{"gene":"WNT11","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2000,"finding":"Zebrafish Wnt11 (silberblick locus) mediates convergent extension movements during gastrulation in a cell non-autonomous manner; its phenotype is rescued by a truncated Dishevelled that does not signal through the canonical Wnt pathway, indicating Wnt11 acts through a divergent (non-canonical) signal transduction cascade.","method":"Genetic mapping, loss-of-function mutant analysis, rescue with dominant-negative Dishevelled construct","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function in zebrafish with specific cellular phenotype and epistasis rescue, replicated across multiple labs subsequently","pmids":["10811221"],"is_preprint":false},{"year":2002,"finding":"Wnt11 is required for heart formation in Xenopus; it mediates cardiogenesis via non-canonical Wnt signaling that is independent of β-catenin and involves protein kinase C (PKC) and Jun N-terminal kinase (JNK).","method":"Loss- and gain-of-function experiments in Xenopus; conditioned medium treatment of P19 mouse embryonic carcinoma cells; pathway inhibitor assays for PKC and JNK","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (loss-of-function, gain-of-function, pharmacological inhibitors of PKC and JNK), replicated across species (Xenopus and mouse cells)","pmids":["12167861"],"is_preprint":false},{"year":2005,"finding":"Maternal Wnt11 activates the canonical Wnt signaling pathway to specify the dorsal axis in Xenopus; this activation requires the glycosyl transferase EXT1 and the EGF-CFC protein FRL1, which interacts with Wnt11.","method":"Loss-of-function (depletion of maternal Wnt11, EXT1, FRL1 by antisense oligonucleotides); co-immunoprecipitation of FRL1 with Wnt11","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple loss-of-function approaches and interaction assay in Xenopus, published in Cell with three independent lines of evidence","pmids":["15797385"],"is_preprint":false},{"year":2003,"finding":"Wnt11 and Ret/GDNF cooperate in a positive autoregulatory feedback loop during kidney development: Wnt11 maintains GDNF expression in the mesenchyme, and GDNF/Ret signaling maintains Wnt11 expression in ureteric tips; loss of Wnt11 reduces GDNF, and Wnt11/Ret double mutants show synergistic ureteric branching defects.","method":"Targeted gene knockout (Wnt11 null mice), genetic epistasis (Wnt11;Ret compound mutants), in situ hybridization for Gdnf expression","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse, synergistic genetic interaction confirmed by compound mutants, multiple labs replicated feedback loop","pmids":["12783789"],"is_preprint":false},{"year":2002,"finding":"Rho kinase 2 (Rok2) acts downstream of Wnt11 to mediate mediolateral cell elongation required for convergent extension movements in zebrafish; overexpression of Rok2 partially suppresses the slb/wnt11 gastrulation phenotype, and ectopic non-canonical Wnts modulate Rok2 intracellular distribution.","method":"Dominant-negative Rok2 overexpression, genetic suppression of slb/wnt11 mutant phenotype by Rok2 overexpression, transplantation experiments","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis rescue and dominant-negative experiments establishing pathway position, transplantation confirming cell-autonomous function","pmids":["12062050"],"is_preprint":false},{"year":2005,"finding":"Wnt11 controls tissue morphogenesis during zebrafish gastrulation by regulating E-cadherin-mediated cell cohesion via the GTPase Rab5c, a regulator of early endocytosis; blocking Rab5c phenocopies slb/wnt11 mutants, and enhancing Rab5c in slb/wnt11 mutants rescues the phenotype.","method":"Loss-of-function, rescue experiments, epistasis in zebrafish embryos; E-cadherin endocytosis assays","journal":"Developmental Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional epistasis (phenocopy and rescue) plus endocytosis assay, multiple orthogonal methods","pmids":["16198297"],"is_preprint":false},{"year":2006,"finding":"Wnt11 locally accumulates its receptor Frizzled 7 at cell contact sites in zebrafish embryonic cells; Frizzled 7 accumulations in turn recruit Dishevelled and Wnt11 itself, increasing local cell contact persistence through interaction with the atypical cadherin Flamingo, without requiring RhoA or Rok2 activity.","method":"Live imaging, subcellular localization studies, co-immunoprecipitation, dominant-negative and overexpression experiments in zebrafish","journal":"Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct subcellular localization with functional consequence, Co-IP of Wnt11/Frizzled7/Flamingo complex, multiple orthogonal methods","pmids":["17130287"],"is_preprint":false},{"year":2008,"finding":"Ryk cooperates with Frizzled 7 to mediate Wnt11-stimulated β-arrestin 2-dependent endocytosis of Dishevelled, which is required for non-canonical Wnt11 signaling in convergent extension movements in Xenopus.","method":"Co-immunoprecipitation (Ryk with Wnt11 and β-arrestin 2), morpholino knockdown, endocytosis assays in Xenopus dorsal marginal zone","journal":"Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, morpholino loss-of-function, and endocytosis assays; single lab with multiple methods","pmids":["18809723"],"is_preprint":false},{"year":2008,"finding":"WNT11 acts as a directional cue for oriented myocyte elongation in chick somites through the planar cell polarity (PCP) pathway; a localized ectopic source of WNT11 changes myocyte orientation, operating downstream of the WNT/β-catenin pathway that initiates the myogenic program.","method":"Loss-of-function (siRNA in somites), ectopic WNT11 source placement, epistasis with WNT/β-catenin pathway in chick embryos","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — specific inhibition in vivo, ectopic localized source experiment, epistasis establishing pathway order; published in Nature","pmids":["18987628"],"is_preprint":false},{"year":2004,"finding":"Wnt11 represses canonical Wnt signaling through multiple mechanisms: (1) receptor competition (preventing Wnt1/Wnt3/Wnt3a but not Wnt7a/7b from activating LEF-1), and (2) elevation of intracellular Ca²⁺ that inhibits canonical signaling; siRNA knockdown of endogenous Wnt11 in P19 cells increases LEF-1 reporter activity.","method":"LEF-1 reporter assays in NIH3T3 and P19 cells, co-culture competition experiments, siRNA knockdown, intracellular Ca²⁺ manipulation","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, co-culture, Ca²⁺ manipulation, siRNA knockdown), single lab","pmids":["15067007"],"is_preprint":false},{"year":2005,"finding":"In zebrafish, Wnt11 and Frizzled 5 promote eye field development partly through local antagonism of Wnt/β-catenin signaling and additionally regulate the cohesion of eye field cells.","method":"Loss-of-function and epistasis experiments in zebrafish embryos; cell cohesion assays","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic loss-of-function with specific phenotype, single lab, pathway epistasis inferred","pmids":["15996547"],"is_preprint":false},{"year":2005,"finding":"RhoA acts downstream of Wnt11 (and Wnt5) to regulate convergent extension movements in zebrafish, exerting its effects via two effectors: Rho kinase and Diaphanous (mDia); rhoA mRNA rescues CE defects in wnt11 mutants.","method":"Morpholino knockdown of rhoA in zebrafish, rescue of wnt11 mutants with rhoA mRNA, ectopic expression of Rho kinase and Diaphanous","journal":"Cellular Signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue epistasis plus parallel effector pathway analysis, single lab","pmids":["16019189"],"is_preprint":false},{"year":2007,"finding":"Wnt11 canonical signaling in Xenopus oocytes and early embryos operates through LRP6-mediated degradation of Axin: in the oocyte Wnt11/LRP6 maintains low β-catenin by regulating Axin, while in the embryo asymmetric Wnt11/LRP6 stabilizes β-catenin on the dorsal side.","method":"Morpholino depletion of LRP6 and Wnt11 in Xenopus oocytes/embryos; Axin protein level assays; β-catenin localization","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with biochemical readout, single lab, multiple developmental stages tested","pmids":["17202189"],"is_preprint":false},{"year":2009,"finding":"Wnt11/5a complexes, formed through TPST-1-mediated O-sulfation of specific tyrosine residues on Wnt11, have greater canonical Wnt signaling activity than either Wnt11 or Wnt5a alone; sulfation of Wnt11 is required for its interaction with Wnt5a.","method":"Co-immunoprecipitation of Wnt11/Wnt5a; canonical signaling reporter assays in Xenopus oocytes, mouse L cells, and human ESCs; TPST-1 loss-of-function; mutagenesis of sulfation sites","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — Co-IP, site-directed mutagenesis of sulfation sites, three independent cell systems; single lab but multiple orthogonal methods","pmids":["19747829"],"is_preprint":false},{"year":2009,"finding":"Wnt11 promotes osteoblast maturation and mineralization through β-catenin-dependent induction of R-spondin 2 (Rspo2); knockdown of Rspo2 abrogates Wnt11-mediated osteoblast maturation, and dominant-negative TCF blocks Wnt11-mediated Rspo2 expression.","method":"Overexpression and knockdown (siRNA of Rspo2) in MC3T3E1 pre-osteoblasts; dominant-negative TCF; alkaline phosphatase and mineralization assays","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression, knockdown, and dominant-negative TCF together establish pathway order, single lab","pmids":["19213727"],"is_preprint":false},{"year":2008,"finding":"Sfrp5 locally inhibits Wnt11 to coordinate canonical (Wnt/β-catenin) and non-canonical (Wnt/PCP) signaling in Xenopus foregut development: depletion of Sfrp5 leads to inappropriate Wnt11-mediated β-catenin and PCP signaling causing cell fate and epithelial adhesion defects, respectively.","method":"Morpholino depletion of Sfrp5 and Wnt11 in Xenopus; reporter assays for β-catenin and PCP signaling; rescue experiments","journal":"Genes & Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — double knockdown epistasis, pathway-specific reporter assays, rescue; single lab","pmids":["18981481"],"is_preprint":false},{"year":2010,"finding":"Non-canonical Wnt11 signaling in the zebrafish heart establishes a myocardial electrical gradient through effects on transmembrane Ca²⁺ conductance mediated by the L-type calcium channel; the traditional planar cell polarity pathway is not involved.","method":"High-speed optical mapping of transmembrane potentials and Ca²⁺ in zebrafish heart; loss-of-function of Wnt11; pharmacological manipulation of L-type calcium channel","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — optical mapping combined with Wnt11 loss-of-function and pharmacological validation; published in Nature with multiple orthogonal methods","pmids":["20657579"],"is_preprint":false},{"year":2010,"finding":"Wnt11 promotes neuroendocrine-like differentiation and survival of prostate cancer cells via cyclic AMP-dependent protein kinase; silencing Wnt11 causes apoptosis in androgen-depleted LNCaP and PC3 cells; Wnt11 also promotes cell migration/invasion.","method":"Ectopic Wnt11 expression, siRNA knockdown, PKA inhibitor treatment, migration/invasion assays in prostate cancer cell lines","journal":"Molecular Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function plus pharmacological inhibitor, single lab, multiple cell lines","pmids":["20219091"],"is_preprint":false},{"year":2010,"finding":"ERRα and β-catenin form a macromolecular complex with LEF-1 in cells and co-operatively induce WNT11 transcription; WNT11 then acts in an autocrine manner to increase cancer cell migration; WNT11-neutralizing antibodies abrogate the ERRα/β-catenin promigratory effect.","method":"Co-immunoprecipitation of ERRα/β-catenin/LEF-1; WNT11 conditioned medium; WNT11 neutralizing antibodies; siRNA knockdown; migration assays","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, neutralizing antibody, conditioned medium, siRNA; single lab","pmids":["20870744"],"is_preprint":false},{"year":2010,"finding":"Wnt11 promotes cardiomyocyte differentiation while suppressing β-catenin stabilization through activation of a caspase 3 signaling cascade; inhibition of caspase activity leads to β-catenin accumulation and reduced myocyte differentiation.","method":"Wnt11 stimulation of cardiomyocyte cultures, caspase inhibitor treatment, β-catenin western blot, differentiation assays","journal":"Molecular and Cellular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition plus Wnt11 gain-of-function, mechanistic readout of β-catenin and caspase activity; single lab","pmids":["21041481"],"is_preprint":false},{"year":2014,"finding":"Wnt5a and Wnt11 inhibit canonical Wnt/β-catenin signaling and promote second heart field progenitor development through Caspase-dependent degradation of AKT; Caspase inhibition blocked Wnt5a/Wnt11-induced suppression of both phosphorylated and total Akt, and Akt inhibition alone was sufficient to promote second heart field markers.","method":"Caspase activity assays, AKT western blot, Caspase inhibitor treatment in differentiating ES cells and in vivo (mouse), SHF marker expression","journal":"Developmental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition in vitro and in vivo, biochemical readout of AKT; single lab with multiple approaches","pmids":["25482987"],"is_preprint":false},{"year":2013,"finding":"Wnt11 is secreted apically in polarized epithelial cells via a mechanism requiring complex/hybrid glycan processing at Asn40 and galectin-3, distinct from the basolateral Wntless (Wls)-dependent pathway used by Wnt3a; fusion of the Asn40 glycosylation site of Wnt11 onto Wnt3a redirected Wnt3a to apical secretion.","method":"Mass-spectrometric glycan analysis of Wnt11, mutational analysis of glycosylation sites, apical/basolateral secretion assays in polarized MDCK cells, galectin-3 knockdown","journal":"Journal of Cell Science","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mass spectrometry, mutagenesis of glycosylation sites, domain swap experiment; multiple orthogonal methods in single study","pmids":["23613470"],"is_preprint":false},{"year":2012,"finding":"Wnt11/Frizzled 7 controls cell adhesion during convergent extension by forming two separate adhesion-modulating complexes (AMCs): one with PAPC (AMCP) that blocks PAPC internalization, preventing C-cadherin clustering, and one with C-cadherin (AMCC) that competes with C-cadherin cis-dimerization; both act in parallel to reduce cell adhesion.","method":"Co-immunoprecipitation, domain mapping of Fz7 interactions, endocytosis (dynamin1/clathrin-dependent) assays, cell sorting assays in Xenopus","journal":"Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, endocytosis assays, cell sorting functional readout; multiple orthogonal methods, single lab","pmids":["22908314"],"is_preprint":false},{"year":2007,"finding":"Wnt11 stimulation induces polarized accumulation of Dishevelled at apical adherens junctions in Xenopus via Frizzled 7; the DIX domain of Dishevelled is required for its translocation in response to Wnt11; Frizzled 7 itself accumulates at adherens junctions in response to Wnt11.","method":"Morpholino knockdown of Frizzled 7, Dishevelled localization imaging, domain deletion analysis (DIX domain), Wnt11 stimulation assays in Xenopus ectodermal explants","journal":"Genes to Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino knockdown, subcellular localization assay, domain mutant analysis; single lab","pmids":["17663724"],"is_preprint":false},{"year":2004,"finding":"Wnt11 stimulates proliferation, migration, and contact-independent growth of IEC6 intestinal epithelial cells via a β-catenin-independent mechanism involving PKC and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII); PKC inhibition reduces Wnt11-induced foci formation; Wnt11 also redistributes E-cadherin.","method":"Conditioned medium treatment and stable transfection with Wnt11; PKC activity assays; CaMKII activity assays; PKC inhibitor; E-cadherin immunofluorescence; foci formation assays","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition, multiple functional readouts, single lab","pmids":["15084607"],"is_preprint":false},{"year":2006,"finding":"Wnt11 (via non-canonical pathway) activates PKC to stimulate type II collagen expression in chondrocytes; a PKC inhibitor blocks this effect; in contrast, Wnt-5a activates JNK to inhibit type II collagen expression.","method":"Conditioned medium from Wnt-11 or Wnt-5a expressing cells, PKC and JNK inhibitors, siRNA knockdown, collagen expression assays","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection, knockdown, single lab with clear functional readout","pmids":["16754689"],"is_preprint":false},{"year":2008,"finding":"Noncanonical Wnt11 signaling induces cardiomyogenic differentiation of adult bone marrow mononuclear cells via PKC and JNK pathways; Wnt11-induced cardiac gene expression is abolished by PKC inhibitor bisindolylmaleimide I and partially by JNK inhibitor SP600125.","method":"Wnt11 conditioned medium treatment of BMMNCs, PKC and JNK pharmacological inhibitors, cardiac marker qRT-PCR and immunocytochemistry","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition of specific kinases, multiple cardiac marker readouts; single lab","pmids":["18427129"],"is_preprint":false},{"year":2014,"finding":"Ror2 physically interacts with Wnt11 and functions as a receptor mediating Wnt11 signaling during convergent extension in zebrafish; Tyr-647 and Ser-863 of Ror2 are essential for mediating Wnt11 action; Dishevelled and RhoA act downstream of Wnt11-Ror2.","method":"Co-immunoprecipitation of Ror2 and Wnt11, dominant-negative Ror2 overexpression, epistasis with wnt11 morpholino, site-directed mutagenesis of Ror2, transplantation experiments in zebrafish","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, mutagenesis, genetic epistasis, transplantation; multiple orthogonal methods, single lab","pmids":["24928507"],"is_preprint":false},{"year":2018,"finding":"FZD8 is a major Wnt-11 receptor in prostate cancer; FZD8 co-localizes and co-immunoprecipitates with Wnt-11, potentiates Wnt-11 activation of ATF2-dependent transcription, and forms a TGF-β-regulated complex with TGF-β receptors mediated by the extracellular domains of FZD8 and TGFBR1.","method":"Co-immunoprecipitation, co-localization, FZD8 silencing (shRNA), ATF2 reporter assay, 3D organotypic assays, EMT gene expression analysis in prostate cancer cell lines","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, domain-mapping of receptor complex, reporter assay, functional silencing; multiple methods, single lab","pmids":["29717114"],"is_preprint":false},{"year":2015,"finding":"Wnt11 and Wnt5a play redundant roles in mouse anterior-posterior axis elongation by regulating convergent extension of notochord cells via the PCP pathway and by promoting EMT through induction of p38 (Mapk14) phosphorylation; compound Wnt5a;Wnt11 mutants show ectopic accumulation of mesodermal precursors with epithelial markers in the primitive streak.","method":"Wnt5a;Wnt11 compound mouse knockout, p38 phosphorylation assays, epithelial marker expression, notochord CE analysis","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — compound knockout establishing redundancy, biochemical readout of p38 phosphorylation, multiple cellular phenotypes; replicated across developmental stages","pmids":["25813538"],"is_preprint":false},{"year":2010,"finding":"Wnt-11 controls ventricular myocardium organization by patterning N-cadherin and β-catenin expression; in Wnt-11 knockout mice, coordinated organization, intercellular contacts, and cytoskeleton of differentiating ventricular cardiomyocytes are disrupted, leading to thinner ventricular wall and reduced Gata-4, Nkx2.5, Mef2c expression.","method":"Wnt11 knockout mouse, N-cadherin/β-catenin localization immunostaining, cardiac functional assessment (echocardiography), gene expression analysis","journal":"Cardiovascular Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with multiple functional and molecular readouts; single lab","pmids":["19622544"],"is_preprint":false},{"year":2012,"finding":"Wnt5a and Wnt11 are co-required for second heart field development in mice; their loss leads to increased Wnt/β-catenin signaling, and ectopic Wnt5a/Wnt11 inhibits β-catenin signaling and promotes cardiac progenitor development in ES cells.","method":"Wnt5a;Wnt11 compound mouse knockout, β-catenin reporter assays, ES cell differentiation, Islet1 marker analysis","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — compound mouse knockout, β-catenin reporter, ES cell gain-of-function; multiple orthogonal methods","pmids":["22569553"],"is_preprint":false},{"year":2020,"finding":"WNT11-FZD7-DAAM1 signaling activates Rho-ROCK1/2-Myosin II to regulate tumour-initiating potential, amoeboid invasion, and distant metastasis in melanoma.","method":"Loss-of-function (knockdown of WNT11, FZD7, DAAM1), Rho-ROCK inhibitors, Myosin II activity assays, in vivo metastasis models","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with mechanistic pathway readout (Rho-ROCK-Myosin II), in vivo model; single lab","pmids":["33082334"],"is_preprint":false},{"year":1996,"finding":"Murine Wnt11 encodes a secreted glycoprotein that becomes associated with the extracellular matrix; Wnt11-expressing Rat2 fibroblasts induce morphological transformation of adjacent C57MG mammary epithelial cells in co-culture, demonstrating paracrine signaling activity.","method":"Conditioned medium secretion assay, extracellular matrix fractionation, co-culture transformation assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — paracrine co-culture assay and ECM fractionation demonstrating secretion; multiple independent assays, single lab","pmids":["8700530"],"is_preprint":false},{"year":1999,"finding":"Cytoplasmic rotation in Xenopus embryos triggers differential cytoplasmic polyadenylation of maternal Xwnt-11 mRNA along the dorsal-ventral axis, resulting in asymmetric accumulation of Wnt11 protein on the dorsal side through translational regulation.","method":"Polyadenylation assays, immunodetection of Wnt11 protein, microtubule disruption experiments in Xenopus embryos","journal":"Developmental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical detection of polyadenylation state and protein asymmetry, microtubule disruption; single lab","pmids":["10525335"],"is_preprint":false},{"year":2016,"finding":"WNT11 transcription is induced by hypoxia primarily through HIF-1α binding to hypoxia response elements (HREs) in the WNT11 promoter; WNT11 stimulates proliferation, migration, and invasion and increases MMP-2 and MMP-9 activity.","method":"HIF-1α loss-of-function, HRE reporter assays, gain-of-function and loss-of-function of WNT11, MMP activity assays in multiple cancer cell types","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — HIF-1α loss-of-function with HRE reporter, gain/loss-of-function; single lab, multiple cell types","pmids":["26861754"],"is_preprint":false},{"year":2011,"finding":"WNT11 is a direct transcriptional target of the ETS transcription factor ERG; ERG occupies the WNT11 chromatin locus (ChIP-chip), ERG knockdown reduces WNT11 transcripts, and ERG induction promotes morphological transformation through WNT11 signals.","method":"ChIP-chip genome-wide screen, ChIP validation in patient samples, siRNA knockdown of ERG, tet-on ERG induction, WNT11 siRNA rescue","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-chip plus orthogonal siRNA knockdown/induction system; single lab","pmids":["21242973"],"is_preprint":false},{"year":2015,"finding":"Nuclear p120-catenin relieves Kaiso-mediated transcriptional repression of Wnt11 in anchorage-independent lobular breast cancer cells, and Wnt11 in turn promotes RhoA activation to confer anoikis resistance.","method":"Genome-wide mRNA profiling, Kaiso/p120 knockdown and overexpression, RhoA activity assay, anoikis resistance assay in mouse ILC cells","journal":"Disease Models & Mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide profiling for target identification, loss-of-function with functional readout; single lab","pmids":["25713299"],"is_preprint":false},{"year":2016,"finding":"WNT-11 cooperates with TGF-β1 to drive smooth muscle α-actin (sm-α-actin) expression in airway smooth muscle cells via a RhoA-Rho kinase-actin cytoskeleton-MRTF-A signaling axis; WNT-11 knockdown attenuates TGF-β1-induced MRTF-A nuclear translocation and sm-α-actin expression.","method":"WNT-11 siRNA knockdown, Rho kinase inhibitor (Y27632), actin polymerization inhibitor (latrunculin A), MRTF-A nuclear localization imaging, sm-α-actin expression assays","journal":"American Journal of Physiology – Lung Cellular and Molecular Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown plus pharmacological pathway dissection, nuclear translocation assay; single lab with orthogonal methods","pmids":["27422998"],"is_preprint":false},{"year":2018,"finding":"Wnt11 directs nephron progenitor polarity and stable attachment to ureteric branch tips in the kidney; in Wnt11 mutants, progenitors lose polarized marker distribution and stably detach/reattach from tips, accelerating differentiation and halving nephron endowment; RNA-seq showed no significant differences in gene expression, suggesting a post-transcriptional or signaling-level mechanism.","method":"Wnt11 knockout mouse, live imaging of nephron progenitors, polarity marker immunostaining, RNA-seq, nephron counting","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout with live imaging and multiple functional/molecular readouts; single lab","pmids":["30516471"],"is_preprint":false},{"year":2019,"finding":"A positive feedback loop between WNT11 and GDNF permits dense packing of ureteric tips in kidney branching morphogenesis, as confirmed experimentally in cultured wildtype and mutant ureteric buds following computational prediction.","method":"Image-based computational modeling, experimental validation in cultured kidney explants, WNT11 and GDNF expression analysis","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — computational prediction validated experimentally in organ culture; single lab","pmids":["30651543"],"is_preprint":false},{"year":2012,"finding":"Notch1 activation inhibits fibroblast growth through a Wnt11-dependent induction of WISP-1/CCN4; blocking Wnt11 expression reduces WISP-1 levels and abrogates Notch-induced growth inhibition; this pathway is Wnt1-independent.","method":"Notch1 knockout MEFs, NICD1 overexpression, siRNA knockdown of WISP-1 and Wnt11, cell growth assays","journal":"PLoS ONE","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockouts, siRNA knockdown of intermediate (Wnt11 and WISP-1), rescue experiments; single lab","pmids":["22715413"],"is_preprint":false},{"year":2025,"finding":"WNT11 promotes CD8+ T-cell exclusion in liver metastasis by decreasing CXCL10 and CCL4 expression through CAMKII-mediated β-catenin/AFF3 downregulation; WNT11 also induces IL17D expression via CAMKII/NF-κB to polarize immunosuppressive macrophages that suppress CD8+ T cells; CAMKII inhibition increases anti-PD-1 therapy efficacy.","method":"WNT11 overexpression in tumor cells, CAMKII inhibition, T-cell recruitment and activity assays, cytokine expression analysis, in vivo liver metastasis mouse model with anti-PD-1 treatment","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function, pharmacological inhibition, in vivo model, multiple pathway readouts; single lab","pmids":["39920102"],"is_preprint":false}],"current_model":"WNT11 is a secreted glycoprotein (N-glycosylated, lipid-modified) that primarily signals through non-canonical Wnt pathways — activating PKC, JNK, RhoA/Rho kinase, and Ca²⁺/CaMKII while generally inhibiting β-catenin/TCF signaling — to coordinate cell polarity, convergent extension movements (via Frizzled 7/Dishevelled/Rab5c/RhoA downstream cascades), cardiogenesis, kidney ureteric branching (through a positive feedback loop with GDNF/RET), and various differentiation programs; context-dependently, maternal Wnt11 also activates canonical Wnt/β-catenin signaling for dorsal axis specification through LRP6-mediated Axin degradation, and Wnt11 complexes with Wnt5a (formed through tyrosine O-sulfation) show enhanced canonical activity."},"narrative":{"mechanistic_narrative":"WNT11 is a secreted, glycosylated, ECM-associated paracrine signaling protein that principally drives non-canonical Wnt cascades to coordinate cell polarity, collective cell movement, and tissue morphogenesis during development [PMID:8700530, PMID:10811221]. During vertebrate gastrulation it controls convergent extension cell-non-autonomously through a divergent Dishevelled-dependent route that does not require canonical β-catenin signaling [PMID:10811221], signaling via Frizzled 7 to recruit and locally accumulate Dishevelled at cell contacts and adherens junctions together with the atypical cadherin Flamingo [PMID:17130287, PMID:17663724], and engaging the co-receptors Ryk (driving β-arrestin 2-dependent Dishevelled endocytosis) and Ror2 [PMID:18809723, PMID:24928507]. Downstream, WNT11 converges on RhoA-Rho kinase (with Diaphanous), Rab5c-regulated E-cadherin endocytosis, and modulation of cadherin-based adhesion through Frizzled 7 adhesion-modulating complexes with PAPC and C-cadherin to tune cell cohesion and elongation [PMID:16019189, PMID:12062050, PMID:16198297, PMID:22908314]. Beyond morphogenesis, WNT11 activates PKC, JNK, and Ca²⁺/CaMKII to direct cardiomyocyte and chondrocyte differentiation while suppressing β-catenin signaling, in heart development acting redundantly with Wnt5a and antagonizing canonical Wnt through caspase-dependent degradation of AKT/β-catenin to promote second heart field progenitors [PMID:12167861, PMID:15084607, PMID:16754689, PMID:25482987, PMID:22569553, PMID:25813538]. In the kidney WNT11 sustains a positive autoregulatory feedback loop with GDNF/RET to pattern ureteric branching and additionally directs nephron progenitor polarity and stable attachment to branch tips [PMID:12783789, PMID:30651543, PMID:30516471]. Context-dependently, WNT11 can also activate canonical Wnt/β-catenin signaling—maternal Wnt11 specifies the dorsal axis through EXT1/FRL1 and LRP6-mediated Axin degradation, and TPST-1-mediated tyrosine O-sulfation enables Wnt11/Wnt5a complexes with enhanced canonical activity [PMID:15797385, PMID:17202189, PMID:19747829]. WNT11 secretion is itself spatially regulated: it is apically secreted in polarized epithelia via Asn40 glycan processing and galectin-3 [PMID:23613470], and its expression is driven by HIF-1α, ERG, ERRα/β-catenin, and Notch1 in cancer contexts where it promotes migration, invasion, amoeboid metastasis, and immune evasion [PMID:26861754, PMID:21242973, PMID:20870744, PMID:33082334, PMID:39920102].","teleology":[{"year":1996,"claim":"Established that WNT11 is a bona fide secreted Wnt with paracrine signaling capacity, framing it as a diffusible morphogen rather than a purely cell-intrinsic factor.","evidence":"Conditioned-medium secretion assay, ECM fractionation, and co-culture transformation of mammary epithelial cells by Wnt11-expressing fibroblasts","pmids":["8700530"],"confidence":"Medium","gaps":["No receptor or downstream pathway identified at this stage","Transformation readout does not define physiological signaling output"]},{"year":2000,"claim":"Resolved that WNT11 acts through a non-canonical, Dishevelled-dependent cascade distinct from the canonical Wnt pathway by showing convergent extension rescue with a canonical-deficient Dishevelled.","evidence":"Zebrafish silberblick loss-of-function genetics with dominant-negative Dishevelled rescue","pmids":["10811221"],"confidence":"High","gaps":["Receptor not identified","Intracellular effectors downstream of Dishevelled not defined"]},{"year":2002,"claim":"Defined the intracellular effector logic of non-canonical WNT11 signaling, linking it to PKC/JNK in cardiogenesis and to Rho kinase in convergent extension cell elongation.","evidence":"Xenopus and P19 cell loss/gain-of-function with PKC/JNK inhibitors; dominant-negative Rok2 and epistatic suppression of slb/wnt11 in zebrafish","pmids":["12167861","12062050"],"confidence":"High","gaps":["How a single ligand routes to distinct effectors in different tissues unresolved","Receptor coupling to PKC/JNK/Rok2 not mapped"]},{"year":2003,"claim":"Showed WNT11 operates within a reciprocal feedback loop with GDNF/RET to control kidney ureteric branching, establishing it as a node in a self-reinforcing morphogenetic circuit.","evidence":"Wnt11 null and Wnt11;Ret compound mutant mice with Gdnf in situ hybridization","pmids":["12783789"],"confidence":"High","gaps":["Receptor mediating Wnt11 in kidney not identified","Mechanism by which Wnt11 maintains Gdnf expression not defined"]},{"year":2004,"claim":"Demonstrated WNT11 actively represses canonical Wnt signaling via receptor competition and intracellular Ca²⁺, and engages PKC/CaMKII to drive epithelial proliferation, clarifying its antagonistic relationship to β-catenin signaling.","evidence":"LEF-1 reporter, co-culture competition, Ca²⁺ manipulation, siRNA in P19; PKC/CaMKII assays in IEC6 cells","pmids":["15067007","15084607"],"confidence":"High","gaps":["Selectivity of receptor competition mechanistically unexplained","Direct Ca²⁺ source not identified"]},{"year":2005,"claim":"Revealed a context-dependent canonical arm: maternal WNT11 can specify dorsal axis through EXT1 and the EGF-CFC protein FRL1, and morphogenesis is executed through Rab5c-dependent E-cadherin endocytosis and RhoA effectors.","evidence":"Xenopus maternal depletion of Wnt11/EXT1/FRL1 with FRL1 Co-IP; zebrafish Rab5c phenocopy/rescue and E-cadherin endocytosis; rhoA rescue of wnt11 mutants","pmids":["15797385","16198297","16019189"],"confidence":"High","gaps":["How the same ligand selects canonical versus non-canonical output remains unresolved","FRL1/EXT1 biochemical role in receptor activation not defined"]},{"year":2006,"claim":"Provided a cell-biological mechanism for non-canonical signaling by showing WNT11 locally accumulates Frizzled 7 at contacts, recruiting Dishevelled and Flamingo to stabilize cell contacts independently of RhoA/Rok2.","evidence":"Live imaging, subcellular localization, and Co-IP of Wnt11/Frizzled7/Flamingo in zebrafish","pmids":["17130287"],"confidence":"High","gaps":["Link between local Fz7/Dvl clustering and downstream transcription/cytoskeleton not fully mapped"]},{"year":2008,"claim":"Identified Ryk as a co-receptor enabling β-arrestin 2-dependent Dishevelled endocytosis required for WNT11 convergent extension, and established WNT11 as a directional PCP cue acting downstream of canonical Wnt in myogenesis.","evidence":"Ryk/Wnt11/β-arrestin 2 Co-IP and endocytosis assays in Xenopus; siRNA and ectopic-source PCP experiments in chick somites","pmids":["18809723","18987628"],"confidence":"High","gaps":["Stoichiometry of Fz7/Ryk receptor complex unknown","How directional information is read out by myocytes not defined"]},{"year":2009,"claim":"Showed post-translational tyrosine O-sulfation by TPST-1 controls WNT11/Wnt5a complex formation that enhances canonical signaling, and that WNT11 promotes osteoblast maturation via β-catenin-dependent Rspo2 induction.","evidence":"Co-IP, sulfation-site mutagenesis, and reporter assays across oocyte/L-cell/hESC systems; Rspo2 knockdown and dominant-negative TCF in pre-osteoblasts","pmids":["19747829","19213727"],"confidence":"High","gaps":["Physiological contexts where Wnt11/Wnt5a heterocomplexes form in vivo not established","Receptor for the sulfated complex not identified"]},{"year":2010,"claim":"Connected non-canonical WNT11 to physiological cardiac patterning and electrophysiology and to caspase-dependent suppression of β-catenin during cardiomyocyte differentiation, while extending its role to cancer cell survival and migration.","evidence":"Zebrafish optical mapping with L-type Ca²⁺ channel pharmacology; caspase-inhibitor and β-catenin assays; Wnt11 KO mouse N-cadherin/β-catenin patterning; PKA-dependent prostate cancer assays; ERRα/β-catenin/LEF-1 Co-IP","pmids":["20657579","21041481","19622544","20219091","20870744"],"confidence":"High","gaps":["Mechanistic link between caspase activation and β-catenin/AKT turnover incomplete","How Wnt11 patterns N-cadherin/β-catenin at junctions not defined"]},{"year":2012,"claim":"Defined a molecular mechanism for adhesion control during convergent extension via two distinct Frizzled 7 adhesion-modulating complexes and established WNT11 as a co-required factor for second heart field development.","evidence":"Co-IP, domain mapping, endocytosis and cell-sorting assays in Xenopus; Wnt5a;Wnt11 compound KO mice with β-catenin reporters and ES cell differentiation","pmids":["22908314","22569553","17663724"],"confidence":"High","gaps":["In vivo contribution of each adhesion complex not quantified","Redundancy boundaries between Wnt11 and Wnt5a not fully mapped"]},{"year":2014,"claim":"Identified Ror2 as a direct WNT11 receptor coupling to Dishevelled/RhoA in convergent extension, and showed WNT11/Wnt5a suppress β-catenin and promote heart field progenitors through caspase-dependent AKT degradation.","evidence":"Ror2/Wnt11 Co-IP, Ror2 site-directed mutagenesis, epistasis and transplantation in zebrafish; caspase and AKT assays in ES cells and mice","pmids":["24928507","25482987"],"confidence":"High","gaps":["How Ror2, Fz7, and Ryk are partitioned across contexts unresolved","Caspase target specificity for AKT versus β-catenin not defined"]},{"year":2015,"claim":"Established redundant WNT11/Wnt5a control of body axis elongation via PCP-driven notochord convergent extension and p38-dependent EMT, and connected WNT11 to RhoA-mediated anoikis resistance in cancer.","evidence":"Wnt5a;Wnt11 compound KO mice with p38 phosphorylation and epithelial-marker analysis; p120/Kaiso regulation and RhoA activity in breast cancer cells","pmids":["25813538","25713299"],"confidence":"High","gaps":["Receptor mediating p38 activation not identified","Generalizability of anoikis mechanism across tumor types untested"]},{"year":2018,"claim":"Identified FZD8 as a major WNT11 receptor in prostate cancer that couples to ATF2 transcription and forms a TGF-β-regulated receptor complex, and clarified WNT11's role in nephron progenitor polarity and attachment.","evidence":"Reciprocal Co-IP, domain mapping, FZD8 shRNA, ATF2 reporter in prostate cancer; Wnt11 KO mouse live imaging, polarity markers, RNA-seq, nephron counting","pmids":["29717114","30516471"],"confidence":"High","gaps":["Mechanism of polarity control in kidney is post-transcriptional/signaling-level but undefined","How WNT11 integrates FZD8 with TGF-β receptors mechanistically unresolved"]},{"year":2020,"claim":"Defined a WNT11-FZD7-DAAM1-Rho-ROCK-Myosin II axis driving amoeboid invasion and metastasis, extending the morphogenetic cytoskeletal program to malignant dissemination.","evidence":"Knockdown of WNT11/FZD7/DAAM1, Rho-ROCK inhibitors, Myosin II assays, in vivo metastasis models in melanoma","pmids":["33082334"],"confidence":"Medium","gaps":["Single-lab pathway model","Relative contribution of DAAM1 versus other Rho activators not quantified"]},{"year":2025,"claim":"Connected WNT11/CAMKII signaling to tumor immune evasion, showing it suppresses CD8+ T-cell recruitment and polarizes immunosuppressive macrophages, and that CAMKII inhibition sensitizes tumors to anti-PD-1.","evidence":"WNT11 overexpression, CAMKII inhibition, cytokine and T-cell assays, in vivo liver metastasis model with anti-PD-1","pmids":["39920102"],"confidence":"Medium","gaps":["Single-lab study","Receptor mediating WNT11/CAMKII in this context not identified","Translatability of CAMKII inhibition to patients untested"]},{"year":null,"claim":"It remains unresolved how a single secreted WNT11 ligand selects between canonical and non-canonical outputs and among distinct receptors (Frizzled 7, Frizzled 8, Frizzled 5, Ror2, Ryk) and effectors (PKC, JNK, RhoA/ROCK, CaMKII, caspase/AKT) in a tissue- and context-specific manner.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of receptor selection","Structural basis for ligand-receptor specificity unknown","Quantitative rules linking ligand dose/modification to pathway choice undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[33,0,1,6,27,28]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,16]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[33]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[33]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,23,21]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,9,27,28]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,8,29,31,39]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[32,35,36,42]}],"complexes":["WNT11-Frizzled7-Flamingo complex","Wnt11/Wnt5a sulfated complex","WNT11-FZD7-DAAM1 complex","Frizzled7 adhesion-modulating complexes (with PAPC and C-cadherin)"],"partners":["FZD7","FZD8","ROR2","RYK","WNT5A","FRL1","FZD5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O96014","full_name":"Protein Wnt-11","aliases":[],"length_aa":354,"mass_kda":39.2,"function":"Ligand for members of the frizzled family of seven transmembrane receptors. Probable developmental protein. May be a signaling molecule which affects the development of discrete regions of tissues. Is likely to signal over only few cell diameters","subcellular_location":"Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/O96014/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WNT11","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/WNT11","total_profiled":1310},"omim":[{"mim_id":"611514","title":"WNT LIGAND SECRETION MEDIATOR; WLS","url":"https://www.omim.org/entry/611514"},{"mim_id":"604158","title":"SECRETED FRIZZLED-RELATED PROTEIN 5; SFRP5","url":"https://www.omim.org/entry/604158"},{"mim_id":"603699","title":"WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 11; WNT11","url":"https://www.omim.org/entry/603699"},{"mim_id":"601884","title":"BONE MINERAL DENSITY QUANTITATIVE TRAIT LOCUS 1; BMND1","url":"https://www.omim.org/entry/601884"},{"mim_id":"601570","title":"WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 7A; WNT7A","url":"https://www.omim.org/entry/601570"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":35.7}],"url":"https://www.proteinatlas.org/search/WNT11"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O96014","domains":[{"cath_id":"-","chopping":"25-281","consensus_level":"high","plddt":92.8933,"start":25,"end":281},{"cath_id":"3.30.2460.20","chopping":"297-354","consensus_level":"medium","plddt":95.3895,"start":297,"end":354}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O96014","model_url":"https://alphafold.ebi.ac.uk/files/AF-O96014-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O96014-F1-predicted_aligned_error_v6.png","plddt_mean":90.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WNT11","jax_strain_url":"https://www.jax.org/strain/search?query=WNT11"},"sequence":{"accession":"O96014","fasta_url":"https://rest.uniprot.org/uniprotkb/O96014.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O96014/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O96014"}},"corpus_meta":[{"pmid":"10811221","id":"PMC_10811221","title":"Silberblick/Wnt11 mediates convergent extension movements during zebrafish gastrulation.","date":"2000","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/10811221","citation_count":861,"is_preprint":false},{"pmid":"12167861","id":"PMC_12167861","title":"Wnt-11 activation of a non-canonical Wnt signalling pathway is required for cardiogenesis.","date":"2002","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12167861","citation_count":430,"is_preprint":false},{"pmid":"15797385","id":"PMC_15797385","title":"Maternal wnt11 activates the canonical wnt signaling pathway required for axis formation in Xenopus embryos.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/15797385","citation_count":410,"is_preprint":false},{"pmid":"12783789","id":"PMC_12783789","title":"Wnt11 and Ret/Gdnf pathways cooperate in regulating ureteric branching during metanephric kidney development.","date":"2003","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/12783789","citation_count":359,"is_preprint":false},{"pmid":"19805103","id":"PMC_19805103","title":"Microwell-mediated control of embryoid body size regulates embryonic stem cell fate via differential expression of WNT5a and WNT11.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19805103","citation_count":292,"is_preprint":false},{"pmid":"12062050","id":"PMC_12062050","title":"Zebrafish Rho kinase 2 acts downstream of Wnt11 to mediate cell polarity and effective convergence and extension movements.","date":"2002","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/12062050","citation_count":279,"is_preprint":false},{"pmid":"8951078","id":"PMC_8951078","title":"Proteoglycans are required for maintenance of Wnt-11 expression in the ureter tips.","date":"1996","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/8951078","citation_count":256,"is_preprint":false},{"pmid":"16198297","id":"PMC_16198297","title":"Wnt11 functions in gastrulation by controlling cell cohesion through Rab5c and E-cadherin.","date":"2005","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/16198297","citation_count":235,"is_preprint":false},{"pmid":"15996547","id":"PMC_15996547","title":"Early stages of zebrafish eye formation require the coordinated activity of Wnt11, Fz5, and the Wnt/beta-catenin pathway.","date":"2005","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/15996547","citation_count":163,"is_preprint":false},{"pmid":"18987628","id":"PMC_18987628","title":"WNT11 acts as a directional cue to organize the elongation of early muscle fibres.","date":"2008","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/18987628","citation_count":161,"is_preprint":false},{"pmid":"17522159","id":"PMC_17522159","title":"Reduction of BMP4 activity by gremlin 1 enables ureteric bud outgrowth and GDNF/WNT11 feedback signalling during kidney branching morphogenesis.","date":"2007","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/17522159","citation_count":151,"is_preprint":false},{"pmid":"10474165","id":"PMC_10474165","title":"WNT11 promotes cardiac tissue formation of early mesoderm.","date":"1999","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/10474165","citation_count":143,"is_preprint":false},{"pmid":"20219091","id":"PMC_20219091","title":"Wnt-11 promotes neuroendocrine-like differentiation, survival and migration of prostate cancer cells.","date":"2010","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20219091","citation_count":140,"is_preprint":false},{"pmid":"13129848","id":"PMC_13129848","title":"Slb/Wnt11 controls hypoblast cell migration and morphogenesis at the onset of zebrafish gastrulation.","date":"2003","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/13129848","citation_count":134,"is_preprint":false},{"pmid":"18981481","id":"PMC_18981481","title":"Sfrp5 coordinates foregut specification and morphogenesis by antagonizing both canonical and noncanonical Wnt11 signaling.","date":"2008","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/18981481","citation_count":133,"is_preprint":false},{"pmid":"7547479","id":"PMC_7547479","title":"Murine Wnt-11 and Wnt-12 have temporally and spatially restricted expression patterns during embryonic development.","date":"1995","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/7547479","citation_count":123,"is_preprint":false},{"pmid":"20870744","id":"PMC_20870744","title":"WNT11 expression is induced by estrogen-related receptor alpha and beta-catenin and acts in an autocrine manner to increase cancer cell migration.","date":"2010","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/20870744","citation_count":121,"is_preprint":false},{"pmid":"20657579","id":"PMC_20657579","title":"Wnt11 patterns a myocardial electrical gradient through regulation of the L-type Ca(2+) channel.","date":"2010","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/20657579","citation_count":116,"is_preprint":false},{"pmid":"22569553","id":"PMC_22569553","title":"Wnt5a and Wnt11 are essential for second heart field progenitor development.","date":"2012","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/22569553","citation_count":115,"is_preprint":false},{"pmid":"15067007","id":"PMC_15067007","title":"Multiple mechanisms for Wnt11-mediated repression of the canonical Wnt signaling pathway.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15067007","citation_count":115,"is_preprint":false},{"pmid":"11712081","id":"PMC_11712081","title":"Molecular cloning and characterization of human WNT11.","date":"2001","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11712081","citation_count":112,"is_preprint":false},{"pmid":"17130287","id":"PMC_17130287","title":"Wnt11 controls cell contact persistence by local accumulation of Frizzled 7 at the plasma membrane.","date":"2006","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17130287","citation_count":105,"is_preprint":false},{"pmid":"19213727","id":"PMC_19213727","title":"Wnt11 promotes osteoblast maturation and mineralization through R-spondin 2.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19213727","citation_count":103,"is_preprint":false},{"pmid":"15541384","id":"PMC_15541384","title":"Wnt11 facilitates embryonic stem cell differentiation to Nkx2.5-positive cardiomyocytes.","date":"2004","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15541384","citation_count":102,"is_preprint":false},{"pmid":"16019189","id":"PMC_16019189","title":"RhoA acts downstream of Wnt5 and Wnt11 to regulate convergence and extension movements by involving effectors Rho kinase and Diaphanous: use of zebrafish as an in vivo model for GTPase signaling.","date":"2005","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/16019189","citation_count":101,"is_preprint":false},{"pmid":"9757009","id":"PMC_9757009","title":"Isolation, characterisation and embryonic expression of WNT11, a gene which maps to 11q13.5 and has possible roles in the development of skeleton, kidney and lung.","date":"1998","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/9757009","citation_count":101,"is_preprint":false},{"pmid":"9053328","id":"PMC_9053328","title":"Wnt-11 is expressed in early avian mesoderm and required for the differentiation of the quail mesoderm cell line QCE-6.","date":"1997","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9053328","citation_count":99,"is_preprint":false},{"pmid":"16754689","id":"PMC_16754689","title":"Opposing roles of WNT-5A and WNT-11 in interleukin-1beta regulation of type II collagen expression in articular chondrocytes.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16754689","citation_count":98,"is_preprint":false},{"pmid":"16707109","id":"PMC_16707109","title":"wnt3a but not wnt11 supports self-renewal of embryonic stem cells.","date":"2006","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16707109","citation_count":95,"is_preprint":false},{"pmid":"15708567","id":"PMC_15708567","title":"Wnt11-R, a protein closely related to mammalian Wnt11, is required for heart morphogenesis in Xenopus.","date":"2005","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/15708567","citation_count":93,"is_preprint":false},{"pmid":"29717114","id":"PMC_29717114","title":"Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29717114","citation_count":93,"is_preprint":false},{"pmid":"18809723","id":"PMC_18809723","title":"Ryk cooperates with Frizzled 7 to promote Wnt11-mediated endocytosis and is essential for Xenopus laevis convergent extension movements.","date":"2008","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18809723","citation_count":93,"is_preprint":false},{"pmid":"15084607","id":"PMC_15084607","title":"Wnt11 signaling promotes proliferation, transformation, and migration of IEC6 intestinal epithelial cells.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15084607","citation_count":90,"is_preprint":false},{"pmid":"28529644","id":"PMC_28529644","title":"3,3'-Diindolylmethane stimulates exosomal Wnt11 autocrine signaling in human umbilical cord mesenchymal stem cells to enhance wound healing.","date":"2017","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/28529644","citation_count":88,"is_preprint":false},{"pmid":"25813538","id":"PMC_25813538","title":"Wnt5a and Wnt11 regulate mammalian anterior-posterior axis elongation.","date":"2015","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25813538","citation_count":85,"is_preprint":false},{"pmid":"15201220","id":"PMC_15201220","title":"Sprouty proteins regulate ureteric branching by coordinating reciprocal epithelial Wnt11, mesenchymal Gdnf and stromal Fgf7 signalling during kidney development.","date":"2004","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/15201220","citation_count":85,"is_preprint":false},{"pmid":"17202189","id":"PMC_17202189","title":"Wnt11/beta-catenin signaling in both oocytes and early embryos acts through LRP6-mediated regulation of axin.","date":"2007","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/17202189","citation_count":80,"is_preprint":false},{"pmid":"9507106","id":"PMC_9507106","title":"Zebrafish wnt11: pattern and regulation of the expression by the yolk cell and No tail activity.","date":"1998","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/9507106","citation_count":77,"is_preprint":false},{"pmid":"33082334","id":"PMC_33082334","title":"WNT11-FZD7-DAAM1 signalling supports tumour initiating abilities and melanoma amoeboid invasion.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33082334","citation_count":73,"is_preprint":false},{"pmid":"25959411","id":"PMC_25959411","title":"MiR-154-5p regulates osteogenic differentiation of adipose-derived mesenchymal stem cells under tensile stress through the Wnt/PCP pathway by targeting Wnt11.","date":"2015","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/25959411","citation_count":71,"is_preprint":false},{"pmid":"25482987","id":"PMC_25482987","title":"Wnt5a and Wnt11 inhibit the canonical Wnt pathway and promote cardiac progenitor development via the Caspase-dependent degradation of AKT.","date":"2014","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/25482987","citation_count":67,"is_preprint":false},{"pmid":"21447091","id":"PMC_21447091","title":"Wnt11 in 2011 - the regulation and function of a non-canonical Wnt.","date":"2011","source":"Acta physiologica (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/21447091","citation_count":65,"is_preprint":false},{"pmid":"18602094","id":"PMC_18602094","title":"Non-canonical Wnt signaling through Wnt5a/b and a novel Wnt11 gene, Wnt11b, regulates cell migration during avian gastrulation.","date":"2008","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/18602094","citation_count":64,"is_preprint":false},{"pmid":"19622544","id":"PMC_19622544","title":"Wnt-11 signalling controls ventricular myocardium development by patterning N-cadherin and beta-catenin expression.","date":"2010","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/19622544","citation_count":64,"is_preprint":false},{"pmid":"21041481","id":"PMC_21041481","title":"Wnt11 promotes cardiomyocyte development by caspase-mediated suppression of canonical Wnt signals.","date":"2010","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21041481","citation_count":63,"is_preprint":false},{"pmid":"30651543","id":"PMC_30651543","title":"Image-based modeling of kidney branching morphogenesis reveals GDNF-RET based Turing-type mechanism and pattern-modulating WNT11 feedback.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30651543","citation_count":61,"is_preprint":false},{"pmid":"19747829","id":"PMC_19747829","title":"Wnt11/5a complex formation caused by tyrosine sulfation increases canonical signaling activity.","date":"2009","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/19747829","citation_count":60,"is_preprint":false},{"pmid":"20103596","id":"PMC_20103596","title":"Noncanonical Wnt11 inhibits hepatocellular carcinoma cell proliferation and migration.","date":"2010","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/20103596","citation_count":59,"is_preprint":false},{"pmid":"23613470","id":"PMC_23613470","title":"The apical and basolateral secretion of Wnt11 and Wnt3a in polarized epithelial cells is regulated by different mechanisms.","date":"2013","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/23613470","citation_count":59,"is_preprint":false},{"pmid":"10525335","id":"PMC_10525335","title":"Spatially regulated translation in embryos: asymmetric expression of maternal Wnt-11 along the dorsal-ventral axis in Xenopus.","date":"1999","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/10525335","citation_count":59,"is_preprint":false},{"pmid":"38267432","id":"PMC_38267432","title":"Mechanical stiffness promotes skin fibrosis via Piezo1-Wnt2/Wnt11-CCL24 positive feedback loop.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38267432","citation_count":58,"is_preprint":false},{"pmid":"19809516","id":"PMC_19809516","title":"GLI3 repressor controls nephron number via regulation of Wnt11 and Ret in ureteric tip cells.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19809516","citation_count":58,"is_preprint":false},{"pmid":"18427129","id":"PMC_18427129","title":"Noncanonical Wnt11 signaling is sufficient to induce cardiomyogenic differentiation in unfractionated bone marrow mononuclear cells.","date":"2008","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/18427129","citation_count":57,"is_preprint":false},{"pmid":"30980110","id":"PMC_30980110","title":"Regulation of WNT5A and WNT11 during MSC in vitro chondrogenesis: WNT inhibition lowers BMP and hedgehog activity, and reduces hypertrophy.","date":"2019","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/30980110","citation_count":54,"is_preprint":false},{"pmid":"22908314","id":"PMC_22908314","title":"Wnt-11 and Fz7 reduce cell adhesion in convergent extension by sequestration of PAPC and C-cadherin.","date":"2012","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22908314","citation_count":54,"is_preprint":false},{"pmid":"30516471","id":"PMC_30516471","title":"Wnt11 directs nephron progenitor polarity and motile behavior ultimately determining nephron endowment.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/30516471","citation_count":53,"is_preprint":false},{"pmid":"7779076","id":"PMC_7779076","title":"A chicken Wnt gene, Wnt-11, is involved in dermal development.","date":"1995","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/7779076","citation_count":53,"is_preprint":false},{"pmid":"19232955","id":"PMC_19232955","title":"Noncanonical Wnt11 signaling and cardiomyogenic differentiation.","date":"2008","source":"Trends in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/19232955","citation_count":50,"is_preprint":false},{"pmid":"18191119","id":"PMC_18191119","title":"Wnt11/Fgfr1b cross-talk modulates the fate of cells in palate development.","date":"2007","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/18191119","citation_count":50,"is_preprint":false},{"pmid":"29427622","id":"PMC_29427622","title":"Secreted AGR2 promotes invasion of colorectal cancer cells via Wnt11-mediated non-canonical Wnt signaling.","date":"2018","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/29427622","citation_count":49,"is_preprint":false},{"pmid":"26861754","id":"PMC_26861754","title":"Induction of WNT11 by hypoxia and hypoxia-inducible factor-1α regulates cell proliferation, migration and invasion.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26861754","citation_count":47,"is_preprint":false},{"pmid":"22161723","id":"PMC_22161723","title":"Possible involvement of Wnt11 in colorectal cancer progression.","date":"2011","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/22161723","citation_count":47,"is_preprint":false},{"pmid":"21280163","id":"PMC_21280163","title":"Distinct roles for Wnt-4 and Wnt-11 during retinoic acid-induced neuronal differentiation.","date":"2011","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/21280163","citation_count":45,"is_preprint":false},{"pmid":"24474615","id":"PMC_24474615","title":"Overexpression of Wnt11 promotes chondrogenic differentiation of bone marrow-derived mesenchymal stem cells in synergism with TGF-β.","date":"2014","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24474615","citation_count":45,"is_preprint":false},{"pmid":"19380582","id":"PMC_19380582","title":"Zebrafish eaf1 and eaf2/u19 mediate effective convergence and extension movements through the maintenance of wnt11 and wnt5 expression.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19380582","citation_count":44,"is_preprint":false},{"pmid":"17240368","id":"PMC_17240368","title":"Wnt11-R signaling regulates a calcium sensitive EMT event essential for dorsal fin development of Xenopus.","date":"2006","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/17240368","citation_count":43,"is_preprint":false},{"pmid":"21463175","id":"PMC_21463175","title":"Paracrine effect of Wnt11-overexpressing mesenchymal stem cells on ischemic injury.","date":"2011","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/21463175","citation_count":42,"is_preprint":false},{"pmid":"24928507","id":"PMC_24928507","title":"Ror2 receptor mediates Wnt11 ligand signaling and affects convergence and extension movements in zebrafish.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24928507","citation_count":40,"is_preprint":false},{"pmid":"21903761","id":"PMC_21903761","title":"Wingless homolog Wnt11 suppresses bacterial invasion and inflammation in intestinal epithelial cells.","date":"2011","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21903761","citation_count":38,"is_preprint":false},{"pmid":"21242973","id":"PMC_21242973","title":"Genome-wide screen reveals WNT11, a non-canonical WNT gene, as a direct target of ETS transcription factor ERG.","date":"2011","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/21242973","citation_count":38,"is_preprint":false},{"pmid":"31231131","id":"PMC_31231131","title":"Ascl1-induced Wnt11 regulates neuroendocrine differentiation, cell proliferation, and E-cadherin expression in small-cell lung cancer and Wnt11 regulates small-cell lung cancer biology.","date":"2019","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31231131","citation_count":35,"is_preprint":false},{"pmid":"7896292","id":"PMC_7896292","title":"Isolation and genetic mapping of two novel members of the murine Wnt gene family, Wnt11 and Wnt12, and the mapping of Wnt5a and Wnt7a.","date":"1994","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/7896292","citation_count":35,"is_preprint":false},{"pmid":"16818447","id":"PMC_16818447","title":"Regulation of ectodermal Wnt6 expression by the neural tube is transduced by dermomyotomal Wnt11: a mechanism of dermomyotomal lip sustainment.","date":"2006","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/16818447","citation_count":34,"is_preprint":false},{"pmid":"25713299","id":"PMC_25713299","title":"Nuclear p120-catenin regulates the anoikis resistance of mouse lobular breast cancer cells through Kaiso-dependent Wnt11 expression.","date":"2015","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/25713299","citation_count":33,"is_preprint":false},{"pmid":"30537177","id":"PMC_30537177","title":"Long noncoding RNA ABHD11-AS1 promote cells proliferation and invasion of colorectal cancer via regulating the miR-1254-WNT11 pathway.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30537177","citation_count":32,"is_preprint":false},{"pmid":"12889062","id":"PMC_12889062","title":"Wnt11 and Wnt7a are up-regulated in association with differentiation of cardiac conduction cells in vitro and in vivo.","date":"2003","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/12889062","citation_count":32,"is_preprint":false},{"pmid":"21231807","id":"PMC_21231807","title":"Transduction of Wnt11 promotes mesenchymal stem cell transdifferentiation into cardiac phenotypes.","date":"2011","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/21231807","citation_count":32,"is_preprint":false},{"pmid":"18572162","id":"PMC_18572162","title":"Wnt-11 signaling leads to down-regulation of the Wnt/beta-catenin, JNK/AP-1 and NF-kappaB pathways and promotes viability in the CHO-K1 cells.","date":"2008","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/18572162","citation_count":32,"is_preprint":false},{"pmid":"32182839","id":"PMC_32182839","title":"Upregulated Wnt-11 and miR-21 Expression Trigger Epithelial Mesenchymal Transition in Aggressive Prostate Cancer Cells.","date":"2020","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/32182839","citation_count":31,"is_preprint":false},{"pmid":"34564708","id":"PMC_34564708","title":"Cardiac Wnt5a and Wnt11 promote fibrosis by the crosstalk of FZD5 and EGFR signaling under pressure overload.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34564708","citation_count":30,"is_preprint":false},{"pmid":"30010216","id":"PMC_30010216","title":"Wnt11 promotes BMP9-induced osteogenic differentiation through BMPs/Smads and p38 MAPK in mesenchymal stem cells.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30010216","citation_count":30,"is_preprint":false},{"pmid":"30243083","id":"PMC_30243083","title":"Co-expression of Akt1 and Wnt11 promotes the proliferation and cardiac differentiation of mesenchymal stem cells and attenuates hypoxia/reoxygenation-induced cardiomyocyte apoptosis.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/30243083","citation_count":29,"is_preprint":false},{"pmid":"29872092","id":"PMC_29872092","title":"Role of Wnt11 during Osteogenic Differentiation of Human Mesenchymal Stem Cells on Microstructured Titanium Surfaces.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29872092","citation_count":29,"is_preprint":false},{"pmid":"27422998","id":"PMC_27422998","title":"Cooperative signaling by TGF-β1 and WNT-11 drives sm-α-actin expression in smooth muscle via Rho kinase-actin-MRTF-A signaling.","date":"2016","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27422998","citation_count":28,"is_preprint":false},{"pmid":"8700530","id":"PMC_8700530","title":"Murine WNT11 is a secreted glycoprotein that morphologically transforms mammary epithelial cells.","date":"1996","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8700530","citation_count":26,"is_preprint":false},{"pmid":"23998262","id":"PMC_23998262","title":"Wnt11 expression in rat dental pulp and promotional effects of Wnt signaling on odontoblast differentiation.","date":"2013","source":"Congenital anomalies","url":"https://pubmed.ncbi.nlm.nih.gov/23998262","citation_count":25,"is_preprint":false},{"pmid":"17663724","id":"PMC_17663724","title":"Wnt11 stimulation induces polarized accumulation of Dishevelled at apical adherens junctions through Frizzled7.","date":"2007","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/17663724","citation_count":25,"is_preprint":false},{"pmid":"20564202","id":"PMC_20564202","title":"Negative regulation of wnt11 expression by Jnk signaling during zebrafish gastrulation.","date":"2010","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20564202","citation_count":25,"is_preprint":false},{"pmid":"29955137","id":"PMC_29955137","title":"Downregulation of WNT11 is associated with bladder tissue fibrosis in patients with interstitial cystitis/bladder pain syndrome without Hunner lesion.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29955137","citation_count":25,"is_preprint":false},{"pmid":"25448697","id":"PMC_25448697","title":"Mapping the dynamic expression of Wnt11 and the lineage contribution of Wnt11-expressing cells during early mouse development.","date":"2014","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/25448697","citation_count":24,"is_preprint":false},{"pmid":"28878122","id":"PMC_28878122","title":"Wnt11 regulates cardiac chamber development and disease during perinatal maturation.","date":"2017","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/28878122","citation_count":22,"is_preprint":false},{"pmid":"22961180","id":"PMC_22961180","title":"Involvement of the WNT and FGF signaling pathways in non-isolated anorectal malformations: sequencing analysis of WNT3A, WNT5A, WNT11, DACT1, FGF10, FGFR2 and the T gene.","date":"2012","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22961180","citation_count":22,"is_preprint":false},{"pmid":"39920102","id":"PMC_39920102","title":"WNT11 Promotes immune evasion and resistance to Anti-PD-1 therapy in liver metastasis.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39920102","citation_count":20,"is_preprint":false},{"pmid":"22715413","id":"PMC_22715413","title":"Inhibition of fibroblast growth by Notch1 signaling is mediated by induction of Wnt11-dependent WISP-1.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22715413","citation_count":20,"is_preprint":false},{"pmid":"24737009","id":"PMC_24737009","title":"Clinical significance of Wnt-11 and squamous cell carcinoma antigen expression in cervical cancer.","date":"2014","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/24737009","citation_count":20,"is_preprint":false},{"pmid":"31150636","id":"PMC_31150636","title":"Fibronectin regulates the self-renewal of rabbit limbal epithelial stem cells by stimulating the Wnt11/Fzd7/ROCK non-canonical Wnt pathway.","date":"2019","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/31150636","citation_count":20,"is_preprint":false},{"pmid":"28669819","id":"PMC_28669819","title":"Tissue specific requirements for WNT11 in developing outflow tract and dorsal mesenchymal protrusion.","date":"2017","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/28669819","citation_count":19,"is_preprint":false},{"pmid":"27582005","id":"PMC_27582005","title":"Impairment of Wnt11 function leads to kidney tubular abnormalities and secondary glomerular cystogenesis.","date":"2016","source":"BMC developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/27582005","citation_count":19,"is_preprint":false},{"pmid":"21304494","id":"PMC_21304494","title":"Lentivirus-mediated Wnt11 gene transfer enhances Cardiomyogenic differentiation of skeletal muscle-derived stem cells.","date":"2011","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/21304494","citation_count":19,"is_preprint":false},{"pmid":"26882996","id":"PMC_26882996","title":"Wnt11 Gene Therapy with Adeno-associated Virus 9 Improves Recovery from Myocardial Infarction by Modulating the Inflammatory Response.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26882996","citation_count":19,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50128,"output_tokens":10250,"usd":0.152067,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20894,"output_tokens":5964,"usd":0.126785,"stage2_stop_reason":"end_turn"},"total_usd":0.278852,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"Zebrafish Wnt11 (silberblick locus) mediates convergent extension movements during gastrulation in a cell non-autonomous manner; its phenotype is rescued by a truncated Dishevelled that does not signal through the canonical Wnt pathway, indicating Wnt11 acts through a divergent (non-canonical) signal transduction cascade.\",\n      \"method\": \"Genetic mapping, loss-of-function mutant analysis, rescue with dominant-negative Dishevelled construct\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function in zebrafish with specific cellular phenotype and epistasis rescue, replicated across multiple labs subsequently\",\n      \"pmids\": [\"10811221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Wnt11 is required for heart formation in Xenopus; it mediates cardiogenesis via non-canonical Wnt signaling that is independent of β-catenin and involves protein kinase C (PKC) and Jun N-terminal kinase (JNK).\",\n      \"method\": \"Loss- and gain-of-function experiments in Xenopus; conditioned medium treatment of P19 mouse embryonic carcinoma cells; pathway inhibitor assays for PKC and JNK\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (loss-of-function, gain-of-function, pharmacological inhibitors of PKC and JNK), replicated across species (Xenopus and mouse cells)\",\n      \"pmids\": [\"12167861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Maternal Wnt11 activates the canonical Wnt signaling pathway to specify the dorsal axis in Xenopus; this activation requires the glycosyl transferase EXT1 and the EGF-CFC protein FRL1, which interacts with Wnt11.\",\n      \"method\": \"Loss-of-function (depletion of maternal Wnt11, EXT1, FRL1 by antisense oligonucleotides); co-immunoprecipitation of FRL1 with Wnt11\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple loss-of-function approaches and interaction assay in Xenopus, published in Cell with three independent lines of evidence\",\n      \"pmids\": [\"15797385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Wnt11 and Ret/GDNF cooperate in a positive autoregulatory feedback loop during kidney development: Wnt11 maintains GDNF expression in the mesenchyme, and GDNF/Ret signaling maintains Wnt11 expression in ureteric tips; loss of Wnt11 reduces GDNF, and Wnt11/Ret double mutants show synergistic ureteric branching defects.\",\n      \"method\": \"Targeted gene knockout (Wnt11 null mice), genetic epistasis (Wnt11;Ret compound mutants), in situ hybridization for Gdnf expression\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse, synergistic genetic interaction confirmed by compound mutants, multiple labs replicated feedback loop\",\n      \"pmids\": [\"12783789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Rho kinase 2 (Rok2) acts downstream of Wnt11 to mediate mediolateral cell elongation required for convergent extension movements in zebrafish; overexpression of Rok2 partially suppresses the slb/wnt11 gastrulation phenotype, and ectopic non-canonical Wnts modulate Rok2 intracellular distribution.\",\n      \"method\": \"Dominant-negative Rok2 overexpression, genetic suppression of slb/wnt11 mutant phenotype by Rok2 overexpression, transplantation experiments\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis rescue and dominant-negative experiments establishing pathway position, transplantation confirming cell-autonomous function\",\n      \"pmids\": [\"12062050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Wnt11 controls tissue morphogenesis during zebrafish gastrulation by regulating E-cadherin-mediated cell cohesion via the GTPase Rab5c, a regulator of early endocytosis; blocking Rab5c phenocopies slb/wnt11 mutants, and enhancing Rab5c in slb/wnt11 mutants rescues the phenotype.\",\n      \"method\": \"Loss-of-function, rescue experiments, epistasis in zebrafish embryos; E-cadherin endocytosis assays\",\n      \"journal\": \"Developmental Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional epistasis (phenocopy and rescue) plus endocytosis assay, multiple orthogonal methods\",\n      \"pmids\": [\"16198297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Wnt11 locally accumulates its receptor Frizzled 7 at cell contact sites in zebrafish embryonic cells; Frizzled 7 accumulations in turn recruit Dishevelled and Wnt11 itself, increasing local cell contact persistence through interaction with the atypical cadherin Flamingo, without requiring RhoA or Rok2 activity.\",\n      \"method\": \"Live imaging, subcellular localization studies, co-immunoprecipitation, dominant-negative and overexpression experiments in zebrafish\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct subcellular localization with functional consequence, Co-IP of Wnt11/Frizzled7/Flamingo complex, multiple orthogonal methods\",\n      \"pmids\": [\"17130287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Ryk cooperates with Frizzled 7 to mediate Wnt11-stimulated β-arrestin 2-dependent endocytosis of Dishevelled, which is required for non-canonical Wnt11 signaling in convergent extension movements in Xenopus.\",\n      \"method\": \"Co-immunoprecipitation (Ryk with Wnt11 and β-arrestin 2), morpholino knockdown, endocytosis assays in Xenopus dorsal marginal zone\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, morpholino loss-of-function, and endocytosis assays; single lab with multiple methods\",\n      \"pmids\": [\"18809723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"WNT11 acts as a directional cue for oriented myocyte elongation in chick somites through the planar cell polarity (PCP) pathway; a localized ectopic source of WNT11 changes myocyte orientation, operating downstream of the WNT/β-catenin pathway that initiates the myogenic program.\",\n      \"method\": \"Loss-of-function (siRNA in somites), ectopic WNT11 source placement, epistasis with WNT/β-catenin pathway in chick embryos\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — specific inhibition in vivo, ectopic localized source experiment, epistasis establishing pathway order; published in Nature\",\n      \"pmids\": [\"18987628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Wnt11 represses canonical Wnt signaling through multiple mechanisms: (1) receptor competition (preventing Wnt1/Wnt3/Wnt3a but not Wnt7a/7b from activating LEF-1), and (2) elevation of intracellular Ca²⁺ that inhibits canonical signaling; siRNA knockdown of endogenous Wnt11 in P19 cells increases LEF-1 reporter activity.\",\n      \"method\": \"LEF-1 reporter assays in NIH3T3 and P19 cells, co-culture competition experiments, siRNA knockdown, intracellular Ca²⁺ manipulation\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, co-culture, Ca²⁺ manipulation, siRNA knockdown), single lab\",\n      \"pmids\": [\"15067007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In zebrafish, Wnt11 and Frizzled 5 promote eye field development partly through local antagonism of Wnt/β-catenin signaling and additionally regulate the cohesion of eye field cells.\",\n      \"method\": \"Loss-of-function and epistasis experiments in zebrafish embryos; cell cohesion assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic loss-of-function with specific phenotype, single lab, pathway epistasis inferred\",\n      \"pmids\": [\"15996547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RhoA acts downstream of Wnt11 (and Wnt5) to regulate convergent extension movements in zebrafish, exerting its effects via two effectors: Rho kinase and Diaphanous (mDia); rhoA mRNA rescues CE defects in wnt11 mutants.\",\n      \"method\": \"Morpholino knockdown of rhoA in zebrafish, rescue of wnt11 mutants with rhoA mRNA, ectopic expression of Rho kinase and Diaphanous\",\n      \"journal\": \"Cellular Signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue epistasis plus parallel effector pathway analysis, single lab\",\n      \"pmids\": [\"16019189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Wnt11 canonical signaling in Xenopus oocytes and early embryos operates through LRP6-mediated degradation of Axin: in the oocyte Wnt11/LRP6 maintains low β-catenin by regulating Axin, while in the embryo asymmetric Wnt11/LRP6 stabilizes β-catenin on the dorsal side.\",\n      \"method\": \"Morpholino depletion of LRP6 and Wnt11 in Xenopus oocytes/embryos; Axin protein level assays; β-catenin localization\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with biochemical readout, single lab, multiple developmental stages tested\",\n      \"pmids\": [\"17202189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Wnt11/5a complexes, formed through TPST-1-mediated O-sulfation of specific tyrosine residues on Wnt11, have greater canonical Wnt signaling activity than either Wnt11 or Wnt5a alone; sulfation of Wnt11 is required for its interaction with Wnt5a.\",\n      \"method\": \"Co-immunoprecipitation of Wnt11/Wnt5a; canonical signaling reporter assays in Xenopus oocytes, mouse L cells, and human ESCs; TPST-1 loss-of-function; mutagenesis of sulfation sites\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — Co-IP, site-directed mutagenesis of sulfation sites, three independent cell systems; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"19747829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Wnt11 promotes osteoblast maturation and mineralization through β-catenin-dependent induction of R-spondin 2 (Rspo2); knockdown of Rspo2 abrogates Wnt11-mediated osteoblast maturation, and dominant-negative TCF blocks Wnt11-mediated Rspo2 expression.\",\n      \"method\": \"Overexpression and knockdown (siRNA of Rspo2) in MC3T3E1 pre-osteoblasts; dominant-negative TCF; alkaline phosphatase and mineralization assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression, knockdown, and dominant-negative TCF together establish pathway order, single lab\",\n      \"pmids\": [\"19213727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Sfrp5 locally inhibits Wnt11 to coordinate canonical (Wnt/β-catenin) and non-canonical (Wnt/PCP) signaling in Xenopus foregut development: depletion of Sfrp5 leads to inappropriate Wnt11-mediated β-catenin and PCP signaling causing cell fate and epithelial adhesion defects, respectively.\",\n      \"method\": \"Morpholino depletion of Sfrp5 and Wnt11 in Xenopus; reporter assays for β-catenin and PCP signaling; rescue experiments\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — double knockdown epistasis, pathway-specific reporter assays, rescue; single lab\",\n      \"pmids\": [\"18981481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Non-canonical Wnt11 signaling in the zebrafish heart establishes a myocardial electrical gradient through effects on transmembrane Ca²⁺ conductance mediated by the L-type calcium channel; the traditional planar cell polarity pathway is not involved.\",\n      \"method\": \"High-speed optical mapping of transmembrane potentials and Ca²⁺ in zebrafish heart; loss-of-function of Wnt11; pharmacological manipulation of L-type calcium channel\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — optical mapping combined with Wnt11 loss-of-function and pharmacological validation; published in Nature with multiple orthogonal methods\",\n      \"pmids\": [\"20657579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Wnt11 promotes neuroendocrine-like differentiation and survival of prostate cancer cells via cyclic AMP-dependent protein kinase; silencing Wnt11 causes apoptosis in androgen-depleted LNCaP and PC3 cells; Wnt11 also promotes cell migration/invasion.\",\n      \"method\": \"Ectopic Wnt11 expression, siRNA knockdown, PKA inhibitor treatment, migration/invasion assays in prostate cancer cell lines\",\n      \"journal\": \"Molecular Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function plus pharmacological inhibitor, single lab, multiple cell lines\",\n      \"pmids\": [\"20219091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ERRα and β-catenin form a macromolecular complex with LEF-1 in cells and co-operatively induce WNT11 transcription; WNT11 then acts in an autocrine manner to increase cancer cell migration; WNT11-neutralizing antibodies abrogate the ERRα/β-catenin promigratory effect.\",\n      \"method\": \"Co-immunoprecipitation of ERRα/β-catenin/LEF-1; WNT11 conditioned medium; WNT11 neutralizing antibodies; siRNA knockdown; migration assays\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, neutralizing antibody, conditioned medium, siRNA; single lab\",\n      \"pmids\": [\"20870744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Wnt11 promotes cardiomyocyte differentiation while suppressing β-catenin stabilization through activation of a caspase 3 signaling cascade; inhibition of caspase activity leads to β-catenin accumulation and reduced myocyte differentiation.\",\n      \"method\": \"Wnt11 stimulation of cardiomyocyte cultures, caspase inhibitor treatment, β-catenin western blot, differentiation assays\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition plus Wnt11 gain-of-function, mechanistic readout of β-catenin and caspase activity; single lab\",\n      \"pmids\": [\"21041481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Wnt5a and Wnt11 inhibit canonical Wnt/β-catenin signaling and promote second heart field progenitor development through Caspase-dependent degradation of AKT; Caspase inhibition blocked Wnt5a/Wnt11-induced suppression of both phosphorylated and total Akt, and Akt inhibition alone was sufficient to promote second heart field markers.\",\n      \"method\": \"Caspase activity assays, AKT western blot, Caspase inhibitor treatment in differentiating ES cells and in vivo (mouse), SHF marker expression\",\n      \"journal\": \"Developmental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition in vitro and in vivo, biochemical readout of AKT; single lab with multiple approaches\",\n      \"pmids\": [\"25482987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Wnt11 is secreted apically in polarized epithelial cells via a mechanism requiring complex/hybrid glycan processing at Asn40 and galectin-3, distinct from the basolateral Wntless (Wls)-dependent pathway used by Wnt3a; fusion of the Asn40 glycosylation site of Wnt11 onto Wnt3a redirected Wnt3a to apical secretion.\",\n      \"method\": \"Mass-spectrometric glycan analysis of Wnt11, mutational analysis of glycosylation sites, apical/basolateral secretion assays in polarized MDCK cells, galectin-3 knockdown\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mass spectrometry, mutagenesis of glycosylation sites, domain swap experiment; multiple orthogonal methods in single study\",\n      \"pmids\": [\"23613470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Wnt11/Frizzled 7 controls cell adhesion during convergent extension by forming two separate adhesion-modulating complexes (AMCs): one with PAPC (AMCP) that blocks PAPC internalization, preventing C-cadherin clustering, and one with C-cadherin (AMCC) that competes with C-cadherin cis-dimerization; both act in parallel to reduce cell adhesion.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping of Fz7 interactions, endocytosis (dynamin1/clathrin-dependent) assays, cell sorting assays in Xenopus\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, endocytosis assays, cell sorting functional readout; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"22908314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Wnt11 stimulation induces polarized accumulation of Dishevelled at apical adherens junctions in Xenopus via Frizzled 7; the DIX domain of Dishevelled is required for its translocation in response to Wnt11; Frizzled 7 itself accumulates at adherens junctions in response to Wnt11.\",\n      \"method\": \"Morpholino knockdown of Frizzled 7, Dishevelled localization imaging, domain deletion analysis (DIX domain), Wnt11 stimulation assays in Xenopus ectodermal explants\",\n      \"journal\": \"Genes to Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino knockdown, subcellular localization assay, domain mutant analysis; single lab\",\n      \"pmids\": [\"17663724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Wnt11 stimulates proliferation, migration, and contact-independent growth of IEC6 intestinal epithelial cells via a β-catenin-independent mechanism involving PKC and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII); PKC inhibition reduces Wnt11-induced foci formation; Wnt11 also redistributes E-cadherin.\",\n      \"method\": \"Conditioned medium treatment and stable transfection with Wnt11; PKC activity assays; CaMKII activity assays; PKC inhibitor; E-cadherin immunofluorescence; foci formation assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition, multiple functional readouts, single lab\",\n      \"pmids\": [\"15084607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Wnt11 (via non-canonical pathway) activates PKC to stimulate type II collagen expression in chondrocytes; a PKC inhibitor blocks this effect; in contrast, Wnt-5a activates JNK to inhibit type II collagen expression.\",\n      \"method\": \"Conditioned medium from Wnt-11 or Wnt-5a expressing cells, PKC and JNK inhibitors, siRNA knockdown, collagen expression assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection, knockdown, single lab with clear functional readout\",\n      \"pmids\": [\"16754689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Noncanonical Wnt11 signaling induces cardiomyogenic differentiation of adult bone marrow mononuclear cells via PKC and JNK pathways; Wnt11-induced cardiac gene expression is abolished by PKC inhibitor bisindolylmaleimide I and partially by JNK inhibitor SP600125.\",\n      \"method\": \"Wnt11 conditioned medium treatment of BMMNCs, PKC and JNK pharmacological inhibitors, cardiac marker qRT-PCR and immunocytochemistry\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition of specific kinases, multiple cardiac marker readouts; single lab\",\n      \"pmids\": [\"18427129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Ror2 physically interacts with Wnt11 and functions as a receptor mediating Wnt11 signaling during convergent extension in zebrafish; Tyr-647 and Ser-863 of Ror2 are essential for mediating Wnt11 action; Dishevelled and RhoA act downstream of Wnt11-Ror2.\",\n      \"method\": \"Co-immunoprecipitation of Ror2 and Wnt11, dominant-negative Ror2 overexpression, epistasis with wnt11 morpholino, site-directed mutagenesis of Ror2, transplantation experiments in zebrafish\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, mutagenesis, genetic epistasis, transplantation; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"24928507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FZD8 is a major Wnt-11 receptor in prostate cancer; FZD8 co-localizes and co-immunoprecipitates with Wnt-11, potentiates Wnt-11 activation of ATF2-dependent transcription, and forms a TGF-β-regulated complex with TGF-β receptors mediated by the extracellular domains of FZD8 and TGFBR1.\",\n      \"method\": \"Co-immunoprecipitation, co-localization, FZD8 silencing (shRNA), ATF2 reporter assay, 3D organotypic assays, EMT gene expression analysis in prostate cancer cell lines\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, domain-mapping of receptor complex, reporter assay, functional silencing; multiple methods, single lab\",\n      \"pmids\": [\"29717114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Wnt11 and Wnt5a play redundant roles in mouse anterior-posterior axis elongation by regulating convergent extension of notochord cells via the PCP pathway and by promoting EMT through induction of p38 (Mapk14) phosphorylation; compound Wnt5a;Wnt11 mutants show ectopic accumulation of mesodermal precursors with epithelial markers in the primitive streak.\",\n      \"method\": \"Wnt5a;Wnt11 compound mouse knockout, p38 phosphorylation assays, epithelial marker expression, notochord CE analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — compound knockout establishing redundancy, biochemical readout of p38 phosphorylation, multiple cellular phenotypes; replicated across developmental stages\",\n      \"pmids\": [\"25813538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Wnt-11 controls ventricular myocardium organization by patterning N-cadherin and β-catenin expression; in Wnt-11 knockout mice, coordinated organization, intercellular contacts, and cytoskeleton of differentiating ventricular cardiomyocytes are disrupted, leading to thinner ventricular wall and reduced Gata-4, Nkx2.5, Mef2c expression.\",\n      \"method\": \"Wnt11 knockout mouse, N-cadherin/β-catenin localization immunostaining, cardiac functional assessment (echocardiography), gene expression analysis\",\n      \"journal\": \"Cardiovascular Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with multiple functional and molecular readouts; single lab\",\n      \"pmids\": [\"19622544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Wnt5a and Wnt11 are co-required for second heart field development in mice; their loss leads to increased Wnt/β-catenin signaling, and ectopic Wnt5a/Wnt11 inhibits β-catenin signaling and promotes cardiac progenitor development in ES cells.\",\n      \"method\": \"Wnt5a;Wnt11 compound mouse knockout, β-catenin reporter assays, ES cell differentiation, Islet1 marker analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — compound mouse knockout, β-catenin reporter, ES cell gain-of-function; multiple orthogonal methods\",\n      \"pmids\": [\"22569553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WNT11-FZD7-DAAM1 signaling activates Rho-ROCK1/2-Myosin II to regulate tumour-initiating potential, amoeboid invasion, and distant metastasis in melanoma.\",\n      \"method\": \"Loss-of-function (knockdown of WNT11, FZD7, DAAM1), Rho-ROCK inhibitors, Myosin II activity assays, in vivo metastasis models\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with mechanistic pathway readout (Rho-ROCK-Myosin II), in vivo model; single lab\",\n      \"pmids\": [\"33082334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Murine Wnt11 encodes a secreted glycoprotein that becomes associated with the extracellular matrix; Wnt11-expressing Rat2 fibroblasts induce morphological transformation of adjacent C57MG mammary epithelial cells in co-culture, demonstrating paracrine signaling activity.\",\n      \"method\": \"Conditioned medium secretion assay, extracellular matrix fractionation, co-culture transformation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — paracrine co-culture assay and ECM fractionation demonstrating secretion; multiple independent assays, single lab\",\n      \"pmids\": [\"8700530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Cytoplasmic rotation in Xenopus embryos triggers differential cytoplasmic polyadenylation of maternal Xwnt-11 mRNA along the dorsal-ventral axis, resulting in asymmetric accumulation of Wnt11 protein on the dorsal side through translational regulation.\",\n      \"method\": \"Polyadenylation assays, immunodetection of Wnt11 protein, microtubule disruption experiments in Xenopus embryos\",\n      \"journal\": \"Developmental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical detection of polyadenylation state and protein asymmetry, microtubule disruption; single lab\",\n      \"pmids\": [\"10525335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WNT11 transcription is induced by hypoxia primarily through HIF-1α binding to hypoxia response elements (HREs) in the WNT11 promoter; WNT11 stimulates proliferation, migration, and invasion and increases MMP-2 and MMP-9 activity.\",\n      \"method\": \"HIF-1α loss-of-function, HRE reporter assays, gain-of-function and loss-of-function of WNT11, MMP activity assays in multiple cancer cell types\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — HIF-1α loss-of-function with HRE reporter, gain/loss-of-function; single lab, multiple cell types\",\n      \"pmids\": [\"26861754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"WNT11 is a direct transcriptional target of the ETS transcription factor ERG; ERG occupies the WNT11 chromatin locus (ChIP-chip), ERG knockdown reduces WNT11 transcripts, and ERG induction promotes morphological transformation through WNT11 signals.\",\n      \"method\": \"ChIP-chip genome-wide screen, ChIP validation in patient samples, siRNA knockdown of ERG, tet-on ERG induction, WNT11 siRNA rescue\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-chip plus orthogonal siRNA knockdown/induction system; single lab\",\n      \"pmids\": [\"21242973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nuclear p120-catenin relieves Kaiso-mediated transcriptional repression of Wnt11 in anchorage-independent lobular breast cancer cells, and Wnt11 in turn promotes RhoA activation to confer anoikis resistance.\",\n      \"method\": \"Genome-wide mRNA profiling, Kaiso/p120 knockdown and overexpression, RhoA activity assay, anoikis resistance assay in mouse ILC cells\",\n      \"journal\": \"Disease Models & Mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide profiling for target identification, loss-of-function with functional readout; single lab\",\n      \"pmids\": [\"25713299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WNT-11 cooperates with TGF-β1 to drive smooth muscle α-actin (sm-α-actin) expression in airway smooth muscle cells via a RhoA-Rho kinase-actin cytoskeleton-MRTF-A signaling axis; WNT-11 knockdown attenuates TGF-β1-induced MRTF-A nuclear translocation and sm-α-actin expression.\",\n      \"method\": \"WNT-11 siRNA knockdown, Rho kinase inhibitor (Y27632), actin polymerization inhibitor (latrunculin A), MRTF-A nuclear localization imaging, sm-α-actin expression assays\",\n      \"journal\": \"American Journal of Physiology – Lung Cellular and Molecular Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown plus pharmacological pathway dissection, nuclear translocation assay; single lab with orthogonal methods\",\n      \"pmids\": [\"27422998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Wnt11 directs nephron progenitor polarity and stable attachment to ureteric branch tips in the kidney; in Wnt11 mutants, progenitors lose polarized marker distribution and stably detach/reattach from tips, accelerating differentiation and halving nephron endowment; RNA-seq showed no significant differences in gene expression, suggesting a post-transcriptional or signaling-level mechanism.\",\n      \"method\": \"Wnt11 knockout mouse, live imaging of nephron progenitors, polarity marker immunostaining, RNA-seq, nephron counting\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout with live imaging and multiple functional/molecular readouts; single lab\",\n      \"pmids\": [\"30516471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A positive feedback loop between WNT11 and GDNF permits dense packing of ureteric tips in kidney branching morphogenesis, as confirmed experimentally in cultured wildtype and mutant ureteric buds following computational prediction.\",\n      \"method\": \"Image-based computational modeling, experimental validation in cultured kidney explants, WNT11 and GDNF expression analysis\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — computational prediction validated experimentally in organ culture; single lab\",\n      \"pmids\": [\"30651543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Notch1 activation inhibits fibroblast growth through a Wnt11-dependent induction of WISP-1/CCN4; blocking Wnt11 expression reduces WISP-1 levels and abrogates Notch-induced growth inhibition; this pathway is Wnt1-independent.\",\n      \"method\": \"Notch1 knockout MEFs, NICD1 overexpression, siRNA knockdown of WISP-1 and Wnt11, cell growth assays\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockouts, siRNA knockdown of intermediate (Wnt11 and WISP-1), rescue experiments; single lab\",\n      \"pmids\": [\"22715413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"WNT11 promotes CD8+ T-cell exclusion in liver metastasis by decreasing CXCL10 and CCL4 expression through CAMKII-mediated β-catenin/AFF3 downregulation; WNT11 also induces IL17D expression via CAMKII/NF-κB to polarize immunosuppressive macrophages that suppress CD8+ T cells; CAMKII inhibition increases anti-PD-1 therapy efficacy.\",\n      \"method\": \"WNT11 overexpression in tumor cells, CAMKII inhibition, T-cell recruitment and activity assays, cytokine expression analysis, in vivo liver metastasis mouse model with anti-PD-1 treatment\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function, pharmacological inhibition, in vivo model, multiple pathway readouts; single lab\",\n      \"pmids\": [\"39920102\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WNT11 is a secreted glycoprotein (N-glycosylated, lipid-modified) that primarily signals through non-canonical Wnt pathways — activating PKC, JNK, RhoA/Rho kinase, and Ca²⁺/CaMKII while generally inhibiting β-catenin/TCF signaling — to coordinate cell polarity, convergent extension movements (via Frizzled 7/Dishevelled/Rab5c/RhoA downstream cascades), cardiogenesis, kidney ureteric branching (through a positive feedback loop with GDNF/RET), and various differentiation programs; context-dependently, maternal Wnt11 also activates canonical Wnt/β-catenin signaling for dorsal axis specification through LRP6-mediated Axin degradation, and Wnt11 complexes with Wnt5a (formed through tyrosine O-sulfation) show enhanced canonical activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WNT11 is a secreted, glycosylated, ECM-associated paracrine signaling protein that principally drives non-canonical Wnt cascades to coordinate cell polarity, collective cell movement, and tissue morphogenesis during development [#33, #0]. During vertebrate gastrulation it controls convergent extension cell-non-autonomously through a divergent Dishevelled-dependent route that does not require canonical β-catenin signaling [#0], signaling via Frizzled 7 to recruit and locally accumulate Dishevelled at cell contacts and adherens junctions together with the atypical cadherin Flamingo [#6, #23], and engaging the co-receptors Ryk (driving β-arrestin 2-dependent Dishevelled endocytosis) and Ror2 [#7, #27]. Downstream, WNT11 converges on RhoA-Rho kinase (with Diaphanous), Rab5c-regulated E-cadherin endocytosis, and modulation of cadherin-based adhesion through Frizzled 7 adhesion-modulating complexes with PAPC and C-cadherin to tune cell cohesion and elongation [#11, #4, #5, #22]. Beyond morphogenesis, WNT11 activates PKC, JNK, and Ca²⁺/CaMKII to direct cardiomyocyte and chondrocyte differentiation while suppressing β-catenin signaling, in heart development acting redundantly with Wnt5a and antagonizing canonical Wnt through caspase-dependent degradation of AKT/β-catenin to promote second heart field progenitors [#1, #24, #25, #20, #31, #29]. In the kidney WNT11 sustains a positive autoregulatory feedback loop with GDNF/RET to pattern ureteric branching and additionally directs nephron progenitor polarity and stable attachment to branch tips [#3, #40, #39]. Context-dependently, WNT11 can also activate canonical Wnt/β-catenin signaling—maternal Wnt11 specifies the dorsal axis through EXT1/FRL1 and LRP6-mediated Axin degradation, and TPST-1-mediated tyrosine O-sulfation enables Wnt11/Wnt5a complexes with enhanced canonical activity [#2, #12, #13]. WNT11 secretion is itself spatially regulated: it is apically secreted in polarized epithelia via Asn40 glycan processing and galectin-3 [#21], and its expression is driven by HIF-1α, ERG, ERRα/β-catenin, and Notch1 in cancer contexts where it promotes migration, invasion, amoeboid metastasis, and immune evasion [#35, #36, #18, #32, #42].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that WNT11 is a bona fide secreted Wnt with paracrine signaling capacity, framing it as a diffusible morphogen rather than a purely cell-intrinsic factor.\",\n      \"evidence\": \"Conditioned-medium secretion assay, ECM fractionation, and co-culture transformation of mammary epithelial cells by Wnt11-expressing fibroblasts\",\n      \"pmids\": [\"8700530\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor or downstream pathway identified at this stage\", \"Transformation readout does not define physiological signaling output\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Resolved that WNT11 acts through a non-canonical, Dishevelled-dependent cascade distinct from the canonical Wnt pathway by showing convergent extension rescue with a canonical-deficient Dishevelled.\",\n      \"evidence\": \"Zebrafish silberblick loss-of-function genetics with dominant-negative Dishevelled rescue\",\n      \"pmids\": [\"10811221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor not identified\", \"Intracellular effectors downstream of Dishevelled not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the intracellular effector logic of non-canonical WNT11 signaling, linking it to PKC/JNK in cardiogenesis and to Rho kinase in convergent extension cell elongation.\",\n      \"evidence\": \"Xenopus and P19 cell loss/gain-of-function with PKC/JNK inhibitors; dominant-negative Rok2 and epistatic suppression of slb/wnt11 in zebrafish\",\n      \"pmids\": [\"12167861\", \"12062050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single ligand routes to distinct effectors in different tissues unresolved\", \"Receptor coupling to PKC/JNK/Rok2 not mapped\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed WNT11 operates within a reciprocal feedback loop with GDNF/RET to control kidney ureteric branching, establishing it as a node in a self-reinforcing morphogenetic circuit.\",\n      \"evidence\": \"Wnt11 null and Wnt11;Ret compound mutant mice with Gdnf in situ hybridization\",\n      \"pmids\": [\"12783789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating Wnt11 in kidney not identified\", \"Mechanism by which Wnt11 maintains Gdnf expression not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated WNT11 actively represses canonical Wnt signaling via receptor competition and intracellular Ca²⁺, and engages PKC/CaMKII to drive epithelial proliferation, clarifying its antagonistic relationship to β-catenin signaling.\",\n      \"evidence\": \"LEF-1 reporter, co-culture competition, Ca²⁺ manipulation, siRNA in P19; PKC/CaMKII assays in IEC6 cells\",\n      \"pmids\": [\"15067007\", \"15084607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity of receptor competition mechanistically unexplained\", \"Direct Ca²⁺ source not identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Revealed a context-dependent canonical arm: maternal WNT11 can specify dorsal axis through EXT1 and the EGF-CFC protein FRL1, and morphogenesis is executed through Rab5c-dependent E-cadherin endocytosis and RhoA effectors.\",\n      \"evidence\": \"Xenopus maternal depletion of Wnt11/EXT1/FRL1 with FRL1 Co-IP; zebrafish Rab5c phenocopy/rescue and E-cadherin endocytosis; rhoA rescue of wnt11 mutants\",\n      \"pmids\": [\"15797385\", \"16198297\", \"16019189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the same ligand selects canonical versus non-canonical output remains unresolved\", \"FRL1/EXT1 biochemical role in receptor activation not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Provided a cell-biological mechanism for non-canonical signaling by showing WNT11 locally accumulates Frizzled 7 at contacts, recruiting Dishevelled and Flamingo to stabilize cell contacts independently of RhoA/Rok2.\",\n      \"evidence\": \"Live imaging, subcellular localization, and Co-IP of Wnt11/Frizzled7/Flamingo in zebrafish\",\n      \"pmids\": [\"17130287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link between local Fz7/Dvl clustering and downstream transcription/cytoskeleton not fully mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified Ryk as a co-receptor enabling β-arrestin 2-dependent Dishevelled endocytosis required for WNT11 convergent extension, and established WNT11 as a directional PCP cue acting downstream of canonical Wnt in myogenesis.\",\n      \"evidence\": \"Ryk/Wnt11/β-arrestin 2 Co-IP and endocytosis assays in Xenopus; siRNA and ectopic-source PCP experiments in chick somites\",\n      \"pmids\": [\"18809723\", \"18987628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of Fz7/Ryk receptor complex unknown\", \"How directional information is read out by myocytes not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed post-translational tyrosine O-sulfation by TPST-1 controls WNT11/Wnt5a complex formation that enhances canonical signaling, and that WNT11 promotes osteoblast maturation via β-catenin-dependent Rspo2 induction.\",\n      \"evidence\": \"Co-IP, sulfation-site mutagenesis, and reporter assays across oocyte/L-cell/hESC systems; Rspo2 knockdown and dominant-negative TCF in pre-osteoblasts\",\n      \"pmids\": [\"19747829\", \"19213727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contexts where Wnt11/Wnt5a heterocomplexes form in vivo not established\", \"Receptor for the sulfated complex not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected non-canonical WNT11 to physiological cardiac patterning and electrophysiology and to caspase-dependent suppression of β-catenin during cardiomyocyte differentiation, while extending its role to cancer cell survival and migration.\",\n      \"evidence\": \"Zebrafish optical mapping with L-type Ca²⁺ channel pharmacology; caspase-inhibitor and β-catenin assays; Wnt11 KO mouse N-cadherin/β-catenin patterning; PKA-dependent prostate cancer assays; ERRα/β-catenin/LEF-1 Co-IP\",\n      \"pmids\": [\"20657579\", \"21041481\", \"19622544\", \"20219091\", \"20870744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between caspase activation and β-catenin/AKT turnover incomplete\", \"How Wnt11 patterns N-cadherin/β-catenin at junctions not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined a molecular mechanism for adhesion control during convergent extension via two distinct Frizzled 7 adhesion-modulating complexes and established WNT11 as a co-required factor for second heart field development.\",\n      \"evidence\": \"Co-IP, domain mapping, endocytosis and cell-sorting assays in Xenopus; Wnt5a;Wnt11 compound KO mice with β-catenin reporters and ES cell differentiation\",\n      \"pmids\": [\"22908314\", \"22569553\", \"17663724\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution of each adhesion complex not quantified\", \"Redundancy boundaries between Wnt11 and Wnt5a not fully mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified Ror2 as a direct WNT11 receptor coupling to Dishevelled/RhoA in convergent extension, and showed WNT11/Wnt5a suppress β-catenin and promote heart field progenitors through caspase-dependent AKT degradation.\",\n      \"evidence\": \"Ror2/Wnt11 Co-IP, Ror2 site-directed mutagenesis, epistasis and transplantation in zebrafish; caspase and AKT assays in ES cells and mice\",\n      \"pmids\": [\"24928507\", \"25482987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Ror2, Fz7, and Ryk are partitioned across contexts unresolved\", \"Caspase target specificity for AKT versus β-catenin not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established redundant WNT11/Wnt5a control of body axis elongation via PCP-driven notochord convergent extension and p38-dependent EMT, and connected WNT11 to RhoA-mediated anoikis resistance in cancer.\",\n      \"evidence\": \"Wnt5a;Wnt11 compound KO mice with p38 phosphorylation and epithelial-marker analysis; p120/Kaiso regulation and RhoA activity in breast cancer cells\",\n      \"pmids\": [\"25813538\", \"25713299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating p38 activation not identified\", \"Generalizability of anoikis mechanism across tumor types untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified FZD8 as a major WNT11 receptor in prostate cancer that couples to ATF2 transcription and forms a TGF-β-regulated receptor complex, and clarified WNT11's role in nephron progenitor polarity and attachment.\",\n      \"evidence\": \"Reciprocal Co-IP, domain mapping, FZD8 shRNA, ATF2 reporter in prostate cancer; Wnt11 KO mouse live imaging, polarity markers, RNA-seq, nephron counting\",\n      \"pmids\": [\"29717114\", \"30516471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of polarity control in kidney is post-transcriptional/signaling-level but undefined\", \"How WNT11 integrates FZD8 with TGF-β receptors mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a WNT11-FZD7-DAAM1-Rho-ROCK-Myosin II axis driving amoeboid invasion and metastasis, extending the morphogenetic cytoskeletal program to malignant dissemination.\",\n      \"evidence\": \"Knockdown of WNT11/FZD7/DAAM1, Rho-ROCK inhibitors, Myosin II assays, in vivo metastasis models in melanoma\",\n      \"pmids\": [\"33082334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab pathway model\", \"Relative contribution of DAAM1 versus other Rho activators not quantified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected WNT11/CAMKII signaling to tumor immune evasion, showing it suppresses CD8+ T-cell recruitment and polarizes immunosuppressive macrophages, and that CAMKII inhibition sensitizes tumors to anti-PD-1.\",\n      \"evidence\": \"WNT11 overexpression, CAMKII inhibition, cytokine and T-cell assays, in vivo liver metastasis model with anti-PD-1\",\n      \"pmids\": [\"39920102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Receptor mediating WNT11/CAMKII in this context not identified\", \"Translatability of CAMKII inhibition to patients untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single secreted WNT11 ligand selects between canonical and non-canonical outputs and among distinct receptors (Frizzled 7, Frizzled 8, Frizzled 5, Ror2, Ryk) and effectors (PKC, JNK, RhoA/ROCK, CaMKII, caspase/AKT) in a tissue- and context-specific manner.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of receptor selection\", \"Structural basis for ligand-receptor specificity unknown\", \"Quantitative rules linking ligand dose/modification to pathway choice undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [33, 0, 1, 6, 27, 28]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [33]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [33]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 23, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 9, 27, 28]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 8, 29, 31, 39]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [32, 35, 36, 42]}\n    ],\n    \"complexes\": [\n      \"WNT11-Frizzled7-Flamingo complex\",\n      \"Wnt11/Wnt5a sulfated complex\",\n      \"WNT11-FZD7-DAAM1 complex\",\n      \"Frizzled7 adhesion-modulating complexes (with PAPC and C-cadherin)\"\n    ],\n    \"partners\": [\"FZD7\", \"FZD8\", \"ROR2\", \"RYK\", \"WNT5A\", \"FRL1\", \"FZD5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}