{"gene":"WNT5A","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2002,"finding":"WNT5A overexpression in melanoma cells causes actin reorganization, increased cell adhesion, and increased PKC activation without increasing β-catenin expression or nuclear translocation; blocking the WNT5A receptor Frizzled-5 inhibited PKC activity and cellular invasion, placing WNT5A upstream of PKC in a non-canonical pathway driving melanoma invasiveness.","method":"Constitutive overexpression of WNT5A in melanoma cell lines, antibody blocking of Frizzled-5, PKC activity assays, invasion assays","journal":"Cancer Cell","confidence":"High","confidence_rationale":"Tier 2 — gain-of-function + receptor blocking + biochemical readout, replicated across multiple melanoma lines","pmids":["12086864"],"is_preprint":false},{"year":2009,"finding":"ROR2 requires tyrosine kinase activity to mediate WNT5A signaling; mutation/deletion analysis showed that specific domains and residues in ROR2, including those necessary for kinase activity, are required for WNT5A-mediated inhibition of canonical Wnt/β-catenin signaling; Ror2-null mice show increased Axin2(LacZ) reporter activity, confirming Ror2 inhibits canonical Wnt signaling in vivo.","method":"Deletion and point mutagenesis of ROR2 domains, β-catenin reporter assays, Ror2 knockout mice with Axin2(LacZ) reporter","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis + in vivo genetic validation with reporter","pmids":["19720827"],"is_preprint":false},{"year":2009,"finding":"ROR2 is a receptor for WNT5A in melanoma; WNT5A increases ROR2 expression and induces PKC-dependent, clathrin-mediated internalization of ROR2; siRNA knockdown of WNT5A decreases ROR2 expression, while ROR2 knockdown decreases downstream WNT5A signaling and inhibits WNT5A-mediated melanoma metastasis in vitro and in vivo.","method":"siRNA knockdown, in vitro and in vivo metastasis assays, tissue microarray, receptor internalization studies","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — reciprocal knockdown experiments + in vivo validation, multiple orthogonal methods","pmids":["19802008"],"is_preprint":false},{"year":2008,"finding":"WNT5A controls cell polarity and directional movement in melanoma by recruiting actin, myosin IIB, Frizzled 3, and melanoma cell adhesion molecule (MCAM) into a Wnt-mediated receptor-actin-myosin polarity (W-RAMP) intracellular structure; this process requires endosome trafficking associated with multivesicular bodies and is regulated by WNT5A through small GTPases Rab4 and RhoB.","method":"Live cell imaging, fluorescence microscopy, dominant-negative GTPases, endosome trafficking inhibitors, chemokine gradient assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal imaging and genetic approaches in single study, mechanistic resolution of pathway components","pmids":["18420933"],"is_preprint":false},{"year":2010,"finding":"WNT5A promotes prostate cancer invasion through Frizzled2 and ROR2 as receptors, activating JNK via protein kinase D (PKD); PKD inhibition suppressed WNT5A-dependent cell migration and invasion; WNT5A induced metalloproteinase-1 (MMP-1) expression through recruitment of JunD to its promoter.","method":"Knockdown and overexpression of WNT5A, PKD inhibitors, JNK signaling assays, ChIP for JunD at MMP-1 promoter, invasion assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP + pharmacological inhibition + gain/loss of function with defined mechanistic pathway","pmids":["20101234"],"is_preprint":false},{"year":2012,"finding":"WNT5A expressed by osteoblast-lineage cells signals through ROR2 expressed on osteoclast precursors to enhance osteoclastogenesis; WNT5A-ROR2 activates JNK and recruits c-Jun to the RANK gene promoter, increasing RANK expression and thus sensitizing precursors to RANKL-induced osteoclastogenesis; mice deficient in either Wnt5a or Ror2 show impaired osteoclastogenesis.","method":"Cell-type-specific conditional knockouts, JNK activation assays, ChIP for c-Jun at RANK promoter, osteoclast differentiation assays, arthritis mouse models","journal":"Nature Medicine","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP + conditional KO mice + multiple cell type-specific genetic models, replicated in vivo","pmids":["22344299"],"is_preprint":false},{"year":2003,"finding":"WNT5A signals through the noncanonical Wnt/Ca2+ pathway to suppress cyclin D1 expression and negatively regulate B cell proliferation; Wnt5a hemizygous mice develop myeloid leukemias and B cell lymphomas with loss of Wnt5a function in tumor tissues, identifying Wnt5a as a tumor suppressor in hematopoietic tissue.","method":"Wnt5a knockout/hemizygous mice, cell proliferation assays, cyclin D1 western blot, Ca2+ pathway signaling assays","journal":"Cancer Cell","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic mouse model + biochemical pathway placement","pmids":["14667502"],"is_preprint":false},{"year":2016,"finding":"WNT5A induces ROR1 to oligomerize with ROR2, which recruits guanine exchange factors (GEFs) that activate Rac1 and RhoA to promote CLL cell proliferation and chemokine-directed migration; the extracellular Kringle domain is required for ROR1/ROR2 heterooligomerization, and the cysteine-rich domain or intracellular proline-rich domain is required for GEF recruitment.","method":"Co-immunoprecipitation, ectopic expression of ROR1/ROR2 mutants, GEF recruitment assays, Rac1/RhoA activation assays, in vivo engraftment in immune-deficient mice","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 1-2 — domain mutagenesis + Co-IP + in vivo validation + multiple orthogonal methods","pmids":["26690702"],"is_preprint":false},{"year":2017,"finding":"WNT5A signaling through ROR2 promotes bone resorption by activating RhoA (a small GTPase); Rho effector kinase PKN3 then binds to and enhances c-Src activity, which is critical for actin ring formation in osteoclasts; osteoclast-specific Ror2-deficient mice and global Pkn3-deficient mice both show increased bone mass and impaired bone resorption.","method":"Conditional and global knockout mice, co-immunoprecipitation of PKN3 with c-Src, kinase activity assays, actin ring formation assays, constitutively active RhoA rescue experiments","journal":"Science Signaling","confidence":"High","confidence_rationale":"Tier 1-2 — multiple KO models + biochemical pathway reconstitution + domain analysis + rescue experiments","pmids":["28851822"],"is_preprint":false},{"year":2016,"finding":"WNT5A causes ROR1 to complex with and phosphorylate cortactin at Y421; phosphorylated cortactin recruits ARHGEF1 and activates RhoA, enhancing CLL cell migration; the proline-rich domain of ROR1, specifically position P841, is required for cortactin binding and subsequent F-actin polymerization.","method":"Co-immunoprecipitation, ROR1 domain mutagenesis (single amino acid substitutions), cortactin phosphorylation assays, F-actin polymerization assays, migration assays","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 1-2 — precise mutagenesis + Co-IP + biochemical signaling assays identifying specific residue","pmids":["30568170"],"is_preprint":false},{"year":2018,"finding":"WNT5A signaling results in APT1 (acyl protein thioesterase 1) phosphorylation which increases APT1 depalmitoylating activity and reduces APT1 dimerization; APT1-mediated depalmitoylation of CD44 and MCAM promotes melanoma invasion.","method":"Phosphorylation assays, depalmitoylation activity assays, dimerization assays, in vitro invasion assays, phospho-specific analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical enzyme activity assays + multiple mechanistic readouts in single study","pmids":["29648538"],"is_preprint":false},{"year":2016,"finding":"WNT5A signals through Dishevelled1 (DVL1) to suppress rDNA transcription by RNA Polymerase I in breast cancer cells; DVL1 accumulates at nucleolar organizer regions (NORs) and binds rDNA, causing SIRT7 to release from rDNA loci and disassembly of Pol I transcription machinery at the rDNA promoter.","method":"ChIP, co-immunoprecipitation, rDNA transcription assays, DVL1 nuclear localization imaging, siRNA knockdown","journal":"PLoS Genetics","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP + nuclear fractionation + transcription assays + genetic validation","pmids":["27500936"],"is_preprint":false},{"year":2016,"finding":"WNT5A induces renal AQP2 expression, phosphorylation, and apical membrane trafficking via calcineurin signaling, bypassing the vasopressin/cAMP/PKA pathway; this WNT5A-calcineurin axis increases urine osmolality in a nephrogenic diabetes insipidus (NDI) mouse model.","method":"AQP2 phosphorylation and trafficking assays, calcineurin inhibitor experiments, urine osmolality measurement in NDI mouse model, in vitro cell assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — in vivo NDI model + multiple mechanistic assays + specific pathway inhibition","pmids":["27892464"],"is_preprint":false},{"year":2019,"finding":"WNT5A transported by exosomes activates non-canonical signaling in human cardiac fibroblasts, including phosphorylation of ERK1/2 and JNK and stimulation of IL-6 production, but does not activate β-catenin-dependent signaling, in contrast to WNT3a-containing exosomes which activate canonical signaling.","method":"Exosome isolation and characterization, β-catenin reporter assays, ERK/JNK phosphorylation western blot, IL-6 ELISA, exosome marker characterization","journal":"International Journal of Molecular Sciences","confidence":"Medium","confidence_rationale":"Tier 2 — cell-based assays with multiple pathway readouts, single study","pmids":["30901906"],"is_preprint":false},{"year":2013,"finding":"WNT5A promotes glioblastoma cell invasion via the Daam1/RhoA signaling pathway; WNT5A activates Daam1 and RhoA (but not Cdc42 or Rac1) to promote stress fiber formation and invasion; Daam1 siRNA or RhoA inhibitor abolished WNT5A-induced invasion without affecting proliferation.","method":"Pull-down assays for Daam1 activation, small G-protein activation assays for RhoA/Rac1/Cdc42, siRNA knockdown, RhoA inhibitor treatment, invasion assays","journal":"Oncology Reports","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical pathway assays + specific siRNA + pharmacological validation, single lab","pmids":["29207169"],"is_preprint":false},{"year":2013,"finding":"WNT5A promotes Ewing sarcoma cell migration by upregulating CXCR4 expression via the JNK/c-Jun pathway; WNT5A shRNA and JNK inhibitor both reduced CXCR4 expression and cell migration, and SFRP5 (an antagonist that directly binds WNT5A) suppressed these effects.","method":"shRNA knockdown, recombinant WNT5A treatment, JNK inhibitor, migration assays, CXCR4 expression analysis","journal":"BMC Cancer","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, multiple consistent methods showing pathway dependence","pmids":["23075330"],"is_preprint":false},{"year":2015,"finding":"WNT5A inhibits hepatocyte proliferation and concludes liver regeneration by acting as a negative regulator of β-catenin signaling through the Frizzled-2 receptor; exogenous WNT5A decreased β-catenin-TCF4 interaction, cyclin D1 expression, and cell proliferation in primary hepatocytes and liver tumor cells.","method":"Liver-specific Wntless (Wls) knockout mice, Wnt5a liver-specific knockout, exogenous WNT5A treatment of primary hepatocytes, co-immunoprecipitation of β-catenin-TCF4, cyclin D1 western blot, partial hepatectomy model","journal":"American Journal of Pathology","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic mouse models + in vitro mechanistic assays, clear pathway placement","pmids":["26100214"],"is_preprint":false},{"year":2013,"finding":"WNT5A is required for cortical axon outgrowth and repulsive guidance through calcium signaling and tau-mediated reorganization of dynamic microtubules; WNT5A increases axon outgrowth by reorganizing dynamic MTs from splayed to bundled arrays; CaMKII phosphorylates tau at Ser262, detaching tau from MTs to increase dynamics required for growth cone steering; mutation of the Ser262 site abolished WNT5A-induced axon outgrowth and repulsion.","method":"Live cell imaging of EGFP-EB3 labeled MTs, tau Ser262 mutant transfection, CaMKII inhibitor, nocodazole/taxol MT dynamics inhibitors, calcium imaging","journal":"Developmental Neurobiology","confidence":"High","confidence_rationale":"Tier 1-2 — live imaging + site-specific mutagenesis + pharmacological validation, multiple orthogonal approaches","pmids":["23818454"],"is_preprint":false},{"year":2020,"finding":"A WNT5A-ROR2-Vangl2 cascade in the planar cell polarity (PCP) pathway is required for alveologenesis in mammalian lungs; this axis confers cellular properties including PDGF secretion from alveolar epithelial cells, type I cell shape changes, and myofibroblast migration through cytoskeletal reorganization.","method":"Conditional knockout mice (epithelial and myofibroblast-specific), cytoskeletal analysis, PDGF secretion assays, cell shape and migration quantification","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — multiple cell-type-specific genetic knockouts + multiple cellular phenotype readouts","pmids":["32394892"],"is_preprint":false},{"year":2021,"finding":"RNF43, an E3 ubiquitin ligase, inhibits WNT5A-driven noncanonical signaling by interacting with ROR1, ROR2, VANGL1, and VANGL2; RNF43 triggers VANGL2 ubiquitination and proteasomal degradation and clathrin-dependent internalization of ROR1, and inhibits ROR2 activation, thereby blocking WNT5A-mediated melanoma invasion.","method":"BioID interactome, co-immunoprecipitation, ubiquitination assays, proteasome inhibitor treatment, clathrin inhibition, invasion assays, in vivo melanoma models","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — interactome mapping + ubiquitination assays + in vivo validation + multiple orthogonal methods","pmids":["34702444"],"is_preprint":false},{"year":2019,"finding":"WNT5A activates the NF-κB pathway in melanoma via ROR1, Dvl2, and Akt (from WNT5A pathway) converging on TRAF2 and RIP (from NF-κB pathway); this induces p65 phosphorylation, IKK phosphorylation, IκB degradation, nuclear translocation of p65, and secretion of IL-6, IL-8, IL-11, MCP-1, and TNF-sRI; an autocrine WNT5A loop maintains constitutive NF-κB activity.","method":"cDNA overexpression, siRNA knockdown, dominant negative mutants, NF-κB reporter assays, cytokine/chemokine secretion assays, phosphorylation western blots","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — multiple genetic tools + reporter assays + biochemical readouts, single lab","pmids":["31510045"],"is_preprint":false},{"year":2023,"finding":"WNT5A signaling through ROR2 activates the Hippo pathway to suppress YAP1 activity and tumor growth; WNT5A caused ROR2-dependent increased phosphorylation of MST1/2, LATS1, MOB1, and YAP1; deletion of MST1/2 abrogated the WNT5A response; in ROR2-negative cells, WNT5A instead suppressed Hippo via increased inhibitory phosphorylation of NF2/Merlin; YAP1 activity also positively regulates ROR2 and WNT5A, forming a negative feedback loop.","method":"Prostate cancer organoid and xenograft models, MST1/2 deletion, Hippo pathway phosphorylation western blots, ROR2-expressing vs ROR2-negative cell comparison, clinical dataset correlation","journal":"Cancer Research","confidence":"High","confidence_rationale":"Tier 2 — genetic deletion + phosphorylation cascade mapping + in vivo models + context-dependent receptor comparison","pmids":["36622276"],"is_preprint":false},{"year":2020,"finding":"WNT5A deficiency under Klotho deficiency promotes salt-sensitive hypertension via non-canonical WNT5A/RhoA signaling in vascular smooth muscle cells; WNT5A and angiotensin II (Ang II) increase RhoA activity (measured by p-MYPT1); siRNA knockdown of WNT5A abolishes Ang II-induced Rho/ROCK activation, and Klotho supplementation inhibits WNT5A-mediated p-MYPT1 upregulation.","method":"Wnt5a siRNA in cultured VSMCs, Klotho knockout and supplementation mice, blood pressure measurement, renal blood flow assays, p-MYPT1 as RhoA activity readout","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 — in vivo mouse models + siRNA + multiple mechanistic readouts + pharmacological inhibitors","pmids":["32597829"],"is_preprint":false},{"year":2019,"finding":"WNT5A signals through ROR1 to activate Rac1 in CLL cells, promoting cell proliferation and survival; ibrutinib (BTK inhibitor) does not block this WNT5A-ROR1-Rac1 axis; the anti-ROR1 mAb cirmtuzumab blocks WNT5A-induced Rac1 activation and enhances ibrutinib activity in vivo.","method":"Rac1 activation assays, CLL cell proliferation assays, in vivo leukemia clearance models, ibrutinib + cirmtuzumab combination treatment","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical activation assays + in vivo model, single lab","pmids":["27904138"],"is_preprint":false},{"year":2019,"finding":"STAT3 binds to the WNT5A gene promoter and transcriptionally activates WNT5A expression in CLL cells; STAT3 shRNA downregulates WNT5A mRNA and protein; WNT5A and its receptor ROR1 are co-expressed on CLL cell surface; WNT5A siRNA increases spontaneous apoptosis of CLL cells, indicating an autocrine survival loop.","method":"ChIP, EMSA, luciferase reporter assay for STAT3-WNT5A promoter interaction, STAT3 shRNA, WNT5A siRNA, apoptosis assays, flow cytometry","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP + EMSA + reporter assay + functional siRNA validation, multiple orthogonal methods","pmids":["31645416"],"is_preprint":false},{"year":2021,"finding":"WNT5A is a crucial component of the lysosomal cholesterol export machinery; it increases lysosomal acid lipase expression, decreases mTORC1 signaling, and physically binds to NPC1 and NPC2 to promote lysosomal cholesterol egress to the endoplasmic reticulum; Wnt5a deletion in vascular smooth muscle cells disrupts lysosomal function and promotes atherosclerosis.","method":"Vascular smooth muscle cell-specific Wnt5a knockout mice, CRISPR/Cas9 knockout of WNT5A in human VSMCs, co-immunoprecipitation with NPC1/NPC2, lysosomal acid lipase assays, mTORC1 activity assays, cholesterol trafficking assays","journal":"Circulation Research","confidence":"High","confidence_rationale":"Tier 1-2 — physical binding to NPC1/NPC2 + cell-type-specific KO + human cell CRISPR KO + multiple biochemical pathway assays","pmids":["34886684"],"is_preprint":false},{"year":2017,"finding":"WNT5A in cardiac fibroblasts activates ERK1/2 signaling (without affecting β-catenin levels) to induce dose-dependent upregulation and release of IL-6 and TIMP-1; ERK1/2 inhibition attenuates WNT5A-induced IL-6 and TIMP-1 release.","method":"Recombinant WNT5A treatment of primary mouse and human cardiac fibroblasts, ERK1/2 inhibitor, western blot, cytokine measurement","journal":"Journal of Molecular Medicine","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological pathway inhibition + primary cell assays, single lab","pmids":["28357477"],"is_preprint":false},{"year":2022,"finding":"A neuron-to-astrocyte WNT5A-ROR2 signaling axis controls astrogliosis in HIV-associated pain; conditional knockout of WNT5A in neurons or ROR2 in astrocytes abolished gp120-induced astrogliosis, hyperalgesia, and neural circuit polarization; the astrogliosis promotes IL-1β expression via a WNT5A-ROR2-MMP2 axis.","method":"Conditional neuronal Wnt5a knockout, conditional astrocytic Ror2 knockout, behavioral pain assays, spinal cord circuit analysis","journal":"Brain","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific conditional knockouts + behavioral + circuit-level phenotypes","pmids":["35040478"],"is_preprint":false},{"year":2022,"finding":"Morphine-induced astrogliosis requires WNT5A signaling from neurons to astrocytes via ROR2; conditional knockout of neuronal Wnt5a or astrocytic Ror2 blocked morphine-induced astrogliosis, opioid-induced hyperalgesia, and neural circuit polarization; the WNT5A-ROR2 astrogliosis promotes OIH via inflammasome-regulated IL-1β.","method":"Conditional neuronal Wnt5a and astrocytic Ror2 knockouts, opioid-induced hyperalgesia behavioral assays, neural circuit polarization analysis, inflammasome/IL-1β measurement","journal":"Molecular Psychiatry","confidence":"High","confidence_rationale":"Tier 2 — dual cell-type-specific conditional KOs + in vivo behavioral and molecular phenotypes","pmids":["36203006"],"is_preprint":false},{"year":2019,"finding":"WNT5A signals through ROR1 and ROR2 to activate RhoA (via DAAM1) in esophageal squamous cell carcinoma; ROR1 and ROR2 form a complex in ESCC cells; DAAM1 is required for RhoA activation downstream of ROR1/ROR2, and a RhoA inhibitor blocks invasion but not DAAM1 activity.","method":"Anti-ROR1 antibody, ROR2 shRNA, DAAM1 shRNA, RhoA inhibitor, Rho activation assays, co-immunoprecipitation of ROR1-ROR2, invasion assays, actin filament staining","journal":"Cancer Management and Research","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical Co-IP + pathway inhibition + rescue experiment, single lab","pmids":["31114334"],"is_preprint":false},{"year":2022,"finding":"Microglial WNT5A is the most abundantly expressed WNT in microglia and promotes neuronal dendritic spine maturation and synaptic density; silencing microglial Wnt5a in co-culture with neurons reduces spine density, reduces PSD95 and synaptic density, and significantly decreases neuronal firing rate.","method":"Neuron-microglia co-culture, Wnt5a siRNA knockdown in microglia, confocal imaging of dendritic spines and synaptic markers, multiple electrode array recording","journal":"Brain, Behavior, and Immunity","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA + electrophysiology + imaging, single lab","pmids":["36395958"],"is_preprint":false},{"year":2019,"finding":"WNT5A/ROR2 pathway promotes cholesterol accumulation and inflammatory response in vascular smooth muscle cells by inhibiting ABCA1 expression; Wnt5a overexpression inhibited ABCA1, impaired cholesterol efflux, facilitated NF-κB nuclear translocation, and promoted inflammatory cytokine secretion; ROR2 knockdown reversed these effects.","method":"Wnt5a overexpression and knockdown, ROR2 knockdown, ABCA1 expression assays, cholesterol efflux assays, NF-κB nuclear translocation assays, ApoE-/- mouse model","journal":"Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids","confidence":"Medium","confidence_rationale":"Tier 2 — gain/loss of function + receptor knockdown + in vivo mouse model, single lab","pmids":["31678514"],"is_preprint":false},{"year":2018,"finding":"WNT5A induces castration-resistant prostate cancer via CCL2; WNT5A-induced CCL2 expression is mediated by the MAPK/ERK signaling pathway; in vivo, WNT5A overexpression promoted castration resistance which was inhibited by macrophage depletion, indicating WNT5A drives CRPC via macrophage recruitment through CCL2.","method":"Doxycycline-inducible WNT5A overexpression, MAPK/ERK pathway inhibitors, CCL2 ELISA, clodronate liposome macrophage depletion, in vivo castration resistance model","journal":"British Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 — inducible overexpression + pathway inhibitor + in vivo macrophage depletion, single lab","pmids":["29381686"],"is_preprint":false},{"year":2019,"finding":"WNT5A promotes ESCC and glioblastoma invasion; in glioblastoma, WNT5A specifically activates RhoA (not Rac1) downstream of ROR1/ROR2 and DAAM1 to promote actin stress fiber formation and invasion.","method":"Small G-protein activation assays, DAAM1 pull-down, ROR1/2 and DAAM1 siRNA, invasion assays","journal":"Cancer Management and Research","confidence":"Medium","confidence_rationale":"Tier 2 — G-protein biochemical assays + siRNA + rescue experiments, single lab","pmids":["31114334"],"is_preprint":false},{"year":2023,"finding":"PRMT2-mediated asymmetric dimethylation of H3R8 (H3R8me2a) at the WNT5A promoter region enhances WNT5A transcriptional expression, thereby activating Wnt signaling and promoting RCC cell proliferation and metastasis.","method":"ChIP for H3R8me2a at WNT5A promoter, PRMT2 overexpression and knockdown, WNT5A expression assays, in vitro and in vivo proliferation/metastasis assays","journal":"Cell Death and Disease","confidence":"Medium","confidence_rationale":"Tier 1-2 — ChIP demonstrating epigenetic mark at WNT5A promoter + functional validation, single lab","pmids":["37173306"],"is_preprint":false},{"year":2020,"finding":"PGC1α silencing (via H3K27me3 promoter methylation) activates TCF12, which increases WNT5A expression; WNT5A in turn stabilizes YAP protein levels to promote melanoma migration and metastasis; inhibition of TCF12, WNT5A, or YAP blocked melanoma migration in vitro and metastasis in vivo.","method":"EZH2 inhibitor, PGC1α and TCF12 genetic manipulation, WNT5A knockdown, YAP protein stability assays, in vitro migration and in vivo metastasis assays","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 — epigenetic drug + genetic pathway dissection + in vivo metastasis validation","pmids":["31929186"],"is_preprint":false},{"year":2021,"finding":"Cardiac WNT5A and WNT11 promote cardiac fibrosis by activation of the crosstalk between FZD5 and EGFR; exogenous WNT5A activated ERK and p38, promoted EGFR phosphorylation, and increased FZD5 expression in cardiac fibroblasts; FZD5 knockdown suppressed WNT5A-induced EGFR phosphorylation and pro-fibrotic effects, and EGFR inhibition attenuated FZD5 upregulation.","method":"TAC mouse model, shRNA knockdown of Wnt5a and Wnt11, exogenous WNT5A treatment of cardiac fibroblasts, EGFR and FZD5 siRNA, ERK/p38/EGFR phosphorylation western blots","journal":"Cell Death and Disease","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo model + reciprocal knockdown experiments + biochemical signaling, single lab","pmids":["34564708"],"is_preprint":false},{"year":2013,"finding":"WNT5A-conditioned medium inhibits canonical Wnt signaling and strongly activates JNK/PCP signaling in mandibular chondrocytes; excess WNT5A stimulates cartilage matrix degradation through non-canonical JNK pathway by upregulating MMP1, MMP13, and ADAMTS5; JNK antagonism (but not DKK1) partially rescued the WNT5A-induced matrix loss phenotype.","method":"Luciferase reporter assays for canonical and JNK/PCP pathways, Marimastat MMP/aggrecanase inhibitor, DKK1 canonical pathway inhibitor, JNK small molecule antagonist, mandibular micromass cultures, in vivo retroviral overexpression","journal":"Matrix Biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple pathway reporter assays + pharmacological dissection + in vivo and in vitro convergence, single lab","pmids":["23474397"],"is_preprint":false},{"year":2022,"finding":"Myeloid-derived suppressor cells (MDSCs) are a major source of WNT5A in the melanoma tumor microenvironment; myeloid-specific WNT5A knockdown decreased MDSC and Treg infiltration, reduced MDSC immunosuppressive activity (TGFβ1, arginase 1), decreased lung metastasis, and reduced PD-1/LAG3 expression on tumor-infiltrating lymphocytes.","method":"Myeloid-specific WNT5A knockdown (in vivo), flow cytometry for immune cell populations and exhaustion markers, TGFβ1/arginase 1 measurement, lung metastasis quantification","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 — cell-type-specific in vivo knockdown + multiple immune phenotype readouts, single lab","pmids":["33262126"],"is_preprint":false},{"year":2019,"finding":"WNT5A upregulates ABCG2 expression in pancreatic cancer cells through FZD7 receptor signaling; FZD7 siRNA or inhibitors blocked WNT5A-induced ABCG2 upregulation and attenuated WNT5A-induced gemcitabine resistance.","method":"Recombinant WNT5A treatment, FZD7 siRNA, FZD7 inhibitors, ABCG2 expression assays, gemcitabine resistance assays","journal":"Molecular Medicine Reports","confidence":"Medium","confidence_rationale":"Tier 3 — receptor siRNA + pharmacological approach + functional resistance readout, single lab","pmids":["33200805"],"is_preprint":false},{"year":2019,"finding":"WNT5A induces MCP-1 expression in gastric cancer cells via IL-1β, which in turn promotes macrophage chemotaxis and cytoskeletal changes; IL-1 receptor antagonist suppressed WNT5A-conditioned medium-induced macrophage migration.","method":"WNT5A overexpression vector, WNT5A siRNA, IL-1β ELISA, MCP-1 expression assay, macrophage transwell migration, FITC-phalloidin cytoskeleton staining, IL-1Ra treatment","journal":"BMC Cancer","confidence":"Medium","confidence_rationale":"Tier 3 — gain/loss of function + indirect pathway via IL-1β + functional migration readout, single lab","pmids":["24993819"],"is_preprint":false}],"current_model":"WNT5A is a secreted glycoprotein that predominantly activates β-catenin-independent (non-canonical) Wnt signaling by binding to receptors including Frizzled family members, ROR1, ROR2, and RYK, triggering downstream cascades (PKC, JNK, PCP/RhoA via DAAM1, Ca²⁺/calcineurin, ERK, Rac1, Hippo/MST1-LATS-YAP) to control cell polarity, migration, invasion, cytoskeletal reorganization, immune function, and tissue homeostasis; context-dependently, WNT5A can also inhibit canonical Wnt/β-catenin signaling (through ROR2 kinase activity and Frizzled-2), with the specific outcome determined by receptor availability, co-receptor expression, and cellular context."},"narrative":{"teleology":[{"year":2002,"claim":"The first evidence that WNT5A activates a non-canonical PKC pathway to drive cancer invasion, establishing that WNT5A signals independently of β-catenin in melanoma through the receptor Frizzled-5.","evidence":"WNT5A overexpression in melanoma cells with Frizzled-5 blocking antibody; PKC activity and invasion assays","pmids":["12086864"],"confidence":"High","gaps":["Identity of intermediates between Frizzled-5 and PKC not defined","No ROR co-receptor involvement tested at this point"]},{"year":2003,"claim":"WNT5A was identified as a tumor suppressor in hematopoietic tissue, demonstrating that the same ligand can have opposing roles (tumor suppressor vs. invasion promoter) depending on cell context.","evidence":"Wnt5a hemizygous mice developing myeloid leukemias and B-cell lymphomas; Ca²⁺ pathway suppression of cyclin D1","pmids":["14667502"],"confidence":"High","gaps":["Receptor mediating tumor suppression not identified","Whether Ca²⁺ pathway is sufficient or necessary for suppression not fully dissected"]},{"year":2008,"claim":"WNT5A was shown to organize a novel intracellular polarity structure (W-RAMP) involving actin, myosin IIB, Frizzled-3, and MCAM, revealing how WNT5A translates signaling into directional cell movement through endosomal trafficking.","evidence":"Live cell imaging, dominant-negative GTPases (Rab4, RhoB), endosome trafficking inhibitors in melanoma cells","pmids":["18420933"],"confidence":"High","gaps":["Upstream signal linking WNT5A receptor engagement to W-RAMP assembly not fully resolved","Generalizability beyond melanoma unknown"]},{"year":2009,"claim":"ROR2 was established as a key WNT5A receptor whose tyrosine kinase activity is required for inhibition of canonical Wnt/β-catenin signaling, confirmed by Ror2-null mice showing elevated canonical Wnt reporter activity.","evidence":"ROR2 domain/point mutagenesis with β-catenin reporter; Ror2 KO mice with Axin2(LacZ)","pmids":["19720827","19802008"],"confidence":"High","gaps":["Direct kinase substrates of ROR2 upon WNT5A binding not identified","Whether kinase-dead ROR2 retains any non-canonical signaling capacity not tested"]},{"year":2010,"claim":"WNT5A was shown to drive cancer invasion through a defined Frizzled2/ROR2→PKD→JNK→JunD signaling cascade that transcriptionally activates MMP-1, providing a complete pathway from ligand to effector gene.","evidence":"ChIP for JunD at MMP-1 promoter, PKD inhibitors, JNK assays in prostate cancer cells","pmids":["20101234"],"confidence":"High","gaps":["Relative contribution of ROR2 vs. Frizzled2 at receptor level not separated","Whether PKD activation requires direct ROR2 kinase activity unknown"]},{"year":2012,"claim":"A physiological WNT5A-ROR2 paracrine axis was demonstrated between osteoblasts and osteoclast precursors, where JNK/c-Jun activation transcriptionally upregulates RANK to sensitize precursors to RANKL-induced differentiation, linking WNT5A to bone remodeling.","evidence":"Cell-type-specific conditional knockouts, ChIP for c-Jun at RANK promoter, osteoclast differentiation assays","pmids":["22344299"],"confidence":"High","gaps":["Whether WNT5A-ROR2 also modulates osteoblast differentiation through an autocrine mechanism not tested"]},{"year":2013,"claim":"WNT5A's role in axon guidance was mechanistically resolved: WNT5A calcium signaling activates CaMKII, which phosphorylates tau at Ser262 to detach it from microtubules and increase microtubule dynamics required for growth cone steering.","evidence":"Live MT imaging (EGFP-EB3), tau Ser262 mutant, CaMKII inhibitor, calcium imaging in cortical neurons","pmids":["23818454"],"confidence":"High","gaps":["Receptor mediating WNT5A-calcium signaling in neurons not identified","Relevance in vivo during cortical wiring not tested"]},{"year":2013,"claim":"WNT5A was linked to cartilage matrix degradation through JNK/PCP-dependent upregulation of MMPs and ADAMTS5, and to cancer cell migration via DAAM1-RhoA, consolidating the RhoA branch of non-canonical signaling.","evidence":"JNK/PCP reporter assays, Daam1 pull-down, RhoA activation assays in glioblastoma and chondrocytes","pmids":["23474397","29207169"],"confidence":"Medium","gaps":["Whether DAAM1 is universally required for WNT5A-RhoA in all cell types not established","Structural basis for DAAM1 activation by WNT5A receptors unknown"]},{"year":2015,"claim":"WNT5A was identified as a negative regulator of liver regeneration that suppresses β-catenin–TCF4 interaction and cyclin D1 through Frizzled-2, defining a tissue context where WNT5A actively antagonizes canonical Wnt signaling.","evidence":"Liver-specific Wntless and Wnt5a knockout mice, co-IP of β-catenin–TCF4, partial hepatectomy model","pmids":["26100214"],"confidence":"High","gaps":["Mechanism by which Frizzled-2 uncouples β-catenin–TCF4 binding not defined"]},{"year":2016,"claim":"The ROR1–ROR2 heterooligomerization mechanism was dissected: WNT5A induces ROR1/ROR2 complex formation via the Kringle domain, which recruits GEFs to activate Rac1 and RhoA; separately, ROR1 phosphorylates cortactin to recruit ARHGEF1 and promote F-actin polymerization in CLL.","evidence":"Domain mutagenesis, Co-IP, GEF recruitment assays, Rac1/RhoA activation, cortactin phosphorylation at Y421, in vivo engraftment","pmids":["26690702","30568170"],"confidence":"High","gaps":["Whether ROR1 kinase activity is direct or requires a co-kinase not fully resolved","Crystal structure of the ROR1-ROR2 complex unavailable"]},{"year":2016,"claim":"WNT5A was shown to suppress rDNA transcription by Pol I through DVL1 accumulation at nucleolar organizer regions, displacing SIRT7 from rDNA, revealing a nuclear transcriptional function for non-canonical Wnt signaling.","evidence":"ChIP, Co-IP, rDNA transcription assays, DVL1 nuclear imaging, siRNA in breast cancer cells","pmids":["27500936"],"confidence":"High","gaps":["Mechanism of DVL1 nuclear import not defined","Whether this function operates in non-cancer cells unknown"]},{"year":2016,"claim":"WNT5A was connected to a vasopressin-independent renal water balance mechanism: WNT5A induces AQP2 expression, phosphorylation, and apical trafficking via calcineurin, rescuing urine-concentrating ability in nephrogenic diabetes insipidus mice.","evidence":"AQP2 trafficking assays, calcineurin inhibitor experiments, NDI mouse model urine osmolality","pmids":["27892464"],"confidence":"High","gaps":["Receptor(s) mediating calcineurin activation in collecting duct cells not identified","Long-term efficacy and safety of WNT5A pathway activation in NDI not assessed"]},{"year":2017,"claim":"A complete WNT5A→ROR2→RhoA→PKN3→c-Src signaling cascade was mapped in osteoclasts, showing that PKN3 binds and activates c-Src for actin ring formation and bone resorption, validated by double-KO phenotypes.","evidence":"Conditional Ror2 and global Pkn3 KO mice, Co-IP of PKN3 with c-Src, kinase assays, constitutively active RhoA rescue","pmids":["28851822"],"confidence":"High","gaps":["Whether PKN3 is recruited directly by active RhoA or via an intermediate not resolved","Pharmacological targeting of PKN3 not tested"]},{"year":2018,"claim":"WNT5A was shown to regulate the depalmitoylation machinery: WNT5A phosphorylates APT1, which increases its depalmitoylation activity toward CD44 and MCAM, promoting melanoma invasion through altered membrane protein dynamics.","evidence":"Phosphorylation assays, depalmitoylation activity, dimerization assays, invasion assays in melanoma cells","pmids":["29648538"],"confidence":"High","gaps":["Kinase directly phosphorylating APT1 downstream of WNT5A not identified","Whether other palmitoylated substrates are affected not tested"]},{"year":2019,"claim":"An autocrine WNT5A survival loop was defined in CLL: STAT3 transcriptionally activates WNT5A, which signals through ROR1 to activate Rac1 and NF-κB (via DVL2/Akt/TRAF2/RIP), sustaining cell survival and cytokine secretion.","evidence":"ChIP + EMSA for STAT3 at WNT5A promoter, Rac1 activation assays, NF-κB reporter, WNT5A siRNA apoptosis","pmids":["31645416","31510045","27904138"],"confidence":"High","gaps":["Whether STAT3-WNT5A transcriptional axis operates in solid tumors not determined","Relative contribution of ROR1 vs. ROR2 to NF-κB activation not separated"]},{"year":2020,"claim":"WNT5A was positioned in vascular biology as both a hypertension mediator (through RhoA/ROCK in VSMCs under Klotho deficiency) and an alveologenesis regulator (through PCP/Vangl2), demonstrating tissue-specific developmental and pathological functions.","evidence":"VSMC-specific Wnt5a siRNA, Klotho KO mice, blood pressure measurement; epithelial and myofibroblast conditional KO for alveologenesis","pmids":["32597829","32394892"],"confidence":"High","gaps":["Direct mechanism linking Klotho to WNT5A expression/activity not fully defined","Whether Vangl2 acts as a co-receptor or downstream effector in alveolar cells not distinguished"]},{"year":2021,"claim":"WNT5A was discovered to directly bind NPC1 and NPC2 and function in lysosomal cholesterol export machinery, linking WNT5A to lipid metabolism beyond its canonical role as a signaling ligand; Wnt5a deletion in VSMCs disrupted lysosomal function and promoted atherosclerosis.","evidence":"Co-IP with NPC1/NPC2, CRISPR KO in human VSMCs, VSMC-specific Wnt5a KO mice, cholesterol trafficking assays","pmids":["34886684"],"confidence":"High","gaps":["Whether WNT5A acts inside lysosomes or at the lysosomal membrane not determined","Structural basis for WNT5A–NPC1/NPC2 interaction unknown"]},{"year":2021,"claim":"RNF43 was identified as a negative regulator of WNT5A non-canonical signaling: it ubiquitinates VANGL2 for proteasomal degradation and triggers clathrin-dependent internalization of ROR1, providing a defined turnoff mechanism for the pathway.","evidence":"BioID interactome, ubiquitination assays, proteasome and clathrin inhibitors, in vivo melanoma models","pmids":["34702444"],"confidence":"High","gaps":["Whether RNF43 ubiquitinates ROR2 directly not tested","Regulation of RNF43 expression in non-canonical Wnt contexts not explored"]},{"year":2022,"claim":"A neuron-to-astrocyte WNT5A-ROR2 paracrine axis was established as essential for astrogliosis in both HIV-associated and morphine-induced pain, activating MMP2/inflammasome/IL-1β to rewire spinal neural circuits.","evidence":"Conditional neuronal Wnt5a and astrocytic Ror2 KO, behavioral hyperalgesia assays, circuit polarization analysis","pmids":["35040478","36203006"],"confidence":"High","gaps":["Whether other WNT ligands compensate in WNT5A-deficient neurons not tested","Downstream signaling from ROR2 to MMP2 in astrocytes not fully mapped"]},{"year":2023,"claim":"WNT5A-ROR2 was connected to Hippo pathway regulation: in ROR2-positive cells, WNT5A activates MST1/2-LATS-YAP phosphorylation to suppress tumor growth, while in ROR2-negative cells it suppresses Hippo via NF2/Merlin phosphorylation, establishing receptor-dependent pathway switching.","evidence":"MST1/2 deletion, Hippo phosphorylation cascades, prostate cancer organoids and xenografts, ROR2+/− comparison","pmids":["36622276"],"confidence":"High","gaps":["Direct kinase linking ROR2 to MST1/2 activation not identified","Whether other Wnt ligands can similarly engage Hippo not tested"]},{"year":null,"claim":"Key open questions include: how receptor availability (FZD, ROR1, ROR2) is coordinated to determine pathway choice in a given cell; the structural basis of WNT5A–receptor complexes; and whether the newly discovered lysosomal cholesterol export function of WNT5A operates independently of classical receptor signaling.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal structure of WNT5A bound to any receptor complex","Mechanism of context-dependent pathway switching between tumor suppression and invasion not resolved at the molecular level","Whether intracellular/lysosomal WNT5A functions require secretion and receptor re-engagement is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,2,4,5,7,12,18,21,22]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,5,7,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,6,16,21]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,4,5,7,12,13,18,22,25]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[25]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,4,5,7,8,9,12,16,18,21,22]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[17,18,30]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,23,24,38]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[3,18]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[25,31]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[17,27,28,30]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,2,4,6,7,9,20,23,32,35]}],"complexes":[],"partners":["ROR2","ROR1","FZD5","FZD2","DAAM1","NPC1","NPC2","DVL1"],"other_free_text":[]},"mechanistic_narrative":"WNT5A is a secreted glycoprotein that functions as a central ligand in β-catenin-independent (non-canonical) Wnt signaling, coordinating cell polarity, migration, invasion, immune modulation, and tissue homeostasis across diverse developmental and pathological contexts. WNT5A engages Frizzled family receptors (FZD2, FZD3, FZD5, FZD7) and co-receptors ROR1, ROR2, and RYK to activate multiple downstream cascades including PKC, JNK/c-Jun, RhoA (via DAAM1), Rac1, Ca²⁺/calcineurin, ERK, and Hippo/MST-LATS-YAP, with the specific output determined by receptor context [PMID:12086864, PMID:19720827, PMID:26690702, PMID:36622276]. Through ROR2, WNT5A suppresses canonical Wnt/β-catenin signaling by disrupting β-catenin–TCF4 interaction, acting as a negative regulator of proliferation in hepatocytes and hematopoietic cells—where Wnt5a haploinsufficiency leads to myeloid leukemias and B-cell lymphomas—while simultaneously driving invasion, cytoskeletal reorganization, and pro-inflammatory cytokine production in melanoma, prostate cancer, CLL, and other malignancies [PMID:14667502, PMID:26100214, PMID:22344299, PMID:29648538]. WNT5A also mediates intercellular communication in non-cancer contexts, including neuron-to-astrocyte signaling controlling astrogliosis and pain sensitization via ROR2/MMP2/IL-1β, microglial promotion of dendritic spine maturation, osteoblast-to-osteoclast precursor signaling via JNK/c-Jun–dependent RANK upregulation, renal AQP2 trafficking through calcineurin, vascular smooth muscle RhoA/ROCK activation in hypertension, and lysosomal cholesterol export through direct binding to NPC1 and NPC2 [PMID:35040478, PMID:36395958, PMID:22344299, PMID:27892464, PMID:32597829, PMID:34886684]."},"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":"12086864","id":"PMC_12086864","title":"Wnt5a 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melanoma cell lines, antibody blocking of Frizzled-5, PKC activity assays, invasion assays\",\n      \"journal\": \"Cancer Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function + receptor blocking + biochemical readout, replicated across multiple melanoma lines\",\n      \"pmids\": [\"12086864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ROR2 requires tyrosine kinase activity to mediate WNT5A signaling; mutation/deletion analysis showed that specific domains and residues in ROR2, including those necessary for kinase activity, are required for WNT5A-mediated inhibition of canonical Wnt/β-catenin signaling; Ror2-null mice show increased Axin2(LacZ) reporter activity, confirming Ror2 inhibits canonical Wnt signaling in vivo.\",\n      \"method\": \"Deletion and point mutagenesis of ROR2 domains, β-catenin reporter assays, Ror2 knockout mice with Axin2(LacZ) reporter\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis + in vivo genetic validation with reporter\",\n      \"pmids\": [\"19720827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ROR2 is a receptor for WNT5A in melanoma; WNT5A increases ROR2 expression and induces PKC-dependent, clathrin-mediated internalization of ROR2; siRNA knockdown of WNT5A decreases ROR2 expression, while ROR2 knockdown decreases downstream WNT5A signaling and inhibits WNT5A-mediated melanoma metastasis in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown, in vitro and in vivo metastasis assays, tissue microarray, receptor internalization studies\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal knockdown experiments + in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"19802008\"],\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 melanoma cell adhesion molecule (MCAM) into a Wnt-mediated receptor-actin-myosin polarity (W-RAMP) intracellular structure; this process requires endosome trafficking associated with multivesicular bodies and is regulated by WNT5A through small GTPases Rab4 and RhoB.\",\n      \"method\": \"Live cell imaging, fluorescence microscopy, dominant-negative GTPases, endosome trafficking inhibitors, chemokine gradient assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal imaging and genetic approaches in single study, mechanistic resolution of pathway components\",\n      \"pmids\": [\"18420933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"WNT5A promotes prostate cancer invasion through Frizzled2 and ROR2 as receptors, activating JNK via protein kinase D (PKD); PKD inhibition suppressed WNT5A-dependent cell migration and invasion; WNT5A induced metalloproteinase-1 (MMP-1) expression through recruitment of JunD to its promoter.\",\n      \"method\": \"Knockdown and overexpression of WNT5A, PKD inhibitors, JNK signaling assays, ChIP for JunD at MMP-1 promoter, invasion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP + pharmacological inhibition + gain/loss of function with defined mechanistic pathway\",\n      \"pmids\": [\"20101234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"WNT5A expressed by osteoblast-lineage cells signals through ROR2 expressed on osteoclast precursors to enhance osteoclastogenesis; WNT5A-ROR2 activates JNK and recruits c-Jun to the RANK gene promoter, increasing RANK expression and thus sensitizing precursors to RANKL-induced osteoclastogenesis; mice deficient in either Wnt5a or Ror2 show impaired osteoclastogenesis.\",\n      \"method\": \"Cell-type-specific conditional knockouts, JNK activation assays, ChIP for c-Jun at RANK promoter, osteoclast differentiation assays, arthritis mouse models\",\n      \"journal\": \"Nature Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP + conditional KO mice + multiple cell type-specific genetic models, replicated in vivo\",\n      \"pmids\": [\"22344299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"WNT5A signals through the noncanonical Wnt/Ca2+ pathway to suppress cyclin D1 expression and negatively regulate B cell proliferation; Wnt5a hemizygous mice develop myeloid leukemias and B cell lymphomas with loss of Wnt5a function in tumor tissues, identifying Wnt5a as a tumor suppressor in hematopoietic tissue.\",\n      \"method\": \"Wnt5a knockout/hemizygous mice, cell proliferation assays, cyclin D1 western blot, Ca2+ pathway signaling assays\",\n      \"journal\": \"Cancer Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic mouse model + biochemical pathway placement\",\n      \"pmids\": [\"14667502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WNT5A induces ROR1 to oligomerize with ROR2, which recruits guanine exchange factors (GEFs) that activate Rac1 and RhoA to promote CLL cell proliferation and chemokine-directed migration; the extracellular Kringle domain is required for ROR1/ROR2 heterooligomerization, and the cysteine-rich domain or intracellular proline-rich domain is required for GEF recruitment.\",\n      \"method\": \"Co-immunoprecipitation, ectopic expression of ROR1/ROR2 mutants, GEF recruitment assays, Rac1/RhoA activation assays, in vivo engraftment in immune-deficient mice\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — domain mutagenesis + Co-IP + in vivo validation + multiple orthogonal methods\",\n      \"pmids\": [\"26690702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"WNT5A signaling through ROR2 promotes bone resorption by activating RhoA (a small GTPase); Rho effector kinase PKN3 then binds to and enhances c-Src activity, which is critical for actin ring formation in osteoclasts; osteoclast-specific Ror2-deficient mice and global Pkn3-deficient mice both show increased bone mass and impaired bone resorption.\",\n      \"method\": \"Conditional and global knockout mice, co-immunoprecipitation of PKN3 with c-Src, kinase activity assays, actin ring formation assays, constitutively active RhoA rescue experiments\",\n      \"journal\": \"Science Signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple KO models + biochemical pathway reconstitution + domain analysis + rescue experiments\",\n      \"pmids\": [\"28851822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WNT5A causes ROR1 to complex with and phosphorylate cortactin at Y421; phosphorylated cortactin recruits ARHGEF1 and activates RhoA, enhancing CLL cell migration; the proline-rich domain of ROR1, specifically position P841, is required for cortactin binding and subsequent F-actin polymerization.\",\n      \"method\": \"Co-immunoprecipitation, ROR1 domain mutagenesis (single amino acid substitutions), cortactin phosphorylation assays, F-actin polymerization assays, migration assays\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — precise mutagenesis + Co-IP + biochemical signaling assays identifying specific residue\",\n      \"pmids\": [\"30568170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"WNT5A signaling results in APT1 (acyl protein thioesterase 1) phosphorylation which increases APT1 depalmitoylating activity and reduces APT1 dimerization; APT1-mediated depalmitoylation of CD44 and MCAM promotes melanoma invasion.\",\n      \"method\": \"Phosphorylation assays, depalmitoylation activity assays, dimerization assays, in vitro invasion assays, phospho-specific analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical enzyme activity assays + multiple mechanistic readouts in single study\",\n      \"pmids\": [\"29648538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WNT5A signals through Dishevelled1 (DVL1) to suppress rDNA transcription by RNA Polymerase I in breast cancer cells; DVL1 accumulates at nucleolar organizer regions (NORs) and binds rDNA, causing SIRT7 to release from rDNA loci and disassembly of Pol I transcription machinery at the rDNA promoter.\",\n      \"method\": \"ChIP, co-immunoprecipitation, rDNA transcription assays, DVL1 nuclear localization imaging, siRNA knockdown\",\n      \"journal\": \"PLoS Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP + nuclear fractionation + transcription assays + genetic validation\",\n      \"pmids\": [\"27500936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WNT5A induces renal AQP2 expression, phosphorylation, and apical membrane trafficking via calcineurin signaling, bypassing the vasopressin/cAMP/PKA pathway; this WNT5A-calcineurin axis increases urine osmolality in a nephrogenic diabetes insipidus (NDI) mouse model.\",\n      \"method\": \"AQP2 phosphorylation and trafficking assays, calcineurin inhibitor experiments, urine osmolality measurement in NDI mouse model, in vitro cell assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo NDI model + multiple mechanistic assays + specific pathway inhibition\",\n      \"pmids\": [\"27892464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WNT5A transported by exosomes activates non-canonical signaling in human cardiac fibroblasts, including phosphorylation of ERK1/2 and JNK and stimulation of IL-6 production, but does not activate β-catenin-dependent signaling, in contrast to WNT3a-containing exosomes which activate canonical signaling.\",\n      \"method\": \"Exosome isolation and characterization, β-catenin reporter assays, ERK/JNK phosphorylation western blot, IL-6 ELISA, exosome marker characterization\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-based assays with multiple pathway readouts, single study\",\n      \"pmids\": [\"30901906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"WNT5A promotes glioblastoma cell invasion via the Daam1/RhoA signaling pathway; WNT5A activates Daam1 and RhoA (but not Cdc42 or Rac1) to promote stress fiber formation and invasion; Daam1 siRNA or RhoA inhibitor abolished WNT5A-induced invasion without affecting proliferation.\",\n      \"method\": \"Pull-down assays for Daam1 activation, small G-protein activation assays for RhoA/Rac1/Cdc42, siRNA knockdown, RhoA inhibitor treatment, invasion assays\",\n      \"journal\": \"Oncology Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical pathway assays + specific siRNA + pharmacological validation, single lab\",\n      \"pmids\": [\"29207169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"WNT5A promotes Ewing sarcoma cell migration by upregulating CXCR4 expression via the JNK/c-Jun pathway; WNT5A shRNA and JNK inhibitor both reduced CXCR4 expression and cell migration, and SFRP5 (an antagonist that directly binds WNT5A) suppressed these effects.\",\n      \"method\": \"shRNA knockdown, recombinant WNT5A treatment, JNK inhibitor, migration assays, CXCR4 expression analysis\",\n      \"journal\": \"BMC Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, multiple consistent methods showing pathway dependence\",\n      \"pmids\": [\"23075330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"WNT5A inhibits hepatocyte proliferation and concludes liver regeneration by acting as a negative regulator of β-catenin signaling through the Frizzled-2 receptor; exogenous WNT5A decreased β-catenin-TCF4 interaction, cyclin D1 expression, and cell proliferation in primary hepatocytes and liver tumor cells.\",\n      \"method\": \"Liver-specific Wntless (Wls) knockout mice, Wnt5a liver-specific knockout, exogenous WNT5A treatment of primary hepatocytes, co-immunoprecipitation of β-catenin-TCF4, cyclin D1 western blot, partial hepatectomy model\",\n      \"journal\": \"American Journal of Pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic mouse models + in vitro mechanistic assays, clear pathway placement\",\n      \"pmids\": [\"26100214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"WNT5A is required for cortical axon outgrowth and repulsive guidance through calcium signaling and tau-mediated reorganization of dynamic microtubules; WNT5A increases axon outgrowth by reorganizing dynamic MTs from splayed to bundled arrays; CaMKII phosphorylates tau at Ser262, detaching tau from MTs to increase dynamics required for growth cone steering; mutation of the Ser262 site abolished WNT5A-induced axon outgrowth and repulsion.\",\n      \"method\": \"Live cell imaging of EGFP-EB3 labeled MTs, tau Ser262 mutant transfection, CaMKII inhibitor, nocodazole/taxol MT dynamics inhibitors, calcium imaging\",\n      \"journal\": \"Developmental Neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — live imaging + site-specific mutagenesis + pharmacological validation, multiple orthogonal approaches\",\n      \"pmids\": [\"23818454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A WNT5A-ROR2-Vangl2 cascade in the planar cell polarity (PCP) pathway is required for alveologenesis in mammalian lungs; this axis confers cellular properties including PDGF secretion from alveolar epithelial cells, type I cell shape changes, and myofibroblast migration through cytoskeletal reorganization.\",\n      \"method\": \"Conditional knockout mice (epithelial and myofibroblast-specific), cytoskeletal analysis, PDGF secretion assays, cell shape and migration quantification\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple cell-type-specific genetic knockouts + multiple cellular phenotype readouts\",\n      \"pmids\": [\"32394892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RNF43, an E3 ubiquitin ligase, inhibits WNT5A-driven noncanonical signaling by interacting with ROR1, ROR2, VANGL1, and VANGL2; RNF43 triggers VANGL2 ubiquitination and proteasomal degradation and clathrin-dependent internalization of ROR1, and inhibits ROR2 activation, thereby blocking WNT5A-mediated melanoma invasion.\",\n      \"method\": \"BioID interactome, co-immunoprecipitation, ubiquitination assays, proteasome inhibitor treatment, clathrin inhibition, invasion assays, in vivo melanoma models\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — interactome mapping + ubiquitination assays + in vivo validation + multiple orthogonal methods\",\n      \"pmids\": [\"34702444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WNT5A activates the NF-κB pathway in melanoma via ROR1, Dvl2, and Akt (from WNT5A pathway) converging on TRAF2 and RIP (from NF-κB pathway); this induces p65 phosphorylation, IKK phosphorylation, IκB degradation, nuclear translocation of p65, and secretion of IL-6, IL-8, IL-11, MCP-1, and TNF-sRI; an autocrine WNT5A loop maintains constitutive NF-κB activity.\",\n      \"method\": \"cDNA overexpression, siRNA knockdown, dominant negative mutants, NF-κB reporter assays, cytokine/chemokine secretion assays, phosphorylation western blots\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic tools + reporter assays + biochemical readouts, single lab\",\n      \"pmids\": [\"31510045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WNT5A signaling through ROR2 activates the Hippo pathway to suppress YAP1 activity and tumor growth; WNT5A caused ROR2-dependent increased phosphorylation of MST1/2, LATS1, MOB1, and YAP1; deletion of MST1/2 abrogated the WNT5A response; in ROR2-negative cells, WNT5A instead suppressed Hippo via increased inhibitory phosphorylation of NF2/Merlin; YAP1 activity also positively regulates ROR2 and WNT5A, forming a negative feedback loop.\",\n      \"method\": \"Prostate cancer organoid and xenograft models, MST1/2 deletion, Hippo pathway phosphorylation western blots, ROR2-expressing vs ROR2-negative cell comparison, clinical dataset correlation\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic deletion + phosphorylation cascade mapping + in vivo models + context-dependent receptor comparison\",\n      \"pmids\": [\"36622276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WNT5A deficiency under Klotho deficiency promotes salt-sensitive hypertension via non-canonical WNT5A/RhoA signaling in vascular smooth muscle cells; WNT5A and angiotensin II (Ang II) increase RhoA activity (measured by p-MYPT1); siRNA knockdown of WNT5A abolishes Ang II-induced Rho/ROCK activation, and Klotho supplementation inhibits WNT5A-mediated p-MYPT1 upregulation.\",\n      \"method\": \"Wnt5a siRNA in cultured VSMCs, Klotho knockout and supplementation mice, blood pressure measurement, renal blood flow assays, p-MYPT1 as RhoA activity readout\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse models + siRNA + multiple mechanistic readouts + pharmacological inhibitors\",\n      \"pmids\": [\"32597829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WNT5A signals through ROR1 to activate Rac1 in CLL cells, promoting cell proliferation and survival; ibrutinib (BTK inhibitor) does not block this WNT5A-ROR1-Rac1 axis; the anti-ROR1 mAb cirmtuzumab blocks WNT5A-induced Rac1 activation and enhances ibrutinib activity in vivo.\",\n      \"method\": \"Rac1 activation assays, CLL cell proliferation assays, in vivo leukemia clearance models, ibrutinib + cirmtuzumab combination treatment\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical activation assays + in vivo model, single lab\",\n      \"pmids\": [\"27904138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STAT3 binds to the WNT5A gene promoter and transcriptionally activates WNT5A expression in CLL cells; STAT3 shRNA downregulates WNT5A mRNA and protein; WNT5A and its receptor ROR1 are co-expressed on CLL cell surface; WNT5A siRNA increases spontaneous apoptosis of CLL cells, indicating an autocrine survival loop.\",\n      \"method\": \"ChIP, EMSA, luciferase reporter assay for STAT3-WNT5A promoter interaction, STAT3 shRNA, WNT5A siRNA, apoptosis assays, flow cytometry\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP + EMSA + reporter assay + functional siRNA validation, multiple orthogonal methods\",\n      \"pmids\": [\"31645416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WNT5A is a crucial component of the lysosomal cholesterol export machinery; it increases lysosomal acid lipase expression, decreases mTORC1 signaling, and physically binds to NPC1 and NPC2 to promote lysosomal cholesterol egress to the endoplasmic reticulum; Wnt5a deletion in vascular smooth muscle cells disrupts lysosomal function and promotes atherosclerosis.\",\n      \"method\": \"Vascular smooth muscle cell-specific Wnt5a knockout mice, CRISPR/Cas9 knockout of WNT5A in human VSMCs, co-immunoprecipitation with NPC1/NPC2, lysosomal acid lipase assays, mTORC1 activity assays, cholesterol trafficking assays\",\n      \"journal\": \"Circulation Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — physical binding to NPC1/NPC2 + cell-type-specific KO + human cell CRISPR KO + multiple biochemical pathway assays\",\n      \"pmids\": [\"34886684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"WNT5A in cardiac fibroblasts activates ERK1/2 signaling (without affecting β-catenin levels) to induce dose-dependent upregulation and release of IL-6 and TIMP-1; ERK1/2 inhibition attenuates WNT5A-induced IL-6 and TIMP-1 release.\",\n      \"method\": \"Recombinant WNT5A treatment of primary mouse and human cardiac fibroblasts, ERK1/2 inhibitor, western blot, cytokine measurement\",\n      \"journal\": \"Journal of Molecular Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological pathway inhibition + primary cell assays, single lab\",\n      \"pmids\": [\"28357477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A neuron-to-astrocyte WNT5A-ROR2 signaling axis controls astrogliosis in HIV-associated pain; conditional knockout of WNT5A in neurons or ROR2 in astrocytes abolished gp120-induced astrogliosis, hyperalgesia, and neural circuit polarization; the astrogliosis promotes IL-1β expression via a WNT5A-ROR2-MMP2 axis.\",\n      \"method\": \"Conditional neuronal Wnt5a knockout, conditional astrocytic Ror2 knockout, behavioral pain assays, spinal cord circuit analysis\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific conditional knockouts + behavioral + circuit-level phenotypes\",\n      \"pmids\": [\"35040478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Morphine-induced astrogliosis requires WNT5A signaling from neurons to astrocytes via ROR2; conditional knockout of neuronal Wnt5a or astrocytic Ror2 blocked morphine-induced astrogliosis, opioid-induced hyperalgesia, and neural circuit polarization; the WNT5A-ROR2 astrogliosis promotes OIH via inflammasome-regulated IL-1β.\",\n      \"method\": \"Conditional neuronal Wnt5a and astrocytic Ror2 knockouts, opioid-induced hyperalgesia behavioral assays, neural circuit polarization analysis, inflammasome/IL-1β measurement\",\n      \"journal\": \"Molecular Psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — dual cell-type-specific conditional KOs + in vivo behavioral and molecular phenotypes\",\n      \"pmids\": [\"36203006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WNT5A signals through ROR1 and ROR2 to activate RhoA (via DAAM1) in esophageal squamous cell carcinoma; ROR1 and ROR2 form a complex in ESCC cells; DAAM1 is required for RhoA activation downstream of ROR1/ROR2, and a RhoA inhibitor blocks invasion but not DAAM1 activity.\",\n      \"method\": \"Anti-ROR1 antibody, ROR2 shRNA, DAAM1 shRNA, RhoA inhibitor, Rho activation assays, co-immunoprecipitation of ROR1-ROR2, invasion assays, actin filament staining\",\n      \"journal\": \"Cancer Management and Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical Co-IP + pathway inhibition + rescue experiment, single lab\",\n      \"pmids\": [\"31114334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Microglial WNT5A is the most abundantly expressed WNT in microglia and promotes neuronal dendritic spine maturation and synaptic density; silencing microglial Wnt5a in co-culture with neurons reduces spine density, reduces PSD95 and synaptic density, and significantly decreases neuronal firing rate.\",\n      \"method\": \"Neuron-microglia co-culture, Wnt5a siRNA knockdown in microglia, confocal imaging of dendritic spines and synaptic markers, multiple electrode array recording\",\n      \"journal\": \"Brain, Behavior, and Immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA + electrophysiology + imaging, single lab\",\n      \"pmids\": [\"36395958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WNT5A/ROR2 pathway promotes cholesterol accumulation and inflammatory response in vascular smooth muscle cells by inhibiting ABCA1 expression; Wnt5a overexpression inhibited ABCA1, impaired cholesterol efflux, facilitated NF-κB nuclear translocation, and promoted inflammatory cytokine secretion; ROR2 knockdown reversed these effects.\",\n      \"method\": \"Wnt5a overexpression and knockdown, ROR2 knockdown, ABCA1 expression assays, cholesterol efflux assays, NF-κB nuclear translocation assays, ApoE-/- mouse model\",\n      \"journal\": \"Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain/loss of function + receptor knockdown + in vivo mouse model, single lab\",\n      \"pmids\": [\"31678514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"WNT5A induces castration-resistant prostate cancer via CCL2; WNT5A-induced CCL2 expression is mediated by the MAPK/ERK signaling pathway; in vivo, WNT5A overexpression promoted castration resistance which was inhibited by macrophage depletion, indicating WNT5A drives CRPC via macrophage recruitment through CCL2.\",\n      \"method\": \"Doxycycline-inducible WNT5A overexpression, MAPK/ERK pathway inhibitors, CCL2 ELISA, clodronate liposome macrophage depletion, in vivo castration resistance model\",\n      \"journal\": \"British Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — inducible overexpression + pathway inhibitor + in vivo macrophage depletion, single lab\",\n      \"pmids\": [\"29381686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WNT5A promotes ESCC and glioblastoma invasion; in glioblastoma, WNT5A specifically activates RhoA (not Rac1) downstream of ROR1/ROR2 and DAAM1 to promote actin stress fiber formation and invasion.\",\n      \"method\": \"Small G-protein activation assays, DAAM1 pull-down, ROR1/2 and DAAM1 siRNA, invasion assays\",\n      \"journal\": \"Cancer Management and Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — G-protein biochemical assays + siRNA + rescue experiments, single lab\",\n      \"pmids\": [\"31114334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRMT2-mediated asymmetric dimethylation of H3R8 (H3R8me2a) at the WNT5A promoter region enhances WNT5A transcriptional expression, thereby activating Wnt signaling and promoting RCC cell proliferation and metastasis.\",\n      \"method\": \"ChIP for H3R8me2a at WNT5A promoter, PRMT2 overexpression and knockdown, WNT5A expression assays, in vitro and in vivo proliferation/metastasis assays\",\n      \"journal\": \"Cell Death and Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP demonstrating epigenetic mark at WNT5A promoter + functional validation, single lab\",\n      \"pmids\": [\"37173306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PGC1α silencing (via H3K27me3 promoter methylation) activates TCF12, which increases WNT5A expression; WNT5A in turn stabilizes YAP protein levels to promote melanoma migration and metastasis; inhibition of TCF12, WNT5A, or YAP blocked melanoma migration in vitro and metastasis in vivo.\",\n      \"method\": \"EZH2 inhibitor, PGC1α and TCF12 genetic manipulation, WNT5A knockdown, YAP protein stability assays, in vitro migration and in vivo metastasis assays\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epigenetic drug + genetic pathway dissection + in vivo metastasis validation\",\n      \"pmids\": [\"31929186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cardiac WNT5A and WNT11 promote cardiac fibrosis by activation of the crosstalk between FZD5 and EGFR; exogenous WNT5A activated ERK and p38, promoted EGFR phosphorylation, and increased FZD5 expression in cardiac fibroblasts; FZD5 knockdown suppressed WNT5A-induced EGFR phosphorylation and pro-fibrotic effects, and EGFR inhibition attenuated FZD5 upregulation.\",\n      \"method\": \"TAC mouse model, shRNA knockdown of Wnt5a and Wnt11, exogenous WNT5A treatment of cardiac fibroblasts, EGFR and FZD5 siRNA, ERK/p38/EGFR phosphorylation western blots\",\n      \"journal\": \"Cell Death and Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo model + reciprocal knockdown experiments + biochemical signaling, single lab\",\n      \"pmids\": [\"34564708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"WNT5A-conditioned medium inhibits canonical Wnt signaling and strongly activates JNK/PCP signaling in mandibular chondrocytes; excess WNT5A stimulates cartilage matrix degradation through non-canonical JNK pathway by upregulating MMP1, MMP13, and ADAMTS5; JNK antagonism (but not DKK1) partially rescued the WNT5A-induced matrix loss phenotype.\",\n      \"method\": \"Luciferase reporter assays for canonical and JNK/PCP pathways, Marimastat MMP/aggrecanase inhibitor, DKK1 canonical pathway inhibitor, JNK small molecule antagonist, mandibular micromass cultures, in vivo retroviral overexpression\",\n      \"journal\": \"Matrix Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple pathway reporter assays + pharmacological dissection + in vivo and in vitro convergence, single lab\",\n      \"pmids\": [\"23474397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Myeloid-derived suppressor cells (MDSCs) are a major source of WNT5A in the melanoma tumor microenvironment; myeloid-specific WNT5A knockdown decreased MDSC and Treg infiltration, reduced MDSC immunosuppressive activity (TGFβ1, arginase 1), decreased lung metastasis, and reduced PD-1/LAG3 expression on tumor-infiltrating lymphocytes.\",\n      \"method\": \"Myeloid-specific WNT5A knockdown (in vivo), flow cytometry for immune cell populations and exhaustion markers, TGFβ1/arginase 1 measurement, lung metastasis quantification\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific in vivo knockdown + multiple immune phenotype readouts, single lab\",\n      \"pmids\": [\"33262126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WNT5A upregulates ABCG2 expression in pancreatic cancer cells through FZD7 receptor signaling; FZD7 siRNA or inhibitors blocked WNT5A-induced ABCG2 upregulation and attenuated WNT5A-induced gemcitabine resistance.\",\n      \"method\": \"Recombinant WNT5A treatment, FZD7 siRNA, FZD7 inhibitors, ABCG2 expression assays, gemcitabine resistance assays\",\n      \"journal\": \"Molecular Medicine Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — receptor siRNA + pharmacological approach + functional resistance readout, single lab\",\n      \"pmids\": [\"33200805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WNT5A induces MCP-1 expression in gastric cancer cells via IL-1β, which in turn promotes macrophage chemotaxis and cytoskeletal changes; IL-1 receptor antagonist suppressed WNT5A-conditioned medium-induced macrophage migration.\",\n      \"method\": \"WNT5A overexpression vector, WNT5A siRNA, IL-1β ELISA, MCP-1 expression assay, macrophage transwell migration, FITC-phalloidin cytoskeleton staining, IL-1Ra treatment\",\n      \"journal\": \"BMC Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — gain/loss of function + indirect pathway via IL-1β + functional migration readout, single lab\",\n      \"pmids\": [\"24993819\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WNT5A is a secreted glycoprotein that predominantly activates β-catenin-independent (non-canonical) Wnt signaling by binding to receptors including Frizzled family members, ROR1, ROR2, and RYK, triggering downstream cascades (PKC, JNK, PCP/RhoA via DAAM1, Ca²⁺/calcineurin, ERK, Rac1, Hippo/MST1-LATS-YAP) to control cell polarity, migration, invasion, cytoskeletal reorganization, immune function, and tissue homeostasis; context-dependently, WNT5A can also inhibit canonical Wnt/β-catenin signaling (through ROR2 kinase activity and Frizzled-2), with the specific outcome determined by receptor availability, co-receptor expression, and cellular context.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"WNT5A is a secreted glycoprotein that functions as a central ligand in β-catenin-independent (non-canonical) Wnt signaling, coordinating cell polarity, migration, invasion, immune modulation, and tissue homeostasis across diverse developmental and pathological contexts. WNT5A engages Frizzled family receptors (FZD2, FZD3, FZD5, FZD7) and co-receptors ROR1, ROR2, and RYK to activate multiple downstream cascades including PKC, JNK/c-Jun, RhoA (via DAAM1), Rac1, Ca²⁺/calcineurin, ERK, and Hippo/MST-LATS-YAP, with the specific output determined by receptor context [PMID:12086864, PMID:19720827, PMID:26690702, PMID:36622276]. Through ROR2, WNT5A suppresses canonical Wnt/β-catenin signaling by disrupting β-catenin–TCF4 interaction, acting as a negative regulator of proliferation in hepatocytes and hematopoietic cells—where Wnt5a haploinsufficiency leads to myeloid leukemias and B-cell lymphomas—while simultaneously driving invasion, cytoskeletal reorganization, and pro-inflammatory cytokine production in melanoma, prostate cancer, CLL, and other malignancies [PMID:14667502, PMID:26100214, PMID:22344299, PMID:29648538]. WNT5A also mediates intercellular communication in non-cancer contexts, including neuron-to-astrocyte signaling controlling astrogliosis and pain sensitization via ROR2/MMP2/IL-1β, microglial promotion of dendritic spine maturation, osteoblast-to-osteoclast precursor signaling via JNK/c-Jun–dependent RANK upregulation, renal AQP2 trafficking through calcineurin, vascular smooth muscle RhoA/ROCK activation in hypertension, and lysosomal cholesterol export through direct binding to NPC1 and NPC2 [PMID:35040478, PMID:36395958, PMID:22344299, PMID:27892464, PMID:32597829, PMID:34886684].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"The first evidence that WNT5A activates a non-canonical PKC pathway to drive cancer invasion, establishing that WNT5A signals independently of β-catenin in melanoma through the receptor Frizzled-5.\",\n      \"evidence\": \"WNT5A overexpression in melanoma cells with Frizzled-5 blocking antibody; PKC activity and invasion assays\",\n      \"pmids\": [\"12086864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of intermediates between Frizzled-5 and PKC not defined\", \"No ROR co-receptor involvement tested at this point\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"WNT5A was identified as a tumor suppressor in hematopoietic tissue, demonstrating that the same ligand can have opposing roles (tumor suppressor vs. invasion promoter) depending on cell context.\",\n      \"evidence\": \"Wnt5a hemizygous mice developing myeloid leukemias and B-cell lymphomas; Ca²⁺ pathway suppression of cyclin D1\",\n      \"pmids\": [\"14667502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating tumor suppression not identified\", \"Whether Ca²⁺ pathway is sufficient or necessary for suppression not fully dissected\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"WNT5A was shown to organize a novel intracellular polarity structure (W-RAMP) involving actin, myosin IIB, Frizzled-3, and MCAM, revealing how WNT5A translates signaling into directional cell movement through endosomal trafficking.\",\n      \"evidence\": \"Live cell imaging, dominant-negative GTPases (Rab4, RhoB), endosome trafficking inhibitors in melanoma cells\",\n      \"pmids\": [\"18420933\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signal linking WNT5A receptor engagement to W-RAMP assembly not fully resolved\", \"Generalizability beyond melanoma unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"ROR2 was established as a key WNT5A receptor whose tyrosine kinase activity is required for inhibition of canonical Wnt/β-catenin signaling, confirmed by Ror2-null mice showing elevated canonical Wnt reporter activity.\",\n      \"evidence\": \"ROR2 domain/point mutagenesis with β-catenin reporter; Ror2 KO mice with Axin2(LacZ)\",\n      \"pmids\": [\"19720827\", \"19802008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase substrates of ROR2 upon WNT5A binding not identified\", \"Whether kinase-dead ROR2 retains any non-canonical signaling capacity not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"WNT5A was shown to drive cancer invasion through a defined Frizzled2/ROR2→PKD→JNK→JunD signaling cascade that transcriptionally activates MMP-1, providing a complete pathway from ligand to effector gene.\",\n      \"evidence\": \"ChIP for JunD at MMP-1 promoter, PKD inhibitors, JNK assays in prostate cancer cells\",\n      \"pmids\": [\"20101234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of ROR2 vs. Frizzled2 at receptor level not separated\", \"Whether PKD activation requires direct ROR2 kinase activity unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"A physiological WNT5A-ROR2 paracrine axis was demonstrated between osteoblasts and osteoclast precursors, where JNK/c-Jun activation transcriptionally upregulates RANK to sensitize precursors to RANKL-induced differentiation, linking WNT5A to bone remodeling.\",\n      \"evidence\": \"Cell-type-specific conditional knockouts, ChIP for c-Jun at RANK promoter, osteoclast differentiation assays\",\n      \"pmids\": [\"22344299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether WNT5A-ROR2 also modulates osteoblast differentiation through an autocrine mechanism not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"WNT5A's role in axon guidance was mechanistically resolved: WNT5A calcium signaling activates CaMKII, which phosphorylates tau at Ser262 to detach it from microtubules and increase microtubule dynamics required for growth cone steering.\",\n      \"evidence\": \"Live MT imaging (EGFP-EB3), tau Ser262 mutant, CaMKII inhibitor, calcium imaging in cortical neurons\",\n      \"pmids\": [\"23818454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating WNT5A-calcium signaling in neurons not identified\", \"Relevance in vivo during cortical wiring not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"WNT5A was linked to cartilage matrix degradation through JNK/PCP-dependent upregulation of MMPs and ADAMTS5, and to cancer cell migration via DAAM1-RhoA, consolidating the RhoA branch of non-canonical signaling.\",\n      \"evidence\": \"JNK/PCP reporter assays, Daam1 pull-down, RhoA activation assays in glioblastoma and chondrocytes\",\n      \"pmids\": [\"23474397\", \"29207169\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DAAM1 is universally required for WNT5A-RhoA in all cell types not established\", \"Structural basis for DAAM1 activation by WNT5A receptors unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"WNT5A was identified as a negative regulator of liver regeneration that suppresses β-catenin–TCF4 interaction and cyclin D1 through Frizzled-2, defining a tissue context where WNT5A actively antagonizes canonical Wnt signaling.\",\n      \"evidence\": \"Liver-specific Wntless and Wnt5a knockout mice, co-IP of β-catenin–TCF4, partial hepatectomy model\",\n      \"pmids\": [\"26100214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Frizzled-2 uncouples β-catenin–TCF4 binding not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The ROR1–ROR2 heterooligomerization mechanism was dissected: WNT5A induces ROR1/ROR2 complex formation via the Kringle domain, which recruits GEFs to activate Rac1 and RhoA; separately, ROR1 phosphorylates cortactin to recruit ARHGEF1 and promote F-actin polymerization in CLL.\",\n      \"evidence\": \"Domain mutagenesis, Co-IP, GEF recruitment assays, Rac1/RhoA activation, cortactin phosphorylation at Y421, in vivo engraftment\",\n      \"pmids\": [\"26690702\", \"30568170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ROR1 kinase activity is direct or requires a co-kinase not fully resolved\", \"Crystal structure of the ROR1-ROR2 complex unavailable\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"WNT5A was shown to suppress rDNA transcription by Pol I through DVL1 accumulation at nucleolar organizer regions, displacing SIRT7 from rDNA, revealing a nuclear transcriptional function for non-canonical Wnt signaling.\",\n      \"evidence\": \"ChIP, Co-IP, rDNA transcription assays, DVL1 nuclear imaging, siRNA in breast cancer cells\",\n      \"pmids\": [\"27500936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of DVL1 nuclear import not defined\", \"Whether this function operates in non-cancer cells unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"WNT5A was connected to a vasopressin-independent renal water balance mechanism: WNT5A induces AQP2 expression, phosphorylation, and apical trafficking via calcineurin, rescuing urine-concentrating ability in nephrogenic diabetes insipidus mice.\",\n      \"evidence\": \"AQP2 trafficking assays, calcineurin inhibitor experiments, NDI mouse model urine osmolality\",\n      \"pmids\": [\"27892464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor(s) mediating calcineurin activation in collecting duct cells not identified\", \"Long-term efficacy and safety of WNT5A pathway activation in NDI not assessed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"A complete WNT5A→ROR2→RhoA→PKN3→c-Src signaling cascade was mapped in osteoclasts, showing that PKN3 binds and activates c-Src for actin ring formation and bone resorption, validated by double-KO phenotypes.\",\n      \"evidence\": \"Conditional Ror2 and global Pkn3 KO mice, Co-IP of PKN3 with c-Src, kinase assays, constitutively active RhoA rescue\",\n      \"pmids\": [\"28851822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PKN3 is recruited directly by active RhoA or via an intermediate not resolved\", \"Pharmacological targeting of PKN3 not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"WNT5A was shown to regulate the depalmitoylation machinery: WNT5A phosphorylates APT1, which increases its depalmitoylation activity toward CD44 and MCAM, promoting melanoma invasion through altered membrane protein dynamics.\",\n      \"evidence\": \"Phosphorylation assays, depalmitoylation activity, dimerization assays, invasion assays in melanoma cells\",\n      \"pmids\": [\"29648538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase directly phosphorylating APT1 downstream of WNT5A not identified\", \"Whether other palmitoylated substrates are affected not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"An autocrine WNT5A survival loop was defined in CLL: STAT3 transcriptionally activates WNT5A, which signals through ROR1 to activate Rac1 and NF-κB (via DVL2/Akt/TRAF2/RIP), sustaining cell survival and cytokine secretion.\",\n      \"evidence\": \"ChIP + EMSA for STAT3 at WNT5A promoter, Rac1 activation assays, NF-κB reporter, WNT5A siRNA apoptosis\",\n      \"pmids\": [\"31645416\", \"31510045\", \"27904138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STAT3-WNT5A transcriptional axis operates in solid tumors not determined\", \"Relative contribution of ROR1 vs. ROR2 to NF-κB activation not separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"WNT5A was positioned in vascular biology as both a hypertension mediator (through RhoA/ROCK in VSMCs under Klotho deficiency) and an alveologenesis regulator (through PCP/Vangl2), demonstrating tissue-specific developmental and pathological functions.\",\n      \"evidence\": \"VSMC-specific Wnt5a siRNA, Klotho KO mice, blood pressure measurement; epithelial and myofibroblast conditional KO for alveologenesis\",\n      \"pmids\": [\"32597829\", \"32394892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanism linking Klotho to WNT5A expression/activity not fully defined\", \"Whether Vangl2 acts as a co-receptor or downstream effector in alveolar cells not distinguished\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"WNT5A was discovered to directly bind NPC1 and NPC2 and function in lysosomal cholesterol export machinery, linking WNT5A to lipid metabolism beyond its canonical role as a signaling ligand; Wnt5a deletion in VSMCs disrupted lysosomal function and promoted atherosclerosis.\",\n      \"evidence\": \"Co-IP with NPC1/NPC2, CRISPR KO in human VSMCs, VSMC-specific Wnt5a KO mice, cholesterol trafficking assays\",\n      \"pmids\": [\"34886684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether WNT5A acts inside lysosomes or at the lysosomal membrane not determined\", \"Structural basis for WNT5A–NPC1/NPC2 interaction unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"RNF43 was identified as a negative regulator of WNT5A non-canonical signaling: it ubiquitinates VANGL2 for proteasomal degradation and triggers clathrin-dependent internalization of ROR1, providing a defined turnoff mechanism for the pathway.\",\n      \"evidence\": \"BioID interactome, ubiquitination assays, proteasome and clathrin inhibitors, in vivo melanoma models\",\n      \"pmids\": [\"34702444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RNF43 ubiquitinates ROR2 directly not tested\", \"Regulation of RNF43 expression in non-canonical Wnt contexts not explored\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A neuron-to-astrocyte WNT5A-ROR2 paracrine axis was established as essential for astrogliosis in both HIV-associated and morphine-induced pain, activating MMP2/inflammasome/IL-1β to rewire spinal neural circuits.\",\n      \"evidence\": \"Conditional neuronal Wnt5a and astrocytic Ror2 KO, behavioral hyperalgesia assays, circuit polarization analysis\",\n      \"pmids\": [\"35040478\", \"36203006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other WNT ligands compensate in WNT5A-deficient neurons not tested\", \"Downstream signaling from ROR2 to MMP2 in astrocytes not fully mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"WNT5A-ROR2 was connected to Hippo pathway regulation: in ROR2-positive cells, WNT5A activates MST1/2-LATS-YAP phosphorylation to suppress tumor growth, while in ROR2-negative cells it suppresses Hippo via NF2/Merlin phosphorylation, establishing receptor-dependent pathway switching.\",\n      \"evidence\": \"MST1/2 deletion, Hippo phosphorylation cascades, prostate cancer organoids and xenografts, ROR2+/− comparison\",\n      \"pmids\": [\"36622276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase linking ROR2 to MST1/2 activation not identified\", \"Whether other Wnt ligands can similarly engage Hippo not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: how receptor availability (FZD, ROR1, ROR2) is coordinated to determine pathway choice in a given cell; the structural basis of WNT5A–receptor complexes; and whether the newly discovered lysosomal cholesterol export function of WNT5A operates independently of classical receptor signaling.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of WNT5A bound to any receptor complex\", \"Mechanism of context-dependent pathway switching between tumor suppression and invasion not resolved at the molecular level\", \"Whether intracellular/lysosomal WNT5A functions require secretion and receptor re-engagement is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5, 7, 12, 18, 21, 22]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 5, 7, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 6, 16, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 4, 5, 7, 12, 13, 18, 22, 25]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [25]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5, 7, 8, 9, 12, 16, 18, 21, 22]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [17, 18, 30]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 23, 24, 38]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [3, 18]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [25, 31]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [17, 27, 28, 30]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 2, 4, 6, 7, 9, 20, 23, 32, 35]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ROR2\",\n      \"ROR1\",\n      \"FZD5\",\n      \"FZD2\",\n      \"DAAM1\",\n      \"NPC1\",\n      \"NPC2\",\n      \"DVL1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}