{"gene":"DVL2","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1999,"finding":"DVL2 co-localizes and co-immunoprecipitates with Axin; Axin residues 603–810 contain DVL2-association determinants. DVL2 activates TCF-dependent transcription upstream of GSK-3β, and this activation is blocked by co-expression of Axin or GSK-3β. Redirecting DVL2 localization via a CAAX motif also redistributes Axin, confirming close physical association.","method":"Co-immunoprecipitation, co-localization with CAAX-motif redirected protein, TCF-luciferase reporter assay, deletion analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-localization, co-IP, functional reporter assay, deletion mapping; replicated across multiple experiments in single rigorous study","pmids":["10329628"],"is_preprint":false},{"year":1996,"finding":"DVL2 is a mammalian homolog of Drosophila dishevelled that can partially rescue segmentation defects in dsh-null fly embryos, demonstrating functional conservation of its role in transducing the Wingless/Wnt signal.","method":"Genetic rescue assay in dsh-null Drosophila embryos; sequence analysis","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic rescue in model organism, single lab, direct functional readout","pmids":["8887313"],"is_preprint":false},{"year":2012,"finding":"DVL2 is phosphorylated at S143 and T224 by CK1ε downstream of Wnt5a signaling. Phosphorylated DVL2 directly interacts with Plk1, forming a DVL2–Plk1 complex that stabilizes HEF1 and activates Aurora-A kinase to drive primary cilia disassembly.","method":"Phosphorylation mapping, co-immunoprecipitation, RNAi knockdown, cilia disassembly assay, kinase inhibitor studies","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (phospho-site mapping, Co-IP of DVL2–Plk1 complex, functional cilia assay, RNAi), single rigorous study with mechanistic resolution","pmids":["22609948"],"is_preprint":false},{"year":2012,"finding":"Wnt5a activates DVL2, which in turn activates Daam1 and RhoA to promote stress fiber formation and breast cancer cell migration. Dominant-negative DVL2 mutants or DVL2 siRNA abolish Wnt5a-induced Daam1/RhoA activation and migration.","method":"siRNA knockdown, dominant-negative overexpression, RhoA activity assay (pulldown), stress fiber staining, Matrigel migration assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (siRNA, dominant-negative, GTPase activity assay, migration assay), single lab","pmids":["22655072"],"is_preprint":false},{"year":2013,"finding":"DVL2 physically binds Rab35 (shown by co-immunoprecipitation and immunofluorescence), and this DVL2–Rab35 interaction is required upstream of Rac1 activation for Wnt5a-driven breast cancer cell migration.","method":"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, Rac1 activity assay, cell migration assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional migration and GTPase assays, single lab","pmids":["23353182"],"is_preprint":false},{"year":2005,"finding":"DVL2 cytoplasmic puncta are protein aggregates formed at high expression levels and are not required for canonical Wnt signaling. They do not co-localize with early or late endocytic markers, and time-lapse analysis shows short-range random movement without originating from the plasma membrane.","method":"Live-cell time-lapse imaging, endosomal marker co-localization, signaling reporter assay at graded expression levels","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging plus functional assays, single lab, multiple orthogonal approaches","pmids":["16263761"],"is_preprint":false},{"year":2021,"finding":"WWP1 E3 ubiquitin ligase directly interacts with DVL2 and stabilizes it via K27-linked polyubiquitination, thereby activating the DVL2/CaMKII/HDAC4/MEF2C pathway and driving cardiac hypertrophy. WWP1 knockout prevents TAC-induced hypertrophy.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assay (K27-linkage specific), pulse-chase assay, reporter gene assay, AAV9-shRNA in vivo model, echocardiography","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro ubiquitination assay, K27-linkage characterization, in vivo KO and AAV rescue, multiple orthogonal methods","pmids":["34139860"],"is_preprint":false},{"year":2019,"finding":"USP9X deubiquitylates DVL2; USP9X-mediated deubiquitylation promotes canonical Wnt activation, whereas increased DVL2 ubiquitylation (by WWP1) is associated with DVL2 localization to actin-rich projections and activation of the PCP pathway. Thus a WWP1–USP9X ubiquitin rheostat on DVL2 specifies canonical vs. PCP pathway output.","method":"Deubiquitylase assay, Co-IP, ubiquitin mutant analysis, pathway reporter assay, fluorescence localization","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — enzymatic deubiquitylase activity demonstrated, pathway bifurcation established with multiple orthogonal assays, mechanistic epistasis","pmids":["31340145"],"is_preprint":false},{"year":2011,"finding":"GABARAPL1 interacts with DVL2 (via p62 adaptor) and mediates its degradation through the autophagy pathway, thereby suppressing Wnt/β-catenin signaling. Blocking autophagy with 3-MA prevents DVL2 degradation.","method":"Yeast two-hybrid screening, co-immunoprecipitation, autophagy inhibitor (3-MA) rescue, luciferase reporter assay","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus pharmacological rescue, single lab","pmids":["21691068"],"is_preprint":false},{"year":2014,"finding":"The DVL2 DEP domain binds phosphatidic acid (PA) through its basic helix 3 and a contiguous loop in a pH-dependent manner. PA binding induces conformational changes in helix 2 and β-strand 4. Interaction is pH-dependent, resembling deprotonation of PA.","method":"NMR spectroscopy, molecular-dynamics simulations, site-directed mutagenesis, biophysical binding assays","journal":"Biophysical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural characterization plus mutagenesis plus MD simulation, multiple orthogonal methods in single study","pmids":["24606934"],"is_preprint":false},{"year":2014,"finding":"RNF185 E3 ubiquitin ligase interacts with DVL2, promotes its ubiquitination and proteasomal degradation, thereby inhibiting canonical Wnt/β-catenin signaling and negatively regulating osteogenic differentiation of MC3T3-E1 cells.","method":"Co-immunoprecipitation, ubiquitination assay, Western blot for protein levels, luciferase reporter assay, ALP activity assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional osteogenic assay, single lab","pmids":["24727453"],"is_preprint":false},{"year":2018,"finding":"PP5 (PPP5C) is a phosphatase of DVL2 that directly interacts with and dephosphorylates DVL2, including at S143 and the 10B5 cluster. PP5 knockdown elevates DVL2 phosphorylation at basal levels and upon Wnt stimulation. PP5 is distinct from PP2A in which DVL2 phosphorylation sites it regulates. PP5 localizes to the basal body of primary cilia where S143-phosphorylated DVL2 also resides.","method":"Co-immunoprecipitation, in vitro phosphatase assay, siRNA knockdown with phospho-specific antibodies, immunofluorescence localization, ciliogenesis assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — direct in vitro dephosphorylation assay plus Co-IP plus localization, single lab","pmids":["29426949"],"is_preprint":false},{"year":2016,"finding":"DDX3, a subunit of CK1ε, facilitates CK1ε-mediated phosphorylation of DVL2, which promotes β-catenin/TCF activation and tumor invasion in colorectal cancer. Pharmacological inhibition of CK1ε suppresses DVL2 phosphorylation and invasion.","method":"Western blotting for pDVL2, CK1ε inhibitor (PF4800567) treatment, TCF reporter assay, invasion assay, xenograft model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter plus kinase inhibitor plus in vivo xenograft, single lab","pmids":["26892600"],"is_preprint":false},{"year":2005,"finding":"DVL2 is present in post-developmental endothelial cells as a phosphoprotein, localized in both F-actin-free and F-actin-associated cytoplasmic pools. siRNA-mediated silencing of DVL2 causes aberrant membrane activity, failure to extend lamellipodia, and actin filament disorganization, indicating DVL2 regulates cell migration via actin cytoskeleton.","method":"siRNA knockdown, immunolabeling, Western blotting, time-lapse cell motility assay","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with direct actin and motility phenotype readouts, single lab","pmids":["15593083"],"is_preprint":false},{"year":2011,"finding":"Stau1 RNA-binding protein binds the 3′ UTR of Dvl2 mRNA and stabilizes it in undifferentiated myoblasts. Stau1 knockdown shortens Dvl2 mRNA half-life; during myogenic differentiation, Stau1 dissociates from Dvl2 3′ UTR, reducing Dvl2 mRNA levels. Forced Dvl2 expression inhibits myogenic differentiation.","method":"RNA immunoprecipitation, mRNA stability assay, Western blot, qRT-PCR, overexpression in C2C12 differentiation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus mRNA stability assay plus functional overexpression phenotype, single lab","pmids":["22166206"],"is_preprint":false},{"year":2022,"finding":"Endogenous DVL2 (tagged with mEos3.2 at its genomic locus) forms Wnt-dependent supramolecular condensates (~1 per cell at physiological levels) that localize to γ-tubulin- and CEP164-positive centrosomal structures in a cell cycle-dependent manner. Single-molecule PALM/DNA-PAINT demonstrates repetitive internal organization of these condensates.","method":"CRISPR genome-engineered endogenous mEos3.2-DVL2, live-cell superresolution imaging (PALM), DNA-PAINT, immunofluorescence co-localization, Wnt pathway reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — endogenous tagging by genome engineering, superresolution single-molecule imaging, multiple pathway validation assays, rigorous controls","pmids":["35867833"],"is_preprint":false},{"year":2020,"finding":"The Daple–CK1ε–DVL2 trimeric complex is required for CK1ε-mediated phosphorylation of DVL2 at T224. Daple lacking its C-terminal DVL-binding motif (ΔGCV) retains CK1ε binding but cannot induce DVL2 phosphorylation. T224 phosphorylation is required for full β-catenin transcriptional activity. Wnt3a stimulation increases Daple membrane localization and Daple–DVL2 association.","method":"Co-immunoprecipitation, dominant-negative Daple mutants, phospho-specific Western blot, TCF/LEF luciferase reporter assay, siRNA knockdown","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with deletion mutants, phospho-site functional analysis, reporter assay, single lab","pmids":["32888647"],"is_preprint":false},{"year":2013,"finding":"Sestd1 forms complexes with DVL2 independently of both Dact1 and Vangl2. DVL2 enhances Dact1/Sestd1-mediated Rho family GTPase activation in cell-based assays consistent with PCP pathway function. Genetic synergy: Dvl2 KO is recessive alone but causes dominant embryonic lethality in Sestd1 or Dact1 KO backgrounds.","method":"Co-immunoprecipitation, Rho GTPase activation assay, genetic epistasis in double/triple KO mice","journal":"Communicative & integrative biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus GTPase assay plus genetic epistasis, single lab","pmids":["24505507"],"is_preprint":false},{"year":2020,"finding":"CCNG2 promotes polyubiquitination-mediated degradation of DVL2 via the E3 ligase RNF123. RNF123 interacts with DVL2; CCNG2 upregulates RNF123, leading to DVL2 destabilization, suppression of Wnt/PCP-JNK signaling, and impaired trophoblast migration and invasion.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown (RNF123), Western blot, JNK activity assay, migration/invasion assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of RNF123-DVL2, ubiquitination assay, functional rescue by siRNA, single lab","pmids":["33205477"],"is_preprint":false},{"year":2021,"finding":"DVL2 interacts with the C-terminus of TNFR1 and mediates TNFR1 endocytosis, thereby inhibiting NF-κB signaling. IL-13 upregulates DVL2 expression via STAT6. This mechanism coordinates NF-κB and Wnt signaling in colitis-associated colorectal cancer.","method":"Co-immunoprecipitation, endocytosis assay, STAT6 inhibitor, siRNA knockdown, NF-κB reporter assay","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of DVL2–TNFR1, functional endocytosis and NF-κB assays, single lab","pmids":["34807493"],"is_preprint":false},{"year":2024,"finding":"DVL2 oligomers form at endogenous protein concentrations via two distinct regions in its C-terminus: LCR4 (low-complexity region 4) mediates pre-oligomerization via aggregating residues, while adjacent CD2 promotes condensate formation via phenylalanine stickers. Point mutations inactivating these sites impair Wnt/β-catenin pathway activation by DVL2.","method":"Biochemical ultracentrifugation assay at endogenous levels, deletion/fusion constructs, point mutagenesis, condensate microscopy, Wnt reporter assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical assay at endogenous levels, mutagenesis of interaction sites with functional validation, multiple orthogonal approaches in single study","pmids":["39652469"],"is_preprint":false},{"year":2022,"finding":"METTL16 methyltransferase suppresses DVL2 protein levels via m6A modification of DVL2 mRNA, inhibiting its translation and thereby suppressing Wnt/β-catenin signaling in pancreatic ductal adenocarcinoma.","method":"m6A sequencing/mapping, METTL16 overexpression/knockdown, Western blot for DVL2, Wnt reporter assay, in vitro and in vivo metastasis assays","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A modification mapped to DVL2 mRNA, translational suppression demonstrated, functional rescue, single lab","pmids":["37859814"],"is_preprint":false},{"year":2020,"finding":"Low disturbed fluid shear stress (1 dyne/cm²) promotes primary cilia assembly via DVL2 in endothelial cells. DVL2 co-immunoprecipitates with Bbs8 and γ-tubulin. DVL2 overexpression increases ciliated cell percentages under shear; DVL2 silencing decreases them and reduces Bbs8 and γ-tubulin expression, indicating DVL2 facilitates basal body apical docking through Bbs8 and γ-tubulin.","method":"Microfluidic chamber, co-immunoprecipitation, siRNA knockdown, overexpression, immunofluorescence","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus siRNA/overexpression with quantitative ciliation readout, single lab","pmids":["32776193"],"is_preprint":false},{"year":2019,"finding":"TM4SF1 interacts with DVL2 and strengthens the DVL2–Axin interaction, thereby promoting β-catenin/TCF signaling in hepatocellular carcinoma. TM4SF1 downregulation increases β-catenin ubiquitination.","method":"Co-immunoprecipitation, ubiquitination assay, TCF reporter assay, siRNA knockdown","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating DVL2–TM4SF1 and DVL2–Axin interactions, functional reporter and ubiquitination assays, single lab","pmids":["31876386"],"is_preprint":false},{"year":2022,"finding":"DACT1 missense variants located in its DVL2 interaction region show reduced binding to DVL2 in biochemical characterization and associate with CAKUT in humans, establishing the DVL2–DACT1 protein–protein interaction as functionally required for normal kidney development.","method":"Whole-exome sequencing, biochemical binding assay (reduced DVL2 binding of mutant DACT1), CRISPR/Cas9 Dact1 KO in murine collecting duct cells (branching morphogenesis assay)","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical interaction assay with patient variants, functional KO morphogenesis assay, single lab","pmids":["36066768"],"is_preprint":false},{"year":2015,"finding":"APPL1 endocytic adaptor physically interacts with DVL2 and synergizes with it to potentiate AP-1 (c-Jun)-driven transcription in non-canonical Wnt signaling, specifically increasing MMP1 expression in a JNK-dependent manner. This function requires endosomal recruitment of APPL1.","method":"Co-immunoprecipitation, AP-1/TCF reporter assay, JNK inhibitor, endosomal localization assay, MMP1 expression measurement","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional reporter and gene expression assays with mechanistic inhibitor controls, single lab","pmids":["25622892"],"is_preprint":false},{"year":2023,"finding":"Wnt5a–Ror1 signaling at the cell surface requires Rif (a Rho-family GTPase) to activate DVL2 phosphorylation. Rif interacts with Ror1 and is required for 3D matrix-induced polarized filopodia in lung adenocarcinoma cells.","method":"Co-immunoprecipitation, Western blot for pDVL2, siRNA knockdown of Rif and Ror1, 3D Matrigel culture, in vivo tumor assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus phospho-DVL2 readout after RNAi, functional tumor assay, single lab","pmids":["37703992"],"is_preprint":false},{"year":2023,"finding":"HCMV viral protein pUL8 interacts with DVL2 and β-catenin via a PDZ-binding domain; loss of pUL8 interaction with the β-catenin–DVL2 complex restricts viral reactivation in CD34+ hematopoietic progenitor cells.","method":"Co-immunoprecipitation, PDZ-binding domain mutant analysis, viral reactivation assay in CD34+ HPCs","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping plus viral functional assay, single lab","pmids":["37772824"],"is_preprint":false},{"year":2025,"finding":"LINC01612 lncRNA interacts with DVL2 protein and enhances DVL2 stability by reducing its ubiquitination, thereby maintaining WNT signaling required for human definitive endoderm differentiation. DVL2 overexpression rescues endoderm differentiation defects caused by LINC01612 loss.","method":"shRNA knockdown, Co-IP of LINC01612 with DVL2, ubiquitination assay, WNT reporter assay, CRISPR promoter deletion, rescue by DVL2 overexpression","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, genetic rescue, single lab","pmids":["41135528"],"is_preprint":false},{"year":2024,"finding":"In macrophages, DVL2 promotes nuclear YAP–HSF1 interaction, which activates HSF1 target gene eEF2, thereby inhibiting NOD1/caspase-1/GSDMD pyroptosis and NF-κB signaling. Myeloid-specific Dvl2 KO reduces YAP–HSF1 colocalization, enhances NOD1-driven pyroptosis, and worsens ischemia/reperfusion liver injury.","method":"Myeloid-specific KO mouse model, co-immunoprecipitation (YAP–HSF1), caspase-1/GSDMD activation assays, adoptive macrophage transfer, hepatocyte co-culture assay","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with mechanistic Co-IP and functional pyroptosis assays, single lab","pmids":["39644526"],"is_preprint":false},{"year":2026,"finding":"AJUBA acts as a co-activator of C/EBPβ to enhance NEDD4 transcription; NEDD4 then promotes ubiquitin-mediated degradation of DVL2, preventing Ca²⁺/CaMKII/HDAC4 pathway activation and protecting against cardiac hypertrophy. AJUBA KO worsens cardiac hypertrophy and dysfunction.","method":"AJUBA KO mouse, reporter assay for C/EBPβ/NEDD4 transcription, co-immunoprecipitation, ubiquitination assay, echocardiography","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus transcriptional and ubiquitination mechanistic assays, single lab","pmids":["41793265"],"is_preprint":false},{"year":2026,"finding":"E3 ubiquitin ligase Itch promotes K48-linked ubiquitination of DVL2 at lysine 343, leading to its proteasomal degradation and suppression of GSK-3β/β-catenin signaling, thereby alleviating kidney fibrosis. Itch KO mice show exacerbated fibrosis and increased DVL2 levels.","method":"Co-immunoprecipitation, site-specific ubiquitination assay (K343 mutation), Itch KO mice, Western blot, fibrosis markers","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — site-specific ubiquitination assay with K343 identification plus KO in vivo, single lab","pmids":["42168361"],"is_preprint":false},{"year":2025,"finding":"PRICKLE3 interacts with USP9X and DVL2 in a tripartite complex; PRICKLE3–USP9X interaction inhibits DVL2 ubiquitination, stabilizing DVL2 and activating canonical WNT signaling. PRICKLE3–DVL2 interaction also enhances β-catenin phosphorylation at S675 to promote its nuclear translocation.","method":"Co-immunoprecipitation, ubiquitination assay, Western blot, PRICKLE3 KO/OE in NSCLC cells, in vivo tumor model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tripartite Co-IP, ubiquitination assay, functional KO/OE with pathway readouts, single lab","pmids":["40973792"],"is_preprint":false},{"year":2022,"finding":"Cancer-associated SF3B1 mutation causes aberrant 3′ splice site selection in DVL2 pre-mRNA using an alternative branchpoint sequence (BPS) with higher affinity for U2 snRNA than the canonical BPS. The aberrant splicing does not require the canonical 3′ splice site or polypyrimidine tract; BPS position and U2 snRNA affinity together determine BPS selection.","method":"Minigene splicing assay, BPS swapping mutagenesis, U2 snRNA affinity analysis, SF3B1 mutant cell lines","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis of BPS positions with functional splicing readout, mechanistic dissection of spliceosome selectivity, single lab","pmids":["33561744"],"is_preprint":false},{"year":2025,"finding":"Profilin2 directly interacts with DVL2 in vitro via the extreme C-terminus of DVL2 (beyond the polyproline motif), without engaging the PDZ or DEP domains. DVL2 adopts an autoinhibited conformation through intramolecular binding of its extreme C-terminus to its PDZ domain, yet profilin2 retains binding in this autoinhibited state.","method":"Co-localization (fluorescence), in vitro pulldown assay, deletion/domain mapping, autoinhibition assay","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vitro pulldown with domain mapping, preprint, single lab, no functional pathway validation","pmids":["bio_10.1101_2025.10.09.681388"],"is_preprint":true},{"year":2025,"finding":"The C-terminus of DVL2 interacts with the centrosomal protein Kizuna (Kiz); Kiz induces an open DVL2 conformation enabling recruitment of PKCδ to stabilize the apical microtubule meshwork. This DVL2–Kiz–PKCδ axis is required for primary cilia formation (primary cilia in the eye, multicilia in MCE, and mono-motile cilia in the GRP) in Xenopus.","method":"Co-immunoprecipitation (DVL2–Kiz), conformational assay, in vivo Xenopus loss-of-function, ciliogenesis readout","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — Co-IP and in vivo functional data in Xenopus, preprint not yet peer-reviewed, single lab","pmids":["bio_10.1101_2025.11.12.688108"],"is_preprint":true},{"year":2025,"finding":"Daple and its paralog Girdin-L bear unique extended C-terminal PDZ-binding motifs that bind the DVL2 PDZ domain with exceptionally high affinity. Deletion of these motifs or DVL2's PDZ domain results in elongated primary cilia unresponsive to Wnt5a-stimulated disassembly, establishing this DVL2 PDZ–Daple/Girdin-L interaction as the molecular basis for Wnt5a-driven cilia disassembly.","method":"Proximity labeling, structural/biophysical analysis, deletion mutants, Wnt5a cilia disassembly assay in HEK293T cells","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 1–2 / Weak — structural/biophysical plus functional cilia assay, but preprint not yet peer-reviewed, single lab","pmids":["bio_10.1101_2025.09.26.678488"],"is_preprint":true},{"year":2025,"finding":"CK1δ/ε inhibition blocks DVL2 condensate formation, as shown by image-based screening with CK1δ/ε kinase inhibitors; genetic epistasis with APC, Axin1, and MCC loss-of-function alleles modulates this effect on Wnt signaling, placing CK1δ/ε-mediated DVL2 phosphorylation upstream of condensate dynamics in the Wnt pathway.","method":"Image-based high-throughput screen, CK1δ/ε inhibitors, endogenous DVL2-mEos3.2, phosphoproteomics, genetic epistasis (APC/Axin1/MCC KO)","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — pharmacological screen plus genetic epistasis, preprint, single lab","pmids":["bio_10.1101_2025.01.11.632522"],"is_preprint":true}],"current_model":"DVL2 is a multidomain cytoplasmic scaffold (DIX, PDZ, DEP domains plus a C-terminal LCR4/CD2 region) that forms Wnt-dependent biomolecular condensates at centrosomal structures and acts as a central hub transmitting both canonical Wnt/β-catenin and non-canonical (PCP, Wnt/Ca²⁺) signals: upon Wnt stimulation it is phosphorylated by CK1ε (at S143/T224, facilitated by Daple) and dephosphorylated by PP5/PP2A, recruits Axin to disrupt the β-catenin destruction complex, engages Daam1/RhoA and Rab35/Rac1 for cell migration, and drives primary cilia disassembly via a DVL2–Plk1–HEF1–Aurora-A axis downstream of Wnt5a–CK1ε; its stability and pathway choice are regulated by a ubiquitin rheostat in which WWP1-mediated K27-ubiquitylation stabilizes DVL2 and promotes PCP, while USP9X-mediated deubiquitylation favors canonical signaling, and additional E3 ligases (RNF185, RNF123, NEDD4, Itch/K48-K343) promote its proteasomal or autophagic degradation."},"narrative":{"mechanistic_narrative":"DVL2 is a cytoplasmic scaffold that transduces both canonical Wnt/β-catenin and non-canonical (PCP, Wnt/Ca²⁺) signals, functionally conserved from Drosophila dishevelled [PMID:8887313] and acting genetically upstream of GSK-3β to activate TCF-dependent transcription [PMID:10329628]. In canonical signaling DVL2 co-localizes and co-immunoprecipitates with Axin and redirecting DVL2 redistributes Axin, establishing it as an Axin-recruiting hub that engages the β-catenin destruction complex [PMID:10329628]. Pathway activation depends on CK1ε-mediated phosphorylation of DVL2 at S143 and T224, which is facilitated by the DDX3 subunit of CK1ε and by a Daple–CK1ε–DVL2 trimeric complex, with T224 phosphorylation required for full β-catenin transcriptional output [PMID:22609948, PMID:26892600, PMID:32888647]; this phosphorylation is reversed by the phosphatase PP5, which acts at S143 and the 10B5 cluster and localizes with phospho-DVL2 to the basal body [PMID:29426949]. At endogenous concentrations DVL2 forms Wnt-dependent supramolecular condensates at γ-tubulin/CEP164-positive centrosomal structures, driven by C-terminal LCR4 and CD2 regions whose aggregating residues and phenylalanine stickers are required for Wnt/β-catenin activation [PMID:35867833, PMID:39652469]. Through its non-canonical outputs DVL2 activates Daam1/RhoA and binds Rab35 to drive Rac1-dependent breast cancer cell migration and actin/lamellipodial dynamics [PMID:22655072, PMID:23353182, PMID:15593083], and it nucleates a DVL2–Plk1–HEF1–Aurora-A axis downstream of Wnt5a–CK1ε to drive primary cilia disassembly [PMID:22609948]. DVL2 abundance and pathway choice are set by a ubiquitin rheostat: WWP1 stabilizes DVL2 via K27-linked polyubiquitylation to favor PCP signaling while USP9X deubiquitylates it to favor canonical signaling, and multiple E3 ligases (RNF185, RNF123, NEDD4, Itch via K48-linked K343) target DVL2 for proteasomal degradation while GABARAPL1/p62 routes it to autophagic degradation [PMID:34139860, PMID:31340145, PMID:21691068, PMID:24727453, PMID:33205477, PMID:41793265, PMID:42168361]. The DVL2 DEP domain binds phosphatidic acid in a pH-dependent manner [PMID:24606934], and a DACT1 missense variant that weakens DACT1–DVL2 binding associates with congenital kidney malformation (CAKUT), implicating the interaction in kidney development [PMID:36066768].","teleology":[{"year":1996,"claim":"Established that the mammalian protein is a functional dishevelled ortholog, anchoring DVL2 in Wnt signal transduction rather than being a sequence homolog of unknown function.","evidence":"Genetic rescue of segmentation defects in dsh-null Drosophila embryos","pmids":["8887313"],"confidence":"Medium","gaps":["Did not define which mammalian pathway branch (canonical vs PCP) is rescued","No molecular partners identified"]},{"year":1999,"claim":"Defined where DVL2 sits in the canonical cascade by showing it acts upstream of GSK-3β and physically associates with Axin, identifying DVL2 as an Axin-recruiting node of the destruction complex.","evidence":"Co-IP, CAAX-redirected co-localization, deletion mapping, and TCF-luciferase reporter assays","pmids":["10329628"],"confidence":"High","gaps":["Mechanism by which Axin recruitment disrupts the destruction complex not resolved","No structural detail of the DVL2–Axin interface"]},{"year":2005,"claim":"Distinguished pathologic overexpression aggregates from functional puncta and tied endogenous DVL2 to actin-based migration, separating signaling-relevant condensates from artifacts.","evidence":"Live-cell time-lapse imaging with endosomal markers at graded expression; siRNA with actin/motility readouts in endothelial cells","pmids":["16263761","15593083"],"confidence":"Medium","gaps":["Did not identify the molecular basis of physiological condensates","Cytoskeletal effectors downstream of DVL2 not defined here"]},{"year":2012,"claim":"Connected Wnt5a/CK1ε-driven DVL2 phosphorylation to specific non-canonical effectors, defining how DVL2 drives migration and cilia disassembly.","evidence":"Phospho-site mapping (S143/T224), Co-IP of DVL2–Plk1, cilia disassembly assays, and Daam1/RhoA GTPase/migration assays","pmids":["22609948","22655072"],"confidence":"High","gaps":["How phosphorylation switches DVL2 between effector complexes unclear","Direct vs indirect DVL2–Plk1 binding not fully resolved"]},{"year":2013,"claim":"Extended the non-canonical effector map by placing Rab35 upstream of Rac1 in DVL2-driven migration and linking DVL2 to Dact1/Sestd1 PCP complexes through genetic synergy.","evidence":"Co-IP, Rac1/Rho GTPase activity assays, migration assays, and double/triple KO mouse epistasis","pmids":["23353182","24505507"],"confidence":"Medium","gaps":["Direct vs scaffolded nature of DVL2–Rab35 binding not resolved","How DVL2 partitions among competing PCP complexes unknown"]},{"year":2014,"claim":"Provided biophysical insight into DEP-domain membrane engagement and identified DVL2 as a proteasomal degradation target, beginning to define the lipid- and stability-control layers.","evidence":"NMR/MD/mutagenesis of DEP–phosphatidic acid binding; Co-IP and ubiquitination assays for RNF185","pmids":["24606934","24727453"],"confidence":"Medium","gaps":["Functional consequence of DEP–PA binding for signaling not established","Ubiquitin linkage type used by RNF185 not characterized"]},{"year":2016,"claim":"Refined the CK1ε activation step by showing DDX3 acts as a CK1ε subunit facilitating DVL2 phosphorylation, linking it to tumor invasion.","evidence":"Phospho-DVL2 Western blot, CK1ε inhibitor, TCF reporter, invasion and xenograft assays","pmids":["26892600"],"confidence":"Medium","gaps":["Whether DDX3 helicase activity is required not addressed","Direct DDX3–DVL2 contact not mapped"]},{"year":2018,"claim":"Identified PP5 as a DVL2 phosphatase counteracting CK1ε, establishing reversible phosphorylation at the basal body as a control point for ciliogenesis.","evidence":"In vitro dephosphorylation assay, Co-IP, phospho-specific siRNA analysis, basal-body localization","pmids":["29426949"],"confidence":"Medium","gaps":["Relative contributions of PP5 vs PP2A in vivo not quantified","How phosphatase recruitment is timed to cilia dynamics unknown"]},{"year":2019,"claim":"Defined a WWP1–USP9X ubiquitin rheostat as the molecular switch specifying canonical versus PCP output from DVL2, explaining how one scaffold routes distinct signals.","evidence":"Deubiquitylase assays, Co-IP, ubiquitin-mutant analysis, pathway reporters, localization","pmids":["31340145"],"confidence":"High","gaps":["How ubiquitin status mechanically alters DVL2 conformation/partner choice unclear","Upstream signals controlling WWP1 vs USP9X balance not defined"]},{"year":2020,"claim":"Resolved how Daple licenses CK1ε phosphorylation of DVL2 at T224 and added RNF123/CCNG2 as a degradation arm controlling PCP-JNK output.","evidence":"Co-IP with Daple ΔGCV mutants, phospho-specific WB, reporter assays; RNF123 ubiquitination and migration assays","pmids":["32888647","33205477"],"confidence":"Medium","gaps":["Stoichiometry of the Daple–CK1ε–DVL2 trimer unknown","Whether RNF123 and WWP1 compete on shared lysines untested"]},{"year":2022,"claim":"Demonstrated that endogenous DVL2 forms Wnt-dependent condensates at centrosomal structures, reframing DVL2 puncta as physiological signaling organelles rather than aggregates.","evidence":"CRISPR mEos3.2 knock-in, PALM/DNA-PAINT superresolution, centrosomal co-localization, Wnt reporters","pmids":["35867833"],"confidence":"High","gaps":["Functional role of centrosomal localization for β-catenin output not fully defined","Relationship between condensate and destruction-complex assembly unresolved"]},{"year":2024,"claim":"Identified the C-terminal LCR4 and CD2 regions as the sequence determinants of endogenous DVL2 oligomerization/condensation required for pathway activation, mechanistically linking material properties to signaling.","evidence":"Ultracentrifugation at endogenous levels, deletion/fusion constructs, sticker point mutagenesis, Wnt reporter","pmids":["39652469"],"confidence":"High","gaps":["How DIX-mediated polymerization integrates with LCR4/CD2 condensation not resolved","Regulation of these regions by phosphorylation/ubiquitination untested"]},{"year":2025,"claim":"Expanded the degradation network and stability modulators of DVL2 across disease contexts, including K48/K343 Itch ubiquitylation, PRICKLE3–USP9X stabilization, and lncRNA-mediated stabilization.","evidence":"Site-specific ubiquitination assays, KO mice, tripartite Co-IP, lncRNA RIP and rescue assays","pmids":["42168361","40973792","41135528"],"confidence":"Medium","gaps":["How competing ligases/deubiquitinases are coordinated on DVL2 in a single context unknown","Lysine usage overlap among Itch, WWP1, RNF123 not mapped"]},{"year":null,"claim":"How DVL2's phosphorylation code, ubiquitin rheostat, condensate material state, and conformational autoinhibition are integrated in real time to select between canonical and non-canonical outputs remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model linking DEP-PA binding, LCR4/CD2 condensation, and ubiquitin status","Autoinhibition and partner-specific conformational changes characterized mainly in preprints"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,23]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[9]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[15,20]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,13]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[15,22]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[13]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[2,11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[24,28]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,7,10,31]}],"complexes":["Daple–CK1ε–DVL2 complex","DVL2–Plk1 complex","DVL2 Wnt-dependent centrosomal condensate"],"partners":["AXIN1","PLK1","RAB35","DAAM1","WWP1","USP9X","CSNK1E","DACT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14641","full_name":"Segment polarity protein dishevelled homolog DVL-2","aliases":["DSH homolog 2"],"length_aa":736,"mass_kda":78.9,"function":"Plays a role in the signal transduction pathways mediated by multiple Wnt genes (PubMed:24616100). 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DVL2 activates TCF-dependent transcription upstream of GSK-3β, and this activation is blocked by co-expression of Axin or GSK-3β. Redirecting DVL2 localization via a CAAX motif also redistributes Axin, confirming close physical association.\",\n      \"method\": \"Co-immunoprecipitation, co-localization with CAAX-motif redirected protein, TCF-luciferase reporter assay, deletion analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-localization, co-IP, functional reporter assay, deletion mapping; replicated across multiple experiments in single rigorous study\",\n      \"pmids\": [\"10329628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"DVL2 is a mammalian homolog of Drosophila dishevelled that can partially rescue segmentation defects in dsh-null fly embryos, demonstrating functional conservation of its role in transducing the Wingless/Wnt signal.\",\n      \"method\": \"Genetic rescue assay in dsh-null Drosophila embryos; sequence analysis\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic rescue in model organism, single lab, direct functional readout\",\n      \"pmids\": [\"8887313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DVL2 is phosphorylated at S143 and T224 by CK1ε downstream of Wnt5a signaling. Phosphorylated DVL2 directly interacts with Plk1, forming a DVL2–Plk1 complex that stabilizes HEF1 and activates Aurora-A kinase to drive primary cilia disassembly.\",\n      \"method\": \"Phosphorylation mapping, co-immunoprecipitation, RNAi knockdown, cilia disassembly assay, kinase inhibitor studies\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (phospho-site mapping, Co-IP of DVL2–Plk1 complex, functional cilia assay, RNAi), single rigorous study with mechanistic resolution\",\n      \"pmids\": [\"22609948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Wnt5a activates DVL2, which in turn activates Daam1 and RhoA to promote stress fiber formation and breast cancer cell migration. Dominant-negative DVL2 mutants or DVL2 siRNA abolish Wnt5a-induced Daam1/RhoA activation and migration.\",\n      \"method\": \"siRNA knockdown, dominant-negative overexpression, RhoA activity assay (pulldown), stress fiber staining, Matrigel migration assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (siRNA, dominant-negative, GTPase activity assay, migration assay), single lab\",\n      \"pmids\": [\"22655072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DVL2 physically binds Rab35 (shown by co-immunoprecipitation and immunofluorescence), and this DVL2–Rab35 interaction is required upstream of Rac1 activation for Wnt5a-driven breast cancer cell migration.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, Rac1 activity assay, cell migration assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional migration and GTPase assays, single lab\",\n      \"pmids\": [\"23353182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"DVL2 cytoplasmic puncta are protein aggregates formed at high expression levels and are not required for canonical Wnt signaling. They do not co-localize with early or late endocytic markers, and time-lapse analysis shows short-range random movement without originating from the plasma membrane.\",\n      \"method\": \"Live-cell time-lapse imaging, endosomal marker co-localization, signaling reporter assay at graded expression levels\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging plus functional assays, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"16263761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WWP1 E3 ubiquitin ligase directly interacts with DVL2 and stabilizes it via K27-linked polyubiquitination, thereby activating the DVL2/CaMKII/HDAC4/MEF2C pathway and driving cardiac hypertrophy. WWP1 knockout prevents TAC-induced hypertrophy.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assay (K27-linkage specific), pulse-chase assay, reporter gene assay, AAV9-shRNA in vivo model, echocardiography\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro ubiquitination assay, K27-linkage characterization, in vivo KO and AAV rescue, multiple orthogonal methods\",\n      \"pmids\": [\"34139860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP9X deubiquitylates DVL2; USP9X-mediated deubiquitylation promotes canonical Wnt activation, whereas increased DVL2 ubiquitylation (by WWP1) is associated with DVL2 localization to actin-rich projections and activation of the PCP pathway. Thus a WWP1–USP9X ubiquitin rheostat on DVL2 specifies canonical vs. PCP pathway output.\",\n      \"method\": \"Deubiquitylase assay, Co-IP, ubiquitin mutant analysis, pathway reporter assay, fluorescence localization\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — enzymatic deubiquitylase activity demonstrated, pathway bifurcation established with multiple orthogonal assays, mechanistic epistasis\",\n      \"pmids\": [\"31340145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"GABARAPL1 interacts with DVL2 (via p62 adaptor) and mediates its degradation through the autophagy pathway, thereby suppressing Wnt/β-catenin signaling. Blocking autophagy with 3-MA prevents DVL2 degradation.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, autophagy inhibitor (3-MA) rescue, luciferase reporter assay\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus pharmacological rescue, single lab\",\n      \"pmids\": [\"21691068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The DVL2 DEP domain binds phosphatidic acid (PA) through its basic helix 3 and a contiguous loop in a pH-dependent manner. PA binding induces conformational changes in helix 2 and β-strand 4. Interaction is pH-dependent, resembling deprotonation of PA.\",\n      \"method\": \"NMR spectroscopy, molecular-dynamics simulations, site-directed mutagenesis, biophysical binding assays\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural characterization plus mutagenesis plus MD simulation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"24606934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RNF185 E3 ubiquitin ligase interacts with DVL2, promotes its ubiquitination and proteasomal degradation, thereby inhibiting canonical Wnt/β-catenin signaling and negatively regulating osteogenic differentiation of MC3T3-E1 cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Western blot for protein levels, luciferase reporter assay, ALP activity assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional osteogenic assay, single lab\",\n      \"pmids\": [\"24727453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PP5 (PPP5C) is a phosphatase of DVL2 that directly interacts with and dephosphorylates DVL2, including at S143 and the 10B5 cluster. PP5 knockdown elevates DVL2 phosphorylation at basal levels and upon Wnt stimulation. PP5 is distinct from PP2A in which DVL2 phosphorylation sites it regulates. PP5 localizes to the basal body of primary cilia where S143-phosphorylated DVL2 also resides.\",\n      \"method\": \"Co-immunoprecipitation, in vitro phosphatase assay, siRNA knockdown with phospho-specific antibodies, immunofluorescence localization, ciliogenesis assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct in vitro dephosphorylation assay plus Co-IP plus localization, single lab\",\n      \"pmids\": [\"29426949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DDX3, a subunit of CK1ε, facilitates CK1ε-mediated phosphorylation of DVL2, which promotes β-catenin/TCF activation and tumor invasion in colorectal cancer. Pharmacological inhibition of CK1ε suppresses DVL2 phosphorylation and invasion.\",\n      \"method\": \"Western blotting for pDVL2, CK1ε inhibitor (PF4800567) treatment, TCF reporter assay, invasion assay, xenograft model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter plus kinase inhibitor plus in vivo xenograft, single lab\",\n      \"pmids\": [\"26892600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"DVL2 is present in post-developmental endothelial cells as a phosphoprotein, localized in both F-actin-free and F-actin-associated cytoplasmic pools. siRNA-mediated silencing of DVL2 causes aberrant membrane activity, failure to extend lamellipodia, and actin filament disorganization, indicating DVL2 regulates cell migration via actin cytoskeleton.\",\n      \"method\": \"siRNA knockdown, immunolabeling, Western blotting, time-lapse cell motility assay\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with direct actin and motility phenotype readouts, single lab\",\n      \"pmids\": [\"15593083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Stau1 RNA-binding protein binds the 3′ UTR of Dvl2 mRNA and stabilizes it in undifferentiated myoblasts. Stau1 knockdown shortens Dvl2 mRNA half-life; during myogenic differentiation, Stau1 dissociates from Dvl2 3′ UTR, reducing Dvl2 mRNA levels. Forced Dvl2 expression inhibits myogenic differentiation.\",\n      \"method\": \"RNA immunoprecipitation, mRNA stability assay, Western blot, qRT-PCR, overexpression in C2C12 differentiation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus mRNA stability assay plus functional overexpression phenotype, single lab\",\n      \"pmids\": [\"22166206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Endogenous DVL2 (tagged with mEos3.2 at its genomic locus) forms Wnt-dependent supramolecular condensates (~1 per cell at physiological levels) that localize to γ-tubulin- and CEP164-positive centrosomal structures in a cell cycle-dependent manner. Single-molecule PALM/DNA-PAINT demonstrates repetitive internal organization of these condensates.\",\n      \"method\": \"CRISPR genome-engineered endogenous mEos3.2-DVL2, live-cell superresolution imaging (PALM), DNA-PAINT, immunofluorescence co-localization, Wnt pathway reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — endogenous tagging by genome engineering, superresolution single-molecule imaging, multiple pathway validation assays, rigorous controls\",\n      \"pmids\": [\"35867833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The Daple–CK1ε–DVL2 trimeric complex is required for CK1ε-mediated phosphorylation of DVL2 at T224. Daple lacking its C-terminal DVL-binding motif (ΔGCV) retains CK1ε binding but cannot induce DVL2 phosphorylation. T224 phosphorylation is required for full β-catenin transcriptional activity. Wnt3a stimulation increases Daple membrane localization and Daple–DVL2 association.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative Daple mutants, phospho-specific Western blot, TCF/LEF luciferase reporter assay, siRNA knockdown\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with deletion mutants, phospho-site functional analysis, reporter assay, single lab\",\n      \"pmids\": [\"32888647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Sestd1 forms complexes with DVL2 independently of both Dact1 and Vangl2. DVL2 enhances Dact1/Sestd1-mediated Rho family GTPase activation in cell-based assays consistent with PCP pathway function. Genetic synergy: Dvl2 KO is recessive alone but causes dominant embryonic lethality in Sestd1 or Dact1 KO backgrounds.\",\n      \"method\": \"Co-immunoprecipitation, Rho GTPase activation assay, genetic epistasis in double/triple KO mice\",\n      \"journal\": \"Communicative & integrative biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus GTPase assay plus genetic epistasis, single lab\",\n      \"pmids\": [\"24505507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CCNG2 promotes polyubiquitination-mediated degradation of DVL2 via the E3 ligase RNF123. RNF123 interacts with DVL2; CCNG2 upregulates RNF123, leading to DVL2 destabilization, suppression of Wnt/PCP-JNK signaling, and impaired trophoblast migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown (RNF123), Western blot, JNK activity assay, migration/invasion assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of RNF123-DVL2, ubiquitination assay, functional rescue by siRNA, single lab\",\n      \"pmids\": [\"33205477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DVL2 interacts with the C-terminus of TNFR1 and mediates TNFR1 endocytosis, thereby inhibiting NF-κB signaling. IL-13 upregulates DVL2 expression via STAT6. This mechanism coordinates NF-κB and Wnt signaling in colitis-associated colorectal cancer.\",\n      \"method\": \"Co-immunoprecipitation, endocytosis assay, STAT6 inhibitor, siRNA knockdown, NF-κB reporter assay\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of DVL2–TNFR1, functional endocytosis and NF-κB assays, single lab\",\n      \"pmids\": [\"34807493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DVL2 oligomers form at endogenous protein concentrations via two distinct regions in its C-terminus: LCR4 (low-complexity region 4) mediates pre-oligomerization via aggregating residues, while adjacent CD2 promotes condensate formation via phenylalanine stickers. Point mutations inactivating these sites impair Wnt/β-catenin pathway activation by DVL2.\",\n      \"method\": \"Biochemical ultracentrifugation assay at endogenous levels, deletion/fusion constructs, point mutagenesis, condensate microscopy, Wnt reporter assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical assay at endogenous levels, mutagenesis of interaction sites with functional validation, multiple orthogonal approaches in single study\",\n      \"pmids\": [\"39652469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL16 methyltransferase suppresses DVL2 protein levels via m6A modification of DVL2 mRNA, inhibiting its translation and thereby suppressing Wnt/β-catenin signaling in pancreatic ductal adenocarcinoma.\",\n      \"method\": \"m6A sequencing/mapping, METTL16 overexpression/knockdown, Western blot for DVL2, Wnt reporter assay, in vitro and in vivo metastasis assays\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A modification mapped to DVL2 mRNA, translational suppression demonstrated, functional rescue, single lab\",\n      \"pmids\": [\"37859814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Low disturbed fluid shear stress (1 dyne/cm²) promotes primary cilia assembly via DVL2 in endothelial cells. DVL2 co-immunoprecipitates with Bbs8 and γ-tubulin. DVL2 overexpression increases ciliated cell percentages under shear; DVL2 silencing decreases them and reduces Bbs8 and γ-tubulin expression, indicating DVL2 facilitates basal body apical docking through Bbs8 and γ-tubulin.\",\n      \"method\": \"Microfluidic chamber, co-immunoprecipitation, siRNA knockdown, overexpression, immunofluorescence\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus siRNA/overexpression with quantitative ciliation readout, single lab\",\n      \"pmids\": [\"32776193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TM4SF1 interacts with DVL2 and strengthens the DVL2–Axin interaction, thereby promoting β-catenin/TCF signaling in hepatocellular carcinoma. TM4SF1 downregulation increases β-catenin ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, TCF reporter assay, siRNA knockdown\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating DVL2–TM4SF1 and DVL2–Axin interactions, functional reporter and ubiquitination assays, single lab\",\n      \"pmids\": [\"31876386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DACT1 missense variants located in its DVL2 interaction region show reduced binding to DVL2 in biochemical characterization and associate with CAKUT in humans, establishing the DVL2–DACT1 protein–protein interaction as functionally required for normal kidney development.\",\n      \"method\": \"Whole-exome sequencing, biochemical binding assay (reduced DVL2 binding of mutant DACT1), CRISPR/Cas9 Dact1 KO in murine collecting duct cells (branching morphogenesis assay)\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical interaction assay with patient variants, functional KO morphogenesis assay, single lab\",\n      \"pmids\": [\"36066768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"APPL1 endocytic adaptor physically interacts with DVL2 and synergizes with it to potentiate AP-1 (c-Jun)-driven transcription in non-canonical Wnt signaling, specifically increasing MMP1 expression in a JNK-dependent manner. This function requires endosomal recruitment of APPL1.\",\n      \"method\": \"Co-immunoprecipitation, AP-1/TCF reporter assay, JNK inhibitor, endosomal localization assay, MMP1 expression measurement\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional reporter and gene expression assays with mechanistic inhibitor controls, single lab\",\n      \"pmids\": [\"25622892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Wnt5a–Ror1 signaling at the cell surface requires Rif (a Rho-family GTPase) to activate DVL2 phosphorylation. Rif interacts with Ror1 and is required for 3D matrix-induced polarized filopodia in lung adenocarcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, Western blot for pDVL2, siRNA knockdown of Rif and Ror1, 3D Matrigel culture, in vivo tumor assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus phospho-DVL2 readout after RNAi, functional tumor assay, single lab\",\n      \"pmids\": [\"37703992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HCMV viral protein pUL8 interacts with DVL2 and β-catenin via a PDZ-binding domain; loss of pUL8 interaction with the β-catenin–DVL2 complex restricts viral reactivation in CD34+ hematopoietic progenitor cells.\",\n      \"method\": \"Co-immunoprecipitation, PDZ-binding domain mutant analysis, viral reactivation assay in CD34+ HPCs\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping plus viral functional assay, single lab\",\n      \"pmids\": [\"37772824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LINC01612 lncRNA interacts with DVL2 protein and enhances DVL2 stability by reducing its ubiquitination, thereby maintaining WNT signaling required for human definitive endoderm differentiation. DVL2 overexpression rescues endoderm differentiation defects caused by LINC01612 loss.\",\n      \"method\": \"shRNA knockdown, Co-IP of LINC01612 with DVL2, ubiquitination assay, WNT reporter assay, CRISPR promoter deletion, rescue by DVL2 overexpression\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, genetic rescue, single lab\",\n      \"pmids\": [\"41135528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In macrophages, DVL2 promotes nuclear YAP–HSF1 interaction, which activates HSF1 target gene eEF2, thereby inhibiting NOD1/caspase-1/GSDMD pyroptosis and NF-κB signaling. Myeloid-specific Dvl2 KO reduces YAP–HSF1 colocalization, enhances NOD1-driven pyroptosis, and worsens ischemia/reperfusion liver injury.\",\n      \"method\": \"Myeloid-specific KO mouse model, co-immunoprecipitation (YAP–HSF1), caspase-1/GSDMD activation assays, adoptive macrophage transfer, hepatocyte co-culture assay\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with mechanistic Co-IP and functional pyroptosis assays, single lab\",\n      \"pmids\": [\"39644526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"AJUBA acts as a co-activator of C/EBPβ to enhance NEDD4 transcription; NEDD4 then promotes ubiquitin-mediated degradation of DVL2, preventing Ca²⁺/CaMKII/HDAC4 pathway activation and protecting against cardiac hypertrophy. AJUBA KO worsens cardiac hypertrophy and dysfunction.\",\n      \"method\": \"AJUBA KO mouse, reporter assay for C/EBPβ/NEDD4 transcription, co-immunoprecipitation, ubiquitination assay, echocardiography\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus transcriptional and ubiquitination mechanistic assays, single lab\",\n      \"pmids\": [\"41793265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"E3 ubiquitin ligase Itch promotes K48-linked ubiquitination of DVL2 at lysine 343, leading to its proteasomal degradation and suppression of GSK-3β/β-catenin signaling, thereby alleviating kidney fibrosis. Itch KO mice show exacerbated fibrosis and increased DVL2 levels.\",\n      \"method\": \"Co-immunoprecipitation, site-specific ubiquitination assay (K343 mutation), Itch KO mice, Western blot, fibrosis markers\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — site-specific ubiquitination assay with K343 identification plus KO in vivo, single lab\",\n      \"pmids\": [\"42168361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRICKLE3 interacts with USP9X and DVL2 in a tripartite complex; PRICKLE3–USP9X interaction inhibits DVL2 ubiquitination, stabilizing DVL2 and activating canonical WNT signaling. PRICKLE3–DVL2 interaction also enhances β-catenin phosphorylation at S675 to promote its nuclear translocation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Western blot, PRICKLE3 KO/OE in NSCLC cells, in vivo tumor model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tripartite Co-IP, ubiquitination assay, functional KO/OE with pathway readouts, single lab\",\n      \"pmids\": [\"40973792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cancer-associated SF3B1 mutation causes aberrant 3′ splice site selection in DVL2 pre-mRNA using an alternative branchpoint sequence (BPS) with higher affinity for U2 snRNA than the canonical BPS. The aberrant splicing does not require the canonical 3′ splice site or polypyrimidine tract; BPS position and U2 snRNA affinity together determine BPS selection.\",\n      \"method\": \"Minigene splicing assay, BPS swapping mutagenesis, U2 snRNA affinity analysis, SF3B1 mutant cell lines\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of BPS positions with functional splicing readout, mechanistic dissection of spliceosome selectivity, single lab\",\n      \"pmids\": [\"33561744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Profilin2 directly interacts with DVL2 in vitro via the extreme C-terminus of DVL2 (beyond the polyproline motif), without engaging the PDZ or DEP domains. DVL2 adopts an autoinhibited conformation through intramolecular binding of its extreme C-terminus to its PDZ domain, yet profilin2 retains binding in this autoinhibited state.\",\n      \"method\": \"Co-localization (fluorescence), in vitro pulldown assay, deletion/domain mapping, autoinhibition assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vitro pulldown with domain mapping, preprint, single lab, no functional pathway validation\",\n      \"pmids\": [\"bio_10.1101_2025.10.09.681388\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The C-terminus of DVL2 interacts with the centrosomal protein Kizuna (Kiz); Kiz induces an open DVL2 conformation enabling recruitment of PKCδ to stabilize the apical microtubule meshwork. This DVL2–Kiz–PKCδ axis is required for primary cilia formation (primary cilia in the eye, multicilia in MCE, and mono-motile cilia in the GRP) in Xenopus.\",\n      \"method\": \"Co-immunoprecipitation (DVL2–Kiz), conformational assay, in vivo Xenopus loss-of-function, ciliogenesis readout\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and in vivo functional data in Xenopus, preprint not yet peer-reviewed, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.11.12.688108\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Daple and its paralog Girdin-L bear unique extended C-terminal PDZ-binding motifs that bind the DVL2 PDZ domain with exceptionally high affinity. Deletion of these motifs or DVL2's PDZ domain results in elongated primary cilia unresponsive to Wnt5a-stimulated disassembly, establishing this DVL2 PDZ–Daple/Girdin-L interaction as the molecular basis for Wnt5a-driven cilia disassembly.\",\n      \"method\": \"Proximity labeling, structural/biophysical analysis, deletion mutants, Wnt5a cilia disassembly assay in HEK293T cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — structural/biophysical plus functional cilia assay, but preprint not yet peer-reviewed, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.09.26.678488\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CK1δ/ε inhibition blocks DVL2 condensate formation, as shown by image-based screening with CK1δ/ε kinase inhibitors; genetic epistasis with APC, Axin1, and MCC loss-of-function alleles modulates this effect on Wnt signaling, placing CK1δ/ε-mediated DVL2 phosphorylation upstream of condensate dynamics in the Wnt pathway.\",\n      \"method\": \"Image-based high-throughput screen, CK1δ/ε inhibitors, endogenous DVL2-mEos3.2, phosphoproteomics, genetic epistasis (APC/Axin1/MCC KO)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — pharmacological screen plus genetic epistasis, preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.01.11.632522\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"DVL2 is a multidomain cytoplasmic scaffold (DIX, PDZ, DEP domains plus a C-terminal LCR4/CD2 region) that forms Wnt-dependent biomolecular condensates at centrosomal structures and acts as a central hub transmitting both canonical Wnt/β-catenin and non-canonical (PCP, Wnt/Ca²⁺) signals: upon Wnt stimulation it is phosphorylated by CK1ε (at S143/T224, facilitated by Daple) and dephosphorylated by PP5/PP2A, recruits Axin to disrupt the β-catenin destruction complex, engages Daam1/RhoA and Rab35/Rac1 for cell migration, and drives primary cilia disassembly via a DVL2–Plk1–HEF1–Aurora-A axis downstream of Wnt5a–CK1ε; its stability and pathway choice are regulated by a ubiquitin rheostat in which WWP1-mediated K27-ubiquitylation stabilizes DVL2 and promotes PCP, while USP9X-mediated deubiquitylation favors canonical signaling, and additional E3 ligases (RNF185, RNF123, NEDD4, Itch/K48-K343) promote its proteasomal or autophagic degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DVL2 is a cytoplasmic scaffold that transduces both canonical Wnt/\\u03b2-catenin and non-canonical (PCP, Wnt/Ca\\u00b2\\u207a) signals, functionally conserved from Drosophila dishevelled [#1] and acting genetically upstream of GSK-3\\u03b2 to activate TCF-dependent transcription [#0]. In canonical signaling DVL2 co-localizes and co-immunoprecipitates with Axin and redirecting DVL2 redistributes Axin, establishing it as an Axin-recruiting hub that engages the \\u03b2-catenin destruction complex [#0]. Pathway activation depends on CK1\\u03b5-mediated phosphorylation of DVL2 at S143 and T224, which is facilitated by the DDX3 subunit of CK1\\u03b5 and by a Daple\\u2013CK1\\u03b5\\u2013DVL2 trimeric complex, with T224 phosphorylation required for full \\u03b2-catenin transcriptional output [#2, #12, #16]; this phosphorylation is reversed by the phosphatase PP5, which acts at S143 and the 10B5 cluster and localizes with phospho-DVL2 to the basal body [#11]. At endogenous concentrations DVL2 forms Wnt-dependent supramolecular condensates at \\u03b3-tubulin/CEP164-positive centrosomal structures, driven by C-terminal LCR4 and CD2 regions whose aggregating residues and phenylalanine stickers are required for Wnt/\\u03b2-catenin activation [#15, #20]. Through its non-canonical outputs DVL2 activates Daam1/RhoA and binds Rab35 to drive Rac1-dependent breast cancer cell migration and actin/lamellipodial dynamics [#3, #4, #13], and it nucleates a DVL2\\u2013Plk1\\u2013HEF1\\u2013Aurora-A axis downstream of Wnt5a\\u2013CK1\\u03b5 to drive primary cilia disassembly [#2]. DVL2 abundance and pathway choice are set by a ubiquitin rheostat: WWP1 stabilizes DVL2 via K27-linked polyubiquitylation to favor PCP signaling while USP9X deubiquitylates it to favor canonical signaling, and multiple E3 ligases (RNF185, RNF123, NEDD4, Itch via K48-linked K343) target DVL2 for proteasomal degradation while GABARAPL1/p62 routes it to autophagic degradation [#6, #7, #8, #10, #18, #30, #31]. The DVL2 DEP domain binds phosphatidic acid in a pH-dependent manner [#9], and a DACT1 missense variant that weakens DACT1\\u2013DVL2 binding associates with congenital kidney malformation (CAKUT), implicating the interaction in kidney development [#24].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that the mammalian protein is a functional dishevelled ortholog, anchoring DVL2 in Wnt signal transduction rather than being a sequence homolog of unknown function.\",\n      \"evidence\": \"Genetic rescue of segmentation defects in dsh-null Drosophila embryos\",\n      \"pmids\": [\"8887313\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define which mammalian pathway branch (canonical vs PCP) is rescued\", \"No molecular partners identified\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined where DVL2 sits in the canonical cascade by showing it acts upstream of GSK-3\\u03b2 and physically associates with Axin, identifying DVL2 as an Axin-recruiting node of the destruction complex.\",\n      \"evidence\": \"Co-IP, CAAX-redirected co-localization, deletion mapping, and TCF-luciferase reporter assays\",\n      \"pmids\": [\"10329628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Axin recruitment disrupts the destruction complex not resolved\", \"No structural detail of the DVL2\\u2013Axin interface\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Distinguished pathologic overexpression aggregates from functional puncta and tied endogenous DVL2 to actin-based migration, separating signaling-relevant condensates from artifacts.\",\n      \"evidence\": \"Live-cell time-lapse imaging with endosomal markers at graded expression; siRNA with actin/motility readouts in endothelial cells\",\n      \"pmids\": [\"16263761\", \"15593083\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the molecular basis of physiological condensates\", \"Cytoskeletal effectors downstream of DVL2 not defined here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected Wnt5a/CK1\\u03b5-driven DVL2 phosphorylation to specific non-canonical effectors, defining how DVL2 drives migration and cilia disassembly.\",\n      \"evidence\": \"Phospho-site mapping (S143/T224), Co-IP of DVL2\\u2013Plk1, cilia disassembly assays, and Daam1/RhoA GTPase/migration assays\",\n      \"pmids\": [\"22609948\", \"22655072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation switches DVL2 between effector complexes unclear\", \"Direct vs indirect DVL2\\u2013Plk1 binding not fully resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the non-canonical effector map by placing Rab35 upstream of Rac1 in DVL2-driven migration and linking DVL2 to Dact1/Sestd1 PCP complexes through genetic synergy.\",\n      \"evidence\": \"Co-IP, Rac1/Rho GTPase activity assays, migration assays, and double/triple KO mouse epistasis\",\n      \"pmids\": [\"23353182\", \"24505507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs scaffolded nature of DVL2\\u2013Rab35 binding not resolved\", \"How DVL2 partitions among competing PCP complexes unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided biophysical insight into DEP-domain membrane engagement and identified DVL2 as a proteasomal degradation target, beginning to define the lipid- and stability-control layers.\",\n      \"evidence\": \"NMR/MD/mutagenesis of DEP\\u2013phosphatidic acid binding; Co-IP and ubiquitination assays for RNF185\",\n      \"pmids\": [\"24606934\", \"24727453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of DEP\\u2013PA binding for signaling not established\", \"Ubiquitin linkage type used by RNF185 not characterized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Refined the CK1\\u03b5 activation step by showing DDX3 acts as a CK1\\u03b5 subunit facilitating DVL2 phosphorylation, linking it to tumor invasion.\",\n      \"evidence\": \"Phospho-DVL2 Western blot, CK1\\u03b5 inhibitor, TCF reporter, invasion and xenograft assays\",\n      \"pmids\": [\"26892600\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DDX3 helicase activity is required not addressed\", \"Direct DDX3\\u2013DVL2 contact not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified PP5 as a DVL2 phosphatase counteracting CK1\\u03b5, establishing reversible phosphorylation at the basal body as a control point for ciliogenesis.\",\n      \"evidence\": \"In vitro dephosphorylation assay, Co-IP, phospho-specific siRNA analysis, basal-body localization\",\n      \"pmids\": [\"29426949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contributions of PP5 vs PP2A in vivo not quantified\", \"How phosphatase recruitment is timed to cilia dynamics unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a WWP1\\u2013USP9X ubiquitin rheostat as the molecular switch specifying canonical versus PCP output from DVL2, explaining how one scaffold routes distinct signals.\",\n      \"evidence\": \"Deubiquitylase assays, Co-IP, ubiquitin-mutant analysis, pathway reporters, localization\",\n      \"pmids\": [\"31340145\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ubiquitin status mechanically alters DVL2 conformation/partner choice unclear\", \"Upstream signals controlling WWP1 vs USP9X balance not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved how Daple licenses CK1\\u03b5 phosphorylation of DVL2 at T224 and added RNF123/CCNG2 as a degradation arm controlling PCP-JNK output.\",\n      \"evidence\": \"Co-IP with Daple \\u0394GCV mutants, phospho-specific WB, reporter assays; RNF123 ubiquitination and migration assays\",\n      \"pmids\": [\"32888647\", \"33205477\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry of the Daple\\u2013CK1\\u03b5\\u2013DVL2 trimer unknown\", \"Whether RNF123 and WWP1 compete on shared lysines untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that endogenous DVL2 forms Wnt-dependent condensates at centrosomal structures, reframing DVL2 puncta as physiological signaling organelles rather than aggregates.\",\n      \"evidence\": \"CRISPR mEos3.2 knock-in, PALM/DNA-PAINT superresolution, centrosomal co-localization, Wnt reporters\",\n      \"pmids\": [\"35867833\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of centrosomal localization for \\u03b2-catenin output not fully defined\", \"Relationship between condensate and destruction-complex assembly unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified the C-terminal LCR4 and CD2 regions as the sequence determinants of endogenous DVL2 oligomerization/condensation required for pathway activation, mechanistically linking material properties to signaling.\",\n      \"evidence\": \"Ultracentrifugation at endogenous levels, deletion/fusion constructs, sticker point mutagenesis, Wnt reporter\",\n      \"pmids\": [\"39652469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DIX-mediated polymerization integrates with LCR4/CD2 condensation not resolved\", \"Regulation of these regions by phosphorylation/ubiquitination untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded the degradation network and stability modulators of DVL2 across disease contexts, including K48/K343 Itch ubiquitylation, PRICKLE3\\u2013USP9X stabilization, and lncRNA-mediated stabilization.\",\n      \"evidence\": \"Site-specific ubiquitination assays, KO mice, tripartite Co-IP, lncRNA RIP and rescue assays\",\n      \"pmids\": [\"42168361\", \"40973792\", \"41135528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How competing ligases/deubiquitinases are coordinated on DVL2 in a single context unknown\", \"Lysine usage overlap among Itch, WWP1, RNF123 not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DVL2's phosphorylation code, ubiquitin rheostat, condensate material state, and conformational autoinhibition are integrated in real time to select between canonical and non-canonical outputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking DEP-PA binding, LCR4/CD2 condensation, and ubiquitin status\", \"Autoinhibition and partner-specific conformational changes characterized mainly in preprints\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 23]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [15, 20]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 13]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [15, 22]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [2, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [24, 28]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 7, 10, 31]}\n    ],\n    \"complexes\": [\n      \"Daple\\u2013CK1\\u03b5\\u2013DVL2 complex\",\n      \"DVL2\\u2013Plk1 complex\",\n      \"DVL2 Wnt-dependent centrosomal condensate\"\n    ],\n    \"partners\": [\n      \"AXIN1\",\n      \"PLK1\",\n      \"RAB35\",\n      \"DAAM1\",\n      \"WWP1\",\n      \"USP9X\",\n      \"CSNK1E\",\n      \"DACT1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}