{"gene":"DVL1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1997,"finding":"Dvl1 knockout mice are viable and fertile but exhibit specific behavioral phenotypes including reduced social interaction and deficits in sensorimotor gating (prepulse inhibition), establishing that Dvl1 is required for normal social behavior and sensorimotor processing in the central nervous system.","method":"Gene targeting/knockout mouse, behavioral assays (social dominance, nest-building, huddling, PPI of acoustic/tactile startle)","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean germline knockout with multiple orthogonal behavioral readouts, replicated at two institutions","pmids":["9298901","14960015"],"is_preprint":false},{"year":2003,"finding":"CKI epsilon (casein kinase I epsilon) phosphorylates Dvl-1 and enhances its binding to Frat-1; the amino acid region 228–250 of Dvl-1 is necessary for binding Frat-1. This complex is required for Wnt-3a-induced accumulation of beta-catenin and activation of TCF-4-dependent transcription.","method":"Co-immunoprecipitation, deletion mutagenesis (Dvl-1 Δ228–250), RNAi knockdown of CKI epsilon, TOPFlash/TCF-4 luciferase reporter assay, beta-catenin accumulation assay in L cells and HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — deletion mutagenesis defining binding region, RNAi loss-of-function, and multiple functional readouts (binding, reporter, beta-catenin accumulation) in one study","pmids":["12556519"],"is_preprint":false},{"year":2011,"finding":"DVL1 promotes hyperphosphorylation of Frizzled3 and prevents its internalization, thereby inhibiting planar cell polarity (PCP) signaling in commissural axon growth cones. Vangl2 antagonizes this by reducing Frizzled3 phosphorylation and promoting its internalization, sharpening PCP signaling at filopodia tips for directional Wnt sensing.","method":"Genetic loss-of-function (PCP component knockouts/mutants), phosphorylation assays, internalization assays, immunolocalization in commissural axon growth cones, axon guidance assays (Wnt5a-stimulated outgrowth and A-P guidance)","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (phosphorylation, internalization, genetic epistasis, localization, functional guidance assay) in a single study","pmids":["21316586"],"is_preprint":false},{"year":1999,"finding":"EPS8 (a substrate of activated EGF receptor) physically interacts with the PDZ domain of Dvl1. In the presence of EPS8, Dvl1 becomes hyperphosphorylated; conversely, Dvl1 inhibits EGF receptor-induced tyrosine phosphorylation of EPS8.","method":"Yeast two-hybrid screening, in vitro binding confirmation, co-transfection/phosphorylation assays, immunohistochemistry showing overlapping expression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus in vitro binding and cellular phosphorylation assays, single lab","pmids":["10581192"],"is_preprint":false},{"year":2010,"finding":"The DIX domain of DVL1 physically interacts with the DIX domain of Axin1 to form a stable complex; co-expression of both DIX domains in a multi-cistronic system stabilizes the otherwise unstable individual DIX domain fragments, enabling complex formation confirmed by affinity chromatography and size-exclusion chromatography.","method":"Multi-cistronic co-expression in E. coli, affinity chromatography, size-exclusion chromatography (SEC), preliminary crystallization of DIX(Dvl1)–DIX(Axin1) complex","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — in vitro reconstitution and biochemical characterization, single lab, no mutagenesis or functional validation beyond complex formation","pmids":["20846493"],"is_preprint":false},{"year":2016,"finding":"Wnt5a signals specifically through DVL1 to repress ribosomal DNA (rDNA) transcription by RNA polymerase I in breast cancer cells. DVL1 accumulates in nucleolar organizer regions (NORs) and binds rDNA chromatin; upon DVL1 binding, the Pol I transcription activator SIRT7 is released from rDNA loci coincident with disassembly of Pol I transcription machinery at the rDNA promoter.","method":"siRNA knockdown of DVL1 (specificity established vs. DVL2/DVL3), chromatin immunoprecipitation (ChIP) for DVL1 binding to rDNA, Pol I transcription assays, SIRT7 ChIP, live-cell imaging/microscopy of DVL1 at NORs, Wnt5a treatment assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — specific DVL1 knockdown with multiple orthogonal methods (ChIP, transcription assays, localization, SIRT7 release) in one study establishing a novel nuclear mechanism","pmids":["27500936"],"is_preprint":false},{"year":2015,"finding":"De novo heterozygous frameshift mutations in DVL1 exon 14 (penultimate exon) cause autosomal-dominant Robinow syndrome. Mutant transcripts escape nonsense-mediated decay and are predicted to generate C-terminally truncated proteins with a distinct -1 reading-frame terminus, implicating loss/alteration of the DVL1 C-terminal domain in non-canonical Wnt-5a pathway disruption.","method":"Whole-exome sequencing, Sanger sequencing, transcript analysis from patient leukocytes confirming NMD escape and expression of both alleles, de novo mutation verification in parent–proband trios","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular characterization of patient variants with transcript-level confirmation of NMD escape, multiple independent families, but functional mechanism is inferred rather than reconstituted","pmids":["25817016"],"is_preprint":false},{"year":2015,"finding":"De novo DVL1 frameshift mutations that delete the C-terminus and replace it with a novel highly basic sequence cause Robinow syndrome with osteosclerosis (RS-OS). In vitro TOPFlash assays showed the mutant allele alone was less active than wild-type in canonical Wnt signaling, but co-expression of mutant and wild-type alleles produced ~2-fold higher canonical Wnt activity than wild-type alone, suggesting a dominant gain-of-function interaction that may underlie the osteosclerotic phenotype.","method":"Whole-exome sequencing, GFP-tagged construct transfection showing unimpaired protein stability, TOPFlash canonical Wnt reporter assay with mutant alone and mutant+WT co-expression, fibroblast transcript analysis","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TOPFlash functional assay with multiple genotypic conditions, GFP-stability assay, transcript confirmation; single lab","pmids":["25817014"],"is_preprint":false},{"year":2019,"finding":"DVL-1 is acetylated on at least 12 lysine residues; acetylation of two key residues, K69 (DIX domain) and K285 (PDZ domain), promotes nuclear over cytoplasmic localization of DVL-1 and influences its binding to gene promoters and regulation of cancer-related genes in triple-negative breast cancer cells.","method":"LC-MS/MS identification of acetylation sites, site-directed mutagenesis (acetylation-mimetic/deficient mutants), subcellular fractionation and immunofluorescence localization, chromatin immunoprecipitation (ChIP) for promoter binding","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification of PTM sites combined with mutagenesis and localization/ChIP functional readouts, single lab","pmids":["31700102"],"is_preprint":false},{"year":2021,"finding":"DVL-1 localizes to the nucleus in breast cancer cells and binds genomic regions including CYP19A1 promoters. DVL-1 peaks co-localize with H3K27me3 and EZH2 repressive chromatin marks, identifying DVL-1 as a transcriptional regulator with an epigenetic association.","method":"ChIP-Seq genome-wide profiling of DVL-1 binding sites, co-localization analysis with H3K27me3 and EZH2 ChIP-Seq datasets","journal":"Genes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP-Seq providing genome-wide binding data, single lab, limited functional follow-up reported in abstract","pmids":["34659647"],"is_preprint":false},{"year":2018,"finding":"DVL-1 and DVL-3 enter the nucleus and localize to at least two breast-cancer-associated CYP19A1 promoters (pII and I.4) and a distal placental promoter (I.1). Loss of DVL-1 function leads to differential changes in aromatase transcript levels and in estrogen (E2) production in breast cancer cells.","method":"ChIP (DVL localization to CYP19A1 promoters), siRNA knockdown of DVL-1 and DVL-3, aromatase transcript quantification, E2 production measurement","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus loss-of-function with functional transcriptional and hormonal output readouts, single lab, two orthogonal methods","pmids":["30479694"],"is_preprint":false},{"year":2018,"finding":"Neuroglobin directly interacts with DVL-1 (Dishevelled-1) and promotes its proteasomal degradation. Neuroglobin overexpression inhibits DVL-1-mediated TCF/LEF (TOPFlash) reporter activity and beta-catenin expression, and also enhances TNF-alpha-induced NFκB activation through DVL-1 downregulation.","method":"Yeast two-hybrid (prior study cited), co-immunoprecipitation confirming interaction, co-localization by immunofluorescence, proteasome inhibitor experiments, TOPFlash luciferase reporter assay, MTT cell viability assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP plus functional reporter and degradation assays; single lab but multiple orthogonal methods","pmids":["30041403"],"is_preprint":false},{"year":2022,"finding":"DVL1 and DVL3 must be present in the nucleus to regulate proliferation in human myoblasts and rhabdomyosarcoma cells, operating through different domain requirements: DVL3 requires DIX and PDZ domains, while DVL1 does not. DVL1 and DVL3 regulate proliferation independently of markedly increased nuclear beta-catenin translocation.","method":"siRNA knockdown of DVL1 and DVL3, nuclear/cytoplasmic fractionation, domain-deletion constructs, proliferation and differentiation assays, beta-catenin localization analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function combined with domain-deletion constructs and subcellular fractionation, single lab, multiple cell types tested","pmids":["35589804"],"is_preprint":false},{"year":2023,"finding":"DVL1 interacts with somatostatin receptor 2 (Sstr2) in a ligand-independent manner and targets Sstr2 for lysosomal degradation. This interaction does not affect receptor internalization, recycling, or adenylyl cyclase signaling but suppresses agonist-stimulated ERK1/2 activation. Wnt overexpression potentiates DVL1-dependent Sstr2 degradation, and Wnt pathway inhibitors boost Sstr2 expression in neuroendocrine tumor cells.","method":"Co-immunoprecipitation (DVL1–Sstr2 interaction), lysosomal inhibitor assays, receptor internalization/recycling assays, adenylyl cyclase signaling assay, ERK1/2 phosphorylation assay, Wnt overexpression and pathway inhibitor treatment experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus multiple downstream functional assays (degradation, signaling endpoints), single lab","pmids":["36965619"],"is_preprint":false},{"year":2016,"finding":"Dvl1 has a dual epithelial and immune cell function required for normal gut homeostasis. Dvl1-/- mice show increased gut transit time, mislocalization of Paneth cells, and increased CD8+ T cells. Bone marrow chimera experiments established that GI dysfunction requires abnormalities in both epithelial and immune compartments. Gut microbiota manipulation rescued transit abnormality without correcting cellular defects.","method":"Dvl1 germline knockout mice, bone marrow chimera experiments, gut transit time measurement, Paneth cell localization, CD8+ T cell quantification, microbiota manipulation/transplantation","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knockout with bone marrow chimera epistasis and multiple cellular/functional readouts establishing dual cell-type requirement","pmids":["27525310"],"is_preprint":false},{"year":2023,"finding":"DVL1 Robinow syndrome frameshift variants (acting as a prototype: DVL1-1519ΔT) cause loss of canonical Wnt signaling and gain of non-canonical Wnt signaling in chicken and Drosophila developmental assays. Expression of variant DVL1 in Drosophila wings and chicken produced major disorganization of cartilage and wing morphology compared to wild-type DVL1.","method":"Transient expression of human WT and variant DVL1 in Drosophila and chicken embryo models, canonical Wnt reporter assays, non-canonical Wnt pathway readouts, morphological phenotype analysis","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays in two independent animal models with canonical and non-canonical pathway readouts, single lab","pmids":["36916233"],"is_preprint":false},{"year":2023,"finding":"DVL1 Robinow syndrome frameshift variants fail to redistribute from cytoplasmic puncta to respond to Wnt ligand stimulation (unlike wild-type DVL1), fail to activate canonical Wnt signaling in TOPFlash assays, and the mutant C-terminal tail interferes with CSNK1E (casein kinase 1 epsilon)-induced phosphorylation of DVL1.","method":"Immunocytochemistry of DVL1 localization in response to Wnt ligands, TOPFlash canonical Wnt reporter assay, CSNK1E co-transfection phosphorylation assay; WT, frameshift, and truncated constructs of DVL1-3 compared","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple functional assays (localization, reporter, phosphorylation) in vitro, preprint, single lab","pmids":["bio_10.1101_2025.08.02.668297"],"is_preprint":true},{"year":2024,"finding":"HECW1 (E3 ubiquitin ligase) promotes ubiquitination and degradation of DVL1, thereby restraining DVL1-mediated Wnt/β-catenin signaling. Inhibition of HECW1 reduced DVL1 ubiquitination and upregulated DVL1 protein, promoting nuclear β-catenin accumulation and cell proliferation in cervical cancer cells.","method":"Ubiquitination assay (DVL1 ubiquitination with HECW1 modulation), Western blot for DVL1 protein levels, nuclear β-catenin fractionation, TOPFlash/TCF-LEF luciferase assay, siRNA knockdown of HECW1 and DVL1, in vivo tumor formation assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ubiquitination assay combined with loss-of-function and downstream functional readouts, single lab","pmids":["38266865"],"is_preprint":false},{"year":2025,"finding":"DACT3 directly interacts with DVL1 (confirmed by co-immunoprecipitation) and inhibits DVL1-induced activation of canonical Wnt signaling. The DACT3–DVL1 interaction inhibits phosphorylation of GSK-3β at serine 9 and β-catenin at serine 675, thereby reducing β-catenin nuclear translocation and downstream transcription. DACT3 suppresses DVL1-driven invasion, proliferation, migration, and cisplatin resistance in NSCLC cells.","method":"Co-immunoprecipitation (DACT3–DVL1 interaction), Western blot (GSK-3β pS9, β-catenin pS675, nuclear β-catenin), TOPFlash luciferase reporter assay, siRNA/cDNA transfection loss/gain of function, immunofluorescence, cell invasion/proliferation/migration assays, in vivo tumorigenesis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP confirming direct interaction plus multiple downstream signaling and functional readouts; single lab","pmids":["40838391"],"is_preprint":false},{"year":2025,"finding":"Dvl1 DVL1 Robinow syndrome variants disrupt epithelial imaginal disc morphology in Drosophila with increased cell death (caspase-dependent) and without changes in cell proliferation; they also cause ectopic MMP1 expression and tissue distortion dependent on JNK signaling, and abnormal accumulation of collagen IV (Viking) in pupal wings, as well as elevated BMP signaling.","method":"Drosophila expression of DVL1 variant (DVL1-1519ΔT), immunofluorescence, caspase inhibitor rescue, MMP1 immunostaining, JNK pathway genetic epistasis, dad-lacZ BMP reporter, Viking (collagen IV) staining in pupal wings","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo Drosophila model with multiple pathway readouts and genetic epistasis (JNK), single lab","pmids":["40600289"],"is_preprint":false},{"year":2025,"finding":"Nup358 interacts with Dvl1 through its N-terminal domain and inhibits Dvl1 spontaneous phase separation (condensate/biomolecular condensate formation). In the absence of Nup358, Dvl1 forms condensates that promote Tankyrase-mediated degradation of Axin1, leading to constitutive β-catenin stabilization and ligand-independent Wnt activation, depleting the transit-amplifying progenitor compartment in intestinal crypts.","method":"Conditional Nup358 knockout in adult mice, co-immunoprecipitation (Nup358–Dvl1 interaction), domain-mapping (N-terminal domain of Nup358), phase separation/condensate assays, Axin1 degradation assay, Tankyrase inhibitor experiments, intestinal crypt histology and ISC/TA compartment analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout combined with co-IP, phase separation assay, and epistasis (Tankyrase), preprint but multiple orthogonal methods","pmids":["41929184"],"is_preprint":true}],"current_model":"DVL1 is a cytoplasmic and nuclear scaffold protein that transduces both canonical (β-catenin-dependent) and non-canonical (PCP/JNK) Wnt signals: in the cytoplasm it binds Frizzled receptors, Frat-1, Axin1 (via DIX–DIX interaction), DACT3, and CSNK1E-dependent phosphorylation to regulate GSK-3β/β-catenin stability; in the nucleus it accumulates at rDNA loci to repress Pol I transcription via SIRT7 displacement, binds gene promoters in a manner regulated by lysine acetylation (K69/K285), and drives proliferation independently of bulk β-catenin nuclear translocation; its steady-state level is controlled by HECW1-mediated ubiquitination/degradation and by Nup358-mediated suppression of its phase separation into condensates that would otherwise promote Axin1 degradation; disease-causing Robinow syndrome frameshift variants in the C-terminal domain trap DVL1 in cytoplasmic puncta unresponsive to Wnt ligand, impair CSNK1E phosphorylation, shift signaling from canonical to non-canonical Wnt, and activate JNK/BMP pathways causing skeletal dysmorphogenesis."},"narrative":{"mechanistic_narrative":"DVL1 is a multifunctional Dishevelled-family scaffold protein that transduces Wnt signals through both canonical (β-catenin-dependent) and non-canonical (planar cell polarity/JNK) branches, and additionally functions as a nuclear transcriptional regulator [PMID:12556519, PMID:21316586, PMID:27500936]. In the canonical cytoplasmic pathway, casein kinase I epsilon (CSNK1E/CKIε) phosphorylates DVL1 and enhances its binding to Frat-1 (via residues 228–250), a complex required for Wnt-3a-induced β-catenin accumulation and TCF-dependent transcription [PMID:12556519]; the DIX domain of DVL1 forms a stable complex with the DIX domain of Axin1 [PMID:20846493]. Its level and signaling output are tuned by multiple regulators: HECW1 ubiquitinates DVL1 to promote its degradation and restrain Wnt/β-catenin signaling [PMID:38266865], DACT3 binds DVL1 to suppress GSK-3β/β-catenin phosphorylation and downstream transcription [PMID:40838391], neuroglobin drives its proteasomal degradation [PMID:30041403], and Nup358 binding suppresses DVL1 phase separation into condensates that otherwise promote Tankyrase-mediated Axin1 degradation and ligand-independent Wnt activation [PMID:41929184]. In non-canonical signaling, DVL1 hyperphosphorylates Frizzled3 and blocks its internalization to control PCP-dependent commissural axon guidance [PMID:21316586]. Independently of receptor signaling, DVL1 enters the nucleus, accumulates at rDNA loci to repress RNA Pol I transcription by displacing SIRT7 [PMID:27500936], binds gene promoters in a manner regulated by lysine acetylation at K69 and K285 [PMID:31700102], and drives proliferation in myoblasts and rhabdomyosarcoma cells without requiring increased nuclear β-catenin [PMID:35589804]. De novo C-terminal frameshift variants in DVL1 cause autosomal-dominant Robinow syndrome: these mutants are trapped in cytoplasmic puncta unresponsive to Wnt ligand, lose canonical and gain non-canonical Wnt activity, and produce skeletal and tissue dysmorphogenesis through JNK and BMP pathway activation [PMID:25817016, PMID:25817014, PMID:36916233, PMID:40600289]. In knockout mice, DVL1 is required for normal social behavior and sensorimotor gating and for gut homeostasis across epithelial and immune compartments [PMID:9298901, PMID:14960015, PMID:27525310].","teleology":[{"year":1997,"claim":"Established that DVL1 has a non-redundant physiological role in the CNS, answering whether this Wnt transducer matters at the organismal level despite paralog redundancy.","evidence":"Germline Dvl1 knockout mice with behavioral assays (social dominance, PPI of startle)","pmids":["9298901","14960015"],"confidence":"High","gaps":["Molecular basis linking DVL1 loss to social/sensorimotor deficits not defined","Cell types and circuits responsible unidentified"]},{"year":1999,"claim":"Identified a DVL1 PDZ-domain interaction with the EGFR substrate EPS8 and reciprocal phosphorylation regulation, hinting at crosstalk between DVL1 and tyrosine-kinase signaling.","evidence":"Yeast two-hybrid, in vitro binding, co-transfection phosphorylation assays","pmids":["10581192"],"confidence":"Medium","gaps":["Functional consequence of DVL1–EPS8 crosstalk in Wnt signaling unclear","Single lab, no in vivo validation"]},{"year":2003,"claim":"Defined how CSNK1E phosphorylation couples DVL1 to canonical Wnt output, showing the CKIε–DVL1–Frat-1 module is required for β-catenin accumulation and TCF transcription.","evidence":"Co-IP, deletion mutagenesis (Δ228–250), CKIε RNAi, TOPFlash reporter, β-catenin assays in L and HEK293 cells","pmids":["12556519"],"confidence":"High","gaps":["Phosphosite map on DVL1 not resolved","Structural basis of Frat-1 binding unknown"]},{"year":2010,"claim":"Demonstrated direct DIX–DIX assembly between DVL1 and Axin1, providing a biochemical basis for the destruction-complex regulatory interface.","evidence":"Multi-cistronic E. coli co-expression, affinity and size-exclusion chromatography, preliminary crystallization","pmids":["20846493"],"confidence":"Medium","gaps":["No mutagenesis or functional validation of the interface","Crystal structure not solved"]},{"year":2011,"claim":"Showed DVL1 acts in non-canonical PCP signaling by hyperphosphorylating Frizzled3 and blocking its internalization, establishing a receptor-trafficking control point for directional Wnt sensing in axon guidance.","evidence":"PCP-component genetic loss-of-function, phosphorylation/internalization assays, growth cone imaging, Wnt5a axon guidance assays","pmids":["21316586"],"confidence":"High","gaps":["Kinase mediating Frizzled3 phosphorylation not identified","DVL1 vs paralog specificity in PCP not fully resolved"]},{"year":2015,"claim":"Linked DVL1 to a human Mendelian disease, establishing that C-terminal frameshift variants escaping NMD cause autosomal-dominant Robinow syndrome via altered Wnt signaling.","evidence":"Whole-exome/Sanger sequencing, trio analysis, patient transcript analysis; TOPFlash assays with mutant and mutant+WT co-expression and GFP stability","pmids":["25817016","25817014"],"confidence":"Medium","gaps":["Functional mechanism inferred rather than reconstituted in the original reports","Connection of TOPFlash gain-of-function to osteosclerosis not directly tested"]},{"year":2016,"claim":"Uncovered an unexpected nuclear function: DVL1 represses RNA Pol I rDNA transcription downstream of Wnt5a by binding rDNA chromatin and displacing the activator SIRT7.","evidence":"DVL1-specific siRNA, ChIP for DVL1 and SIRT7 at rDNA, Pol I transcription assays, NOR imaging in breast cancer cells","pmids":["27500936"],"confidence":"High","gaps":["Mechanism of DVL1 nuclear import/rDNA targeting unknown","Whether SIRT7 release is direct displacement unresolved"]},{"year":2016,"claim":"Defined a dual epithelial and immune requirement for DVL1 in gut homeostasis, showing Paneth cell and T-cell defects combine to drive GI dysfunction.","evidence":"Dvl1 knockout mice, bone marrow chimeras, transit/Paneth/CD8 readouts, microbiota manipulation","pmids":["27525310"],"confidence":"High","gaps":["Wnt-pathway dependence of the gut phenotype not dissected","Cell-intrinsic molecular targets unidentified"]},{"year":2018,"claim":"Identified post-translational and nuclear-transcriptional control of DVL1: neuroglobin-driven proteasomal degradation suppresses Wnt output, while nuclear DVL1 binds CYP19A1 promoters to control aromatase and estrogen production.","evidence":"Co-IP, proteasome inhibitor and TOPFlash assays (neuroglobin); ChIP and siRNA with aromatase/E2 readouts (CYP19A1)","pmids":["30041403","30479694"],"confidence":"Medium","gaps":["E3 ligase mediating neuroglobin-dependent degradation not identified","Direct vs indirect promoter regulation by DVL1 unclear"]},{"year":2019,"claim":"Showed that lysine acetylation at K69 (DIX) and K285 (PDZ) governs DVL1 nuclear localization and promoter binding, defining a PTM switch for its transcriptional role.","evidence":"LC-MS/MS acetyl-site mapping, acetyl-mimetic/deficient mutants, fractionation/IF, ChIP in TNBC cells","pmids":["31700102"],"confidence":"Medium","gaps":["Acetyltransferase/deacetylase enzymes unidentified","Single lab"]},{"year":2021,"claim":"Genome-wide profiling positioned nuclear DVL1 as a chromatin-associated regulator whose binding sites overlap H3K27me3/EZH2 repressive marks.","evidence":"DVL-1 ChIP-Seq with co-localization analysis against H3K27me3/EZH2 datasets","pmids":["34659647"],"confidence":"Medium","gaps":["Direct DVL1–PRC2 interaction not demonstrated","Limited functional follow-up"]},{"year":2022,"claim":"Established that DVL1's nuclear pro-proliferative function is β-catenin-independent and uses domain requirements distinct from DVL3, dissociating its growth role from canonical Wnt output.","evidence":"siRNA, nuclear/cytoplasmic fractionation, domain-deletion constructs, proliferation assays in myoblasts and rhabdomyosarcoma cells","pmids":["35589804"],"confidence":"Medium","gaps":["Nuclear effectors of DVL1-driven proliferation unknown","Domain element required for DVL1 (vs DVL3) not pinpointed"]},{"year":2023,"claim":"Expanded DVL1's regulatory reach to GPCR turnover, showing it targets Sstr2 for lysosomal degradation and selectively dampens agonist-stimulated ERK signaling in a Wnt-modulated manner.","evidence":"Co-IP, lysosomal inhibitor, internalization/recycling, adenylyl cyclase and ERK1/2 assays, Wnt overexpression/inhibitor experiments in NET cells","pmids":["36965619"],"confidence":"Medium","gaps":["Structural basis of DVL1–Sstr2 binding unknown","Generality across other GPCRs untested"]},{"year":2023,"claim":"Mechanistically connected Robinow variants to pathway rewiring, showing they lose canonical and gain non-canonical Wnt activity and produce skeletal/wing dysmorphology in chicken and Drosophila.","evidence":"Transient WT/variant DVL1 expression in Drosophila and chicken with Wnt reporters and morphological analysis; localization, TOPFlash, and CSNK1E phosphorylation assays (preprint)","pmids":["36916233","bio_10.1101_2025.08.02.668297"],"confidence":"Medium","gaps":["Why mutant C-terminus traps DVL1 in puncta not structurally defined","CSNK1E-phosphorylation interference mechanism unresolved"]},{"year":2024,"claim":"Identified HECW1 as an E3 ligase that ubiquitinates and degrades DVL1, defining a degradation node that restrains Wnt/β-catenin-driven proliferation in cervical cancer.","evidence":"Ubiquitination assay, Western blot, nuclear β-catenin fractionation, TOPFlash, siRNA, in vivo tumor assay","pmids":["38266865"],"confidence":"Medium","gaps":["Ubiquitin chain type and DVL1 acceptor sites not mapped","Upstream regulation of HECW1 activity unknown"]},{"year":2025,"claim":"Resolved additional layers of DVL1 control: DACT3 binding suppresses GSK-3β/β-catenin phosphorylation, and Nup358 binding prevents DVL1 phase separation into condensates that otherwise drive Tankyrase-mediated Axin1 degradation and ligand-independent Wnt activation.","evidence":"Co-IP, Western blot, TOPFlash, functional assays in NSCLC (DACT3); conditional Nup358 knockout mice, co-IP, phase-separation and Axin1 degradation assays, Tankyrase inhibitor, crypt histology (Nup358, preprint)","pmids":["40838391","41929184"],"confidence":"Medium","gaps":["Physiological conditions triggering DVL1 condensation not defined","Whether DACT3 and Nup358 control converge mechanistically untested"]},{"year":2025,"claim":"Detailed the tissue-level pathology of Robinow variants, showing JNK-dependent ectopic MMP1, caspase-dependent cell death, collagen IV accumulation, and elevated BMP signaling underlie dysmorphogenesis.","evidence":"Drosophila DVL1-1519ΔT expression, caspase inhibitor rescue, MMP1/Viking staining, JNK epistasis, dad-lacZ BMP reporter","pmids":["40600289"],"confidence":"Medium","gaps":["Direct molecular target of variant DVL1 driving JNK/BMP activation unknown","Relevance to human skeletal phenotype not directly established"]},{"year":null,"claim":"How DVL1's nuclear transcriptional/rDNA-repressive functions are mechanistically integrated with its cytoplasmic Wnt-scaffold role, and what governs its nuclear import and phase behavior in vivo, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of full-length DVL1 in distinct compartments","Nuclear import machinery and condensation triggers undefined","Paralog-specific functional division (DVL1 vs DVL2/DVL3) incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,4,18]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,8,9,10]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5,8,9]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,12,16]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,8,10,12]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[5]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,17,18]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,8,9,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,7,15,19]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,15,19]}],"complexes":[],"partners":["AXIN1","CSNK1E","FRAT1","DACT3","HECW1","SSTR2","EPS8","FZD3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14640","full_name":"Segment polarity protein dishevelled homolog DVL-1","aliases":["DSH homolog 1"],"length_aa":695,"mass_kda":75.2,"function":"Participates in Wnt signaling by binding to the cytoplasmic C-terminus of frizzled family members and transducing the Wnt signal to down-stream effectors. Plays a role both in canonical and non-canonical Wnt signaling. Plays a role in the signal transduction pathways mediated by multiple Wnt genes. Required for LEF1 activation upon WNT1 and WNT3A signaling. DVL1 and PAK1 form a ternary complex with MUSK which is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ)","subcellular_location":"Cell membrane; Cytoplasm, cytosol; Cytoplasmic vesicle","url":"https://www.uniprot.org/uniprotkb/O14640/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DVL1","classification":"Not Classified","n_dependent_lines":71,"n_total_lines":1208,"dependency_fraction":0.058774834437086095},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DVL1","total_profiled":1310},"omim":[{"mim_id":"621363","title":"MAP7 DOMAIN-CONTAINING PROTEIN 1; MAP7D1","url":"https://www.omim.org/entry/621363"},{"mim_id":"617813","title":"TRANSMEMBRANE PROTEIN 88; TMEM88","url":"https://www.omim.org/entry/617813"},{"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"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Focal adhesion sites","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":215.3}],"url":"https://www.proteinatlas.org/search/DVL1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O14640","domains":[{"cath_id":"2.40.240.130","chopping":"5-84","consensus_level":"high","plddt":89.2424,"start":5,"end":84},{"cath_id":"2.30.42.10","chopping":"250-337","consensus_level":"high","plddt":85.4131,"start":250,"end":337},{"cath_id":"1.10.10.10","chopping":"416-507","consensus_level":"high","plddt":87.0833,"start":416,"end":507}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14640","model_url":"https://alphafold.ebi.ac.uk/files/AF-O14640-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O14640-F1-predicted_aligned_error_v6.png","plddt_mean":59.84},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DVL1","jax_strain_url":"https://www.jax.org/strain/search?query=DVL1"},"sequence":{"accession":"O14640","fasta_url":"https://rest.uniprot.org/uniprotkb/O14640.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14640/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14640"}},"corpus_meta":[{"pmid":"9298901","id":"PMC_9298901","title":"Social 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targeting/knockout mouse, behavioral assays (social dominance, nest-building, huddling, PPI of acoustic/tactile startle)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean germline knockout with multiple orthogonal behavioral readouts, replicated at two institutions\",\n      \"pmids\": [\"9298901\", \"14960015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CKI epsilon (casein kinase I epsilon) phosphorylates Dvl-1 and enhances its binding to Frat-1; the amino acid region 228–250 of Dvl-1 is necessary for binding Frat-1. This complex is required for Wnt-3a-induced accumulation of beta-catenin and activation of TCF-4-dependent transcription.\",\n      \"method\": \"Co-immunoprecipitation, deletion mutagenesis (Dvl-1 Δ228–250), RNAi knockdown of CKI epsilon, TOPFlash/TCF-4 luciferase reporter assay, beta-catenin accumulation assay in L cells and HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — deletion mutagenesis defining binding region, RNAi loss-of-function, and multiple functional readouts (binding, reporter, beta-catenin accumulation) in one study\",\n      \"pmids\": [\"12556519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DVL1 promotes hyperphosphorylation of Frizzled3 and prevents its internalization, thereby inhibiting planar cell polarity (PCP) signaling in commissural axon growth cones. Vangl2 antagonizes this by reducing Frizzled3 phosphorylation and promoting its internalization, sharpening PCP signaling at filopodia tips for directional Wnt sensing.\",\n      \"method\": \"Genetic loss-of-function (PCP component knockouts/mutants), phosphorylation assays, internalization assays, immunolocalization in commissural axon growth cones, axon guidance assays (Wnt5a-stimulated outgrowth and A-P guidance)\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (phosphorylation, internalization, genetic epistasis, localization, functional guidance assay) in a single study\",\n      \"pmids\": [\"21316586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"EPS8 (a substrate of activated EGF receptor) physically interacts with the PDZ domain of Dvl1. In the presence of EPS8, Dvl1 becomes hyperphosphorylated; conversely, Dvl1 inhibits EGF receptor-induced tyrosine phosphorylation of EPS8.\",\n      \"method\": \"Yeast two-hybrid screening, in vitro binding confirmation, co-transfection/phosphorylation assays, immunohistochemistry showing overlapping expression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus in vitro binding and cellular phosphorylation assays, single lab\",\n      \"pmids\": [\"10581192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The DIX domain of DVL1 physically interacts with the DIX domain of Axin1 to form a stable complex; co-expression of both DIX domains in a multi-cistronic system stabilizes the otherwise unstable individual DIX domain fragments, enabling complex formation confirmed by affinity chromatography and size-exclusion chromatography.\",\n      \"method\": \"Multi-cistronic co-expression in E. coli, affinity chromatography, size-exclusion chromatography (SEC), preliminary crystallization of DIX(Dvl1)–DIX(Axin1) complex\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — in vitro reconstitution and biochemical characterization, single lab, no mutagenesis or functional validation beyond complex formation\",\n      \"pmids\": [\"20846493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Wnt5a signals specifically through DVL1 to repress ribosomal DNA (rDNA) transcription by RNA polymerase I in breast cancer cells. DVL1 accumulates in nucleolar organizer regions (NORs) and binds rDNA chromatin; upon DVL1 binding, the Pol I transcription activator SIRT7 is released from rDNA loci coincident with disassembly of Pol I transcription machinery at the rDNA promoter.\",\n      \"method\": \"siRNA knockdown of DVL1 (specificity established vs. DVL2/DVL3), chromatin immunoprecipitation (ChIP) for DVL1 binding to rDNA, Pol I transcription assays, SIRT7 ChIP, live-cell imaging/microscopy of DVL1 at NORs, Wnt5a treatment assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific DVL1 knockdown with multiple orthogonal methods (ChIP, transcription assays, localization, SIRT7 release) in one study establishing a novel nuclear mechanism\",\n      \"pmids\": [\"27500936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"De novo heterozygous frameshift mutations in DVL1 exon 14 (penultimate exon) cause autosomal-dominant Robinow syndrome. Mutant transcripts escape nonsense-mediated decay and are predicted to generate C-terminally truncated proteins with a distinct -1 reading-frame terminus, implicating loss/alteration of the DVL1 C-terminal domain in non-canonical Wnt-5a pathway disruption.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing, transcript analysis from patient leukocytes confirming NMD escape and expression of both alleles, de novo mutation verification in parent–proband trios\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular characterization of patient variants with transcript-level confirmation of NMD escape, multiple independent families, but functional mechanism is inferred rather than reconstituted\",\n      \"pmids\": [\"25817016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"De novo DVL1 frameshift mutations that delete the C-terminus and replace it with a novel highly basic sequence cause Robinow syndrome with osteosclerosis (RS-OS). In vitro TOPFlash assays showed the mutant allele alone was less active than wild-type in canonical Wnt signaling, but co-expression of mutant and wild-type alleles produced ~2-fold higher canonical Wnt activity than wild-type alone, suggesting a dominant gain-of-function interaction that may underlie the osteosclerotic phenotype.\",\n      \"method\": \"Whole-exome sequencing, GFP-tagged construct transfection showing unimpaired protein stability, TOPFlash canonical Wnt reporter assay with mutant alone and mutant+WT co-expression, fibroblast transcript analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TOPFlash functional assay with multiple genotypic conditions, GFP-stability assay, transcript confirmation; single lab\",\n      \"pmids\": [\"25817014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DVL-1 is acetylated on at least 12 lysine residues; acetylation of two key residues, K69 (DIX domain) and K285 (PDZ domain), promotes nuclear over cytoplasmic localization of DVL-1 and influences its binding to gene promoters and regulation of cancer-related genes in triple-negative breast cancer cells.\",\n      \"method\": \"LC-MS/MS identification of acetylation sites, site-directed mutagenesis (acetylation-mimetic/deficient mutants), subcellular fractionation and immunofluorescence localization, chromatin immunoprecipitation (ChIP) for promoter binding\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification of PTM sites combined with mutagenesis and localization/ChIP functional readouts, single lab\",\n      \"pmids\": [\"31700102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DVL-1 localizes to the nucleus in breast cancer cells and binds genomic regions including CYP19A1 promoters. DVL-1 peaks co-localize with H3K27me3 and EZH2 repressive chromatin marks, identifying DVL-1 as a transcriptional regulator with an epigenetic association.\",\n      \"method\": \"ChIP-Seq genome-wide profiling of DVL-1 binding sites, co-localization analysis with H3K27me3 and EZH2 ChIP-Seq datasets\",\n      \"journal\": \"Genes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP-Seq providing genome-wide binding data, single lab, limited functional follow-up reported in abstract\",\n      \"pmids\": [\"34659647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DVL-1 and DVL-3 enter the nucleus and localize to at least two breast-cancer-associated CYP19A1 promoters (pII and I.4) and a distal placental promoter (I.1). Loss of DVL-1 function leads to differential changes in aromatase transcript levels and in estrogen (E2) production in breast cancer cells.\",\n      \"method\": \"ChIP (DVL localization to CYP19A1 promoters), siRNA knockdown of DVL-1 and DVL-3, aromatase transcript quantification, E2 production measurement\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus loss-of-function with functional transcriptional and hormonal output readouts, single lab, two orthogonal methods\",\n      \"pmids\": [\"30479694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Neuroglobin directly interacts with DVL-1 (Dishevelled-1) and promotes its proteasomal degradation. Neuroglobin overexpression inhibits DVL-1-mediated TCF/LEF (TOPFlash) reporter activity and beta-catenin expression, and also enhances TNF-alpha-induced NFκB activation through DVL-1 downregulation.\",\n      \"method\": \"Yeast two-hybrid (prior study cited), co-immunoprecipitation confirming interaction, co-localization by immunofluorescence, proteasome inhibitor experiments, TOPFlash luciferase reporter assay, MTT cell viability assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP plus functional reporter and degradation assays; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30041403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DVL1 and DVL3 must be present in the nucleus to regulate proliferation in human myoblasts and rhabdomyosarcoma cells, operating through different domain requirements: DVL3 requires DIX and PDZ domains, while DVL1 does not. DVL1 and DVL3 regulate proliferation independently of markedly increased nuclear beta-catenin translocation.\",\n      \"method\": \"siRNA knockdown of DVL1 and DVL3, nuclear/cytoplasmic fractionation, domain-deletion constructs, proliferation and differentiation assays, beta-catenin localization analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function combined with domain-deletion constructs and subcellular fractionation, single lab, multiple cell types tested\",\n      \"pmids\": [\"35589804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DVL1 interacts with somatostatin receptor 2 (Sstr2) in a ligand-independent manner and targets Sstr2 for lysosomal degradation. This interaction does not affect receptor internalization, recycling, or adenylyl cyclase signaling but suppresses agonist-stimulated ERK1/2 activation. Wnt overexpression potentiates DVL1-dependent Sstr2 degradation, and Wnt pathway inhibitors boost Sstr2 expression in neuroendocrine tumor cells.\",\n      \"method\": \"Co-immunoprecipitation (DVL1–Sstr2 interaction), lysosomal inhibitor assays, receptor internalization/recycling assays, adenylyl cyclase signaling assay, ERK1/2 phosphorylation assay, Wnt overexpression and pathway inhibitor treatment experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus multiple downstream functional assays (degradation, signaling endpoints), single lab\",\n      \"pmids\": [\"36965619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Dvl1 has a dual epithelial and immune cell function required for normal gut homeostasis. Dvl1-/- mice show increased gut transit time, mislocalization of Paneth cells, and increased CD8+ T cells. Bone marrow chimera experiments established that GI dysfunction requires abnormalities in both epithelial and immune compartments. Gut microbiota manipulation rescued transit abnormality without correcting cellular defects.\",\n      \"method\": \"Dvl1 germline knockout mice, bone marrow chimera experiments, gut transit time measurement, Paneth cell localization, CD8+ T cell quantification, microbiota manipulation/transplantation\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout with bone marrow chimera epistasis and multiple cellular/functional readouts establishing dual cell-type requirement\",\n      \"pmids\": [\"27525310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DVL1 Robinow syndrome frameshift variants (acting as a prototype: DVL1-1519ΔT) cause loss of canonical Wnt signaling and gain of non-canonical Wnt signaling in chicken and Drosophila developmental assays. Expression of variant DVL1 in Drosophila wings and chicken produced major disorganization of cartilage and wing morphology compared to wild-type DVL1.\",\n      \"method\": \"Transient expression of human WT and variant DVL1 in Drosophila and chicken embryo models, canonical Wnt reporter assays, non-canonical Wnt pathway readouts, morphological phenotype analysis\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays in two independent animal models with canonical and non-canonical pathway readouts, single lab\",\n      \"pmids\": [\"36916233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DVL1 Robinow syndrome frameshift variants fail to redistribute from cytoplasmic puncta to respond to Wnt ligand stimulation (unlike wild-type DVL1), fail to activate canonical Wnt signaling in TOPFlash assays, and the mutant C-terminal tail interferes with CSNK1E (casein kinase 1 epsilon)-induced phosphorylation of DVL1.\",\n      \"method\": \"Immunocytochemistry of DVL1 localization in response to Wnt ligands, TOPFlash canonical Wnt reporter assay, CSNK1E co-transfection phosphorylation assay; WT, frameshift, and truncated constructs of DVL1-3 compared\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple functional assays (localization, reporter, phosphorylation) in vitro, preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.08.02.668297\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HECW1 (E3 ubiquitin ligase) promotes ubiquitination and degradation of DVL1, thereby restraining DVL1-mediated Wnt/β-catenin signaling. Inhibition of HECW1 reduced DVL1 ubiquitination and upregulated DVL1 protein, promoting nuclear β-catenin accumulation and cell proliferation in cervical cancer cells.\",\n      \"method\": \"Ubiquitination assay (DVL1 ubiquitination with HECW1 modulation), Western blot for DVL1 protein levels, nuclear β-catenin fractionation, TOPFlash/TCF-LEF luciferase assay, siRNA knockdown of HECW1 and DVL1, in vivo tumor formation assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ubiquitination assay combined with loss-of-function and downstream functional readouts, single lab\",\n      \"pmids\": [\"38266865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DACT3 directly interacts with DVL1 (confirmed by co-immunoprecipitation) and inhibits DVL1-induced activation of canonical Wnt signaling. The DACT3–DVL1 interaction inhibits phosphorylation of GSK-3β at serine 9 and β-catenin at serine 675, thereby reducing β-catenin nuclear translocation and downstream transcription. DACT3 suppresses DVL1-driven invasion, proliferation, migration, and cisplatin resistance in NSCLC cells.\",\n      \"method\": \"Co-immunoprecipitation (DACT3–DVL1 interaction), Western blot (GSK-3β pS9, β-catenin pS675, nuclear β-catenin), TOPFlash luciferase reporter assay, siRNA/cDNA transfection loss/gain of function, immunofluorescence, cell invasion/proliferation/migration assays, in vivo tumorigenesis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP confirming direct interaction plus multiple downstream signaling and functional readouts; single lab\",\n      \"pmids\": [\"40838391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Dvl1 DVL1 Robinow syndrome variants disrupt epithelial imaginal disc morphology in Drosophila with increased cell death (caspase-dependent) and without changes in cell proliferation; they also cause ectopic MMP1 expression and tissue distortion dependent on JNK signaling, and abnormal accumulation of collagen IV (Viking) in pupal wings, as well as elevated BMP signaling.\",\n      \"method\": \"Drosophila expression of DVL1 variant (DVL1-1519ΔT), immunofluorescence, caspase inhibitor rescue, MMP1 immunostaining, JNK pathway genetic epistasis, dad-lacZ BMP reporter, Viking (collagen IV) staining in pupal wings\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo Drosophila model with multiple pathway readouts and genetic epistasis (JNK), single lab\",\n      \"pmids\": [\"40600289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nup358 interacts with Dvl1 through its N-terminal domain and inhibits Dvl1 spontaneous phase separation (condensate/biomolecular condensate formation). In the absence of Nup358, Dvl1 forms condensates that promote Tankyrase-mediated degradation of Axin1, leading to constitutive β-catenin stabilization and ligand-independent Wnt activation, depleting the transit-amplifying progenitor compartment in intestinal crypts.\",\n      \"method\": \"Conditional Nup358 knockout in adult mice, co-immunoprecipitation (Nup358–Dvl1 interaction), domain-mapping (N-terminal domain of Nup358), phase separation/condensate assays, Axin1 degradation assay, Tankyrase inhibitor experiments, intestinal crypt histology and ISC/TA compartment analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout combined with co-IP, phase separation assay, and epistasis (Tankyrase), preprint but multiple orthogonal methods\",\n      \"pmids\": [\"41929184\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"DVL1 is a cytoplasmic and nuclear scaffold protein that transduces both canonical (β-catenin-dependent) and non-canonical (PCP/JNK) Wnt signals: in the cytoplasm it binds Frizzled receptors, Frat-1, Axin1 (via DIX–DIX interaction), DACT3, and CSNK1E-dependent phosphorylation to regulate GSK-3β/β-catenin stability; in the nucleus it accumulates at rDNA loci to repress Pol I transcription via SIRT7 displacement, binds gene promoters in a manner regulated by lysine acetylation (K69/K285), and drives proliferation independently of bulk β-catenin nuclear translocation; its steady-state level is controlled by HECW1-mediated ubiquitination/degradation and by Nup358-mediated suppression of its phase separation into condensates that would otherwise promote Axin1 degradation; disease-causing Robinow syndrome frameshift variants in the C-terminal domain trap DVL1 in cytoplasmic puncta unresponsive to Wnt ligand, impair CSNK1E phosphorylation, shift signaling from canonical to non-canonical Wnt, and activate JNK/BMP pathways causing skeletal dysmorphogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DVL1 is a multifunctional Dishevelled-family scaffold protein that transduces Wnt signals through both canonical (β-catenin-dependent) and non-canonical (planar cell polarity/JNK) branches, and additionally functions as a nuclear transcriptional regulator [#1, #2, #5]. In the canonical cytoplasmic pathway, casein kinase I epsilon (CSNK1E/CKIε) phosphorylates DVL1 and enhances its binding to Frat-1 (via residues 228–250), a complex required for Wnt-3a-induced β-catenin accumulation and TCF-dependent transcription [#1]; the DIX domain of DVL1 forms a stable complex with the DIX domain of Axin1 [#4]. Its level and signaling output are tuned by multiple regulators: HECW1 ubiquitinates DVL1 to promote its degradation and restrain Wnt/β-catenin signaling [#17], DACT3 binds DVL1 to suppress GSK-3β/β-catenin phosphorylation and downstream transcription [#18], neuroglobin drives its proteasomal degradation [#11], and Nup358 binding suppresses DVL1 phase separation into condensates that otherwise promote Tankyrase-mediated Axin1 degradation and ligand-independent Wnt activation [#20]. In non-canonical signaling, DVL1 hyperphosphorylates Frizzled3 and blocks its internalization to control PCP-dependent commissural axon guidance [#2]. Independently of receptor signaling, DVL1 enters the nucleus, accumulates at rDNA loci to repress RNA Pol I transcription by displacing SIRT7 [#5], binds gene promoters in a manner regulated by lysine acetylation at K69 and K285 [#8], and drives proliferation in myoblasts and rhabdomyosarcoma cells without requiring increased nuclear β-catenin [#12]. De novo C-terminal frameshift variants in DVL1 cause autosomal-dominant Robinow syndrome: these mutants are trapped in cytoplasmic puncta unresponsive to Wnt ligand, lose canonical and gain non-canonical Wnt activity, and produce skeletal and tissue dysmorphogenesis through JNK and BMP pathway activation [#6, #7, #15, #19]. In knockout mice, DVL1 is required for normal social behavior and sensorimotor gating and for gut homeostasis across epithelial and immune compartments [#0, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that DVL1 has a non-redundant physiological role in the CNS, answering whether this Wnt transducer matters at the organismal level despite paralog redundancy.\",\n      \"evidence\": \"Germline Dvl1 knockout mice with behavioral assays (social dominance, PPI of startle)\",\n      \"pmids\": [\"9298901\", \"14960015\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis linking DVL1 loss to social/sensorimotor deficits not defined\", \"Cell types and circuits responsible unidentified\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified a DVL1 PDZ-domain interaction with the EGFR substrate EPS8 and reciprocal phosphorylation regulation, hinting at crosstalk between DVL1 and tyrosine-kinase signaling.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, co-transfection phosphorylation assays\",\n      \"pmids\": [\"10581192\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of DVL1–EPS8 crosstalk in Wnt signaling unclear\", \"Single lab, no in vivo validation\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined how CSNK1E phosphorylation couples DVL1 to canonical Wnt output, showing the CKIε–DVL1–Frat-1 module is required for β-catenin accumulation and TCF transcription.\",\n      \"evidence\": \"Co-IP, deletion mutagenesis (Δ228–250), CKIε RNAi, TOPFlash reporter, β-catenin assays in L and HEK293 cells\",\n      \"pmids\": [\"12556519\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosite map on DVL1 not resolved\", \"Structural basis of Frat-1 binding unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated direct DIX–DIX assembly between DVL1 and Axin1, providing a biochemical basis for the destruction-complex regulatory interface.\",\n      \"evidence\": \"Multi-cistronic E. coli co-expression, affinity and size-exclusion chromatography, preliminary crystallization\",\n      \"pmids\": [\"20846493\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis or functional validation of the interface\", \"Crystal structure not solved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed DVL1 acts in non-canonical PCP signaling by hyperphosphorylating Frizzled3 and blocking its internalization, establishing a receptor-trafficking control point for directional Wnt sensing in axon guidance.\",\n      \"evidence\": \"PCP-component genetic loss-of-function, phosphorylation/internalization assays, growth cone imaging, Wnt5a axon guidance assays\",\n      \"pmids\": [\"21316586\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase mediating Frizzled3 phosphorylation not identified\", \"DVL1 vs paralog specificity in PCP not fully resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked DVL1 to a human Mendelian disease, establishing that C-terminal frameshift variants escaping NMD cause autosomal-dominant Robinow syndrome via altered Wnt signaling.\",\n      \"evidence\": \"Whole-exome/Sanger sequencing, trio analysis, patient transcript analysis; TOPFlash assays with mutant and mutant+WT co-expression and GFP stability\",\n      \"pmids\": [\"25817016\", \"25817014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional mechanism inferred rather than reconstituted in the original reports\", \"Connection of TOPFlash gain-of-function to osteosclerosis not directly tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Uncovered an unexpected nuclear function: DVL1 represses RNA Pol I rDNA transcription downstream of Wnt5a by binding rDNA chromatin and displacing the activator SIRT7.\",\n      \"evidence\": \"DVL1-specific siRNA, ChIP for DVL1 and SIRT7 at rDNA, Pol I transcription assays, NOR imaging in breast cancer cells\",\n      \"pmids\": [\"27500936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of DVL1 nuclear import/rDNA targeting unknown\", \"Whether SIRT7 release is direct displacement unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a dual epithelial and immune requirement for DVL1 in gut homeostasis, showing Paneth cell and T-cell defects combine to drive GI dysfunction.\",\n      \"evidence\": \"Dvl1 knockout mice, bone marrow chimeras, transit/Paneth/CD8 readouts, microbiota manipulation\",\n      \"pmids\": [\"27525310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Wnt-pathway dependence of the gut phenotype not dissected\", \"Cell-intrinsic molecular targets unidentified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified post-translational and nuclear-transcriptional control of DVL1: neuroglobin-driven proteasomal degradation suppresses Wnt output, while nuclear DVL1 binds CYP19A1 promoters to control aromatase and estrogen production.\",\n      \"evidence\": \"Co-IP, proteasome inhibitor and TOPFlash assays (neuroglobin); ChIP and siRNA with aromatase/E2 readouts (CYP19A1)\",\n      \"pmids\": [\"30041403\", \"30479694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating neuroglobin-dependent degradation not identified\", \"Direct vs indirect promoter regulation by DVL1 unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed that lysine acetylation at K69 (DIX) and K285 (PDZ) governs DVL1 nuclear localization and promoter binding, defining a PTM switch for its transcriptional role.\",\n      \"evidence\": \"LC-MS/MS acetyl-site mapping, acetyl-mimetic/deficient mutants, fractionation/IF, ChIP in TNBC cells\",\n      \"pmids\": [\"31700102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acetyltransferase/deacetylase enzymes unidentified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genome-wide profiling positioned nuclear DVL1 as a chromatin-associated regulator whose binding sites overlap H3K27me3/EZH2 repressive marks.\",\n      \"evidence\": \"DVL-1 ChIP-Seq with co-localization analysis against H3K27me3/EZH2 datasets\",\n      \"pmids\": [\"34659647\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DVL1–PRC2 interaction not demonstrated\", \"Limited functional follow-up\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established that DVL1's nuclear pro-proliferative function is β-catenin-independent and uses domain requirements distinct from DVL3, dissociating its growth role from canonical Wnt output.\",\n      \"evidence\": \"siRNA, nuclear/cytoplasmic fractionation, domain-deletion constructs, proliferation assays in myoblasts and rhabdomyosarcoma cells\",\n      \"pmids\": [\"35589804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear effectors of DVL1-driven proliferation unknown\", \"Domain element required for DVL1 (vs DVL3) not pinpointed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanded DVL1's regulatory reach to GPCR turnover, showing it targets Sstr2 for lysosomal degradation and selectively dampens agonist-stimulated ERK signaling in a Wnt-modulated manner.\",\n      \"evidence\": \"Co-IP, lysosomal inhibitor, internalization/recycling, adenylyl cyclase and ERK1/2 assays, Wnt overexpression/inhibitor experiments in NET cells\",\n      \"pmids\": [\"36965619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of DVL1–Sstr2 binding unknown\", \"Generality across other GPCRs untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mechanistically connected Robinow variants to pathway rewiring, showing they lose canonical and gain non-canonical Wnt activity and produce skeletal/wing dysmorphology in chicken and Drosophila.\",\n      \"evidence\": \"Transient WT/variant DVL1 expression in Drosophila and chicken with Wnt reporters and morphological analysis; localization, TOPFlash, and CSNK1E phosphorylation assays (preprint)\",\n      \"pmids\": [\"36916233\", \"bio_10.1101_2025.08.02.668297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why mutant C-terminus traps DVL1 in puncta not structurally defined\", \"CSNK1E-phosphorylation interference mechanism unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified HECW1 as an E3 ligase that ubiquitinates and degrades DVL1, defining a degradation node that restrains Wnt/β-catenin-driven proliferation in cervical cancer.\",\n      \"evidence\": \"Ubiquitination assay, Western blot, nuclear β-catenin fractionation, TOPFlash, siRNA, in vivo tumor assay\",\n      \"pmids\": [\"38266865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin chain type and DVL1 acceptor sites not mapped\", \"Upstream regulation of HECW1 activity unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved additional layers of DVL1 control: DACT3 binding suppresses GSK-3β/β-catenin phosphorylation, and Nup358 binding prevents DVL1 phase separation into condensates that otherwise drive Tankyrase-mediated Axin1 degradation and ligand-independent Wnt activation.\",\n      \"evidence\": \"Co-IP, Western blot, TOPFlash, functional assays in NSCLC (DACT3); conditional Nup358 knockout mice, co-IP, phase-separation and Axin1 degradation assays, Tankyrase inhibitor, crypt histology (Nup358, preprint)\",\n      \"pmids\": [\"40838391\", \"41929184\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological conditions triggering DVL1 condensation not defined\", \"Whether DACT3 and Nup358 control converge mechanistically untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Detailed the tissue-level pathology of Robinow variants, showing JNK-dependent ectopic MMP1, caspase-dependent cell death, collagen IV accumulation, and elevated BMP signaling underlie dysmorphogenesis.\",\n      \"evidence\": \"Drosophila DVL1-1519ΔT expression, caspase inhibitor rescue, MMP1/Viking staining, JNK epistasis, dad-lacZ BMP reporter\",\n      \"pmids\": [\"40600289\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target of variant DVL1 driving JNK/BMP activation unknown\", \"Relevance to human skeletal phenotype not directly established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DVL1's nuclear transcriptional/rDNA-repressive functions are mechanistically integrated with its cytoplasmic Wnt-scaffold role, and what governs its nuclear import and phase behavior in vivo, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of full-length DVL1 in distinct compartments\", \"Nuclear import machinery and condensation triggers undefined\", \"Paralog-specific functional division (DVL1 vs DVL2/DVL3) incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 4, 18]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 8, 9, 10]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5, 8, 9]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 12, 16]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 8, 10, 12]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 17, 18]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 8, 9, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 7, 15, 19]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 15, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"AXIN1\", \"CSNK1E\", \"FRAT1\", \"DACT3\", \"HECW1\", \"SSTR2\", \"EPS8\", \"FZD3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}