{"gene":"WNT5A","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2006,"finding":"Purified Wnt5a protein inhibits Wnt3a-induced canonical Wnt signaling by downregulating beta-catenin-induced reporter gene expression (not by influencing beta-catenin levels) via the orphan tyrosine kinase Ror2. In the presence of Frizzled 4, the same purified Wnt5a activates beta-catenin signaling, demonstrating that receptor context dictates signaling output. The Wnt5a signal is pertussis toxin insensitive and does not influence cellular calcium levels in this context.","method":"Purified Wnt5a protein (homogeneous), dose-response reporter assays, Ror2 requirement established by functional blocking, Frizzled 4 co-expression experiment","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — purified protein reconstitution with dose-response, multiple receptor contexts tested, orthogonal readouts (reporter, beta-catenin levels, calcium, pertussis toxin sensitivity)","pmids":["16602827"],"is_preprint":false},{"year":2002,"finding":"Wnt5a overexpression in melanoma cells causes actin reorganization, increased cell adhesion, and increased PKC activation without increasing beta-catenin expression or nuclear translocation. Blocking Frizzled-5 with antibodies inhibits PKC activity and cellular invasion, placing Frizzled-5 upstream of PKC in Wnt5a-driven melanoma invasion.","method":"Constitutive overexpression vector transfection, anti-Frizzled-5 antibody blocking, PKC activity assay, invasion assay, actin staining","journal":"Cancer cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (antibody block) with defined cellular phenotype, two orthogonal readouts (PKC activity and invasion), single lab","pmids":["12086864"],"is_preprint":false},{"year":2008,"finding":"Wnt5a induces homodimerization and tyrosine phosphorylation of Ror2 in U2OS osteoblastic cells. Wnt5a also causes phosphorylation of the Ror2 substrate 14-3-3beta. Wnt3a binds Ror2 but does not induce its homodimerization or activation. Ror2 knockdown abolishes Wnt5a-induced osteoblastic differentiation of human mesenchymal stem cells.","method":"Co-immunoprecipitation, tyrosine phosphorylation assay, 14-3-3beta phosphorylation assay, siRNA knockdown of Ror2, calvarial bone explant culture, MSC differentiation assay","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, phosphorylation assays, loss-of-function with functional readout, single lab","pmids":["18615587"],"is_preprint":false},{"year":2007,"finding":"Wnt5a induces serine/threonine phosphorylation of Ror2 through GSK-3 (primarily GSK-3alpha). GSK-3 inhibitors (LiCl, SB216763) or siRNA against GSK-3 block Wnt5a-induced Ror2 phosphorylation. Purified GSK-3alpha and GSK-3beta phosphorylate immunoprecipitated Ror2 in vitro. Wnt5a-induced cell migration is inhibited by GSK-3 suppression.","method":"In vitro kinase assay with purified GSK-3 on immunoprecipitated Ror2, siRNA knockdown of GSK-3, pharmacological inhibitors (LiCl, SB216763), cell migration assay","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase reconstitution combined with siRNA and pharmacological inhibition, functional migration readout, single lab but multiple orthogonal methods","pmids":["17986005"],"is_preprint":false},{"year":2008,"finding":"Wnt5a controls cell polarity and directional movement in melanoma by recruiting actin, myosin IIB, Frizzled 3, and MCAM into an intracellular Wnt-mediated receptor-actin-myosin polarity (W-RAMP) structure. In a chemokine gradient, W-RAMP accumulates asymmetrically at the cell periphery, triggering membrane contractility and nuclear movement. The process requires endosome trafficking, is associated with multivesicular bodies, and is regulated through small GTPases Rab4 and RhoB.","method":"Live imaging, immunofluorescence, dominant-negative Rab4/RhoB expression, chemokine gradient assay, subcellular fractionation/endosome trafficking analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — live imaging with functional consequence, dominant-negative genetic perturbation, multiple orthogonal readouts (polarity, nuclear movement, endosome trafficking), published in high-impact venue","pmids":["18420933"],"is_preprint":false},{"year":2009,"finding":"ROR2 is required for Wnt5a-mediated melanoma metastasis. Wnt5a increases ROR2 expression and promotes PKC-dependent, clathrin-mediated internalization of ROR2. siRNA knockdown of ROR2 decreases downstream Wnt5a signaling and reduces melanoma metastasis in vitro and in vivo.","method":"siRNA knockdown of ROR2, in vitro and in vivo metastasis assays, PKC inhibitor, clathrin inhibitor, melanoma tissue microarrays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with in vivo metastasis readout plus mechanistic dissection of internalization, single lab","pmids":["19802008"],"is_preprint":false},{"year":2010,"finding":"Wnt5a promotes prostate cancer cell invasion through Frizzled2 and Ror2 receptors. Wnt5a activates JNK through protein kinase D (PKD), and PKD inhibition suppresses Wnt5a-dependent cell migration and invasion. Wnt5a induces MMP-1 expression through recruitment of JunD to the MMP-1 promoter.","method":"Wnt5a knockdown and overexpression in prostate cancer cell lines, invasion assay, PKD inhibitor, ChIP assay for JunD at MMP-1 promoter, siRNA for Frizzled2/Ror2","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with defined invasion phenotype, ChIP for transcriptional mechanism, pharmacological dissection of PKD, single lab","pmids":["20101234"],"is_preprint":false},{"year":2013,"finding":"CD146 acts as a functional Wnt5a receptor: CD146 binds Wnt5a with high affinity, and Wnt5a treatment enhances CD146-Dvl2 interaction. CD146-mediated Wnt5a signaling activates Dvl and JNK to promote cell migration and zebrafish convergent extension. Mutation of the Dvl2-binding region of CD146 impairs JNK activation, cell migration, and cell protrusion formation. CD146 also inhibits canonical Wnt signaling by promoting beta-catenin degradation.","method":"Binding affinity assay, co-immunoprecipitation (CD146-Dvl2), domain mutation, JNK activation assay, cell migration assay, zebrafish knockdown/convergent extension assay, beta-catenin degradation assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — binding affinity measurement, domain mutagenesis, in vivo zebrafish model with convergent extension readout, multiple orthogonal methods in one study","pmids":["24335906"],"is_preprint":false},{"year":2016,"finding":"Wnt5a induces ROR1/ROR2 heterooligomerization to recruit guanine exchange factors (GEFs), activating Rac1 and RhoA in CLL cells. The extracellular Kringle domain of ROR1 is required for ROR1/ROR2 heterooligomerization; the cysteine-rich domain or intracellular proline-rich domain is required for Wnt5a-induced GEF recruitment. Silencing either ROR1 or ROR2 blocks these effects.","method":"Co-immunoprecipitation (ROR1/ROR2 heterooligomers), siRNA silencing of ROR1/ROR2, domain mapping with truncation constructs, Rac1/RhoA activation assays, ectopic ROR1 expression in ROR1-deficient MEC1 cells, in vivo engraftment assays in immune-deficient and ROR1-transgenic mice","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, domain mapping, siRNA, in vivo mouse models, multiple orthogonal methods, functionally validated GEF recruitment","pmids":["26690702"],"is_preprint":false},{"year":2015,"finding":"Wnt5a signals through DVL1 to repress ribosomal DNA (rDNA) transcription by RNA Polymerase I. DVL1 accumulates at nucleolar organizer regions and binds rDNA regions. Upon DVL1 binding, SIRT7 (a Pol I transcription activator/deacetylase) dissociates from rDNA loci, concomitant with disassembly of the Pol I transcription machinery at the rDNA promoter.","method":"ChIP of DVL1 at rDNA, co-immunoprecipitation, Pol I transcription assay, SIRT7 displacement assay, DVL1-specific requirement established by siRNA","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, co-IP, and transcription assays in one study; DVL1-specific mechanism distinguished from other Dvl paralogs; single lab","pmids":["27500936"],"is_preprint":false},{"year":2015,"finding":"Wnt5a promotes protein depalmitoylation of MCAM at Cys-590 via acyl protein thioesterase 1 (APT1), resulting in asymmetric MCAM localization. Mutation of Cys-590 to glycine is sufficient to polarize MCAM localization. Inhibition of APT1 blocks Wnt5a-induced depalmitoylation, asymmetric MCAM localization, and cell invasion.","method":"Site-directed mutagenesis (Cys-590), APT1 inhibitor treatment, palmitoylation assay, immunofluorescence for MCAM localization, invasion assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis plus enzymatic inhibition with defined localization and functional readout; single lab","pmids":["25944911"],"is_preprint":false},{"year":2018,"finding":"Wnt5a signaling induces APT1 phosphorylation, which increases APT1 depalmitoylating activity and reduces APT1 dimerization. Phosphorylated APT1 promotes depalmitoylation of pro-metastatic cell adhesion molecules CD44 and MCAM, increasing melanoma invasion in vitro.","method":"Phosphorylation assay of APT1, depalmitoylation activity assay, dimerization assay, invasion assay, correlation with tumor grade","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — enzymatic activity assay with phosphorylation state manipulation, functional invasion readout, single lab","pmids":["29648538"],"is_preprint":false},{"year":2014,"finding":"Wnt5a-induced noncanonical signaling enhances Wnt/beta-catenin signaling during osteoblastogenesis by upregulating expression of co-receptors Lrp5 and Lrp6. Wnt5a knockdown reduces Lrp5/6 expression and impairs osteoblast differentiation while enhancing adipocyte differentiation. Adenovirus-mediated gene transfer of Lrp5 into Wnt5a-deficient osteoblast cells rescues the differentiation phenotype.","method":"Conditional Wnt5a knockout (osteoblast-lineage), shRNA knockdown, adenoviral Lrp5 rescue, Tcf/Lef reporter assay, differentiation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with rescue experiment, reporter assays, and defined differentiation phenotype; single lab","pmids":["24670389"],"is_preprint":false},{"year":2016,"finding":"Wnt5a regulates AQP2 water channel expression, phosphorylation, and apical membrane trafficking in renal collecting duct cells via calcineurin signaling, independently of the vasopressin/cAMP/PKA pathway. Wnt5a increases apical membrane AQP2 localization and urine osmolality in an NDI mouse model. Calcineurin activator arachidonic acid mimics Wnt5a effects.","method":"In vitro Wnt5a stimulation of collecting duct cells, AQP2 phosphorylation and trafficking assays, calcineurin activity assay, cAMP/PKA measurement, NDI mouse model in vivo","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro mechanistic dissection combined with in vivo NDI model, multiple orthogonal methods (phosphorylation, trafficking, cAMP measurement, pharmacological calcineurin manipulation), published in Nature Communications","pmids":["27892464"],"is_preprint":false},{"year":2017,"finding":"Wnt5a-Ror2 signaling in osteoclasts activates RhoA, which engages the Rho effector kinase Pkn3. Pkn3 binds to and enhances the activity of c-Src, promoting actin ring formation and bone resorption. Osteoclast-specific Ror2 knockout mice have increased bone mass and impaired actin ring formation and bone resorption, defects rescued by constitutively active RhoA. Pkn3 global knockout mice show similar increased bone mass phenotype.","method":"Osteoclast-specific Ror2 conditional knockout mice, Pkn3 global knockout mice, constitutively active RhoA rescue experiment, c-Src kinase activity assay, co-immunoprecipitation (Pkn3-c-Src), actin ring formation assay, bone resorption assay","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo mouse models (conditional KO, global KO), epistasis by RhoA rescue, biochemical co-IP and kinase assay, multiple orthogonal methods","pmids":["28851822"],"is_preprint":false},{"year":2016,"finding":"Wnt5a signals through the Ryk receptor to regulate hematopoietic stem cell (HSC) quiescence and hematopoietic repopulation. Ryk inhibition blocks Wnt5a-induced HSC quiescence and suppression of reactive oxygen species (ROS) production, which is a known driver of HSC proliferation.","method":"Ryk blocking antibody or dominant-negative Ryk, HSC quiescence assay, ROS measurement, short- and long-term hematopoietic repopulation assay","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor blocking with defined cellular and in vivo repopulation phenotype, ROS mechanistic link, single lab","pmids":["23939973"],"is_preprint":false},{"year":2016,"finding":"Wnt5a signals through the Ryk receptor in vascular endothelial cells to activate ROCK, leading to phosphorylation of LIMK2 and inactivation of cofilin-1, resulting in enhanced actin stress fiber formation and increased endothelial permeability. Ryk silencing completely prevents Wnt5a-induced endothelial hyperpermeability. WIF1 (which specifically interferes with the WIF domain of Ryk) prevents actin polymerization.","method":"siRNA knockdown of Ryk, trans-endothelial resistance measurement (live), ROCK/LIMK2/cofilin phosphorylation assays, WIF1 antagonist, cytoskeletal live-cell imaging","journal":"Cell adhesion & migration","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with functional permeability readout, phosphorylation cascade dissection, single lab","pmids":["27159116"],"is_preprint":false},{"year":2018,"finding":"Wnt5a induces dormancy of prostate cancer cells in bone via induction of SIAH2 expression, which represses Wnt/beta-catenin signaling. This dormancy effect depends on ROR2, as ROR2 knockdown abolishes Wnt5a-induced dormancy both in vitro and in vivo.","method":"ROR2 siRNA knockdown, SIAH2 expression analysis, beta-catenin activity reporter, in vitro dormancy assay, in vivo bone metastasis mouse model","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with in vivo bone metastasis model, SIAH2 mechanistic link, single lab","pmids":["30593464"],"is_preprint":false},{"year":2021,"finding":"RNF43, an E3 ubiquitin ligase, negatively regulates Wnt5a-induced noncanonical signaling. RNF43 interacts with ROR1, ROR2, VANGL1, and VANGL2. RNF43 triggers VANGL2 ubiquitination and proteasomal degradation and promotes clathrin-dependent internalization of ROR1, and inhibits ROR2 activation. These activities suppress Wnt5a-driven melanoma invasion and resistance to BRAF/MEK inhibitors.","method":"BioID proximity labeling, co-immunoprecipitation (RNF43 with ROR1/2/VANGL1/2), ubiquitination assay, proteasome inhibitor rescue, clathrin inhibitor, ROR2 phosphorylation assay, invasion assay, in vivo melanoma model","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — BioID + reciprocal co-IP, ubiquitination/degradation assay, receptor internalization dissection, in vivo model, multiple orthogonal methods in one study","pmids":["34702444"],"is_preprint":false},{"year":2023,"finding":"WNT5a signaling through ROR2 activates the Hippo pathway (increased phosphorylation of MST1/2, LATS1, MOB1, and YAP1) to suppress YAP1 activity and tumor growth. Deletion of MST1/2 abrogates the WNT5a response. In ROR2-negative cells, WNT5a suppresses Hippo via increased inhibitory phosphorylation of NF2/Merlin. YAP1 activity also stimulates ROR2 and WNT5a expression, forming a negative feedback loop.","method":"WNT5a/Foxy5 treatment, MST1/2 deletion, ROR2 expression/knockdown, phosphorylation of Hippo components by Western blot, prostate cancer organoid and xenograft models, correlation with clinical datasets","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic deletion (MST1/2) and receptor manipulation with in vivo organoid/xenograft models, multiple phosphorylation readouts, single lab","pmids":["36622276"],"is_preprint":false},{"year":2019,"finding":"In melanoma cells, Wnt5a activates the NF-κB pathway through ROR1, Dvl2, and Akt (Wnt5a pathway) and TRAF2 and RIP (NF-κB pathway). Wnt5a induces IKK phosphorylation, IκB degradation, p65 phosphorylation, and p65 nuclear translocation. An autocrine Wnt5a loop is a major regulator of NF-κB and cytokine/chemokine secretion (IL-6, IL-8, IL-11, MCP-1, TNF-sRI) in melanoma.","method":"cDNA overexpression, RNA interference, dominant-negative mutants, NF-κB reporter assay, IκB/IKK phosphorylation Western blot, p65 nuclear translocation imaging, cytokine ELISA, endogenous Wnt5a inhibition","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with dominant-negative mutants, reporter assays, multiple pathway components dissected; single lab","pmids":["31510045"],"is_preprint":false},{"year":2017,"finding":"Wnt5a activates Daam1, which in turn activates RhoA to promote stress fiber formation and glioblastoma cell invasion. siRNA targeting Daam1 inhibits Wnt5a-induced RhoA activation, stress fiber formation, and invasion. The Wnt5a antagonist sFRP2 blocks Wnt5a-induced Daam1 and RhoA activation and invasion.","method":"Daam1 pull-down activation assay, RhoA activation assay, siRNA knockdown of Daam1, RhoA inhibitor (CCG-1423), sFRP2 Wnt5a antagonist, invasion assay","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Daam1 and RhoA activation assays with siRNA and pharmacological dissection, functional invasion readout; single lab","pmids":["29207169"],"is_preprint":false},{"year":2019,"finding":"Wnt5a promotes invasion of esophageal squamous cell carcinoma cells via ROR1 and ROR2 receptors through DAAM1/RhoA signaling. ROR1 and ROR2 associate with each other. Downstream of ROR1/ROR2, DAAM1 activates RhoA (not Rac1/Rac2), and RhoA promotes actin filament reorganization and invasion. DAAM1 shRNA inhibits RhoA activation, which is rescued by wild-type DAAM1 overexpression.","method":"Co-immunoprecipitation (ROR1-ROR2), DAAM1 activity pull-down, RhoA/Rac activation assay, shRNA knockdown, wild-type DAAM1 rescue, RhoA inhibitor CCG-1423, invasion assay, phalloidin actin staining","journal":"Cancer management and research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of receptor complex, activation assays, rescue experiment, functional invasion readout; single lab","pmids":["31114334"],"is_preprint":false},{"year":2015,"finding":"Wnt5a inhibits hepatocyte proliferation and concludes beta-catenin signaling during liver regeneration via the Wnt5a/Frizzled-2 axis. Treatment of primary hepatocytes with Wnt5a decreases beta-catenin-TCF4 activity and cyclin-D1 expression and reduces proliferation. Liver-specific Wntless knockout (impairing Wnt secretion) reduces Wnt5a secretion and prolongs hepatocyte proliferation with increased beta-catenin/TCF4 interaction.","method":"Liver-specific Wntless knockout mice, partial hepatectomy model, Wnt5a treatment of primary hepatocytes, beta-catenin/TCF4 co-immunoprecipitation, cyclin-D1 Western blot, BrdU proliferation assay","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional knockout model combined with in vitro primary cell treatment, co-IP for mechanistic complex; single lab","pmids":["26100214"],"is_preprint":false},{"year":2020,"finding":"Wnt5a promotes lysosomal cholesterol egress by binding to NPC1 and NPC2 lysosomal cholesterol transporters, increasing lysosomal acid lipase expression, and decreasing mTORC1 signaling. Loss of Wnt5a in vascular smooth muscle cells (CRISPR/Cas9 or conditional knockout) disrupts lysosomal function, decreases cholesterol in the endoplasmic reticulum, and promotes atherosclerosis.","method":"Conditional Wnt5a knockout in vascular smooth muscle cells (mouse), CRISPR/Cas9 Wnt5a knockout in human cells, NPC1/NPC2 binding assay, lysosomal acid lipase expression, mTORC1 activity assay, cholesterol trafficking assay","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse conditional KO, human cell CRISPR KO, direct binding to NPC1/NPC2, multiple mechanistic readouts, two independent genetic models","pmids":["34886684"],"is_preprint":false},{"year":2020,"finding":"High-salt diet increases vascular Wnt5a expression, which is required for Ang II-induced RhoA/ROCK activation (measured by p-MYPT1). In cultured vascular smooth muscle cells, siRNA knockdown of Wnt5a abolishes Ang II-induced p-MYPT1 upregulation. Klotho supplementation inhibits Wnt5a- and Ang II-induced p-MYPT1. Wnt5a antagonist Box5 and Wnt inhibitor LGK974 reduce salt-induced hypertension similarly to ROCK inhibitor fasudil.","method":"Wnt5a siRNA in VSMCs, pharmacological Wnt5a antagonist Box5, Klotho supplementation, p-MYPT1 as RhoA/ROCK activity readout, blood pressure measurement, renal blood flow assay, Klotho-knockout and aged mouse models","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA in vitro combined with pharmacological inhibition and in vivo mouse models; mechanistic link between Wnt5a and RhoA/ROCK established; single lab","pmids":["32597829"],"is_preprint":false},{"year":2019,"finding":"STAT3 transcriptionally activates Wnt5a in CLL cells by directly binding to the Wnt5a gene promoter. ChIP and EMSA confirmed STAT3 binding to four putative STAT3 binding sites near the Wnt5a promoter. STAT3 shRNA reduces Wnt5a mRNA and protein levels, and Wnt5a siRNA increases spontaneous apoptosis of CLL cells.","method":"ChIP of STAT3 at Wnt5a promoter, EMSA, luciferase reporter assay, STAT3 shRNA, Wnt5a siRNA, apoptosis assay, flow cytometry","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP + EMSA + reporter assay for STAT3-Wnt5a transcriptional relationship, functional siRNA validation; single lab","pmids":["31645416"],"is_preprint":false},{"year":2023,"finding":"PRMT2 mediates H3R8 asymmetric dimethylation (H3R8me2a) at the WNT5A promoter to enhance WNT5A transcriptional expression, leading to activation of Wnt signaling and promotion of RCC cell proliferation and motility. ChIP confirmed H3R8me2a enrichment at the WNT5A promoter by PRMT2.","method":"ChIP for H3R8me2a at WNT5A promoter, PRMT2 overexpression and knockdown, in vitro proliferation and motility assays, in vivo xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with specific histone mark, gain- and loss-of-function with defined phenotype; single lab","pmids":["37173306"],"is_preprint":false},{"year":2019,"finding":"Wnt5a transcription in chondrocytes is activated by transcription factors Trps1 and Gli3A (activator form). ChIP and reporter gene assays identified two upstream regulatory sequences (URS) in the Wnt5a promoter; URS1 is bound by Trps1 and Gli3A in vitro and in vivo. Loss of both transcription factors decreases endogenous Wnt5a mRNA and protein levels during chondrocyte differentiation.","method":"ChIP of Trps1 and Gli3A at Wnt5a promoter URS1, reporter gene assay, Trps1/Gli3 mutant mouse models (double mutants), qRT-PCR and Western blot of Wnt5a","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP in vitro and in vivo, reporter assay, genetic mouse model loss-of-function; single lab","pmids":["31550480"],"is_preprint":false},{"year":2020,"finding":"In PGC1alpha-silenced melanoma, TCF12 is activated and increases WNT5A expression. WNT5A in turn stabilizes YAP protein levels to promote melanoma migration and metastasis. Inhibition of TCF12, WNT5A, or YAP individually blocks melanoma migration in vitro and metastasis in vivo.","method":"EZH2 inhibitor (H3K27me3 removal), TCF12 knockdown/overexpression, WNT5A inhibition, YAP inhibition, in vitro migration assay, in vivo metastasis assay","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic dissection (TCF12→WNT5A→YAP) with loss-of-function at each step, in vivo metastasis validation; single lab","pmids":["31929186"],"is_preprint":false},{"year":2022,"finding":"In HIV gp120-induced pain, neurons secrete Wnt5a which signals to astrocytes via ROR2 to induce astrogliosis. Conditional knockout of Wnt5a in neurons or ROR2 in astrocytes abolishes gp120-induced astrogliosis, mechanical hyperalgesia, and neural circuit polarization. Astrogliosis promotes hyperalgesia via IL-1beta regulated by a Wnt5a-ROR2-MMP2 axis.","method":"Conditional knockout of Wnt5a in neurons and ROR2 in astrocytes, gp120 mouse pain model, IL-1beta measurement, MMP2 inhibition, mechanical hyperalgesia testing","journal":"Brain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific conditional knockouts establishing intercellular Wnt5a/ROR2 signaling axis in vivo, MMP2/IL-1beta mechanistic link; single lab","pmids":["35040478"],"is_preprint":false},{"year":2021,"finding":"In the fourth ventricle choroid plexus, WNT5A is expressed by Foxj1-positive epithelial cells at villous tips and acts locally to activate non-canonical Wnt signaling via ROR1 and ROR2 receptors. Conditional Wnt5a deletion in these epithelial cells impairs branched villous morphology. MEIS1 transcription factor binds the proximal Wnt5a promoter and regulates Wnt5a expression in 4V ChP development.","method":"Conditional Wnt5a knockout (Foxj1-Cre), systemic Wnt5a knockout and overexpression, ChIP of MEIS1 at Wnt5a promoter, MEIS gain/loss-of-function, immunofluorescence for ROR1/ROR2 activation","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with morphological readout, ChIP for upstream regulator, receptor identification; single lab","pmids":["34032267"],"is_preprint":false},{"year":2020,"finding":"Conditional Wnt5a loss-of-function (Wnt5aCAG) during saccular/alveolar lung development reveals that Wnt5a is required for myofibroblast differentiation and migration but not endothelial or epithelial differentiation in alveologenesis. Conditional inactivation of both Ror1 and Ror2 in alveolar myofibroblasts recapitulates the Wnt5aCAG phenotype, demonstrating that myofibroblast defects are the primary cause of arrested alveologenesis downstream of Wnt5a.","method":"Conditional Wnt5a knockout (Wnt5aCAG), conditional Ror1/Ror2 double knockout in myofibroblasts, histological and immunofluorescence analysis, in vitro isolated lung fibroblast assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple conditional KO models with epistatic receptor dissection in vivo; in vitro validation; single lab","pmids":["32046118"],"is_preprint":false},{"year":2022,"finding":"Microglial WNT5A is the most abundant Wnt expressed in microglia and promotes neuronal spine maturation. Co-culture of microglia with neurons increases spine density and reduces turnover; silencing microglial Wnt5a diminishes these effects. Microglial Wnt5a knockdown reduces PSD95 levels, synaptic density, and neuronal firing rate.","method":"shRNA silencing of Wnt5a in microglia, co-culture with Thy1-YFP+ neurons, dendritic spine imaging (density, turnover), PSD95/VGLUT2 co-localization, multi-electrode array neuronal firing","journal":"Brain, behavior, and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function knockdown with multiple synaptic readouts, in vitro co-culture system; single lab","pmids":["36395958"],"is_preprint":false}],"current_model":"WNT5A is a secreted glycoprotein that signals primarily through non-canonical pathways in a receptor-context-dependent manner: binding to ROR2 (inducing homodimerization, tyrosine phosphorylation via GSK-3, and downstream RhoA/JNK/PKD/Hippo activation), to ROR1/ROR2 heterooligomers (recruiting GEFs to activate Rac1/RhoA), to Frizzled receptors (activating PKC, JNK, ERK, or Ca2+/calcineurin depending on cell type), to the Ryk receptor (regulating HSC quiescence via ROS suppression and endothelial permeability via ROCK/LIMK2/cofilin), and to CD146 (activating Dvl/JNK for cell migration); it can also activate canonical beta-catenin signaling through Frizzled 4, or inhibit it through CD146-mediated beta-catenin degradation and DVL1-driven suppression of rDNA transcription, with transcriptional regulation of WNT5A itself provided by STAT3, PRMT2/H3R8me2a, Trps1/Gli3A, MEIS1, FOXE1, and TCF12/PGC1alpha-epigenetic axis, and with its activity negatively regulated by RNF43-mediated ubiquitination and receptor internalization."},"narrative":{"mechanistic_narrative":"WNT5A is a secreted Wnt ligand that signals predominantly through non-canonical pathways whose output is dictated by receptor context, controlling cell polarity, directional migration, tissue morphogenesis, and metabolic homeostasis [PMID:16602827, PMID:18420933]. Purified WNT5A inhibits Wnt3a-driven canonical β-catenin signaling through the orphan receptor tyrosine kinase ROR2 without altering β-catenin levels, yet in the presence of Frizzled-4 the same ligand activates β-catenin signaling, establishing that receptor availability determines whether WNT5A is canonical or non-canonical [PMID:16602827]. A central effector arm runs through ROR2: WNT5A induces ROR2 homodimerization and its tyrosine and GSK-3-dependent serine/threonine phosphorylation [PMID:18615587, PMID:17986005], and downstream of ROR2 engages DAAM1/RhoA, PKD/JNK, and Hippo-pathway kinases (MST1/2, LATS1, YAP1) to drive actin reorganization, invasion, and growth control [PMID:29207169, PMID:20101234, PMID:36622276]. WNT5A also signals through ROR1/ROR2 heterooligomers that recruit GEFs to activate Rac1 and RhoA [PMID:26690702], through CD146/Dvl2 to activate JNK for migration and convergent extension [PMID:24335906], through Frizzled receptors to engage PKC and calcineurin [PMID:18615587, PMID:27892464], and through the Ryk receptor to control HSC quiescence via ROS suppression and endothelial permeability via ROCK/LIMK2/cofilin [PMID:23939973, PMID:27159116]. In melanoma WNT5A organizes a polarized receptor-actin-myosin (W-RAMP) structure dependent on endosomal trafficking and Rab4/RhoB, and promotes invasion by stimulating APT1-mediated depalmitoylation of MCAM and CD44 [PMID:18420933, PMID:25944911, PMID:29648538]. Beyond migration, WNT5A directs osteoblast and osteoclast biology, alveolar myofibroblast differentiation, choroid plexus and chondrocyte morphogenesis, AQP2-dependent renal water handling, lysosomal cholesterol egress via NPC1/NPC2, and microglial control of neuronal spine maturation [PMID:28851822, PMID:32046118, PMID:34032267, PMID:27892464, PMID:34886684, PMID:36395958]. WNT5A transcription is driven by STAT3, PRMT2-deposited H3R8me2a, Trps1/Gli3A, MEIS1, and a TCF12/PGC1α axis [PMID:31645416, PMID:37173306, PMID:31550480, PMID:34032267, PMID:31929186], and its signaling is restrained by the E3 ubiquitin ligase RNF43, which degrades VANGL2 and internalizes ROR1 to dampen non-canonical output [PMID:34702444].","teleology":[{"year":2002,"claim":"Established that WNT5A drives an invasive, non-canonical program independent of β-catenin, defining its role in melanoma motility.","evidence":"WNT5A overexpression with anti-Frizzled-5 antibody blocking, PKC activity and invasion assays in melanoma cells","pmids":["12086864"],"confidence":"Medium","gaps":["Did not resolve the receptor complex composition upstream of PKC","Single cell type"]},{"year":2006,"claim":"Showed that receptor context, not the ligand alone, determines whether WNT5A inhibits or activates canonical signaling, resolving conflicting reports about its directionality.","evidence":"Purified homogeneous WNT5A protein, dose-response reporter assays, ROR2 functional block and Frizzled-4 co-expression","pmids":["16602827"],"confidence":"High","gaps":["Mechanism by which ROR2 inhibits canonical signaling without changing β-catenin levels not fully defined","Performed in reporter cell systems"]},{"year":2007,"claim":"Identified GSK-3 as a kinase phosphorylating ROR2 downstream of WNT5A, linking ligand engagement to receptor activation and migration.","evidence":"In vitro kinase assay with purified GSK-3 on immunoprecipitated ROR2, siRNA and pharmacological inhibition, migration assay","pmids":["17986005"],"confidence":"High","gaps":["Functional consequence of specific phosphosites on ROR2 not mapped","Connection to tyrosine phosphorylation arm unclear"]},{"year":2008,"claim":"Demonstrated that WNT5A specifically induces ROR2 homodimerization and tyrosine phosphorylation (which Wnt3a cannot), and linked this to osteoblast differentiation.","evidence":"Co-IP, tyrosine phosphorylation and 14-3-3β assays, ROR2 siRNA, MSC differentiation and bone explant culture","pmids":["18615587"],"confidence":"Medium","gaps":["Direct kinase responsible for ROR2 tyrosine phosphorylation not identified","Role of 14-3-3β in downstream signaling unresolved"]},{"year":2008,"claim":"Revealed that WNT5A organizes a polarized receptor-actin-myosin (W-RAMP) structure coupling endosomal trafficking to directional migration and nuclear movement.","evidence":"Live imaging, dominant-negative Rab4/RhoB, chemokine gradient and endosome trafficking analysis in melanoma","pmids":["18420933"],"confidence":"High","gaps":["Molecular trigger for asymmetric W-RAMP accumulation not defined","Relationship to ROR2 signaling arm unclear"]},{"year":2009,"claim":"Established ROR2 as required for WNT5A-driven melanoma metastasis and described receptor internalization as a feature of active signaling.","evidence":"ROR2 siRNA, PKC and clathrin inhibitors, in vitro/in vivo metastasis assays, tissue microarrays","pmids":["19802008"],"confidence":"Medium","gaps":["Whether internalization is required for or terminates signaling not resolved","Single lab"]},{"year":2010,"claim":"Connected WNT5A-Frizzled2/ROR2 signaling to a PKD-JNK-JunD transcriptional cascade inducing MMP-1 and prostate cancer invasion.","evidence":"WNT5A knockdown/overexpression, PKD inhibitor, ChIP for JunD at MMP-1 promoter, invasion assay","pmids":["20101234"],"confidence":"Medium","gaps":["Direct link between PKD and JunD recruitment not established","Single cancer type"]},{"year":2013,"claim":"Identified CD146 as a high-affinity WNT5A receptor that activates Dvl2/JNK for migration while also degrading β-catenin, extending WNT5A's receptor repertoire.","evidence":"Binding affinity, CD146-Dvl2 co-IP, domain mutagenesis, JNK and migration assays, zebrafish convergent extension","pmids":["24335906"],"confidence":"High","gaps":["How CD146 coordinates with ROR/Frizzled receptors not addressed","Mechanism of β-catenin degradation via CD146 not fully detailed"]},{"year":2014,"claim":"Showed WNT5A non-canonical signaling can amplify canonical signaling by upregulating LRP5/6 co-receptors during osteoblastogenesis, revealing pathway crosstalk.","evidence":"Conditional Wnt5a knockout, shRNA, adenoviral Lrp5 rescue, Tcf/Lef reporter and differentiation assays","pmids":["24670389"],"confidence":"Medium","gaps":["Mechanism linking non-canonical signaling to LRP5/6 transcription unknown","Single lineage context"]},{"year":2015,"claim":"Defined a nuclear role for WNT5A through DVL1, repressing RNA Pol I rDNA transcription via SIRT7 displacement, an unexpected non-membrane output.","evidence":"DVL1 ChIP at rDNA, co-IP, Pol I transcription and SIRT7 displacement assays, DVL1-specific siRNA","pmids":["27500936"],"confidence":"Medium","gaps":["How WNT5A signaling routes to nucleolar DVL1 unknown","Receptor mediating this output not identified"]},{"year":2015,"claim":"Identified APT1-mediated MCAM depalmitoylation at Cys-590 as the mechanism polarizing adhesion molecules during WNT5A-driven invasion.","evidence":"Cys-590 mutagenesis, APT1 inhibitor, palmitoylation and localization assays, invasion assay","pmids":["25944911"],"confidence":"Medium","gaps":["How WNT5A signaling activates APT1 not resolved here","Single melanoma context"]},{"year":2015,"claim":"Demonstrated WNT5A/Frizzled-2 terminates β-catenin signaling to limit hepatocyte proliferation, defining its role in concluding liver regeneration.","evidence":"Liver-specific Wntless knockout, partial hepatectomy, WNT5A treatment of hepatocytes, β-catenin/TCF4 co-IP, BrdU assay","pmids":["26100214"],"confidence":"Medium","gaps":["Receptor-proximal events linking Frizzled-2 to reduced TCF4 activity not defined","Single lab"]},{"year":2016,"claim":"Resolved the molecular basis of WNT5A-induced ROR1/ROR2 heterooligomerization and GEF recruitment activating Rac1/RhoA in CLL.","evidence":"Reciprocal co-IP, domain mapping, ROR1/ROR2 siRNA, Rac1/RhoA assays, in vivo engraftment mouse models","pmids":["26690702"],"confidence":"High","gaps":["Identity of the specific GEFs recruited not fully defined","Stoichiometry of heterooligomer unknown"]},{"year":2016,"claim":"Established Ryk as a WNT5A receptor controlling HSC quiescence through ROS suppression, extending non-canonical signaling to stem cell maintenance.","evidence":"Ryk blocking antibody/dominant-negative, HSC quiescence and ROS assays, hematopoietic repopulation assay","pmids":["23939973"],"confidence":"Medium","gaps":["Intracellular signaling from Ryk to ROS machinery not mapped","Single lab"]},{"year":2016,"claim":"Defined a WNT5A-Ryk-ROCK-LIMK2-cofilin cascade governing endothelial actin stress fibers and vascular permeability.","evidence":"Ryk siRNA, trans-endothelial resistance, ROCK/LIMK2/cofilin phosphorylation, WIF1 antagonist, live imaging","pmids":["27159116"],"confidence":"Medium","gaps":["How Ryk couples to ROCK not biochemically defined","Single endothelial system"]},{"year":2016,"claim":"Showed WNT5A regulates AQP2 trafficking and renal water handling via calcineurin, independent of the vasopressin/cAMP/PKA pathway.","evidence":"Collecting duct cell stimulation, AQP2 phosphorylation/trafficking, calcineurin and cAMP/PKA assays, NDI mouse model","pmids":["27892464"],"confidence":"High","gaps":["Receptor mediating renal WNT5A-calcineurin signaling not identified","Link to the broader PCP machinery unclear"]},{"year":2017,"claim":"Defined a WNT5A-ROR2-RhoA-Pkn3-c-Src axis driving osteoclast actin ring formation and bone resorption in vivo.","evidence":"Osteoclast-specific Ror2 and global Pkn3 knockout mice, constitutively active RhoA rescue, Pkn3-c-Src co-IP and c-Src activity assay","pmids":["28851822"],"confidence":"High","gaps":["How Pkn3 enhances c-Src activity mechanistically not fully defined","Cross-talk with osteoblast WNT5A signaling not addressed"]},{"year":2017,"claim":"Identified DAAM1 as the effector linking WNT5A to RhoA activation and stress fiber formation in glioblastoma invasion.","evidence":"Daam1 pull-down activation assay, RhoA assay, Daam1 siRNA, RhoA inhibitor, sFRP2 antagonist, invasion assay","pmids":["29207169"],"confidence":"Medium","gaps":["Receptor upstream of DAAM1 in glioblastoma not specified","Single lab"]},{"year":2018,"claim":"Showed WNT5A induces APT1 phosphorylation that increases its depalmitoylating activity toward CD44 and MCAM, mechanistically linking signaling to enzyme activation.","evidence":"APT1 phosphorylation, depalmitoylation activity and dimerization assays, invasion assay, tumor grade correlation","pmids":["29648538"],"confidence":"Medium","gaps":["Kinase phosphorylating APT1 downstream of WNT5A not identified","Single melanoma context"]},{"year":2018,"claim":"Established that WNT5A-ROR2 can induce dormancy of prostate cancer in bone via SIAH2-mediated repression of β-catenin signaling.","evidence":"ROR2 siRNA, SIAH2 expression, β-catenin reporter, in vitro dormancy and in vivo bone metastasis models","pmids":["30593464"],"confidence":"Medium","gaps":["How ROR2 induces SIAH2 expression not defined","Reconciliation with WNT5A's pro-invasive roles elsewhere"]},{"year":2019,"claim":"Linked an autocrine WNT5A-ROR1-Dvl2-Akt loop to NF-κB activation and cytokine secretion in melanoma.","evidence":"Overexpression, RNAi, dominant-negative mutants, NF-κB reporter, IκB/IKK/p65 Western blots, cytokine ELISA","pmids":["31510045"],"confidence":"Medium","gaps":["Direct connection between Akt and TRAF2/RIP not biochemically established","Single lab"]},{"year":2019,"claim":"Showed WNT5A drives ESCC invasion through ROR1/ROR2-DAAM1-RhoA, confirming receptor-complex usage of the DAAM1 arm.","evidence":"ROR1-ROR2 co-IP, DAAM1 pull-down, RhoA/Rac assays, shRNA with WT DAAM1 rescue, invasion and actin staining","pmids":["31114334"],"confidence":"Medium","gaps":["Selectivity for RhoA over Rac not mechanistically explained","Single cancer type"]},{"year":2019,"claim":"Identified STAT3 as a direct transcriptional activator of WNT5A in CLL, defining an upstream regulatory input for survival signaling.","evidence":"STAT3 ChIP at WNT5A promoter, EMSA, luciferase reporter, STAT3 shRNA, WNT5A siRNA apoptosis assay","pmids":["31645416"],"confidence":"Medium","gaps":["Whether STAT3 cooperates with other factors at the promoter unknown","Single disease context"]},{"year":2019,"claim":"Showed Trps1 and Gli3A activate WNT5A transcription during chondrocyte differentiation via defined promoter elements.","evidence":"Trps1/Gli3A ChIP at URS1, reporter assays, double-mutant mouse models, WNT5A qRT-PCR/Western","pmids":["31550480"],"confidence":"Medium","gaps":["Combinatorial logic between Trps1 and Gli3A not resolved","Tissue-specific to chondrocytes"]},{"year":2020,"claim":"Defined WNT5A as a regulator of lysosomal cholesterol egress through NPC1/NPC2 binding and mTORC1 suppression, protecting against atherosclerosis.","evidence":"VSMC conditional and CRISPR Wnt5a knockout, NPC1/NPC2 binding, lysosomal acid lipase and mTORC1 assays, cholesterol trafficking","pmids":["34886684"],"confidence":"High","gaps":["Whether NPC1/NPC2 binding is direct ligand-receptor or intracellular not fully resolved","Receptor mediating this metabolic effect unclear"]},{"year":2020,"claim":"Linked vascular WNT5A to Ang II-induced RhoA/ROCK activation in salt-sensitive hypertension, identifying a therapeutically targetable signaling node.","evidence":"Wnt5a siRNA in VSMCs, Box5 and LGK974 antagonists, Klotho supplementation, p-MYPT1 readout, blood pressure in mouse models","pmids":["32597829"],"confidence":"Medium","gaps":["Receptor coupling WNT5A to RhoA/ROCK in VSMCs not identified","Single lab"]},{"year":2020,"claim":"Established a PGC1α-loss/TCF12/WNT5A/YAP axis driving melanoma metastasis, embedding WNT5A in an epigenetic-transcriptional circuit.","evidence":"EZH2 inhibitor, TCF12 knockdown/overexpression, WNT5A and YAP inhibition, in vitro migration and in vivo metastasis","pmids":["31929186"],"confidence":"Medium","gaps":["Mechanism by which WNT5A stabilizes YAP not defined here","Single tumor type"]},{"year":2020,"claim":"Showed WNT5A is required cell-autonomously in alveolar myofibroblasts via ROR1/ROR2 for alveologenesis, dissecting its developmental requirement by lineage.","evidence":"Conditional Wnt5a and Ror1/Ror2 double knockouts, histology/immunofluorescence, isolated fibroblast assays","pmids":["32046118"],"confidence":"Medium","gaps":["Downstream effectors in myofibroblast differentiation not identified","Single developmental window"]},{"year":2021,"claim":"Established RNF43 as a negative regulator of WNT5A non-canonical signaling through VANGL2 degradation and ROR1 internalization, defining a brake on the pathway.","evidence":"BioID, reciprocal co-IP with ROR1/2 and VANGL1/2, ubiquitination/degradation assays, internalization dissection, in vivo melanoma model","pmids":["34702444"],"confidence":"High","gaps":["How RNF43 selectively distinguishes among receptor substrates unknown","Regulation of RNF43 activity itself not addressed"]},{"year":2021,"claim":"Showed WNT5A is locally expressed in Foxj1+ choroid plexus epithelium under MEIS1 control and shapes villous morphology via ROR1/ROR2.","evidence":"Foxj1-Cre conditional knockout, systemic knockout/overexpression, MEIS1 ChIP at promoter, ROR1/ROR2 activation immunofluorescence","pmids":["34032267"],"confidence":"Medium","gaps":["Downstream non-canonical effectors in villous branching not defined","Single developmental structure"]},{"year":2022,"claim":"Defined a neuron-to-astrocyte WNT5A-ROR2-MMP2-IL-1β axis driving astrogliosis and pain in HIV gp120 models, establishing intercellular WNT5A signaling.","evidence":"Cell-type-specific conditional Wnt5a (neuron) and Ror2 (astrocyte) knockouts, gp120 pain model, IL-1β/MMP2 manipulation, hyperalgesia testing","pmids":["35040478"],"confidence":"Medium","gaps":["How ROR2 induces MMP2/IL-1β in astrocytes not mechanistically detailed","Specific to the gp120 model"]},{"year":2022,"claim":"Identified microglial WNT5A as a regulator of neuronal spine maturation and synaptic function, broadening WNT5A's CNS roles.","evidence":"Microglial Wnt5a shRNA, microglia-neuron co-culture, spine imaging, PSD95/VGLUT2 colocalization, multi-electrode array","pmids":["36395958"],"confidence":"Medium","gaps":["Neuronal receptor mediating microglial WNT5A effect not identified","In vitro co-culture only"]},{"year":2023,"claim":"Showed WNT5A-ROR2 engages the Hippo pathway to suppress YAP1 and tumor growth, with a YAP1-WNT5A feedback loop, integrating WNT5A into growth-control signaling.","evidence":"WNT5a/Foxy5 treatment, MST1/2 deletion, ROR2 manipulation, Hippo component phosphorylation, prostate organoid/xenograft models","pmids":["36622276"],"confidence":"Medium","gaps":["Apparent opposite WNT5A-YAP relationship versus melanoma reports unreconciled","Direct link between ROR2 and MST1/2 not defined"]},{"year":2023,"claim":"Identified PRMT2-deposited H3R8me2a as an epigenetic activator of WNT5A transcription promoting renal cell carcinoma growth.","evidence":"ChIP for H3R8me2a at WNT5A promoter, PRMT2 gain/loss-of-function, proliferation/motility assays, xenograft model","pmids":["37173306"],"confidence":"Medium","gaps":["How PRMT2 is targeted to the WNT5A locus unknown","Single cancer context"]},{"year":null,"claim":"How a single secreted WNT5A ligand is partitioned among its many receptors (ROR1, ROR2, Frizzled, Ryk, CD146) to produce opposite outputs in different tissues, and what governs the switch between canonical-inhibitory, non-canonical-migratory, and metabolic functions, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of receptor selection in a given cell type","Structural basis of context-dependent receptor binding not determined","Reconciliation of opposing YAP/β-catenin effects across tissues"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,2,7,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,18,23]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,8,7,15]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,24]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[4]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[24]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,8,7,19]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[14,31,32,28]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,24,25,30]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[24,13]}],"complexes":["ROR1/ROR2 heterooligomer","ROR2 homodimer","W-RAMP receptor-actin-myosin structure"],"partners":["ROR2","ROR1","FZD4","FZD2","CD146","RYK","RNF43","NPC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P41221","full_name":"Protein Wnt-5a","aliases":[],"length_aa":380,"mass_kda":42.3,"function":"Ligand for members of the frizzled family of seven transmembrane receptors. Can activate or inhibit canonical Wnt signaling, depending on receptor context. In the presence of FZD4, activates beta-catenin signaling. In the presence of ROR2, inhibits the canonical Wnt pathway by promoting beta-catenin degradation through a GSK3-independent pathway which involves down-regulation of beta-catenin-induced reporter gene expression (By similarity). Suppression of the canonical pathway allows chondrogenesis to occur and inhibits tumor formation. Stimulates cell migration. Decreases proliferation, migration, invasiveness and clonogenicity of carcinoma cells and may act as a tumor suppressor (PubMed:15735754). Mediates motility of melanoma cells (PubMed:17426020). Required during embryogenesis for extension of the primary anterior-posterior axis and for outgrowth of limbs and the genital tubercle. Inhibits type II collagen expression in chondrocytes (By similarity)","subcellular_location":"Secreted, extracellular space, extracellular matrix; Secreted","url":"https://www.uniprot.org/uniprotkb/P41221/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WNT5A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/WNT5A","total_profiled":1310},"omim":[{"mim_id":"621363","title":"MAP7 DOMAIN-CONTAINING PROTEIN 1; MAP7D1","url":"https://www.omim.org/entry/621363"},{"mim_id":"614833","title":"MICROCEPHALY, SHORT STATURE, AND POLYMICROGYRIA WITH OR WITHOUT SEIZURES; MSSP","url":"https://www.omim.org/entry/614833"},{"mim_id":"614140","title":"SPERM ANTIGEN WITH CALPONIN HOMOLOGY AND COILED-COIL DOMAINS 1-LIKE; SPECC1L","url":"https://www.omim.org/entry/614140"},{"mim_id":"613380","title":"H6 FAMILY HOMEOBOX 3; HMX3","url":"https://www.omim.org/entry/613380"},{"mim_id":"611514","title":"WNT LIGAND SECRETION MEDIATOR; WLS","url":"https://www.omim.org/entry/611514"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Microtubules","reliability":"Uncertain"},{"location":"Mitotic spindle","reliability":"Uncertain"},{"location":"Primary cilium","reliability":"Uncertain"},{"location":"Nucleoli fibrillar center","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"endometrium 1","ntpm":25.7},{"tissue":"salivary gland","ntpm":32.4}],"url":"https://www.proteinatlas.org/search/WNT5A"},"hgnc":{"alias_symbol":["hWNT5A"],"prev_symbol":[]},"alphafold":{"accession":"P41221","domains":[{"cath_id":"-","chopping":"43-56_69-319","consensus_level":"high","plddt":94.13,"start":43,"end":319},{"cath_id":"3.30.2460.20","chopping":"324-380","consensus_level":"medium","plddt":94.4875,"start":324,"end":380}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P41221","model_url":"https://alphafold.ebi.ac.uk/files/AF-P41221-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P41221-F1-predicted_aligned_error_v6.png","plddt_mean":87.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WNT5A","jax_strain_url":"https://www.jax.org/strain/search?query=WNT5A"},"sequence":{"accession":"P41221","fasta_url":"https://rest.uniprot.org/uniprotkb/P41221.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P41221/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P41221"}},"corpus_meta":[{"pmid":"16602827","id":"PMC_16602827","title":"Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context.","date":"2006","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/16602827","citation_count":1044,"is_preprint":false},{"pmid":"12086864","id":"PMC_12086864","title":"Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma.","date":"2002","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/12086864","citation_count":736,"is_preprint":false},{"pmid":"12538525","id":"PMC_12538525","title":"Wnt5a and Wnt5b exhibit distinct activities in coordinating chondrocyte proliferation and differentiation.","date":"2003","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/12538525","citation_count":328,"is_preprint":false},{"pmid":"21518267","id":"PMC_21518267","title":"Wnt5a: its signalling, functions and implication in diseases.","date":"2011","source":"Acta physiologica (Oxford, 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cancer stemness via WNT5A in bladder cancer.","date":"2022","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/36459995","citation_count":193,"is_preprint":false},{"pmid":"18420933","id":"PMC_18420933","title":"Wnt5a control of cell polarity and directional movement by polarized redistribution of adhesion receptors.","date":"2008","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/18420933","citation_count":193,"is_preprint":false},{"pmid":"19802008","id":"PMC_19802008","title":"The orphan tyrosine kinase receptor, ROR2, mediates Wnt5A signaling in metastatic melanoma.","date":"2009","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/19802008","citation_count":164,"is_preprint":false},{"pmid":"26690702","id":"PMC_26690702","title":"Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation.","date":"2016","source":"The Journal of clinical 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In the presence of Frizzled 4, the same purified Wnt5a activates beta-catenin signaling, demonstrating that receptor context dictates signaling output. The Wnt5a signal is pertussis toxin insensitive and does not influence cellular calcium levels in this context.\",\n      \"method\": \"Purified Wnt5a protein (homogeneous), dose-response reporter assays, Ror2 requirement established by functional blocking, Frizzled 4 co-expression experiment\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — purified protein reconstitution with dose-response, multiple receptor contexts tested, orthogonal readouts (reporter, beta-catenin levels, calcium, pertussis toxin sensitivity)\",\n      \"pmids\": [\"16602827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Wnt5a overexpression in melanoma cells causes actin reorganization, increased cell adhesion, and increased PKC activation without increasing beta-catenin expression or nuclear translocation. Blocking Frizzled-5 with antibodies inhibits PKC activity and cellular invasion, placing Frizzled-5 upstream of PKC in Wnt5a-driven melanoma invasion.\",\n      \"method\": \"Constitutive overexpression vector transfection, anti-Frizzled-5 antibody blocking, PKC activity assay, invasion assay, actin staining\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (antibody block) with defined cellular phenotype, two orthogonal readouts (PKC activity and invasion), single lab\",\n      \"pmids\": [\"12086864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Wnt5a induces homodimerization and tyrosine phosphorylation of Ror2 in U2OS osteoblastic cells. Wnt5a also causes phosphorylation of the Ror2 substrate 14-3-3beta. Wnt3a binds Ror2 but does not induce its homodimerization or activation. Ror2 knockdown abolishes Wnt5a-induced osteoblastic differentiation of human mesenchymal stem cells.\",\n      \"method\": \"Co-immunoprecipitation, tyrosine phosphorylation assay, 14-3-3beta phosphorylation assay, siRNA knockdown of Ror2, calvarial bone explant culture, MSC differentiation assay\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, phosphorylation assays, loss-of-function with functional readout, single lab\",\n      \"pmids\": [\"18615587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Wnt5a induces serine/threonine phosphorylation of Ror2 through GSK-3 (primarily GSK-3alpha). GSK-3 inhibitors (LiCl, SB216763) or siRNA against GSK-3 block Wnt5a-induced Ror2 phosphorylation. Purified GSK-3alpha and GSK-3beta phosphorylate immunoprecipitated Ror2 in vitro. Wnt5a-induced cell migration is inhibited by GSK-3 suppression.\",\n      \"method\": \"In vitro kinase assay with purified GSK-3 on immunoprecipitated Ror2, siRNA knockdown of GSK-3, pharmacological inhibitors (LiCl, SB216763), cell migration assay\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase reconstitution combined with siRNA and pharmacological inhibition, functional migration readout, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17986005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Wnt5a controls cell polarity and directional movement in melanoma by recruiting actin, myosin IIB, Frizzled 3, and MCAM into an intracellular Wnt-mediated receptor-actin-myosin polarity (W-RAMP) structure. In a chemokine gradient, W-RAMP accumulates asymmetrically at the cell periphery, triggering membrane contractility and nuclear movement. The process requires endosome trafficking, is associated with multivesicular bodies, and is regulated through small GTPases Rab4 and RhoB.\",\n      \"method\": \"Live imaging, immunofluorescence, dominant-negative Rab4/RhoB expression, chemokine gradient assay, subcellular fractionation/endosome trafficking analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live imaging with functional consequence, dominant-negative genetic perturbation, multiple orthogonal readouts (polarity, nuclear movement, endosome trafficking), published in high-impact venue\",\n      \"pmids\": [\"18420933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ROR2 is required for Wnt5a-mediated melanoma metastasis. Wnt5a increases ROR2 expression and promotes PKC-dependent, clathrin-mediated internalization of ROR2. siRNA knockdown of ROR2 decreases downstream Wnt5a signaling and reduces melanoma metastasis in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown of ROR2, in vitro and in vivo metastasis assays, PKC inhibitor, clathrin inhibitor, melanoma tissue microarrays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with in vivo metastasis readout plus mechanistic dissection of internalization, single lab\",\n      \"pmids\": [\"19802008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Wnt5a promotes prostate cancer cell invasion through Frizzled2 and Ror2 receptors. Wnt5a activates JNK through protein kinase D (PKD), and PKD inhibition suppresses Wnt5a-dependent cell migration and invasion. Wnt5a induces MMP-1 expression through recruitment of JunD to the MMP-1 promoter.\",\n      \"method\": \"Wnt5a knockdown and overexpression in prostate cancer cell lines, invasion assay, PKD inhibitor, ChIP assay for JunD at MMP-1 promoter, siRNA for Frizzled2/Ror2\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with defined invasion phenotype, ChIP for transcriptional mechanism, pharmacological dissection of PKD, single lab\",\n      \"pmids\": [\"20101234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD146 acts as a functional Wnt5a receptor: CD146 binds Wnt5a with high affinity, and Wnt5a treatment enhances CD146-Dvl2 interaction. CD146-mediated Wnt5a signaling activates Dvl and JNK to promote cell migration and zebrafish convergent extension. Mutation of the Dvl2-binding region of CD146 impairs JNK activation, cell migration, and cell protrusion formation. CD146 also inhibits canonical Wnt signaling by promoting beta-catenin degradation.\",\n      \"method\": \"Binding affinity assay, co-immunoprecipitation (CD146-Dvl2), domain mutation, JNK activation assay, cell migration assay, zebrafish knockdown/convergent extension assay, beta-catenin degradation assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — binding affinity measurement, domain mutagenesis, in vivo zebrafish model with convergent extension readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"24335906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Wnt5a induces ROR1/ROR2 heterooligomerization to recruit guanine exchange factors (GEFs), activating Rac1 and RhoA in CLL cells. The extracellular Kringle domain of ROR1 is required for ROR1/ROR2 heterooligomerization; the cysteine-rich domain or intracellular proline-rich domain is required for Wnt5a-induced GEF recruitment. Silencing either ROR1 or ROR2 blocks these effects.\",\n      \"method\": \"Co-immunoprecipitation (ROR1/ROR2 heterooligomers), siRNA silencing of ROR1/ROR2, domain mapping with truncation constructs, Rac1/RhoA activation assays, ectopic ROR1 expression in ROR1-deficient MEC1 cells, in vivo engraftment assays in immune-deficient and ROR1-transgenic mice\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, domain mapping, siRNA, in vivo mouse models, multiple orthogonal methods, functionally validated GEF recruitment\",\n      \"pmids\": [\"26690702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Wnt5a signals through DVL1 to repress ribosomal DNA (rDNA) transcription by RNA Polymerase I. DVL1 accumulates at nucleolar organizer regions and binds rDNA regions. Upon DVL1 binding, SIRT7 (a Pol I transcription activator/deacetylase) dissociates from rDNA loci, concomitant with disassembly of the Pol I transcription machinery at the rDNA promoter.\",\n      \"method\": \"ChIP of DVL1 at rDNA, co-immunoprecipitation, Pol I transcription assay, SIRT7 displacement assay, DVL1-specific requirement established by siRNA\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, co-IP, and transcription assays in one study; DVL1-specific mechanism distinguished from other Dvl paralogs; single lab\",\n      \"pmids\": [\"27500936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Wnt5a promotes protein depalmitoylation of MCAM at Cys-590 via acyl protein thioesterase 1 (APT1), resulting in asymmetric MCAM localization. Mutation of Cys-590 to glycine is sufficient to polarize MCAM localization. Inhibition of APT1 blocks Wnt5a-induced depalmitoylation, asymmetric MCAM localization, and cell invasion.\",\n      \"method\": \"Site-directed mutagenesis (Cys-590), APT1 inhibitor treatment, palmitoylation assay, immunofluorescence for MCAM localization, invasion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis plus enzymatic inhibition with defined localization and functional readout; single lab\",\n      \"pmids\": [\"25944911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Wnt5a signaling induces APT1 phosphorylation, which increases APT1 depalmitoylating activity and reduces APT1 dimerization. Phosphorylated APT1 promotes depalmitoylation of pro-metastatic cell adhesion molecules CD44 and MCAM, increasing melanoma invasion in vitro.\",\n      \"method\": \"Phosphorylation assay of APT1, depalmitoylation activity assay, dimerization assay, invasion assay, correlation with tumor grade\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — enzymatic activity assay with phosphorylation state manipulation, functional invasion readout, single lab\",\n      \"pmids\": [\"29648538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Wnt5a-induced noncanonical signaling enhances Wnt/beta-catenin signaling during osteoblastogenesis by upregulating expression of co-receptors Lrp5 and Lrp6. Wnt5a knockdown reduces Lrp5/6 expression and impairs osteoblast differentiation while enhancing adipocyte differentiation. Adenovirus-mediated gene transfer of Lrp5 into Wnt5a-deficient osteoblast cells rescues the differentiation phenotype.\",\n      \"method\": \"Conditional Wnt5a knockout (osteoblast-lineage), shRNA knockdown, adenoviral Lrp5 rescue, Tcf/Lef reporter assay, differentiation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with rescue experiment, reporter assays, and defined differentiation phenotype; single lab\",\n      \"pmids\": [\"24670389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Wnt5a regulates AQP2 water channel expression, phosphorylation, and apical membrane trafficking in renal collecting duct cells via calcineurin signaling, independently of the vasopressin/cAMP/PKA pathway. Wnt5a increases apical membrane AQP2 localization and urine osmolality in an NDI mouse model. Calcineurin activator arachidonic acid mimics Wnt5a effects.\",\n      \"method\": \"In vitro Wnt5a stimulation of collecting duct cells, AQP2 phosphorylation and trafficking assays, calcineurin activity assay, cAMP/PKA measurement, NDI mouse model in vivo\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro mechanistic dissection combined with in vivo NDI model, multiple orthogonal methods (phosphorylation, trafficking, cAMP measurement, pharmacological calcineurin manipulation), published in Nature Communications\",\n      \"pmids\": [\"27892464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Wnt5a-Ror2 signaling in osteoclasts activates RhoA, which engages the Rho effector kinase Pkn3. Pkn3 binds to and enhances the activity of c-Src, promoting actin ring formation and bone resorption. Osteoclast-specific Ror2 knockout mice have increased bone mass and impaired actin ring formation and bone resorption, defects rescued by constitutively active RhoA. Pkn3 global knockout mice show similar increased bone mass phenotype.\",\n      \"method\": \"Osteoclast-specific Ror2 conditional knockout mice, Pkn3 global knockout mice, constitutively active RhoA rescue experiment, c-Src kinase activity assay, co-immunoprecipitation (Pkn3-c-Src), actin ring formation assay, bone resorption assay\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo mouse models (conditional KO, global KO), epistasis by RhoA rescue, biochemical co-IP and kinase assay, multiple orthogonal methods\",\n      \"pmids\": [\"28851822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Wnt5a signals through the Ryk receptor to regulate hematopoietic stem cell (HSC) quiescence and hematopoietic repopulation. Ryk inhibition blocks Wnt5a-induced HSC quiescence and suppression of reactive oxygen species (ROS) production, which is a known driver of HSC proliferation.\",\n      \"method\": \"Ryk blocking antibody or dominant-negative Ryk, HSC quiescence assay, ROS measurement, short- and long-term hematopoietic repopulation assay\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor blocking with defined cellular and in vivo repopulation phenotype, ROS mechanistic link, single lab\",\n      \"pmids\": [\"23939973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Wnt5a signals through the Ryk receptor in vascular endothelial cells to activate ROCK, leading to phosphorylation of LIMK2 and inactivation of cofilin-1, resulting in enhanced actin stress fiber formation and increased endothelial permeability. Ryk silencing completely prevents Wnt5a-induced endothelial hyperpermeability. WIF1 (which specifically interferes with the WIF domain of Ryk) prevents actin polymerization.\",\n      \"method\": \"siRNA knockdown of Ryk, trans-endothelial resistance measurement (live), ROCK/LIMK2/cofilin phosphorylation assays, WIF1 antagonist, cytoskeletal live-cell imaging\",\n      \"journal\": \"Cell adhesion & migration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with functional permeability readout, phosphorylation cascade dissection, single lab\",\n      \"pmids\": [\"27159116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Wnt5a induces dormancy of prostate cancer cells in bone via induction of SIAH2 expression, which represses Wnt/beta-catenin signaling. This dormancy effect depends on ROR2, as ROR2 knockdown abolishes Wnt5a-induced dormancy both in vitro and in vivo.\",\n      \"method\": \"ROR2 siRNA knockdown, SIAH2 expression analysis, beta-catenin activity reporter, in vitro dormancy assay, in vivo bone metastasis mouse model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with in vivo bone metastasis model, SIAH2 mechanistic link, single lab\",\n      \"pmids\": [\"30593464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RNF43, an E3 ubiquitin ligase, negatively regulates Wnt5a-induced noncanonical signaling. RNF43 interacts with ROR1, ROR2, VANGL1, and VANGL2. RNF43 triggers VANGL2 ubiquitination and proteasomal degradation and promotes clathrin-dependent internalization of ROR1, and inhibits ROR2 activation. These activities suppress Wnt5a-driven melanoma invasion and resistance to BRAF/MEK inhibitors.\",\n      \"method\": \"BioID proximity labeling, co-immunoprecipitation (RNF43 with ROR1/2/VANGL1/2), ubiquitination assay, proteasome inhibitor rescue, clathrin inhibitor, ROR2 phosphorylation assay, invasion assay, in vivo melanoma model\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — BioID + reciprocal co-IP, ubiquitination/degradation assay, receptor internalization dissection, in vivo model, multiple orthogonal methods in one study\",\n      \"pmids\": [\"34702444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WNT5a signaling through ROR2 activates the Hippo pathway (increased phosphorylation of MST1/2, LATS1, MOB1, and YAP1) to suppress YAP1 activity and tumor growth. Deletion of MST1/2 abrogates the WNT5a response. In ROR2-negative cells, WNT5a suppresses Hippo via increased inhibitory phosphorylation of NF2/Merlin. YAP1 activity also stimulates ROR2 and WNT5a expression, forming a negative feedback loop.\",\n      \"method\": \"WNT5a/Foxy5 treatment, MST1/2 deletion, ROR2 expression/knockdown, phosphorylation of Hippo components by Western blot, prostate cancer organoid and xenograft models, correlation with clinical datasets\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic deletion (MST1/2) and receptor manipulation with in vivo organoid/xenograft models, multiple phosphorylation readouts, single lab\",\n      \"pmids\": [\"36622276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In melanoma cells, Wnt5a activates the NF-κB pathway through ROR1, Dvl2, and Akt (Wnt5a pathway) and TRAF2 and RIP (NF-κB pathway). Wnt5a induces IKK phosphorylation, IκB degradation, p65 phosphorylation, and p65 nuclear translocation. An autocrine Wnt5a loop is a major regulator of NF-κB and cytokine/chemokine secretion (IL-6, IL-8, IL-11, MCP-1, TNF-sRI) in melanoma.\",\n      \"method\": \"cDNA overexpression, RNA interference, dominant-negative mutants, NF-κB reporter assay, IκB/IKK phosphorylation Western blot, p65 nuclear translocation imaging, cytokine ELISA, endogenous Wnt5a inhibition\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with dominant-negative mutants, reporter assays, multiple pathway components dissected; single lab\",\n      \"pmids\": [\"31510045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Wnt5a activates Daam1, which in turn activates RhoA to promote stress fiber formation and glioblastoma cell invasion. siRNA targeting Daam1 inhibits Wnt5a-induced RhoA activation, stress fiber formation, and invasion. The Wnt5a antagonist sFRP2 blocks Wnt5a-induced Daam1 and RhoA activation and invasion.\",\n      \"method\": \"Daam1 pull-down activation assay, RhoA activation assay, siRNA knockdown of Daam1, RhoA inhibitor (CCG-1423), sFRP2 Wnt5a antagonist, invasion assay\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Daam1 and RhoA activation assays with siRNA and pharmacological dissection, functional invasion readout; single lab\",\n      \"pmids\": [\"29207169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Wnt5a promotes invasion of esophageal squamous cell carcinoma cells via ROR1 and ROR2 receptors through DAAM1/RhoA signaling. ROR1 and ROR2 associate with each other. Downstream of ROR1/ROR2, DAAM1 activates RhoA (not Rac1/Rac2), and RhoA promotes actin filament reorganization and invasion. DAAM1 shRNA inhibits RhoA activation, which is rescued by wild-type DAAM1 overexpression.\",\n      \"method\": \"Co-immunoprecipitation (ROR1-ROR2), DAAM1 activity pull-down, RhoA/Rac activation assay, shRNA knockdown, wild-type DAAM1 rescue, RhoA inhibitor CCG-1423, invasion assay, phalloidin actin staining\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of receptor complex, activation assays, rescue experiment, functional invasion readout; single lab\",\n      \"pmids\": [\"31114334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Wnt5a inhibits hepatocyte proliferation and concludes beta-catenin signaling during liver regeneration via the Wnt5a/Frizzled-2 axis. Treatment of primary hepatocytes with Wnt5a decreases beta-catenin-TCF4 activity and cyclin-D1 expression and reduces proliferation. Liver-specific Wntless knockout (impairing Wnt secretion) reduces Wnt5a secretion and prolongs hepatocyte proliferation with increased beta-catenin/TCF4 interaction.\",\n      \"method\": \"Liver-specific Wntless knockout mice, partial hepatectomy model, Wnt5a treatment of primary hepatocytes, beta-catenin/TCF4 co-immunoprecipitation, cyclin-D1 Western blot, BrdU proliferation assay\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional knockout model combined with in vitro primary cell treatment, co-IP for mechanistic complex; single lab\",\n      \"pmids\": [\"26100214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Wnt5a promotes lysosomal cholesterol egress by binding to NPC1 and NPC2 lysosomal cholesterol transporters, increasing lysosomal acid lipase expression, and decreasing mTORC1 signaling. Loss of Wnt5a in vascular smooth muscle cells (CRISPR/Cas9 or conditional knockout) disrupts lysosomal function, decreases cholesterol in the endoplasmic reticulum, and promotes atherosclerosis.\",\n      \"method\": \"Conditional Wnt5a knockout in vascular smooth muscle cells (mouse), CRISPR/Cas9 Wnt5a knockout in human cells, NPC1/NPC2 binding assay, lysosomal acid lipase expression, mTORC1 activity assay, cholesterol trafficking assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse conditional KO, human cell CRISPR KO, direct binding to NPC1/NPC2, multiple mechanistic readouts, two independent genetic models\",\n      \"pmids\": [\"34886684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"High-salt diet increases vascular Wnt5a expression, which is required for Ang II-induced RhoA/ROCK activation (measured by p-MYPT1). In cultured vascular smooth muscle cells, siRNA knockdown of Wnt5a abolishes Ang II-induced p-MYPT1 upregulation. Klotho supplementation inhibits Wnt5a- and Ang II-induced p-MYPT1. Wnt5a antagonist Box5 and Wnt inhibitor LGK974 reduce salt-induced hypertension similarly to ROCK inhibitor fasudil.\",\n      \"method\": \"Wnt5a siRNA in VSMCs, pharmacological Wnt5a antagonist Box5, Klotho supplementation, p-MYPT1 as RhoA/ROCK activity readout, blood pressure measurement, renal blood flow assay, Klotho-knockout and aged mouse models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA in vitro combined with pharmacological inhibition and in vivo mouse models; mechanistic link between Wnt5a and RhoA/ROCK established; single lab\",\n      \"pmids\": [\"32597829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STAT3 transcriptionally activates Wnt5a in CLL cells by directly binding to the Wnt5a gene promoter. ChIP and EMSA confirmed STAT3 binding to four putative STAT3 binding sites near the Wnt5a promoter. STAT3 shRNA reduces Wnt5a mRNA and protein levels, and Wnt5a siRNA increases spontaneous apoptosis of CLL cells.\",\n      \"method\": \"ChIP of STAT3 at Wnt5a promoter, EMSA, luciferase reporter assay, STAT3 shRNA, Wnt5a siRNA, apoptosis assay, flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + EMSA + reporter assay for STAT3-Wnt5a transcriptional relationship, functional siRNA validation; single lab\",\n      \"pmids\": [\"31645416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRMT2 mediates H3R8 asymmetric dimethylation (H3R8me2a) at the WNT5A promoter to enhance WNT5A transcriptional expression, leading to activation of Wnt signaling and promotion of RCC cell proliferation and motility. ChIP confirmed H3R8me2a enrichment at the WNT5A promoter by PRMT2.\",\n      \"method\": \"ChIP for H3R8me2a at WNT5A promoter, PRMT2 overexpression and knockdown, in vitro proliferation and motility assays, in vivo xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with specific histone mark, gain- and loss-of-function with defined phenotype; single lab\",\n      \"pmids\": [\"37173306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Wnt5a transcription in chondrocytes is activated by transcription factors Trps1 and Gli3A (activator form). ChIP and reporter gene assays identified two upstream regulatory sequences (URS) in the Wnt5a promoter; URS1 is bound by Trps1 and Gli3A in vitro and in vivo. Loss of both transcription factors decreases endogenous Wnt5a mRNA and protein levels during chondrocyte differentiation.\",\n      \"method\": \"ChIP of Trps1 and Gli3A at Wnt5a promoter URS1, reporter gene assay, Trps1/Gli3 mutant mouse models (double mutants), qRT-PCR and Western blot of Wnt5a\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP in vitro and in vivo, reporter assay, genetic mouse model loss-of-function; single lab\",\n      \"pmids\": [\"31550480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In PGC1alpha-silenced melanoma, TCF12 is activated and increases WNT5A expression. WNT5A in turn stabilizes YAP protein levels to promote melanoma migration and metastasis. Inhibition of TCF12, WNT5A, or YAP individually blocks melanoma migration in vitro and metastasis in vivo.\",\n      \"method\": \"EZH2 inhibitor (H3K27me3 removal), TCF12 knockdown/overexpression, WNT5A inhibition, YAP inhibition, in vitro migration assay, in vivo metastasis assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic dissection (TCF12→WNT5A→YAP) with loss-of-function at each step, in vivo metastasis validation; single lab\",\n      \"pmids\": [\"31929186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In HIV gp120-induced pain, neurons secrete Wnt5a which signals to astrocytes via ROR2 to induce astrogliosis. Conditional knockout of Wnt5a in neurons or ROR2 in astrocytes abolishes gp120-induced astrogliosis, mechanical hyperalgesia, and neural circuit polarization. Astrogliosis promotes hyperalgesia via IL-1beta regulated by a Wnt5a-ROR2-MMP2 axis.\",\n      \"method\": \"Conditional knockout of Wnt5a in neurons and ROR2 in astrocytes, gp120 mouse pain model, IL-1beta measurement, MMP2 inhibition, mechanical hyperalgesia testing\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific conditional knockouts establishing intercellular Wnt5a/ROR2 signaling axis in vivo, MMP2/IL-1beta mechanistic link; single lab\",\n      \"pmids\": [\"35040478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In the fourth ventricle choroid plexus, WNT5A is expressed by Foxj1-positive epithelial cells at villous tips and acts locally to activate non-canonical Wnt signaling via ROR1 and ROR2 receptors. Conditional Wnt5a deletion in these epithelial cells impairs branched villous morphology. MEIS1 transcription factor binds the proximal Wnt5a promoter and regulates Wnt5a expression in 4V ChP development.\",\n      \"method\": \"Conditional Wnt5a knockout (Foxj1-Cre), systemic Wnt5a knockout and overexpression, ChIP of MEIS1 at Wnt5a promoter, MEIS gain/loss-of-function, immunofluorescence for ROR1/ROR2 activation\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with morphological readout, ChIP for upstream regulator, receptor identification; single lab\",\n      \"pmids\": [\"34032267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Conditional Wnt5a loss-of-function (Wnt5aCAG) during saccular/alveolar lung development reveals that Wnt5a is required for myofibroblast differentiation and migration but not endothelial or epithelial differentiation in alveologenesis. Conditional inactivation of both Ror1 and Ror2 in alveolar myofibroblasts recapitulates the Wnt5aCAG phenotype, demonstrating that myofibroblast defects are the primary cause of arrested alveologenesis downstream of Wnt5a.\",\n      \"method\": \"Conditional Wnt5a knockout (Wnt5aCAG), conditional Ror1/Ror2 double knockout in myofibroblasts, histological and immunofluorescence analysis, in vitro isolated lung fibroblast assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple conditional KO models with epistatic receptor dissection in vivo; in vitro validation; single lab\",\n      \"pmids\": [\"32046118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Microglial WNT5A is the most abundant Wnt expressed in microglia and promotes neuronal spine maturation. Co-culture of microglia with neurons increases spine density and reduces turnover; silencing microglial Wnt5a diminishes these effects. Microglial Wnt5a knockdown reduces PSD95 levels, synaptic density, and neuronal firing rate.\",\n      \"method\": \"shRNA silencing of Wnt5a in microglia, co-culture with Thy1-YFP+ neurons, dendritic spine imaging (density, turnover), PSD95/VGLUT2 co-localization, multi-electrode array neuronal firing\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function knockdown with multiple synaptic readouts, in vitro co-culture system; single lab\",\n      \"pmids\": [\"36395958\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WNT5A is a secreted glycoprotein that signals primarily through non-canonical pathways in a receptor-context-dependent manner: binding to ROR2 (inducing homodimerization, tyrosine phosphorylation via GSK-3, and downstream RhoA/JNK/PKD/Hippo activation), to ROR1/ROR2 heterooligomers (recruiting GEFs to activate Rac1/RhoA), to Frizzled receptors (activating PKC, JNK, ERK, or Ca2+/calcineurin depending on cell type), to the Ryk receptor (regulating HSC quiescence via ROS suppression and endothelial permeability via ROCK/LIMK2/cofilin), and to CD146 (activating Dvl/JNK for cell migration); it can also activate canonical beta-catenin signaling through Frizzled 4, or inhibit it through CD146-mediated beta-catenin degradation and DVL1-driven suppression of rDNA transcription, with transcriptional regulation of WNT5A itself provided by STAT3, PRMT2/H3R8me2a, Trps1/Gli3A, MEIS1, FOXE1, and TCF12/PGC1alpha-epigenetic axis, and with its activity negatively regulated by RNF43-mediated ubiquitination and receptor internalization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WNT5A is a secreted Wnt ligand that signals predominantly through non-canonical pathways whose output is dictated by receptor context, controlling cell polarity, directional migration, tissue morphogenesis, and metabolic homeostasis [#0, #4]. Purified WNT5A inhibits Wnt3a-driven canonical β-catenin signaling through the orphan receptor tyrosine kinase ROR2 without altering β-catenin levels, yet in the presence of Frizzled-4 the same ligand activates β-catenin signaling, establishing that receptor availability determines whether WNT5A is canonical or non-canonical [#0]. A central effector arm runs through ROR2: WNT5A induces ROR2 homodimerization and its tyrosine and GSK-3-dependent serine/threonine phosphorylation [#2, #3], and downstream of ROR2 engages DAAM1/RhoA, PKD/JNK, and Hippo-pathway kinases (MST1/2, LATS1, YAP1) to drive actin reorganization, invasion, and growth control [#21, #6, #19]. WNT5A also signals through ROR1/ROR2 heterooligomers that recruit GEFs to activate Rac1 and RhoA [#8], through CD146/Dvl2 to activate JNK for migration and convergent extension [#7], through Frizzled receptors to engage PKC and calcineurin [#2, #13], and through the Ryk receptor to control HSC quiescence via ROS suppression and endothelial permeability via ROCK/LIMK2/cofilin [#15, #16]. In melanoma WNT5A organizes a polarized receptor-actin-myosin (W-RAMP) structure dependent on endosomal trafficking and Rab4/RhoB, and promotes invasion by stimulating APT1-mediated depalmitoylation of MCAM and CD44 [#4, #10, #11]. Beyond migration, WNT5A directs osteoblast and osteoclast biology, alveolar myofibroblast differentiation, choroid plexus and chondrocyte morphogenesis, AQP2-dependent renal water handling, lysosomal cholesterol egress via NPC1/NPC2, and microglial control of neuronal spine maturation [#14, #32, #31, #13, #24, #33]. WNT5A transcription is driven by STAT3, PRMT2-deposited H3R8me2a, Trps1/Gli3A, MEIS1, and a TCF12/PGC1α axis [#26, #27, #28, #31, #29], and its signaling is restrained by the E3 ubiquitin ligase RNF43, which degrades VANGL2 and internalizes ROR1 to dampen non-canonical output [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that WNT5A drives an invasive, non-canonical program independent of β-catenin, defining its role in melanoma motility.\",\n      \"evidence\": \"WNT5A overexpression with anti-Frizzled-5 antibody blocking, PKC activity and invasion assays in melanoma cells\",\n      \"pmids\": [\"12086864\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve the receptor complex composition upstream of PKC\", \"Single cell type\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed that receptor context, not the ligand alone, determines whether WNT5A inhibits or activates canonical signaling, resolving conflicting reports about its directionality.\",\n      \"evidence\": \"Purified homogeneous WNT5A protein, dose-response reporter assays, ROR2 functional block and Frizzled-4 co-expression\",\n      \"pmids\": [\"16602827\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ROR2 inhibits canonical signaling without changing β-catenin levels not fully defined\", \"Performed in reporter cell systems\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified GSK-3 as a kinase phosphorylating ROR2 downstream of WNT5A, linking ligand engagement to receptor activation and migration.\",\n      \"evidence\": \"In vitro kinase assay with purified GSK-3 on immunoprecipitated ROR2, siRNA and pharmacological inhibition, migration assay\",\n      \"pmids\": [\"17986005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of specific phosphosites on ROR2 not mapped\", \"Connection to tyrosine phosphorylation arm unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that WNT5A specifically induces ROR2 homodimerization and tyrosine phosphorylation (which Wnt3a cannot), and linked this to osteoblast differentiation.\",\n      \"evidence\": \"Co-IP, tyrosine phosphorylation and 14-3-3β assays, ROR2 siRNA, MSC differentiation and bone explant culture\",\n      \"pmids\": [\"18615587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase responsible for ROR2 tyrosine phosphorylation not identified\", \"Role of 14-3-3β in downstream signaling unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed that WNT5A organizes a polarized receptor-actin-myosin (W-RAMP) structure coupling endosomal trafficking to directional migration and nuclear movement.\",\n      \"evidence\": \"Live imaging, dominant-negative Rab4/RhoB, chemokine gradient and endosome trafficking analysis in melanoma\",\n      \"pmids\": [\"18420933\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger for asymmetric W-RAMP accumulation not defined\", \"Relationship to ROR2 signaling arm unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established ROR2 as required for WNT5A-driven melanoma metastasis and described receptor internalization as a feature of active signaling.\",\n      \"evidence\": \"ROR2 siRNA, PKC and clathrin inhibitors, in vitro/in vivo metastasis assays, tissue microarrays\",\n      \"pmids\": [\"19802008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether internalization is required for or terminates signaling not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected WNT5A-Frizzled2/ROR2 signaling to a PKD-JNK-JunD transcriptional cascade inducing MMP-1 and prostate cancer invasion.\",\n      \"evidence\": \"WNT5A knockdown/overexpression, PKD inhibitor, ChIP for JunD at MMP-1 promoter, invasion assay\",\n      \"pmids\": [\"20101234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link between PKD and JunD recruitment not established\", \"Single cancer type\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified CD146 as a high-affinity WNT5A receptor that activates Dvl2/JNK for migration while also degrading β-catenin, extending WNT5A's receptor repertoire.\",\n      \"evidence\": \"Binding affinity, CD146-Dvl2 co-IP, domain mutagenesis, JNK and migration assays, zebrafish convergent extension\",\n      \"pmids\": [\"24335906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CD146 coordinates with ROR/Frizzled receptors not addressed\", \"Mechanism of β-catenin degradation via CD146 not fully detailed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed WNT5A non-canonical signaling can amplify canonical signaling by upregulating LRP5/6 co-receptors during osteoblastogenesis, revealing pathway crosstalk.\",\n      \"evidence\": \"Conditional Wnt5a knockout, shRNA, adenoviral Lrp5 rescue, Tcf/Lef reporter and differentiation assays\",\n      \"pmids\": [\"24670389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking non-canonical signaling to LRP5/6 transcription unknown\", \"Single lineage context\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a nuclear role for WNT5A through DVL1, repressing RNA Pol I rDNA transcription via SIRT7 displacement, an unexpected non-membrane output.\",\n      \"evidence\": \"DVL1 ChIP at rDNA, co-IP, Pol I transcription and SIRT7 displacement assays, DVL1-specific siRNA\",\n      \"pmids\": [\"27500936\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How WNT5A signaling routes to nucleolar DVL1 unknown\", \"Receptor mediating this output not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified APT1-mediated MCAM depalmitoylation at Cys-590 as the mechanism polarizing adhesion molecules during WNT5A-driven invasion.\",\n      \"evidence\": \"Cys-590 mutagenesis, APT1 inhibitor, palmitoylation and localization assays, invasion assay\",\n      \"pmids\": [\"25944911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How WNT5A signaling activates APT1 not resolved here\", \"Single melanoma context\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated WNT5A/Frizzled-2 terminates β-catenin signaling to limit hepatocyte proliferation, defining its role in concluding liver regeneration.\",\n      \"evidence\": \"Liver-specific Wntless knockout, partial hepatectomy, WNT5A treatment of hepatocytes, β-catenin/TCF4 co-IP, BrdU assay\",\n      \"pmids\": [\"26100214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor-proximal events linking Frizzled-2 to reduced TCF4 activity not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved the molecular basis of WNT5A-induced ROR1/ROR2 heterooligomerization and GEF recruitment activating Rac1/RhoA in CLL.\",\n      \"evidence\": \"Reciprocal co-IP, domain mapping, ROR1/ROR2 siRNA, Rac1/RhoA assays, in vivo engraftment mouse models\",\n      \"pmids\": [\"26690702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the specific GEFs recruited not fully defined\", \"Stoichiometry of heterooligomer unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established Ryk as a WNT5A receptor controlling HSC quiescence through ROS suppression, extending non-canonical signaling to stem cell maintenance.\",\n      \"evidence\": \"Ryk blocking antibody/dominant-negative, HSC quiescence and ROS assays, hematopoietic repopulation assay\",\n      \"pmids\": [\"23939973\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intracellular signaling from Ryk to ROS machinery not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a WNT5A-Ryk-ROCK-LIMK2-cofilin cascade governing endothelial actin stress fibers and vascular permeability.\",\n      \"evidence\": \"Ryk siRNA, trans-endothelial resistance, ROCK/LIMK2/cofilin phosphorylation, WIF1 antagonist, live imaging\",\n      \"pmids\": [\"27159116\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How Ryk couples to ROCK not biochemically defined\", \"Single endothelial system\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed WNT5A regulates AQP2 trafficking and renal water handling via calcineurin, independent of the vasopressin/cAMP/PKA pathway.\",\n      \"evidence\": \"Collecting duct cell stimulation, AQP2 phosphorylation/trafficking, calcineurin and cAMP/PKA assays, NDI mouse model\",\n      \"pmids\": [\"27892464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating renal WNT5A-calcineurin signaling not identified\", \"Link to the broader PCP machinery unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a WNT5A-ROR2-RhoA-Pkn3-c-Src axis driving osteoclast actin ring formation and bone resorption in vivo.\",\n      \"evidence\": \"Osteoclast-specific Ror2 and global Pkn3 knockout mice, constitutively active RhoA rescue, Pkn3-c-Src co-IP and c-Src activity assay\",\n      \"pmids\": [\"28851822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Pkn3 enhances c-Src activity mechanistically not fully defined\", \"Cross-talk with osteoblast WNT5A signaling not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified DAAM1 as the effector linking WNT5A to RhoA activation and stress fiber formation in glioblastoma invasion.\",\n      \"evidence\": \"Daam1 pull-down activation assay, RhoA assay, Daam1 siRNA, RhoA inhibitor, sFRP2 antagonist, invasion assay\",\n      \"pmids\": [\"29207169\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor upstream of DAAM1 in glioblastoma not specified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed WNT5A induces APT1 phosphorylation that increases its depalmitoylating activity toward CD44 and MCAM, mechanistically linking signaling to enzyme activation.\",\n      \"evidence\": \"APT1 phosphorylation, depalmitoylation activity and dimerization assays, invasion assay, tumor grade correlation\",\n      \"pmids\": [\"29648538\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase phosphorylating APT1 downstream of WNT5A not identified\", \"Single melanoma context\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established that WNT5A-ROR2 can induce dormancy of prostate cancer in bone via SIAH2-mediated repression of β-catenin signaling.\",\n      \"evidence\": \"ROR2 siRNA, SIAH2 expression, β-catenin reporter, in vitro dormancy and in vivo bone metastasis models\",\n      \"pmids\": [\"30593464\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ROR2 induces SIAH2 expression not defined\", \"Reconciliation with WNT5A's pro-invasive roles elsewhere\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked an autocrine WNT5A-ROR1-Dvl2-Akt loop to NF-κB activation and cytokine secretion in melanoma.\",\n      \"evidence\": \"Overexpression, RNAi, dominant-negative mutants, NF-κB reporter, IκB/IKK/p65 Western blots, cytokine ELISA\",\n      \"pmids\": [\"31510045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct connection between Akt and TRAF2/RIP not biochemically established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed WNT5A drives ESCC invasion through ROR1/ROR2-DAAM1-RhoA, confirming receptor-complex usage of the DAAM1 arm.\",\n      \"evidence\": \"ROR1-ROR2 co-IP, DAAM1 pull-down, RhoA/Rac assays, shRNA with WT DAAM1 rescue, invasion and actin staining\",\n      \"pmids\": [\"31114334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity for RhoA over Rac not mechanistically explained\", \"Single cancer type\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified STAT3 as a direct transcriptional activator of WNT5A in CLL, defining an upstream regulatory input for survival signaling.\",\n      \"evidence\": \"STAT3 ChIP at WNT5A promoter, EMSA, luciferase reporter, STAT3 shRNA, WNT5A siRNA apoptosis assay\",\n      \"pmids\": [\"31645416\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STAT3 cooperates with other factors at the promoter unknown\", \"Single disease context\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed Trps1 and Gli3A activate WNT5A transcription during chondrocyte differentiation via defined promoter elements.\",\n      \"evidence\": \"Trps1/Gli3A ChIP at URS1, reporter assays, double-mutant mouse models, WNT5A qRT-PCR/Western\",\n      \"pmids\": [\"31550480\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Combinatorial logic between Trps1 and Gli3A not resolved\", \"Tissue-specific to chondrocytes\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined WNT5A as a regulator of lysosomal cholesterol egress through NPC1/NPC2 binding and mTORC1 suppression, protecting against atherosclerosis.\",\n      \"evidence\": \"VSMC conditional and CRISPR Wnt5a knockout, NPC1/NPC2 binding, lysosomal acid lipase and mTORC1 assays, cholesterol trafficking\",\n      \"pmids\": [\"34886684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NPC1/NPC2 binding is direct ligand-receptor or intracellular not fully resolved\", \"Receptor mediating this metabolic effect unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked vascular WNT5A to Ang II-induced RhoA/ROCK activation in salt-sensitive hypertension, identifying a therapeutically targetable signaling node.\",\n      \"evidence\": \"Wnt5a siRNA in VSMCs, Box5 and LGK974 antagonists, Klotho supplementation, p-MYPT1 readout, blood pressure in mouse models\",\n      \"pmids\": [\"32597829\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor coupling WNT5A to RhoA/ROCK in VSMCs not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established a PGC1α-loss/TCF12/WNT5A/YAP axis driving melanoma metastasis, embedding WNT5A in an epigenetic-transcriptional circuit.\",\n      \"evidence\": \"EZH2 inhibitor, TCF12 knockdown/overexpression, WNT5A and YAP inhibition, in vitro migration and in vivo metastasis\",\n      \"pmids\": [\"31929186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which WNT5A stabilizes YAP not defined here\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed WNT5A is required cell-autonomously in alveolar myofibroblasts via ROR1/ROR2 for alveologenesis, dissecting its developmental requirement by lineage.\",\n      \"evidence\": \"Conditional Wnt5a and Ror1/Ror2 double knockouts, histology/immunofluorescence, isolated fibroblast assays\",\n      \"pmids\": [\"32046118\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors in myofibroblast differentiation not identified\", \"Single developmental window\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established RNF43 as a negative regulator of WNT5A non-canonical signaling through VANGL2 degradation and ROR1 internalization, defining a brake on the pathway.\",\n      \"evidence\": \"BioID, reciprocal co-IP with ROR1/2 and VANGL1/2, ubiquitination/degradation assays, internalization dissection, in vivo melanoma model\",\n      \"pmids\": [\"34702444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RNF43 selectively distinguishes among receptor substrates unknown\", \"Regulation of RNF43 activity itself not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed WNT5A is locally expressed in Foxj1+ choroid plexus epithelium under MEIS1 control and shapes villous morphology via ROR1/ROR2.\",\n      \"evidence\": \"Foxj1-Cre conditional knockout, systemic knockout/overexpression, MEIS1 ChIP at promoter, ROR1/ROR2 activation immunofluorescence\",\n      \"pmids\": [\"34032267\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream non-canonical effectors in villous branching not defined\", \"Single developmental structure\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a neuron-to-astrocyte WNT5A-ROR2-MMP2-IL-1β axis driving astrogliosis and pain in HIV gp120 models, establishing intercellular WNT5A signaling.\",\n      \"evidence\": \"Cell-type-specific conditional Wnt5a (neuron) and Ror2 (astrocyte) knockouts, gp120 pain model, IL-1β/MMP2 manipulation, hyperalgesia testing\",\n      \"pmids\": [\"35040478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ROR2 induces MMP2/IL-1β in astrocytes not mechanistically detailed\", \"Specific to the gp120 model\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified microglial WNT5A as a regulator of neuronal spine maturation and synaptic function, broadening WNT5A's CNS roles.\",\n      \"evidence\": \"Microglial Wnt5a shRNA, microglia-neuron co-culture, spine imaging, PSD95/VGLUT2 colocalization, multi-electrode array\",\n      \"pmids\": [\"36395958\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Neuronal receptor mediating microglial WNT5A effect not identified\", \"In vitro co-culture only\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed WNT5A-ROR2 engages the Hippo pathway to suppress YAP1 and tumor growth, with a YAP1-WNT5A feedback loop, integrating WNT5A into growth-control signaling.\",\n      \"evidence\": \"WNT5a/Foxy5 treatment, MST1/2 deletion, ROR2 manipulation, Hippo component phosphorylation, prostate organoid/xenograft models\",\n      \"pmids\": [\"36622276\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent opposite WNT5A-YAP relationship versus melanoma reports unreconciled\", \"Direct link between ROR2 and MST1/2 not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified PRMT2-deposited H3R8me2a as an epigenetic activator of WNT5A transcription promoting renal cell carcinoma growth.\",\n      \"evidence\": \"ChIP for H3R8me2a at WNT5A promoter, PRMT2 gain/loss-of-function, proliferation/motility assays, xenograft model\",\n      \"pmids\": [\"37173306\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How PRMT2 is targeted to the WNT5A locus unknown\", \"Single cancer context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single secreted WNT5A ligand is partitioned among its many receptors (ROR1, ROR2, Frizzled, Ryk, CD146) to produce opposite outputs in different tissues, and what governs the switch between canonical-inhibitory, non-canonical-migratory, and metabolic functions, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of receptor selection in a given cell type\", \"Structural basis of context-dependent receptor binding not determined\", \"Reconciliation of opposing YAP/β-catenin effects across tissues\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 2, 7, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 18, 23]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 8, 7, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 24]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 8, 7, 19]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [14, 31, 32, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 24, 25, 30]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [24, 13]}\n    ],\n    \"complexes\": [\n      \"ROR1/ROR2 heterooligomer\",\n      \"ROR2 homodimer\",\n      \"W-RAMP receptor-actin-myosin structure\"\n    ],\n    \"partners\": [\n      \"ROR2\",\n      \"ROR1\",\n      \"FZD4\",\n      \"FZD2\",\n      \"CD146\",\n      \"RYK\",\n      \"RNF43\",\n      \"NPC1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}