotype readouts, single lab","pmids":["30808893"],"is_preprint":false},{"year":2019,"finding":"TLR4 activation by LPS induces Wnt3a and DVL3 expression in primary monocytes. DVL3 acts downstream of Wnt3a to promote β-catenin accumulation and restrain NF-κB activity, reducing pro-inflammatory cytokine production (IL-12, IL-6, TNFα). DVL3 siRNA silencing or Wnt3a inhibition significantly increases pro-inflammatory cytokine production and NF-κB P65 phosphorylation and DNA-binding activity.","method":"Gain- and loss-of-function (siRNA, ectopic expression of DVL3, GSK3β, β-catenin), ELISA, qRT-PCR, Western blot (signaling phosphorylation), murine endotoxin model (in vivo)","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple gain/loss of function approaches with in vivo validation, single lab, defined pathway placement","pmids":["31884387"],"is_preprint":false},{"year":2018,"finding":"DVL1 and DVL3 enter the nucleus and localize to at least two CYP19A1 (aromatase) promoters (pII and I.4) that drive overexpression in breast tumors, as well as a distal placental promoter (I.1). Loss-of-function of DVL-3 leads to differential changes in aromatase transcripts and estradiol (E2) production.","method":"Chromatin immunoprecipitation (ChIP) at CYP19A1 promoters, loss-of-function (DVL knockdown), aromatase transcript quantification, E2 production assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating nuclear DVL3 localization at specific promoters, functional loss-of-function with transcriptional and hormonal readout, single lab","pmids":["30479694"],"is_preprint":false},{"year":2022,"finding":"DVL3 nuclear localization is required for its role in regulating proliferation in human myoblasts. DVL3 requires both the DIX and PDZ domains (unlike DVL1) for nuclear localization-dependent proliferation control. DVL1 and DVL3 regulate proliferation independently of markedly increased nuclear β-CATENIN translocation.","method":"Loss-of-function (knockdown), domain deletion/mutant constructs, nuclear localization imaging, proliferation assays in human myoblasts and rhabdomyosarcoma cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis and localization linked directly to functional proliferation phenotype, single lab","pmids":["35589804"],"is_preprint":false},{"year":2022,"finding":"MEX3A (RNA-binding protein) physically interacts with DVL3 and stabilizes β-catenin in endometrial carcinoma cells, activating Wnt/β-catenin downstream target genes and promoting EMT. This interaction was validated by co-immunoprecipitation.","method":"Co-immunoprecipitation (MEX3A-DVL3), immunofluorescence, siRNA knockdown and overexpression, in vitro and in vivo assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP demonstrating direct interaction, multiple functional assays, single lab","pmids":["36614043"],"is_preprint":false},{"year":2024,"finding":"PNPO (pyridoxine-5'-phosphate oxidase) oxidizes DVL3 at Met282, leading to abnormal activation of the Wnt/β-catenin pathway in multiple myeloma. Disrupting the PNPO-DVL3 interaction (by Eltrombopag) inhibits MM cell growth and reduces bone lesions.","method":"Chemical probe (celastrol) target identification, biochemical oxidation assay (DVL3 Met282 oxidation), Co-IP (PNPO-DVL3 interaction), mouse model, mutagenesis at critical PNPO sites","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical modification identified with specific residue, Co-IP, and in vivo validation, single lab with multiple methods","pmids":["39656865"],"is_preprint":false},{"year":2013,"finding":"AMPK activators (metformin) reduce DVL3 protein levels through two mechanisms: inhibition of mTOR-dependent DVL3 protein synthesis via AMPK/mTOR signaling, and promotion of ubiquitin/proteasomal degradation of DVL3. In vivo ubiquitination assay confirmed metformin-induced DVL3 ubiquitination. Enforced DVL3 expression elevated β-catenin and augmented cervical cancer cell growth, confirming DVL3 as a positive Wnt/β-catenin regulator.","method":"Western blot, in vivo ubiquitination assay, proteasomal inhibitors (MG132, AM114), AMPK inhibitor (Compound C), overexpression/knockdown, xenograft","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo ubiquitination assay with pharmacological controls, multiple complementary methods, single lab","pmids":["23301094"],"is_preprint":false},{"year":2025,"finding":"DVL3 (along with CTNNB1 and PTEN) converges on PBX1 as a downstream target regulating neural progenitor cell (NPC) proliferation. In isogenic iPSC-derived NPCs with DVL3 ASD-related variants, PBX1a overexpression rescued increased NPC proliferation, establishing DVL3 upstream of PBX1 in NPC proliferation control.","method":"Isogenic iPSC-derived 2D NPCs, genetic epistasis (PBX1a overexpression rescue), proliferation assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in isogenic human iPSC model with defined rescue phenotype, single lab, preprint","pmids":["bio_10.1101_2025.03.12.642693"],"is_preprint":true},{"year":2025,"finding":"DVL3 proximity interactome (BioID) identified novel Wnt/PCP pathway components interacting with DVL3 in the cytoplasm. RAI14, EPHA2, and PHACTR4 were found as essential components connecting the PCP receptor complex to effector actomyosin.","method":"Proximity-dependent biotinylation (BioID) of DVL3 and other PCP components, zebrafish loss-of-function validation, subcellular compartment mapping","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity interactomics with in vivo (zebrafish) functional validation, single lab, preprint","pmids":["bio_10.1101_2025.01.15.633117"],"is_preprint":true},{"year":1997,"finding":"Human DVL3 (DVL-3) was cloned as a second human homolog of Drosophila Dishevelled. It encodes a 716 amino acid protein with 98% amino acid identity to mouse Dvl-3 and 49% to Drosophila Dsh. DVL-3 was mapped to chromosome 3q27.","method":"cDNA library screening, sequencing, chromosomal mapping, Northern blot expression analysis","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — definitive molecular cloning and chromosomal mapping, foundational characterization paper","pmids":["9344861"],"is_preprint":false},{"year":2026,"finding":"CCNL1 directly interacts with DVL3 (verified by Co-IP), and this interaction is negatively correlated with DVL3 levels. CCNL1 overexpression activates NF-κB signaling through its interaction with DVL3 and promotes the PI3K/AKT pathway in breast cancer cells.","method":"Co-immunoprecipitation (CCNL1-DVL3), Western blot, overexpression/knockdown, rescue assays","journal":"Molecular carcinogenesis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with limited mechanistic follow-up on DVL3-specific function, single lab","pmids":["41632921"],"is_preprint":false}],"current_model":"DVL3 is a cytoplasmic scaffold protein that relays WNT signals from Frizzled (FZD) receptors to downstream effectors: upon Wnt stimulation, CK1 multiphosphorylates DVL3 to trigger an intramolecular DEP-domain conformational phospho-switch that promotes DVL3 dissociation from FZD and enables downstream β-catenin (canonical) and RAC1-JNK/PCP (non-canonical) signaling; DVL3 also recruits IPMK to the membrane via its PDZ domain, participates in an IGFIR-Shc-Grb2-SOS-DAB2 adaptor complex linking IGF signaling to RAS, undergoes autophagy-dependent selective degradation by ALFY and ubiquitin/proteasomal degradation downstream of AMPK/mTOR, is oxidized by PNPO to activate Wnt/β-catenin in myeloma, translocates to the nucleus to regulate CYP19A1 promoters and proliferation, and modulates inflammatory responses via GSK3β-β-catenin and NF-κB; pathogenic frameshifting variants causing Robinow syndrome disrupt WNT-induced membrane redistribution and CK1-dependent phosphorylation of DVL3."},"narrative":{"mechanistic_narrative":"DVL3 is a cytoplasmic scaffold protein that relays WNT signals from Frizzled (FZD) receptors to both canonical (β-catenin) and non-canonical (planar cell polarity) effectors [PMID:42127203, PMID:39094673]. WNT stimulation drives CK1-mediated multiphosphorylation of DVL3, triggering an intramolecular phospho-switch between the DEP domain and the adjacent disordered region that is mutually exclusive with Frizzled association; charge accumulation near the DEP domain is required for canonical Wnt/β-catenin signaling, and FZD receptors are prominent effectors of this switch [PMID:42127203]. In the non-canonical arm, WNT5B-FZD3 recruits DVL3 to the plasma membrane through its DEP domain, where DVL3 activates RAC1 and downstream JNK signaling [PMID:39094673]. DVL3 functions as a positive regulator of Wnt/β-catenin in multiple contexts, recruiting IPMK to the membrane via its PDZ domain and proline-rich tail [PMID:22940627] and acting as a node whose abundance is tuned by degradation: the autophagy scaffold ALFY selectively clears DVL3 aggregates [PMID:27008544], while AMPK/mTOR signaling and ubiquitin/proteasomal degradation lower DVL3 protein levels [PMID:23301094]. Beyond the membrane, DVL3 translocates to the nucleus, localizing to CYP19A1 (aromatase) promoters to control transcription and estradiol production [PMID:30479694] and driving proliferation in a manner dependent on its DIX and PDZ domains [PMID:35589804]. DVL3 also participates in non-Wnt signaling, residing in an IGFIR-Shc-Grb2-SOS-DAB2 adaptor complex that links IGF signaling to RAS/MEK-ERK [PMID:25168481] and restraining NF-κB-driven inflammatory cytokine production downstream of TLR4/Wnt3a [PMID:31884387]. Pathogenic DVL3 frameshifting variants causing Robinow syndrome generate a novel basic C-terminus that interferes with CSNK1E-induced phosphorylation and abolishes WNT-induced membrane redistribution and canonical signaling [PMID:bio_10.1101_2025.08.02.668297].","teleology":[{"year":1997,"claim":"Established the molecular identity of human DVL3 as a Dishevelled homolog, providing the foundation for studying it as a WNT pathway component.","evidence":"cDNA cloning, sequencing, and chromosomal mapping to 3q27","pmids":["9344861"],"confidence":"High","gaps":["No functional or mechanistic assignment beyond homology","Domain-level activities not characterized"]},{"year":2012,"claim":"Showed DVL3 acts as a membrane-recruitment scaffold, defining how it propagates canonical Wnt signals by relocating an effector kinase.","evidence":"Co-IP, domain deletion mutants, and fractionation/imaging after Wnt3a stimulation; IPMK translocation","pmids":["22940627"],"confidence":"Medium","gaps":["Direct vs. indirect PDZ-mediated IPMK binding not resolved","Single lab"]},{"year":2014,"claim":"Placed DVL3 outside the canonical Wnt axis as a component of an IGFIR-to-RAS adaptor complex, revealing a non-redundant scaffolding role in growth-factor signaling.","evidence":"Genetic screen, Co-IP of DVL3-Shc-Grb2-SOS-DAB2, siRNA, xenograft, MEK-ERK assays","pmids":["25168481"],"confidence":"High","gaps":["Direct binding partner of DVL3 within the complex not pinpointed","Mechanism of ERK suppression unclear"]},{"year":2016,"claim":"Defined a DVL3-specific degradation route, explaining how cellular DVL3 abundance and Wnt output are controlled in development.","evidence":"Human exome sequencing, Drosophila model, autophagy inhibition, isoform-specific knockdowns","pmids":["27008544"],"confidence":"High","gaps":["Molecular basis of ALFY isoform selectivity for DVL3 unknown","Aggregate recognition signal not defined"]},{"year":2018,"claim":"Demonstrated a nuclear function for DVL3, expanding its role from cytoplasmic scaffold to direct chromatin-associated transcriptional regulator.","evidence":"ChIP at CYP19A1 promoters, DVL knockdown, transcript and estradiol quantification","pmids":["30479694"],"confidence":"Medium","gaps":["Nuclear import mechanism not defined","DNA-binding partners at promoters unidentified"]},{"year":2019,"claim":"Linked DVL3 to cytoskeletal organization and to inflammatory tone, broadening its functional repertoire beyond β-catenin transcription.","evidence":"RNAi knockdown in Sertoli cells/testis (cytoskeleton, tight junctions); gain/loss-of-function and endotoxin model (NF-κB restraint)","pmids":["30808893","31884387"],"confidence":"Medium","gaps":["Direct molecular targets in cytoskeletal regulation unknown","Mechanism by which DVL3/β-catenin restrains NF-κB not detailed"]},{"year":2022,"claim":"Tied DVL3 nuclear localization to a proliferation function dependent on specific domains, distinguishing it from DVL1 and from bulk β-catenin translocation.","evidence":"Domain mutants, nuclear imaging, proliferation assays in myoblasts; Co-IP of MEX3A-DVL3 in endometrial carcinoma","pmids":["35589804","36614043"],"confidence":"Medium","gaps":["β-catenin-independent proliferation mechanism not defined","Functional consequence of MEX3A binding on DVL3 itself unclear"]},{"year":2024,"claim":"Identified a redox post-translational modification and a membrane-recruitment route that activate DVL3-dependent Wnt signaling in disease contexts.","evidence":"Met282 oxidation biochemistry and PNPO-DVL3 Co-IP in myeloma; WNT5B-FZD3-DVL3 Co-IP, DEP-domain deletion, RAC1/JNK assays in lung cancer","pmids":["39656865","39094673"],"confidence":"Medium","gaps":["Structural consequence of Met282 oxidation not modeled","Single-lab findings each await independent confirmation"]},{"year":2025,"claim":"Resolved the phospho-regulated conformational logic of DVL3 and connected it to disease, showing how phosphorylation toggles DVL3 between FZD-bound and signaling-competent states.","evidence":"Phospho-switch mutant panel, BioID, in vitro phosphorylation, electrostatic/structural analysis; Robinow frameshift constructs with TOPFlash, ICC, phosphorylation assays; iPSC-NPC epistasis (PBX1 rescue); PCP BioID with zebrafish validation","pmids":["42127203","bio_10.1101_2025.08.02.668297","bio_10.1101_2025.03.12.642693","bio_10.1101_2025.01.15.633117"],"confidence":"High","gaps":["Atomic structure of the DEP-disordered region switch not solved","How distinct C-terminal lengths in Robinow variants impair CK1 phosphorylation mechanistically unclear","Generality of PCP interactors (RAI14, EPHA2, PHACTR4) across tissues untested"]},{"year":null,"claim":"How DVL3's distinct activities — phospho-switch-gated FZD release, nuclear transcriptional roles, the IGFIR-RAS adaptor function, and redox/degradation control — are coordinated within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating cytoplasmic, membrane, and nuclear pools","Domain determinants partitioning canonical vs. non-canonical vs. non-Wnt functions not fully mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,15]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9,10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8]}],"complexes":["IGFIR-Shc-Grb2-SOS-DAB2 adaptor complex","WNT5B-FZD3-DVL3 complex"],"partners":["FZD3","IPMK","WNT5B","DAB2","MEX3A","PNPO","CCNL1","CSNK1E"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92997","full_name":"Segment polarity protein dishevelled homolog DVL-3","aliases":["DSH homolog 3"],"length_aa":716,"mass_kda":78.1,"function":"Involved in the signal transduction pathway mediated by multiple Wnt genes","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q92997/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DVL3","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DVL3","total_profiled":1310},"omim":[{"mim_id":"617520","title":"MICROCEPHALY 18, PRIMARY, AUTOSOMAL DOMINANT; MCPH18","url":"https://www.omim.org/entry/617520"},{"mim_id":"617485","title":"WD REPEAT- AND FYVE DOMAIN-CONTAINING PROTEIN 3; WDFY3","url":"https://www.omim.org/entry/617485"},{"mim_id":"616894","title":"ROBINOW SYNDROME, AUTOSOMAL DOMINANT 3; DRS3","url":"https://www.omim.org/entry/616894"},{"mim_id":"616331","title":"ROBINOW SYNDROME, AUTOSOMAL DOMINANT 2; DRS2","url":"https://www.omim.org/entry/616331"},{"mim_id":"614930","title":"DYNEIN, AXONEMAL, ASSEMBLY FACTOR 11; DNAAF11","url":"https://www.omim.org/entry/614930"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Midbody ring","reliability":"Approved"},{"location":"Basal body","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Intermediate filaments","reliability":"Additional"},{"location":"Centrosome","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DVL3"},"hgnc":{"alias_symbol":["KIAA0208"],"prev_symbol":[]},"alphafold":{"accession":"Q92997","domains":[{"cath_id":"2.40.240.130","chopping":"3-79","consensus_level":"high","plddt":88.884,"start":3,"end":79},{"cath_id":"2.30.42.10","chopping":"246-333","consensus_level":"high","plddt":86.6189,"start":246,"end":333},{"cath_id":"1.10.10.10","chopping":"411-493","consensus_level":"high","plddt":91.0754,"start":411,"end":493}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92997","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92997-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92997-F1-predicted_aligned_error_v6.png","plddt_mean":58.91},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DVL3","jax_strain_url":"https://www.jax.org/strain/search?query=DVL3"},"sequence":{"accession":"Q92997","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92997.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92997/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92997"}},"corpus_meta":[{"pmid":"23301094","id":"PMC_23301094","title":"AMPK activators suppress cervical cancer cell growth through inhibition of DVL3 mediated Wnt/β-catenin signaling activity.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23301094","citation_count":75,"is_preprint":false},{"pmid":"27008544","id":"PMC_27008544","title":"ALFY-Controlled DVL3 Autophagy Regulates Wnt Signaling, Determining Human Brain Size.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27008544","citation_count":73,"is_preprint":false},{"pmid":"25847080","id":"PMC_25847080","title":"miR-204-5p promotes the adipogenic differentiation of human adipose-derived mesenchymal stem cells by modulating DVL3 expression and suppressing Wnt/β-catenin signaling.","date":"2015","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25847080","citation_count":62,"is_preprint":false},{"pmid":"28035400","id":"PMC_28035400","title":"AMPK activators suppress breast cancer cell growth by inhibiting DVL3-facilitated Wnt/β-catenin signaling pathway activity.","date":"2016","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/28035400","citation_count":43,"is_preprint":false},{"pmid":"30479694","id":"PMC_30479694","title":"DVL1 and DVL3 differentially localize to CYP19A1 promoters and regulate aromatase mRNA in breast cancer cells.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/30479694","citation_count":41,"is_preprint":false},{"pmid":"21777508","id":"PMC_21777508","title":"The dopamine D2 receptor regulates Akt and GSK-3 via Dvl-3.","date":"2011","source":"The international journal of neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21777508","citation_count":39,"is_preprint":false},{"pmid":"24933634","id":"PMC_24933634","title":"Brain metastases from lung cancer show increased expression of DVL1, DVL3 and beta-catenin and down-regulation of E-cadherin.","date":"2014","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24933634","citation_count":38,"is_preprint":false},{"pmid":"19815336","id":"PMC_19815336","title":"MSX1 induces the Wnt pathway antagonist genes DKK1, DKK2, DKK3, and SFRP1 in neuroblastoma cells, but does not block Wnt3 and Wnt5A signalling to DVL3.","date":"2009","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/19815336","citation_count":37,"is_preprint":false},{"pmid":"25168481","id":"PMC_25168481","title":"Dsh homolog DVL3 mediates resistance to IGFIR inhibition by regulating IGF-RAS signaling.","date":"2014","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/25168481","citation_count":28,"is_preprint":false},{"pmid":"30808893","id":"PMC_30808893","title":"Planar cell polarity protein Dishevelled 3 (Dvl3) regulates ectoplasmic specialization (ES) dynamics in the testis through changes in cytoskeletal organization.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30808893","citation_count":27,"is_preprint":false},{"pmid":"31884387","id":"PMC_31884387","title":"TLR4 induced Wnt3a-Dvl3 restrains the intensity of inflammation and protects against endotoxin-driven organ failure through GSK3β/β-catenin signaling.","date":"2019","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31884387","citation_count":25,"is_preprint":false},{"pmid":"9344861","id":"PMC_9344861","title":"cDNA cloning of a human dishevelled DVL-3 gene, mapping to 3q27, and expression in human breast and colon carcinomas.","date":"1997","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9344861","citation_count":22,"is_preprint":false},{"pmid":"32414668","id":"PMC_32414668","title":"Silencing DVL3 defeats MTX resistance and attenuates stemness via Notch Signaling Pathway in colorectal cancer.","date":"2020","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/32414668","citation_count":18,"is_preprint":false},{"pmid":"30468298","id":"PMC_30468298","title":"Different behaviour of DVL1, DVL2, DVL3 in astrocytoma malignancy grades and their association to TCF1 and LEF1 upregulation.","date":"2018","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30468298","citation_count":18,"is_preprint":false},{"pmid":"33016900","id":"PMC_33016900","title":"LncRNA testis-specific transcript, Y-linked 15 (TTTY15) promotes proliferation, migration and invasion of colorectal cancer cells via regulating miR-29a-3p/DVL3 axis.","date":"2021","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/33016900","citation_count":18,"is_preprint":false},{"pmid":"29575616","id":"PMC_29575616","title":"Autosomal dominant Robinow syndrome associated with a novel DVL3 splice mutation.","date":"2018","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/29575616","citation_count":17,"is_preprint":false},{"pmid":"33641528","id":"PMC_33641528","title":"LncRNA BLACAT1 Promotes Proliferation, Migration and Invasion of Prostate Cancer Cells via Regulating miR-29a-3p/DVL3 Axis.","date":"2021","source":"Technology in cancer research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/33641528","citation_count":15,"is_preprint":false},{"pmid":"38350242","id":"PMC_38350242","title":"Ginsenoside Rg3 suppresses vasculogenic mimicry by impairing DVL3-maintained stemness via PAAD cell-derived exosomal miR-204 in pancreatic adenocarcinoma.","date":"2024","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38350242","citation_count":15,"is_preprint":false},{"pmid":"30536315","id":"PMC_30536315","title":"Role and mechanism of Dvl3 in the esophageal squamous cell carcinoma.","date":"2018","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30536315","citation_count":14,"is_preprint":false},{"pmid":"35589804","id":"PMC_35589804","title":"DVL1 and DVL3 require nuclear localisation to regulate proliferation in human myoblasts.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35589804","citation_count":14,"is_preprint":false},{"pmid":"36614043","id":"PMC_36614043","title":"RNA-Binding Protein MEX3A Interacting with DVL3 Stabilizes Wnt/β-Catenin Signaling in Endometrial Carcinoma.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36614043","citation_count":13,"is_preprint":false},{"pmid":"35576835","id":"PMC_35576835","title":"E2F1-activated LINC01224 drives esophageal squamous cell carcinoma cell malignant behaviors via targeting miR-6884-5p/DVL3 axis and activating Wnt/β-catenin signaling pathway.","date":"2022","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/35576835","citation_count":13,"is_preprint":false},{"pmid":"39656865","id":"PMC_39656865","title":"PNPO-Mediated Oxidation of DVL3 Promotes Multiple Myeloma Malignancy and Osteoclastogenesis by Activating the Wnt/β-Catenin Pathway.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39656865","citation_count":11,"is_preprint":false},{"pmid":"22940627","id":"PMC_22940627","title":"Dvl3 translocates IPMK to the cell membrane in response to Wnt.","date":"2012","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/22940627","citation_count":10,"is_preprint":false},{"pmid":"39094673","id":"PMC_39094673","title":"WNT5B promotes the malignant phenotype of non-small cell lung cancer via the FZD3-DVL3-RAC1-PCP-JNK pathway.","date":"2024","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/39094673","citation_count":9,"is_preprint":false},{"pmid":"35314912","id":"PMC_35314912","title":"Circ_0101802 Facilitates Colorectal Cancer Progression Depending on the Regulation of miR-665/DVL3 Signaling.","date":"2022","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35314912","citation_count":9,"is_preprint":false},{"pmid":"30242173","id":"PMC_30242173","title":"Dvl3 polymorphism interacts with life events and pro-inflammatory cytokines to influence major depressive disorder susceptibility.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30242173","citation_count":9,"is_preprint":false},{"pmid":"28107606","id":"PMC_28107606","title":"Dishevelled segment polarity protein 3 (DVL3): a novel and easily applicable recurrence predictor in localised prostate adenocarcinoma.","date":"2017","source":"BJU international","url":"https://pubmed.ncbi.nlm.nih.gov/28107606","citation_count":8,"is_preprint":false},{"pmid":"35499309","id":"PMC_35499309","title":"Exosomal Dvl3 promoted the aggressive phenotypic transformation of RA-FLS via wnt pathway.","date":"2022","source":"Autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/35499309","citation_count":5,"is_preprint":false},{"pmid":"38583012","id":"PMC_38583012","title":"Dishevelled Segment Polarity Protein 3 (DVL3) Induced by Bacterial LPS Promotes the Proliferation and Migration of Prostate Cancer Cells through the TLR4 Pathway.","date":"2024","source":"Archivos espanoles de urologia","url":"https://pubmed.ncbi.nlm.nih.gov/38583012","citation_count":5,"is_preprint":false},{"pmid":"34691249","id":"PMC_34691249","title":"Aberrant expression of SFRP1, SFRP3, DVL2 and DVL3 Wnt signaling pathway components in diffuse gastric carcinoma.","date":"2021","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/34691249","citation_count":5,"is_preprint":false},{"pmid":"35126809","id":"PMC_35126809","title":"The Gender-Specific Interaction of DVL3 and GSK3β Polymorphisms on Major Depressive Disorder Susceptibility in a Chinese Han Population: A Case-Control Study.","date":"2022","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/35126809","citation_count":5,"is_preprint":false},{"pmid":"38040867","id":"PMC_38040867","title":"Delivery of microRNA-423-5p by exosome from adipose-derived stem/stromal cells inhibits DVL3 to potentiate autologous fat graft survival through adipogenesis and inflammatory response.","date":"2023","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/38040867","citation_count":4,"is_preprint":false},{"pmid":"37501340","id":"PMC_37501340","title":"Presenilin-2 knock-In mice show severe depressive behavior via DVL3 downregulation.","date":"2023","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/37501340","citation_count":3,"is_preprint":false},{"pmid":"35497711","id":"PMC_35497711","title":"Retracted Article: Panax notoginseng saponins regulate VEGF to suppress esophageal squamous cell carcinoma progression via DVL3-mediated Wnt/β-catenin signaling.","date":"2020","source":"RSC advances","url":"https://pubmed.ncbi.nlm.nih.gov/35497711","citation_count":3,"is_preprint":false},{"pmid":"33038884","id":"PMC_33038884","title":"Polymorphism and expression of the Dvl3 gene in the etiology of depressive disorder.","date":"2020","source":"Psychiatria polska","url":"https://pubmed.ncbi.nlm.nih.gov/33038884","citation_count":1,"is_preprint":false},{"pmid":"41327220","id":"PMC_41327220","title":"E2F7 promotes ESCC progression and cisplatin resistance through transcriptional activation of DVL3 and the Wnt signaling pathway.","date":"2025","source":"World journal of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41327220","citation_count":0,"is_preprint":false},{"pmid":"41632921","id":"PMC_41632921","title":"CCNL1 Activates the NF-κB Pathway Through DVL3 Inhibition and PI3K/AKT Pathway Promotion in Breast Cancer.","date":"2026","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/41632921","citation_count":0,"is_preprint":false},{"pmid":"35680573","id":"PMC_35680573","title":"[Effect of miR-204 targeted regulation of DVL3 gene in silica-induced mouse lung epithelial cells].","date":"2022","source":"Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases","url":"https://pubmed.ncbi.nlm.nih.gov/35680573","citation_count":0,"is_preprint":false},{"pmid":"42127203","id":"PMC_42127203","title":"A Wnt-induced conformational phospho-switch in DVL3 controls association with Frizzled receptors and Wnt/β-catenin signaling.","date":"2026","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/42127203","citation_count":0,"is_preprint":false},{"pmid":"35427054","id":"PMC_35427054","title":"Retraction: Panax notoginseng saponins regulate VEGF to suppress esophageal squamous cell carcinoma progression via DVL3-mediated Wnt/β-catenin signaling.","date":"2021","source":"RSC advances","url":"https://pubmed.ncbi.nlm.nih.gov/35427054","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.10.675378","title":"A Wnt-induced conformational phospho-switch in DVL3 controls interaction with Frizzled receptors and Wnt/β-catenin signaling","date":"2025-09-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.10.675378","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.12.642693","title":"Autism risk genes converge on  <i>PBX1</i>  to govern neural cell growth","date":"2025-03-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.12.642693","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.02.668297","title":"Pathogenic  <i>DVL</i>  frameshifting variants in Robinow syndrome disrupt WNT signaling and cellular dynamics","date":"2025-08-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.02.668297","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.15.633117","title":"Proximity interactomics identifies RAI14, EPHA2 and PHACTR4 as essential components of Wnt/planar cell polarity pathway in vertebrates","date":"2025-01-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.15.633117","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.25.645248","title":"Wnt/Beta-Catenin Signaling Is Active in Neuroendocrine Prostate Cancer","date":"2025-03-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.25.645248","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":26255,"output_tokens":4950,"usd":0.076508,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13163,"output_tokens":3597,"usd":0.07787,"stage2_stop_reason":"end_turn"},"total_usd":0.154378,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2026,\n      \"finding\": \"Wnt stimulation triggers CK1-mediated multiphosphorylation of DVL3 that induces an intramolecular conformational switch between the DEP domain and the adjacent disordered region (phospho-switch), which is mutually exclusive with Frizzled receptor association. Charge accumulation proximal to the DEP domain is required (but not sufficient) for Wnt/β-catenin signaling. Proximity interactomics confirmed FZD receptors as prominent effectors of this phospho-switch.\",\n      \"method\": \"DVL3 phospho-switch mutant panel, proximity interactomics (BioID), in vitro phosphorylation assays, electrostatic/structural analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (mutant panel, proximity interactomics, structural analysis) in a single rigorous study, with mechanistic detail at molecular level\",\n      \"pmids\": [\"42127203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Pathogenic DVL3 frameshifting variants (novel basic C-terminus replacing ≥82 amino acids) fail to redistribute from cytoplasmic puncta to membrane upon WNT stimulation and fail to activate canonical WNT/β-catenin signaling (TOPFlash assay). The mutant C-terminal tail interferes with CSNK1E-induced phosphorylation of DVL3, providing a mechanism for impaired WNT response.\",\n      \"method\": \"Immunocytochemistry (localization), TOPFlash reporter assay (canonical WNT activation), transfection of WT vs. frameshift vs. truncated DVL1-3 constructs, in vitro phosphorylation assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (reporter assay, immunocytochemistry, phosphorylation assay) in single study with defined molecular mechanism\",\n      \"pmids\": [\"bio_10.1101_2025.08.02.668297\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DVL3 translocates IPMK (inositol polyphosphate multikinase) to the cell membrane upon Wnt3a stimulation. This requires the PDZ domain and the C-terminal proline-rich tail of DVL3. Membrane translocation of IPMK is obligate for its function in Wnt signaling, and a deletion mutant of IPMK lacking the NH2-terminal variable region fails to translocate and cannot propagate canonical Wnt signaling.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mutants, cellular fractionation/imaging, Wnt3a stimulation assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional evidence with domain mutants and localization, single lab with multiple methods\",\n      \"pmids\": [\"22940627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WNT5B binding to FZD3 recruits DVL3 to the plasma membrane for phosphorylation in a WNT5B-dependent manner, and the DEP domain of DVL3 is required for this recruitment. DVL3 then activates RAC1 and downstream JNK signaling (non-canonical WNT/PCP pathway) in non-small cell lung cancer cells. Deletion of the DEP domain of DVL3 abrogated these effects.\",\n      \"method\": \"Co-immunoprecipitation (WNT5B-FZD3-DVL3 complex), domain deletion mutants (DEP domain), knockdown/overexpression, membrane fractionation, JNK/RAC1 activation assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and domain mutagenesis with defined signaling readout, single lab\",\n      \"pmids\": [\"39094673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ALFY (an autophagy scaffold protein) specifically removes aggregates of DVL3, but not DVL1 or DVL2, via autophagy-dependent degradation, thereby attenuating canonical Wnt signaling. Loss of ALFY function leads to DVL3 aggregate accumulation and increased Wnt signaling, contributing to brain size determination.\",\n      \"method\": \"Genetic linkage/exome sequencing (human microcephaly), Drosophila transgenic model, molecular biology (autophagy inhibition, aggregate analysis), isoform-specific knockdowns\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics + Drosophila model + molecular mechanism, replicated across model systems with DVL isoform specificity demonstrated\",\n      \"pmids\": [\"27008544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DVL3 is present in an adaptor complex that links IGFIR to RAS signaling, including Shc, Grb2, SOS, and the tumor suppressor DAB2. DVL3 blockade (genetic or pharmacologic) enhances MEK-ERK activation and sensitizes cells to IGFIR inhibition. Dual DVL3 and DAB2 blockade synergizes in activating ERKs, indicating a non-redundant role for DVL3 in the Shc-Grb2-SOS complex.\",\n      \"method\": \"Genetic screen, Co-immunoprecipitation (DVL3-Shc-Grb2-SOS-DAB2 complex), siRNA knockdown, in vivo xenograft, MEK-ERK activation assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP demonstrating complex, genetic validation in vitro and in vivo, multiple orthogonal methods, mechanistic pathway placement\",\n      \"pmids\": [\"25168481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Dvl-3 regulates both GSK-3 phosphorylation state and β-catenin levels downstream of the dopamine D2 receptor (D2DR) in rat brain. Altering Dvl-3 levels in SH-SY5Y cells changes Akt activity and the Wnt pathway similar to D2DR manipulation. Co-immunoprecipitation revealed association between GSK-3 and the D2DR complex that was altered by D2DR agonist/antagonist treatment.\",\n      \"method\": \"Co-immunoprecipitation (GSK-3/D2DR complex), Western blotting, in vitro manipulation of Dvl-3 in SH-SY5Y cells, pharmacological (raclopride, quinpirole) treatment\",\n      \"journal\": \"The international journal of neuropsychopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional cell-based assays, multiple signaling readouts, single lab\",\n      \"pmids\": [\"21777508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DVL3 knockdown in rat Sertoli cells disrupts actin- and microtubule-based cytoskeleton organization, impairing tight junction-permeability barrier function. In vivo Dvl1/2/3 triple knockdown caused spermatid polarity defects, defective spermatid adhesion and transport, and disruptive spatial expression of actin- and MT-regulatory proteins.\",\n      \"method\": \"RNAi knockdown (individual Dvl1, Dvl2, Dvl3 and triple knockdown), physiological/biochemical assays (TJ-permeability barrier), morphological analysis, in vivo testis knockdown\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro RNAi with defined cytoskeletal and functional phenotype readouts, single lab\",\n      \"pmids\": [\"30808893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TLR4 activation by LPS induces Wnt3a and DVL3 expression in primary monocytes. DVL3 acts downstream of Wnt3a to promote β-catenin accumulation and restrain NF-κB activity, reducing pro-inflammatory cytokine production (IL-12, IL-6, TNFα). DVL3 siRNA silencing or Wnt3a inhibition significantly increases pro-inflammatory cytokine production and NF-κB P65 phosphorylation and DNA-binding activity.\",\n      \"method\": \"Gain- and loss-of-function (siRNA, ectopic expression of DVL3, GSK3β, β-catenin), ELISA, qRT-PCR, Western blot (signaling phosphorylation), murine endotoxin model (in vivo)\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple gain/loss of function approaches with in vivo validation, single lab, defined pathway placement\",\n      \"pmids\": [\"31884387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DVL1 and DVL3 enter the nucleus and localize to at least two CYP19A1 (aromatase) promoters (pII and I.4) that drive overexpression in breast tumors, as well as a distal placental promoter (I.1). Loss-of-function of DVL-3 leads to differential changes in aromatase transcripts and estradiol (E2) production.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) at CYP19A1 promoters, loss-of-function (DVL knockdown), aromatase transcript quantification, E2 production assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating nuclear DVL3 localization at specific promoters, functional loss-of-function with transcriptional and hormonal readout, single lab\",\n      \"pmids\": [\"30479694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DVL3 nuclear localization is required for its role in regulating proliferation in human myoblasts. DVL3 requires both the DIX and PDZ domains (unlike DVL1) for nuclear localization-dependent proliferation control. DVL1 and DVL3 regulate proliferation independently of markedly increased nuclear β-CATENIN translocation.\",\n      \"method\": \"Loss-of-function (knockdown), domain deletion/mutant constructs, nuclear localization imaging, proliferation assays in human myoblasts and rhabdomyosarcoma cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis and localization linked directly to functional proliferation phenotype, single lab\",\n      \"pmids\": [\"35589804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MEX3A (RNA-binding protein) physically interacts with DVL3 and stabilizes β-catenin in endometrial carcinoma cells, activating Wnt/β-catenin downstream target genes and promoting EMT. This interaction was validated by co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation (MEX3A-DVL3), immunofluorescence, siRNA knockdown and overexpression, in vitro and in vivo assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP demonstrating direct interaction, multiple functional assays, single lab\",\n      \"pmids\": [\"36614043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PNPO (pyridoxine-5'-phosphate oxidase) oxidizes DVL3 at Met282, leading to abnormal activation of the Wnt/β-catenin pathway in multiple myeloma. Disrupting the PNPO-DVL3 interaction (by Eltrombopag) inhibits MM cell growth and reduces bone lesions.\",\n      \"method\": \"Chemical probe (celastrol) target identification, biochemical oxidation assay (DVL3 Met282 oxidation), Co-IP (PNPO-DVL3 interaction), mouse model, mutagenesis at critical PNPO sites\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical modification identified with specific residue, Co-IP, and in vivo validation, single lab with multiple methods\",\n      \"pmids\": [\"39656865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"AMPK activators (metformin) reduce DVL3 protein levels through two mechanisms: inhibition of mTOR-dependent DVL3 protein synthesis via AMPK/mTOR signaling, and promotion of ubiquitin/proteasomal degradation of DVL3. In vivo ubiquitination assay confirmed metformin-induced DVL3 ubiquitination. Enforced DVL3 expression elevated β-catenin and augmented cervical cancer cell growth, confirming DVL3 as a positive Wnt/β-catenin regulator.\",\n      \"method\": \"Western blot, in vivo ubiquitination assay, proteasomal inhibitors (MG132, AM114), AMPK inhibitor (Compound C), overexpression/knockdown, xenograft\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo ubiquitination assay with pharmacological controls, multiple complementary methods, single lab\",\n      \"pmids\": [\"23301094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DVL3 (along with CTNNB1 and PTEN) converges on PBX1 as a downstream target regulating neural progenitor cell (NPC) proliferation. In isogenic iPSC-derived NPCs with DVL3 ASD-related variants, PBX1a overexpression rescued increased NPC proliferation, establishing DVL3 upstream of PBX1 in NPC proliferation control.\",\n      \"method\": \"Isogenic iPSC-derived 2D NPCs, genetic epistasis (PBX1a overexpression rescue), proliferation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in isogenic human iPSC model with defined rescue phenotype, single lab, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.03.12.642693\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DVL3 proximity interactome (BioID) identified novel Wnt/PCP pathway components interacting with DVL3 in the cytoplasm. RAI14, EPHA2, and PHACTR4 were found as essential components connecting the PCP receptor complex to effector actomyosin.\",\n      \"method\": \"Proximity-dependent biotinylation (BioID) of DVL3 and other PCP components, zebrafish loss-of-function validation, subcellular compartment mapping\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity interactomics with in vivo (zebrafish) functional validation, single lab, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.01.15.633117\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Human DVL3 (DVL-3) was cloned as a second human homolog of Drosophila Dishevelled. It encodes a 716 amino acid protein with 98% amino acid identity to mouse Dvl-3 and 49% to Drosophila Dsh. DVL-3 was mapped to chromosome 3q27.\",\n      \"method\": \"cDNA library screening, sequencing, chromosomal mapping, Northern blot expression analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — definitive molecular cloning and chromosomal mapping, foundational characterization paper\",\n      \"pmids\": [\"9344861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CCNL1 directly interacts with DVL3 (verified by Co-IP), and this interaction is negatively correlated with DVL3 levels. CCNL1 overexpression activates NF-κB signaling through its interaction with DVL3 and promotes the PI3K/AKT pathway in breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (CCNL1-DVL3), Western blot, overexpression/knockdown, rescue assays\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with limited mechanistic follow-up on DVL3-specific function, single lab\",\n      \"pmids\": [\"41632921\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DVL3 is a cytoplasmic scaffold protein that relays WNT signals from Frizzled (FZD) receptors to downstream effectors: upon Wnt stimulation, CK1 multiphosphorylates DVL3 to trigger an intramolecular DEP-domain conformational phospho-switch that promotes DVL3 dissociation from FZD and enables downstream β-catenin (canonical) and RAC1-JNK/PCP (non-canonical) signaling; DVL3 also recruits IPMK to the membrane via its PDZ domain, participates in an IGFIR-Shc-Grb2-SOS-DAB2 adaptor complex linking IGF signaling to RAS, undergoes autophagy-dependent selective degradation by ALFY and ubiquitin/proteasomal degradation downstream of AMPK/mTOR, is oxidized by PNPO to activate Wnt/β-catenin in myeloma, translocates to the nucleus to regulate CYP19A1 promoters and proliferation, and modulates inflammatory responses via GSK3β-β-catenin and NF-κB; pathogenic frameshifting variants causing Robinow syndrome disrupt WNT-induced membrane redistribution and CK1-dependent phosphorylation of DVL3.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DVL3 is a cytoplasmic scaffold protein that relays WNT signals from Frizzled (FZD) receptors to both canonical (β-catenin) and non-canonical (planar cell polarity) effectors [#0, #3]. WNT stimulation drives CK1-mediated multiphosphorylation of DVL3, triggering an intramolecular phospho-switch between the DEP domain and the adjacent disordered region that is mutually exclusive with Frizzled association; charge accumulation near the DEP domain is required for canonical Wnt/β-catenin signaling, and FZD receptors are prominent effectors of this switch [#0]. In the non-canonical arm, WNT5B-FZD3 recruits DVL3 to the plasma membrane through its DEP domain, where DVL3 activates RAC1 and downstream JNK signaling [#3]. DVL3 functions as a positive regulator of Wnt/β-catenin in multiple contexts, recruiting IPMK to the membrane via its PDZ domain and proline-rich tail [#2] and acting as a node whose abundance is tuned by degradation: the autophagy scaffold ALFY selectively clears DVL3 aggregates [#4], while AMPK/mTOR signaling and ubiquitin/proteasomal degradation lower DVL3 protein levels [#13]. Beyond the membrane, DVL3 translocates to the nucleus, localizing to CYP19A1 (aromatase) promoters to control transcription and estradiol production [#9] and driving proliferation in a manner dependent on its DIX and PDZ domains [#10]. DVL3 also participates in non-Wnt signaling, residing in an IGFIR-Shc-Grb2-SOS-DAB2 adaptor complex that links IGF signaling to RAS/MEK-ERK [#5] and restraining NF-κB-driven inflammatory cytokine production downstream of TLR4/Wnt3a [#8]. Pathogenic DVL3 frameshifting variants causing Robinow syndrome generate a novel basic C-terminus that interferes with CSNK1E-induced phosphorylation and abolishes WNT-induced membrane redistribution and canonical signaling [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established the molecular identity of human DVL3 as a Dishevelled homolog, providing the foundation for studying it as a WNT pathway component.\",\n      \"evidence\": \"cDNA cloning, sequencing, and chromosomal mapping to 3q27\",\n      \"pmids\": [\"9344861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional or mechanistic assignment beyond homology\", \"Domain-level activities not characterized\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed DVL3 acts as a membrane-recruitment scaffold, defining how it propagates canonical Wnt signals by relocating an effector kinase.\",\n      \"evidence\": \"Co-IP, domain deletion mutants, and fractionation/imaging after Wnt3a stimulation; IPMK translocation\",\n      \"pmids\": [\"22940627\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect PDZ-mediated IPMK binding not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed DVL3 outside the canonical Wnt axis as a component of an IGFIR-to-RAS adaptor complex, revealing a non-redundant scaffolding role in growth-factor signaling.\",\n      \"evidence\": \"Genetic screen, Co-IP of DVL3-Shc-Grb2-SOS-DAB2, siRNA, xenograft, MEK-ERK assays\",\n      \"pmids\": [\"25168481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding partner of DVL3 within the complex not pinpointed\", \"Mechanism of ERK suppression unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a DVL3-specific degradation route, explaining how cellular DVL3 abundance and Wnt output are controlled in development.\",\n      \"evidence\": \"Human exome sequencing, Drosophila model, autophagy inhibition, isoform-specific knockdowns\",\n      \"pmids\": [\"27008544\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of ALFY isoform selectivity for DVL3 unknown\", \"Aggregate recognition signal not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated a nuclear function for DVL3, expanding its role from cytoplasmic scaffold to direct chromatin-associated transcriptional regulator.\",\n      \"evidence\": \"ChIP at CYP19A1 promoters, DVL knockdown, transcript and estradiol quantification\",\n      \"pmids\": [\"30479694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear import mechanism not defined\", \"DNA-binding partners at promoters unidentified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked DVL3 to cytoskeletal organization and to inflammatory tone, broadening its functional repertoire beyond β-catenin transcription.\",\n      \"evidence\": \"RNAi knockdown in Sertoli cells/testis (cytoskeleton, tight junctions); gain/loss-of-function and endotoxin model (NF-κB restraint)\",\n      \"pmids\": [\"30808893\", \"31884387\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular targets in cytoskeletal regulation unknown\", \"Mechanism by which DVL3/β-catenin restrains NF-κB not detailed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Tied DVL3 nuclear localization to a proliferation function dependent on specific domains, distinguishing it from DVL1 and from bulk β-catenin translocation.\",\n      \"evidence\": \"Domain mutants, nuclear imaging, proliferation assays in myoblasts; Co-IP of MEX3A-DVL3 in endometrial carcinoma\",\n      \"pmids\": [\"35589804\", \"36614043\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"β-catenin-independent proliferation mechanism not defined\", \"Functional consequence of MEX3A binding on DVL3 itself unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a redox post-translational modification and a membrane-recruitment route that activate DVL3-dependent Wnt signaling in disease contexts.\",\n      \"evidence\": \"Met282 oxidation biochemistry and PNPO-DVL3 Co-IP in myeloma; WNT5B-FZD3-DVL3 Co-IP, DEP-domain deletion, RAC1/JNK assays in lung cancer\",\n      \"pmids\": [\"39656865\", \"39094673\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural consequence of Met282 oxidation not modeled\", \"Single-lab findings each await independent confirmation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the phospho-regulated conformational logic of DVL3 and connected it to disease, showing how phosphorylation toggles DVL3 between FZD-bound and signaling-competent states.\",\n      \"evidence\": \"Phospho-switch mutant panel, BioID, in vitro phosphorylation, electrostatic/structural analysis; Robinow frameshift constructs with TOPFlash, ICC, phosphorylation assays; iPSC-NPC epistasis (PBX1 rescue); PCP BioID with zebrafish validation\",\n      \"pmids\": [\"42127203\", \"bio_10.1101_2025.08.02.668297\", \"bio_10.1101_2025.03.12.642693\", \"bio_10.1101_2025.01.15.633117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the DEP-disordered region switch not solved\", \"How distinct C-terminal lengths in Robinow variants impair CK1 phosphorylation mechanistically unclear\", \"Generality of PCP interactors (RAI14, EPHA2, PHACTR4) across tissues untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DVL3's distinct activities — phospho-switch-gated FZD release, nuclear transcriptional roles, the IGFIR-RAS adaptor function, and redox/degradation control — are coordinated within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating cytoplasmic, membrane, and nuclear pools\", \"Domain determinants partitioning canonical vs. non-canonical vs. non-Wnt functions not fully mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 15]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\n      \"IGFIR-Shc-Grb2-SOS-DAB2 adaptor complex\",\n      \"WNT5B-FZD3-DVL3 complex\"\n    ],\n    \"partners\": [\n      \"FZD3\",\n      \"IPMK\",\n      \"WNT5B\",\n      \"DAB2\",\n      \"MEX3A\",\n      \"PNPO\",\n      \"CCNL1\",\n      \"CSNK1E\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}