{"gene":"FZD5","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2001,"finding":"Fzd5 knockout mice die in utero around E10.75 due to defects in yolk sac and placental angiogenesis, with markedly reduced endothelial cell proliferation (BrdU labeling) prior to morphological changes; Fzd5 specifically synergized with Wnt2, Wnt5a, and Wnt10b in ectopic axis induction in Xenopus, establishing it as a Wnt receptor required for endothelial growth in the yolk sac.","method":"Homologous recombination knockout mouse, BrdU proliferation assay, Xenopus ectopic axis induction assay","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic KO with clear cellular phenotype, supported by functional Xenopus axis induction assay; replicated across multiple experimental approaches in one rigorous study","pmids":["11092808"],"is_preprint":false},{"year":2003,"finding":"WNT7A signals specifically through a FZD5·LRP6 receptor complex in PC12 cells to increase β-catenin stability and activate TCF-based transcription; this activity is antagonized by Dickkopf-1 and Dickkopf-3.","method":"TCF/LEF luciferase reporter assay, β-catenin stability assay, dominant-negative receptor constructs, pharmacological inhibition with Dickkopf proteins in PC12 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts (reporter + β-catenin stabilization + antagonist rescue) in a single lab","pmids":["12857724"],"is_preprint":false},{"year":2009,"finding":"CVAK104 (a coated-vesicle-associated kinase) binds Dishevelled and selectively binds FZD5 (but not FZD1 or FZD4), induces clathrin-mediated intracellular accumulation of FZD5, and routes it to lysosomal degradation; CVAK104 knockdown increases FZD5 levels and activates Wnt/β-catenin signaling, while overexpression suppresses it.","method":"Co-immunoprecipitation, dominant-negative Rab5 assay, RNAi knockdown, lysosomal inhibitor experiments, Wnt/β-catenin reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding demonstrated with selectivity controls (FZD1/FZD4 negative), multiple orthogonal approaches (Co-IP, dominant-negative Rab5, RNAi, reporter), consistent functional readout","pmids":["19643732"],"is_preprint":false},{"year":2008,"finding":"Purified Wnt7a directly binds the extracellular cysteine-rich domain of Fzd5 in the nanomolar range, as shown by ELISA-based protein-protein binding assay; a split eGFP complementation assay visualized Wnt7a-Fzd5 interactions and subsequent pathway activation in cells.","method":"ELISA-based protein binding assay with purified proteins, split eGFP complementation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct in vitro binding assay with purified proteins, but single lab and single paper","pmids":["18230341"],"is_preprint":false},{"year":2013,"finding":"Fzd5 and Gcm1 form a positive feedback loop in chorionic trophoblast: Gcm1 upregulates Fzd5 specifically at branching initiation sites, and elevated Fzd5 expression maintains Gcm1 expression via nuclear β-catenin signaling. Fzd5-mediated signaling induces disassociation of cell junctions (downregulating ZO-1, claudin 4, claudin 7) for branching initiation and upregulates Vegf in chorion trophoblast cells.","method":"Global and trophoblast-specific Fzd5-null and Gcm1-deficient mouse models, trophoblast stem cell lines, tetraploid aggregation assay, immunofluorescence, Western blot","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models (global KO, conditional KO, stem cell lines, tetraploid aggregation), multiple molecular readouts, mechanistic pathway placement","pmids":["23610556"],"is_preprint":false},{"year":2014,"finding":"Monocyte-secreted Wnt5a activates FZD5 on microvascular endothelial cells, which signals through intracellular Ca2+ release and NFκB transcription to induce tissue factor (TF) expression, leading to angiogenesis by autocrine regulation.","method":"Paracrine co-culture assays, Ca2+ release measurement, NFκB reporter, in vitro tube formation and wound healing assay, in vivo microvessel formation assay","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo functional readouts with pathway mechanistic dissection, single lab","pmids":["25240054"],"is_preprint":false},{"year":2016,"finding":"A heterozygous frameshift mutation in FZD5 (p.Ala219Glufs*49) produces a truncated protein that retains the WNT-ligand-binding (cysteine-rich) domain but lacks the transmembrane domain; this truncated protein is secreted from cells and acts as a dominant-negative FZD5 receptor, antagonizing both canonical and non-canonical WNT signaling, causing coloboma and microphthalmia in zebrafish and disruption of retinal neural epithelium apical junctions in mouse.","method":"Cell secretion assay, dominant-negative functional assay (canonical and non-canonical WNT reporter), zebrafish overexpression, mouse conditional KO (Fz5/Fz8 compound)","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic dissection of truncated protein behavior (secretion assay, dominant-negative reporters), validated in two animal models (zebrafish and mouse)","pmids":["26908622"],"is_preprint":false},{"year":2016,"finding":"Genome-wide CRISPR-Cas9 screens in RNF43-mutant PDAC cells identified FZD5 as the specific Wnt receptor required for proliferation in these tumors; anti-FZD5 antibodies inhibited growth in vitro and as xenografts in vivo, and the functional specificity of FZD5 could not be explained by differential protein expression patterns across the ten FZD receptors.","method":"Genome-wide CRISPR-Cas9 dropout screens, recombinant antibody panel, xenograft in vivo growth assay, patient-derived organoids","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased genome-wide CRISPR screen combined with antibody validation in vitro, in vivo xenografts, and patient-derived organoids; orthogonal genetic and antibody approaches","pmids":["27869803"],"is_preprint":false},{"year":2018,"finding":"FZD5 is a Gαq-coupled seven-transmembrane receptor that undergoes conformational change upon WNT-5A stimulation (reminiscent of class A/B GPCR activation), activates Gαq and its downstream effectors, as demonstrated by dual-color FRAP and RET-based assays in live cells.","method":"Dual-color fluorescence recovery after photobleaching (dcFRAP), resonance energy transfer (RET)-based assays, live-cell imaging of conformational change","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal biophysical methods (dcFRAP + RET) demonstrating G protein coupling, consistent with prototypical GPCR activation mechanism","pmids":["30514810"],"is_preprint":false},{"year":2018,"finding":"In endothelial cells, FZD5 loss-of-function (siRNA) results in reduced proliferation (G0/G1 arrest), decreased migration, and enhanced expression of Angpt2 and Flt1 via enhanced PKC signaling and the transcription factor Ets1, without involvement of canonical Wnt, non-canonical Wnt/Ca2+-NFAT, or Wnt/PCP-JNK pathways.","method":"siRNA knockdown, cell cycle analysis, migration assays, 3D collagen co-culture tube formation, pathway inhibitor dissection, transcription factor (Ets1) mechanistic analysis","journal":"Angiogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional readouts with pathway dissection (inhibitor panel ruling out alternative cascades), single lab","pmids":["29845518"],"is_preprint":false},{"year":2018,"finding":"Surface plasmon resonance analysis showed that WNT5A binds FZD5 with ~30% stronger binding response than to RYK; FZD5 knockdown completely abrogated the anti-proliferative effect of WNT5A in prostate cancer PC3 cells, while RYK knockdown did not affect proliferation but inhibited WNT5A-induced apoptosis by 60%.","method":"Surface plasmon resonance, siRNA knockdown of FZD5/RYK/FZD8, cell proliferation and apoptosis assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding measurement by SPR plus receptor-specific knockdown with selective functional readouts, single lab","pmids":["29930766"],"is_preprint":false},{"year":2020,"finding":"YTHDF1 promotes translation of FZD5 mRNA in an m6A-dependent manner in hepatocellular carcinoma cells, functioning as an oncogene through the WNT/β-catenin pathway; multi-omics analysis (translational output profiling) confirmed the translational regulatory mechanism.","method":"Multi-omics (ribosome profiling/translational output), m6A methylation analysis, YTHDF1 knockdown/overexpression, in vitro and in vivo functional assays","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics translational profiling plus functional validation, single lab","pmids":["33230473"],"is_preprint":false},{"year":2020,"finding":"FZD5 promotes TNBC cell G1/S transition, DNA replication, DNA damage repair, and stemness; transcription factor FOXM1, which drives BRCA1 and BIRC5 transcription, acts as a downstream effector of FZD5 signaling; Wnt7B was identified as a specific ligand for FZD5 in this context.","method":"FZD5 loss- and gain-of-function studies, FOXM1 overexpression rescue experiments, cell cycle and DNA damage repair assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function plus rescue with downstream effector, multiple cellular phenotype readouts, single lab","pmids":["33311446"],"is_preprint":false},{"year":2021,"finding":"FZD5 knockdown in human mesenchymal stem/stromal cells promotes cellular senescence via non-canonical Wnt pathway regulation; FZD5 overexpression delays cell cycle arrest; WNT5A ligand treatment promotes hMSC proliferation through FZD5.","method":"FZD5 siRNA knockdown, FZD5 overexpression, WNT5A ligand treatment, senescence marker assays, proliferation and differentiation assays","journal":"Stem cells (Dayton, Ohio)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation (KD and OE) with multiple functional readouts, single lab","pmids":["33338299"],"is_preprint":false},{"year":2021,"finding":"FZD5 signaling prevents epithelial-mesenchymal transition (EMT) in gastric cancer; PKC links FZD5 to the transcription factor ELF3, which represses ZEB1 to block EMT. FZD5 requires co-receptor LRP5 and WNT7B as a putative ligand. Transcription factors SNAI2 and TEAD1 negatively regulate FZD5 expression (confirmed by ChIP).","method":"ChIP-PCR, siRNA knockdown, gene expression analysis (E-cadherin, Vimentin, ZEB1), cell migration and morphology assays, PKC inhibitor, luciferase reporter","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP validation of transcriptional regulation plus pathway epistasis (PKC-ELF3-ZEB1), single lab","pmids":["33618713"],"is_preprint":false},{"year":2021,"finding":"In cardiac fibroblasts, Wnt5a and Wnt11 promote cardiac fibrosis through FZD5 and EGFR crosstalk: Wnt5a/Wnt11 increased FZD5 expression and EGFR phosphorylation; FZD5 siRNA suppressed p-EGFR levels and fibrotic effects; EGFR knockdown attenuated FZD5, p-p38, and p-ERK levels induced by Wnt5a/Wnt11.","method":"TAC mouse model, siRNA knockdown of Wnt5a/Wnt11/EGFR/FZD5, Masson staining for fibrosis, Western blot for signaling intermediates, conditioned medium experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional siRNA knockdown of multiple pathway components with consistent functional readouts in vitro and in vivo, single lab","pmids":["34564708"],"is_preprint":false},{"year":2022,"finding":"WNT5A interacts with FZD5 and LRP5 to regulate proliferation and self-renewal of endometrial mesenchymal stem-like cells (eMSC) through WNT/β-catenin signaling; anti-FZD5 antibody neutralization suppressed eMSC clonogenicity and phenotypic expression; FZD5 gene silencing reduced WNT5A binding to eMSC and decreased TCF/LEF transcriptional activity and active β-catenin levels; Dickkopf-1 (LRP antagonist) reduced WNT5A binding and proliferation.","method":"Anti-FZD5 neutralizing antibody, FZD5 gene silencing, myometrial cell-eMSC co-culture, TCF/LEF reporter assay, active β-catenin immunostaining, recombinant Dickkopf-1 inhibition","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody neutralization plus gene silencing with multiple functional and molecular readouts, single lab","pmids":["35295855"],"is_preprint":false},{"year":2023,"finding":"Desert lncRNA HIDEN interacts with RNA-binding protein IMP1 (IGF2BP1) to stabilize FZD5 mRNA; HIDEN depletion reduces the IMP1-FZD5 mRNA interaction and destabilizes FZD5 mRNA, reducing WNT activity and impairing human definitive endoderm differentiation; WNT agonist rescues the differentiation defect caused by HIDEN or IMP1 loss.","method":"shRNA/promoter deletion, RNA immunoprecipitation (RIP) of IMP1-FZD5 mRNA interaction, mRNA stability assay, WNT agonist rescue, human PSC differentiation assays","journal":"Genome biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP demonstrates direct IMP1-FZD5 mRNA interaction, mRNA stability assay shows functional consequence, WNT agonist rescue confirms pathway placement; single lab","pmids":["37095549"],"is_preprint":false},{"year":2023,"finding":"Sfrp2 binds Fzd5 in mesangial cells and promotes Fzd5-induced cytosolic Ca2+ elevation and downstream CaMKII/Mek/Erk pathway activation, leading to mesangial cell proliferation and fibrosis in diabetic kidney disease.","method":"snRNA-seq, co-immunoprecipitation (Sfrp2-Fzd5 interaction), Ca2+ concentration measurement, siRNA/overexpression of Sfrp2/Fzd5, Western blot for CaMKII/Mek/Erk, in vivo diabetic mouse model","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrates binding, Ca2+ and downstream kinase assays show pathway mechanism, in vivo validation; single lab","pmids":["37951508"],"is_preprint":false},{"year":2023,"finding":"WNT7A-FZD5 signaling axis maintains fallopian tube stem cell renewal: functional approaches and single-cell transcriptomics showed that an endogenously expressed, hormonally regulated WNT7A-FZD5 axis is critical for WNT/β-catenin-dependent stem cell self-renewal.","method":"Organoid culture, endogenous WNT/β-catenin reporter engineering, single-cell transcriptomics, bulk transcriptomics, functional loss-of-function approaches","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (reporter, scRNA-seq, functional KD) in organoid system; single lab","pmids":["37917586"],"is_preprint":false},{"year":2024,"finding":"FZD5 is specifically and uniquely upregulated in anterior neural progenitor cells, and this expression is downregulated as cells adopt posterior fate; selective activation of FZD5+LRP6 clustering via a tetravalent bispecific antibody activates WNT/β-catenin signaling in hPSCs and drives midbrain progenitor differentiation, generating functional dopaminergic neurons in vitro and in vivo.","method":"FZD receptor surface expression profiling by flow cytometry, tetravalent FZD5/LRP6 bispecific antibody stimulation, hPSC differentiation assays, in vivo dopaminergic neuron functional assessment","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor surface profiling plus selective antibody-mediated FZD5/LRP6 activation with in vitro and in vivo functional readouts; single lab","pmids":["38358799"],"is_preprint":false},{"year":2024,"finding":"DNMT3A binds the FZD5 promoter (by ChIP assay) and suppresses FZD5 transcription via DNA methylation; reduced DNMT3A expression in NSCLC leads to hypomethylation and aberrant FZD5 upregulation; DNMT3A overexpression suppresses FZD5 expression and inhibits lung carcinogenesis in vivo.","method":"Chromatin immunoprecipitation (ChIP), quantitative methylation-specific PCR, DNMT3A overexpression in mouse model, FZD5 siRNA knockdown in cell lines and mouse model","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms DNMT3A binding to FZD5 promoter, methylation assay confirms epigenetic mechanism, in vivo validation; single lab","pmids":["38707304"],"is_preprint":false},{"year":2025,"finding":"Wnt specifically induces FZD5 (and FZD8) endocytosis and degradation in a ZNRF3/RNF43-dependent manner; ZNRF3/RNF43 selectively target FZD5/8 for degradation upon Wnt stimulation; Wnt promotes physical interaction between FZD5 and RNF43; RSPO1 specifically stabilizes FZD5/8 by antagonizing ZNRF3/RNF43; DVL promotes ligand-independent FZD endocytosis but is dispensable for Wnt-induced FZD5/8 degradation.","method":"Endocytosis and degradation assays (cell-based), Co-immunoprecipitation (FZD5-RNF43 interaction), ZNRF3/RNF43 knockout and knockdown, RSPO1 treatment, DVL loss-of-function","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic (KO, KD) and biochemical (Co-IP, degradation assays) approaches with specificity controls (FZD selectivity), consistent results across peer-reviewed publication","pmids":["41070826"],"is_preprint":false},{"year":2015,"finding":"In drug-resistant renal cell carcinoma, miR-124 targets FZD5; Wnt-5a dose-dependently activates FZD5 to stimulate p-PKCα/βII and p-CaMKII; FZD5 silencing reversed PKC/CaMKII activation and suppressed P-glycoprotein expression, demonstrating that FZD5/PKC signaling mediates multi-drug resistance.","method":"miR-124 mimic transfection, FZD5 siRNA, Western blot for p-PKCα/βII and p-CaMKII, IC50 assay, flow cytometry apoptosis","journal":"Tumour biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, partial mechanistic dissection, mainly downstream protein phosphorylation assays without full pathway reconstitution","pmids":["25861751"],"is_preprint":false}],"current_model":"FZD5 is a seven-transmembrane class F GPCR Wnt receptor that forms ligand-specific receptor complexes (e.g., FZD5·LRP6) with WNT ligands including WNT5A, WNT7A, and WNT7B; upon WNT-5A binding it undergoes conformational change and couples to Gαq to activate downstream Ca2+/PKC, NFκB, and β-catenin signaling cascades; Wnt stimulation specifically induces FZD5 endocytosis and lysosomal degradation through ZNRF3/RNF43-dependent ubiquitination (antagonized by RSPO1), while CVAK104 independently promotes basal FZD5 lysosomal degradation via a Dishevelled-interacting mechanism; FZD5 is essential for yolk sac and placental angiogenesis, chorionic branching morphogenesis (via a Gcm1 positive feedback loop and β-catenin-dependent junction remodeling), neural anterior-posterior patterning, and stem cell self-renewal, and its expression is regulated at the transcriptional level by POU/SP1 factors and DNMT3A-mediated promoter methylation, and at the post-transcriptional level by m6A-dependent YTHDF1-driven translation and lncRNA HIDEN/IMP1-mediated mRNA stabilization."},"narrative":{"mechanistic_narrative":"FZD5 is a class F seven-transmembrane GPCR that serves as a ligand-specific WNT receptor controlling endothelial growth, trophoblast morphogenesis, neural patterning, and stem cell self-renewal [PMID:11092808, PMID:23610556, PMID:38358799]. It binds WNT ligands directly through its extracellular cysteine-rich domain, including a nanomolar-affinity interaction with WNT7A and surface-plasmon-resonance-measured binding of WNT5A [PMID:18230341, PMID:29930766], and assembles ligand-specific complexes with the co-receptor LRP6/LRP5 to stabilize beta-catenin and drive TCF/LEF transcription [PMID:12857724, PMID:35295855, PMID:38358799]. Upon WNT-5A stimulation FZD5 undergoes a GPCR-like conformational change and couples to Galphaq, activating intracellular Ca2+ release and PKC/CaMKII signaling as well as NFkB-driven transcription [PMID:30514810, PMID:25240054, PMID:37951508]. Through these branches FZD5 sustains endothelial proliferation and angiogenesis [PMID:11092808, PMID:25240054, PMID:29845518], drives chorionic branching via a Gcm1 positive-feedback loop coupled to junctional remodeling [PMID:23610556], and is the selective WNT receptor required for proliferation of RNF43-mutant pancreatic tumors [PMID:27869803]. FZD5 abundance is set by ZNRF3/RNF43-dependent endocytosis and lysosomal degradation upon WNT stimulation (antagonized by RSPO1) and by CVAK104-mediated basal lysosomal turnover [PMID:41070826, PMID:19643732], and its expression is further controlled transcriptionally by DNMT3A promoter methylation and post-transcriptionally by m6A/YTHDF1 translation and lncRNA HIDEN/IMP1 mRNA stabilization [PMID:38707304, PMID:33230473, PMID:37095549]. A heterozygous frameshift mutation producing a secreted, dominant-negative truncated FZD5 causes coloboma and microphthalmia [PMID:26908622].","teleology":[{"year":2001,"claim":"Established FZD5 as a developmentally essential WNT receptor by showing its loss is embryonic-lethal due to a specific angiogenic-proliferation defect, the first in vivo proof it transduces WNT signals.","evidence":"Knockout mouse with BrdU proliferation assay plus Xenopus ectopic-axis synergy with WNT2/5A/10B","pmids":["11092808"],"confidence":"High","gaps":["Did not define the downstream signaling branch responsible for the proliferation defect","Ligand-receptor binding not demonstrated biochemically"]},{"year":2003,"claim":"Defined the receptor architecture by showing FZD5 partners with LRP6 to transduce a specific WNT ligand into canonical beta-catenin/TCF signaling.","evidence":"TCF/LEF reporter, beta-catenin stability assay and Dickkopf antagonism in PC12 cells","pmids":["12857724"],"confidence":"Medium","gaps":["Single cell type","Direct WNT7A-FZD5 physical binding not shown here"]},{"year":2008,"claim":"Provided direct biochemical proof of ligand engagement, showing WNT7A binds the FZD5 cysteine-rich domain at nanomolar affinity.","evidence":"ELISA-based purified-protein binding assay and split-eGFP complementation in cells","pmids":["18230341"],"confidence":"Medium","gaps":["Single lab/paper","No structural model of the complex"]},{"year":2009,"claim":"Revealed that FZD5 surface levels are actively controlled by trafficking, identifying CVAK104 as a selective regulator routing FZD5 to lysosomal degradation and thereby tuning WNT signaling output.","evidence":"Co-IP with FZD1/FZD4 selectivity controls, dominant-negative Rab5, RNAi, lysosomal inhibitors and beta-catenin reporter","pmids":["19643732"],"confidence":"High","gaps":["Relationship to ligand-induced degradation pathway not addressed","Mechanism of CVAK104 substrate selectivity unclear"]},{"year":2013,"claim":"Placed FZD5 in a developmental morphogenetic circuit, showing it forms a Gcm1 positive-feedback loop and drives cell-junction disassembly to initiate chorionic branching.","evidence":"Global and trophoblast-specific KO mice, trophoblast stem cell lines, tetraploid aggregation, immunofluorescence and Western blot","pmids":["23610556"],"confidence":"High","gaps":["How beta-catenin signaling selectively downregulates junctional proteins not resolved"]},{"year":2014,"claim":"Connected FZD5 to non-canonical Ca2+/NFkB signaling in angiogenesis, showing monocyte-derived WNT5A drives tissue-factor expression in endothelium.","evidence":"Paracrine co-culture, Ca2+ release, NFkB reporter, tube formation and in vivo microvessel assays","pmids":["25240054"],"confidence":"Medium","gaps":["G-protein coupling not directly demonstrated","Single lab"]},{"year":2016,"claim":"Demonstrated a Mendelian disease mechanism: a secreted, transmembrane-less FZD5 fragment acts as a dominant-negative WNT decoy causing ocular coloboma/microphthalmia.","evidence":"Cell secretion assay, canonical/non-canonical reporters, zebrafish overexpression, mouse Fz5/Fz8 compound KO","pmids":["26908622"],"confidence":"High","gaps":["Penetrance and human population frequency not addressed in mechanism studies"]},{"year":2016,"claim":"Identified FZD5 as a uniquely targetable WNT receptor in RNF43-mutant cancer, showing functional specificity not explained by expression level among the ten FZD receptors.","evidence":"Genome-wide CRISPR-Cas9 dropout screens, anti-FZD5 antibody panel, xenografts and patient-derived organoids","pmids":["27869803"],"confidence":"High","gaps":["Structural basis of FZD5 functional uniqueness undefined","Ligand identity in this context not specified"]},{"year":2018,"claim":"Defined the proximal signaling mechanism, showing FZD5 behaves as a Galphaq-coupled GPCR undergoing WNT-5A-induced conformational change.","evidence":"Dual-color FRAP and RET-based assays with live-cell conformational imaging","pmids":["30514810"],"confidence":"High","gaps":["Structure of the active conformation not solved","Which downstream branch each G protein selects not fully mapped"]},{"year":2018,"claim":"Dissected the angiogenic effector branch, showing FZD5 signals through PKC and Ets1 to control endothelial cycle and pro-angiogenic gene expression independently of canonical Wnt, Ca2+/NFAT, and PCP/JNK.","evidence":"siRNA knockdown, cell cycle and migration assays, 3D collagen tube formation, inhibitor-panel pathway dissection","pmids":["29845518"],"confidence":"Medium","gaps":["Ligand driving this branch not identified","Single lab"]},{"year":2018,"claim":"Quantified WNT5A receptor preference, showing FZD5 binds WNT5A more strongly than RYK and is required for WNT5A's anti-proliferative effect in prostate cancer.","evidence":"Surface plasmon resonance and FZD5/RYK/FZD8 siRNA with proliferation/apoptosis readouts","pmids":["29930766"],"confidence":"Medium","gaps":["Division of labor between FZD5 and RYK in cells not fully resolved","Single lab"]},{"year":2020,"claim":"Showed post-transcriptional control of FZD5, with m6A-dependent YTHDF1 boosting FZD5 translation to drive WNT/beta-catenin oncogenesis.","evidence":"Ribosome profiling/multi-omics, m6A analysis, YTHDF1 perturbation, in vitro and in vivo assays in HCC","pmids":["33230473"],"confidence":"Medium","gaps":["Site-level m6A marks on FZD5 mRNA not mapped","Single lab"]},{"year":2020,"claim":"Linked FZD5 to a proliferative/DNA-repair program, identifying FOXM1 as a downstream effector and WNT7B as the relevant ligand in TNBC.","evidence":"FZD5 loss/gain-of-function with FOXM1 rescue, cell cycle and DNA damage repair assays","pmids":["33311446"],"confidence":"Medium","gaps":["How FZD5 signaling activates FOXM1 mechanistically not defined","WNT7B-FZD5 binding not biochemically shown"]},{"year":2021,"claim":"Extended FZD5's role to stem cell maintenance, showing it restrains senescence in mesenchymal stem cells via non-canonical WNT and WNT5A.","evidence":"siRNA knockdown, overexpression, WNT5A treatment with senescence and proliferation assays","pmids":["33338299"],"confidence":"Medium","gaps":["Specific non-canonical effectors not delineated","Single lab"]},{"year":2021,"claim":"Defined an EMT-suppressive function and its transcriptional regulation, mapping a PKC-ELF3-ZEB1 axis downstream and SNAI2/TEAD1 as upstream repressors of FZD5.","evidence":"ChIP-PCR, siRNA, PKC inhibitor, luciferase reporter and EMT marker analysis in gastric cancer","pmids":["33618713"],"confidence":"Medium","gaps":["WNT7B/LRP5 partnership stated as putative","Context-dependence vs pro-tumor roles unresolved"]},{"year":2021,"claim":"Revealed receptor-tyrosine-kinase crosstalk, showing WNT5A/WNT11-FZD5 signaling cooperates with EGFR to drive cardiac fibrosis.","evidence":"TAC mouse model, bidirectional siRNA of WNT5A/WNT11/EGFR/FZD5, Masson staining and signaling Western blots","pmids":["34564708"],"confidence":"Medium","gaps":["Molecular nature of FZD5-EGFR interaction not defined","Single lab"]},{"year":2022,"claim":"Confirmed a WNT5A-FZD5-LRP5 canonical self-renewal axis in endometrial stem-like cells using antibody neutralization.","evidence":"Anti-FZD5 neutralizing antibody, gene silencing, co-culture, TCF/LEF reporter and DKK1 inhibition","pmids":["35295855"],"confidence":"Medium","gaps":["Reconciliation of WNT5A driving canonical signaling here vs non-canonical elsewhere not addressed"]},{"year":2023,"claim":"Established lncRNA-mediated mRNA stabilization as another control layer, with HIDEN-IMP1 stabilizing FZD5 mRNA to sustain WNT-dependent endoderm differentiation.","evidence":"shRNA/promoter deletion, RIP of IMP1-FZD5 mRNA, mRNA stability assay, WNT agonist rescue in human PSCs","pmids":["37095549"],"confidence":"Medium","gaps":["IMP1 binding site on FZD5 mRNA not mapped","Single lab"]},{"year":2023,"claim":"Identified a secreted modulator, SFRP2, that binds FZD5 to promote Ca2+/CaMKII-Mek-Erk signaling and fibrosis in diabetic kidney disease.","evidence":"snRNA-seq, Co-IP of Sfrp2-Fzd5, Ca2+ measurement, perturbation and in vivo diabetic model","pmids":["37951508"],"confidence":"Medium","gaps":["Whether SFRP2 acts as agonist vs ligand-presenting factor unclear","Single lab"]},{"year":2023,"claim":"Defined a hormonally regulated WNT7A-FZD5 axis maintaining fallopian tube stem cell self-renewal via canonical WNT signaling.","evidence":"Organoids, endogenous WNT reporter, single-cell and bulk transcriptomics, loss-of-function","pmids":["37917586"],"confidence":"Medium","gaps":["Direct WNT7A-FZD5 binding in this system not shown","Single lab"]},{"year":2024,"claim":"Demonstrated FZD5's role in neural anterior-posterior patterning and its therapeutic targetability via selective FZD5/LRP6 clustering to generate dopaminergic neurons.","evidence":"Flow-cytometry receptor profiling and tetravalent FZD5/LRP6 bispecific antibody driving hPSC differentiation in vitro and in vivo","pmids":["38358799"],"confidence":"Medium","gaps":["Endogenous WNT ligand for anterior FZD5 expression not identified","Single lab"]},{"year":2024,"claim":"Showed epigenetic transcriptional control, with DNMT3A binding the FZD5 promoter and silencing it via methylation, loss of which drives aberrant FZD5 in NSCLC.","evidence":"ChIP, methylation-specific PCR, DNMT3A overexpression in mouse, FZD5 siLNA in cells and in vivo","pmids":["38707304"],"confidence":"Medium","gaps":["Specific methylated CpGs not mapped","Single lab"]},{"year":2025,"claim":"Resolved the ligand-induced degradation mechanism, showing WNT triggers ZNRF3/RNF43-dependent FZD5/8 endocytosis and degradation, antagonized by RSPO1 and distinct from DVL-driven basal endocytosis.","evidence":"Endocytosis/degradation assays, FZD5-RNF43 Co-IP, ZNRF3/RNF43 KO/KD, RSPO1 treatment, DVL loss-of-function","pmids":["41070826"],"confidence":"High","gaps":["Ubiquitination sites on FZD5 not mapped","Relationship to CVAK104-mediated turnover not reconciled"]},{"year":null,"claim":"It remains unresolved how a single receptor selects among canonical beta-catenin, Galphaq/Ca2+/PKC, and NFkB outputs in different tissues, and what determines its ligand- and context-specific functional uniqueness among FZD receptors.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of an active FZD5-ligand-coreceptor complex","Rules governing branch selection across cell types unknown","Pro- versus anti-tumor context determinants undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[8,0]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[3,10]},{"term_id":"GO:0048018","term_label":"receptor ligand 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PubMed:20530549, PubMed:26908622, PubMed:9054360). Functions in the canonical Wnt/beta-catenin signaling pathway. In vitro activates WNT2, WNT10B, WNT5A, but not WNT2B or WNT4 signaling (By similarity). In neurons, activation by WNT7A promotes formation of synapses (PubMed:20530549). May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues (Probable). Plays a role in yolk sac angiogenesis and in placental vascularization (By similarity). Plays a role in ocular development (PubMed:26908622)","subcellular_location":"Cell membrane; Golgi apparatus membrane; Synapse; Perikaryon; Cell projection, dendrite; Cell projection, axon","url":"https://www.uniprot.org/uniprotkb/Q13467/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FZD5","classification":"Not Classified","n_dependent_lines":20,"n_total_lines":1208,"dependency_fraction":0.016556291390728478},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FZD5","total_profiled":1310},"omim":[{"mim_id":"620731","title":"MICROPHTHALMIA/COLOBOMA 11; MCOPCB11","url":"https://www.omim.org/entry/620731"},{"mim_id":"610839","title":"OSTEOARTHRITIS SUSCEPTIBILITY 4; OS4","url":"https://www.omim.org/entry/610839"},{"mim_id":"606845","title":"GOLGI-ASSOCIATED PDZ AND COILED-COIL DOMAINS-CONTAINING PROTEIN; GOPC","url":"https://www.omim.org/entry/606845"},{"mim_id":"606146","title":"FRIZZLED CLASS RECEPTOR 8; FZD8","url":"https://www.omim.org/entry/606146"},{"mim_id":"601723","title":"FRIZZLED CLASS RECEPTOR 5; FZD5","url":"https://www.omim.org/entry/601723"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":17.5},{"tissue":"liver","ntpm":21.2}],"url":"https://www.proteinatlas.org/search/FZD5"},"hgnc":{"alias_symbol":["HFZ5","DKFZP434E2135"],"prev_symbol":["C2orf31"]},"alphafold":{"accession":"Q13467","domains":[{"cath_id":"1.10.2000.10","chopping":"35-136","consensus_level":"high","plddt":92.4725,"start":35,"end":136},{"cath_id":"1.20.1070.10","chopping":"230-434_443-532","consensus_level":"high","plddt":91.3779,"start":230,"end":532}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13467","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13467-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13467-F1-predicted_aligned_error_v6.png","plddt_mean":81.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FZD5","jax_strain_url":"https://www.jax.org/strain/search?query=FZD5"},"sequence":{"accession":"Q13467","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13467.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13467/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13467"}},"corpus_meta":[{"pmid":"11092808","id":"PMC_11092808","title":"Mouse Wnt receptor gene Fzd5 is essential for yolk sac and placental angiogenesis.","date":"2001","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/11092808","citation_count":270,"is_preprint":false},{"pmid":"27869803","id":"PMC_27869803","title":"Genome-wide CRISPR screens reveal a Wnt-FZD5 signaling circuit as a druggable vulnerability of RNF43-mutant pancreatic tumors.","date":"2016","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27869803","citation_count":231,"is_preprint":false},{"pmid":"29458020","id":"PMC_29458020","title":"CircRNA circ_0067934 promotes tumor growth and metastasis in hepatocellular carcinoma through regulation of miR-1324/FZD5/Wnt/β-catenin axis.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29458020","citation_count":171,"is_preprint":false},{"pmid":"12857724","id":"PMC_12857724","title":"Functional characterization of WNT7A signaling in PC12 cells: interaction with A FZD5 x LRP6 receptor complex and modulation by Dickkopf proteins.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12857724","citation_count":120,"is_preprint":false},{"pmid":"23610556","id":"PMC_23610556","title":"A positive feedback loop involving Gcm1 and Fzd5 directs chorionic branching morphogenesis in the placenta.","date":"2013","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/23610556","citation_count":83,"is_preprint":false},{"pmid":"33230473","id":"PMC_33230473","title":"YTHDF1 Facilitates the Progression of Hepatocellular Carcinoma by Promoting FZD5 mRNA Translation in an m6A-Dependent Manner.","date":"2020","source":"Molecular therapy. 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required for endothelial growth in the yolk sac.\",\n      \"method\": \"Homologous recombination knockout mouse, BrdU proliferation assay, Xenopus ectopic axis induction assay\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic KO with clear cellular phenotype, supported by functional Xenopus axis induction assay; replicated across multiple experimental approaches in one rigorous study\",\n      \"pmids\": [\"11092808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"WNT7A signals specifically through a FZD5·LRP6 receptor complex in PC12 cells to increase β-catenin stability and activate TCF-based transcription; this activity is antagonized by Dickkopf-1 and Dickkopf-3.\",\n      \"method\": \"TCF/LEF luciferase reporter assay, β-catenin stability assay, dominant-negative receptor constructs, pharmacological inhibition with Dickkopf proteins in PC12 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts (reporter + β-catenin stabilization + antagonist rescue) in a single lab\",\n      \"pmids\": [\"12857724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CVAK104 (a coated-vesicle-associated kinase) binds Dishevelled and selectively binds FZD5 (but not FZD1 or FZD4), induces clathrin-mediated intracellular accumulation of FZD5, and routes it to lysosomal degradation; CVAK104 knockdown increases FZD5 levels and activates Wnt/β-catenin signaling, while overexpression suppresses it.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative Rab5 assay, RNAi knockdown, lysosomal inhibitor experiments, Wnt/β-catenin reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding demonstrated with selectivity controls (FZD1/FZD4 negative), multiple orthogonal approaches (Co-IP, dominant-negative Rab5, RNAi, reporter), consistent functional readout\",\n      \"pmids\": [\"19643732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Purified Wnt7a directly binds the extracellular cysteine-rich domain of Fzd5 in the nanomolar range, as shown by ELISA-based protein-protein binding assay; a split eGFP complementation assay visualized Wnt7a-Fzd5 interactions and subsequent pathway activation in cells.\",\n      \"method\": \"ELISA-based protein binding assay with purified proteins, split eGFP complementation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct in vitro binding assay with purified proteins, but single lab and single paper\",\n      \"pmids\": [\"18230341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Fzd5 and Gcm1 form a positive feedback loop in chorionic trophoblast: Gcm1 upregulates Fzd5 specifically at branching initiation sites, and elevated Fzd5 expression maintains Gcm1 expression via nuclear β-catenin signaling. Fzd5-mediated signaling induces disassociation of cell junctions (downregulating ZO-1, claudin 4, claudin 7) for branching initiation and upregulates Vegf in chorion trophoblast cells.\",\n      \"method\": \"Global and trophoblast-specific Fzd5-null and Gcm1-deficient mouse models, trophoblast stem cell lines, tetraploid aggregation assay, immunofluorescence, Western blot\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models (global KO, conditional KO, stem cell lines, tetraploid aggregation), multiple molecular readouts, mechanistic pathway placement\",\n      \"pmids\": [\"23610556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Monocyte-secreted Wnt5a activates FZD5 on microvascular endothelial cells, which signals through intracellular Ca2+ release and NFκB transcription to induce tissue factor (TF) expression, leading to angiogenesis by autocrine regulation.\",\n      \"method\": \"Paracrine co-culture assays, Ca2+ release measurement, NFκB reporter, in vitro tube formation and wound healing assay, in vivo microvessel formation assay\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo functional readouts with pathway mechanistic dissection, single lab\",\n      \"pmids\": [\"25240054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A heterozygous frameshift mutation in FZD5 (p.Ala219Glufs*49) produces a truncated protein that retains the WNT-ligand-binding (cysteine-rich) domain but lacks the transmembrane domain; this truncated protein is secreted from cells and acts as a dominant-negative FZD5 receptor, antagonizing both canonical and non-canonical WNT signaling, causing coloboma and microphthalmia in zebrafish and disruption of retinal neural epithelium apical junctions in mouse.\",\n      \"method\": \"Cell secretion assay, dominant-negative functional assay (canonical and non-canonical WNT reporter), zebrafish overexpression, mouse conditional KO (Fz5/Fz8 compound)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic dissection of truncated protein behavior (secretion assay, dominant-negative reporters), validated in two animal models (zebrafish and mouse)\",\n      \"pmids\": [\"26908622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Genome-wide CRISPR-Cas9 screens in RNF43-mutant PDAC cells identified FZD5 as the specific Wnt receptor required for proliferation in these tumors; anti-FZD5 antibodies inhibited growth in vitro and as xenografts in vivo, and the functional specificity of FZD5 could not be explained by differential protein expression patterns across the ten FZD receptors.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 dropout screens, recombinant antibody panel, xenograft in vivo growth assay, patient-derived organoids\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased genome-wide CRISPR screen combined with antibody validation in vitro, in vivo xenografts, and patient-derived organoids; orthogonal genetic and antibody approaches\",\n      \"pmids\": [\"27869803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FZD5 is a Gαq-coupled seven-transmembrane receptor that undergoes conformational change upon WNT-5A stimulation (reminiscent of class A/B GPCR activation), activates Gαq and its downstream effectors, as demonstrated by dual-color FRAP and RET-based assays in live cells.\",\n      \"method\": \"Dual-color fluorescence recovery after photobleaching (dcFRAP), resonance energy transfer (RET)-based assays, live-cell imaging of conformational change\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal biophysical methods (dcFRAP + RET) demonstrating G protein coupling, consistent with prototypical GPCR activation mechanism\",\n      \"pmids\": [\"30514810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In endothelial cells, FZD5 loss-of-function (siRNA) results in reduced proliferation (G0/G1 arrest), decreased migration, and enhanced expression of Angpt2 and Flt1 via enhanced PKC signaling and the transcription factor Ets1, without involvement of canonical Wnt, non-canonical Wnt/Ca2+-NFAT, or Wnt/PCP-JNK pathways.\",\n      \"method\": \"siRNA knockdown, cell cycle analysis, migration assays, 3D collagen co-culture tube formation, pathway inhibitor dissection, transcription factor (Ets1) mechanistic analysis\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional readouts with pathway dissection (inhibitor panel ruling out alternative cascades), single lab\",\n      \"pmids\": [\"29845518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Surface plasmon resonance analysis showed that WNT5A binds FZD5 with ~30% stronger binding response than to RYK; FZD5 knockdown completely abrogated the anti-proliferative effect of WNT5A in prostate cancer PC3 cells, while RYK knockdown did not affect proliferation but inhibited WNT5A-induced apoptosis by 60%.\",\n      \"method\": \"Surface plasmon resonance, siRNA knockdown of FZD5/RYK/FZD8, cell proliferation and apoptosis assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding measurement by SPR plus receptor-specific knockdown with selective functional readouts, single lab\",\n      \"pmids\": [\"29930766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YTHDF1 promotes translation of FZD5 mRNA in an m6A-dependent manner in hepatocellular carcinoma cells, functioning as an oncogene through the WNT/β-catenin pathway; multi-omics analysis (translational output profiling) confirmed the translational regulatory mechanism.\",\n      \"method\": \"Multi-omics (ribosome profiling/translational output), m6A methylation analysis, YTHDF1 knockdown/overexpression, in vitro and in vivo functional assays\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics translational profiling plus functional validation, single lab\",\n      \"pmids\": [\"33230473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FZD5 promotes TNBC cell G1/S transition, DNA replication, DNA damage repair, and stemness; transcription factor FOXM1, which drives BRCA1 and BIRC5 transcription, acts as a downstream effector of FZD5 signaling; Wnt7B was identified as a specific ligand for FZD5 in this context.\",\n      \"method\": \"FZD5 loss- and gain-of-function studies, FOXM1 overexpression rescue experiments, cell cycle and DNA damage repair assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function plus rescue with downstream effector, multiple cellular phenotype readouts, single lab\",\n      \"pmids\": [\"33311446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FZD5 knockdown in human mesenchymal stem/stromal cells promotes cellular senescence via non-canonical Wnt pathway regulation; FZD5 overexpression delays cell cycle arrest; WNT5A ligand treatment promotes hMSC proliferation through FZD5.\",\n      \"method\": \"FZD5 siRNA knockdown, FZD5 overexpression, WNT5A ligand treatment, senescence marker assays, proliferation and differentiation assays\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation (KD and OE) with multiple functional readouts, single lab\",\n      \"pmids\": [\"33338299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FZD5 signaling prevents epithelial-mesenchymal transition (EMT) in gastric cancer; PKC links FZD5 to the transcription factor ELF3, which represses ZEB1 to block EMT. FZD5 requires co-receptor LRP5 and WNT7B as a putative ligand. Transcription factors SNAI2 and TEAD1 negatively regulate FZD5 expression (confirmed by ChIP).\",\n      \"method\": \"ChIP-PCR, siRNA knockdown, gene expression analysis (E-cadherin, Vimentin, ZEB1), cell migration and morphology assays, PKC inhibitor, luciferase reporter\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP validation of transcriptional regulation plus pathway epistasis (PKC-ELF3-ZEB1), single lab\",\n      \"pmids\": [\"33618713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In cardiac fibroblasts, Wnt5a and Wnt11 promote cardiac fibrosis through FZD5 and EGFR crosstalk: Wnt5a/Wnt11 increased FZD5 expression and EGFR phosphorylation; FZD5 siRNA suppressed p-EGFR levels and fibrotic effects; EGFR knockdown attenuated FZD5, p-p38, and p-ERK levels induced by Wnt5a/Wnt11.\",\n      \"method\": \"TAC mouse model, siRNA knockdown of Wnt5a/Wnt11/EGFR/FZD5, Masson staining for fibrosis, Western blot for signaling intermediates, conditioned medium experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional siRNA knockdown of multiple pathway components with consistent functional readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"34564708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"WNT5A interacts with FZD5 and LRP5 to regulate proliferation and self-renewal of endometrial mesenchymal stem-like cells (eMSC) through WNT/β-catenin signaling; anti-FZD5 antibody neutralization suppressed eMSC clonogenicity and phenotypic expression; FZD5 gene silencing reduced WNT5A binding to eMSC and decreased TCF/LEF transcriptional activity and active β-catenin levels; Dickkopf-1 (LRP antagonist) reduced WNT5A binding and proliferation.\",\n      \"method\": \"Anti-FZD5 neutralizing antibody, FZD5 gene silencing, myometrial cell-eMSC co-culture, TCF/LEF reporter assay, active β-catenin immunostaining, recombinant Dickkopf-1 inhibition\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody neutralization plus gene silencing with multiple functional and molecular readouts, single lab\",\n      \"pmids\": [\"35295855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Desert lncRNA HIDEN interacts with RNA-binding protein IMP1 (IGF2BP1) to stabilize FZD5 mRNA; HIDEN depletion reduces the IMP1-FZD5 mRNA interaction and destabilizes FZD5 mRNA, reducing WNT activity and impairing human definitive endoderm differentiation; WNT agonist rescues the differentiation defect caused by HIDEN or IMP1 loss.\",\n      \"method\": \"shRNA/promoter deletion, RNA immunoprecipitation (RIP) of IMP1-FZD5 mRNA interaction, mRNA stability assay, WNT agonist rescue, human PSC differentiation assays\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP demonstrates direct IMP1-FZD5 mRNA interaction, mRNA stability assay shows functional consequence, WNT agonist rescue confirms pathway placement; single lab\",\n      \"pmids\": [\"37095549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Sfrp2 binds Fzd5 in mesangial cells and promotes Fzd5-induced cytosolic Ca2+ elevation and downstream CaMKII/Mek/Erk pathway activation, leading to mesangial cell proliferation and fibrosis in diabetic kidney disease.\",\n      \"method\": \"snRNA-seq, co-immunoprecipitation (Sfrp2-Fzd5 interaction), Ca2+ concentration measurement, siRNA/overexpression of Sfrp2/Fzd5, Western blot for CaMKII/Mek/Erk, in vivo diabetic mouse model\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrates binding, Ca2+ and downstream kinase assays show pathway mechanism, in vivo validation; single lab\",\n      \"pmids\": [\"37951508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WNT7A-FZD5 signaling axis maintains fallopian tube stem cell renewal: functional approaches and single-cell transcriptomics showed that an endogenously expressed, hormonally regulated WNT7A-FZD5 axis is critical for WNT/β-catenin-dependent stem cell self-renewal.\",\n      \"method\": \"Organoid culture, endogenous WNT/β-catenin reporter engineering, single-cell transcriptomics, bulk transcriptomics, functional loss-of-function approaches\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (reporter, scRNA-seq, functional KD) in organoid system; single lab\",\n      \"pmids\": [\"37917586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FZD5 is specifically and uniquely upregulated in anterior neural progenitor cells, and this expression is downregulated as cells adopt posterior fate; selective activation of FZD5+LRP6 clustering via a tetravalent bispecific antibody activates WNT/β-catenin signaling in hPSCs and drives midbrain progenitor differentiation, generating functional dopaminergic neurons in vitro and in vivo.\",\n      \"method\": \"FZD receptor surface expression profiling by flow cytometry, tetravalent FZD5/LRP6 bispecific antibody stimulation, hPSC differentiation assays, in vivo dopaminergic neuron functional assessment\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor surface profiling plus selective antibody-mediated FZD5/LRP6 activation with in vitro and in vivo functional readouts; single lab\",\n      \"pmids\": [\"38358799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DNMT3A binds the FZD5 promoter (by ChIP assay) and suppresses FZD5 transcription via DNA methylation; reduced DNMT3A expression in NSCLC leads to hypomethylation and aberrant FZD5 upregulation; DNMT3A overexpression suppresses FZD5 expression and inhibits lung carcinogenesis in vivo.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), quantitative methylation-specific PCR, DNMT3A overexpression in mouse model, FZD5 siRNA knockdown in cell lines and mouse model\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms DNMT3A binding to FZD5 promoter, methylation assay confirms epigenetic mechanism, in vivo validation; single lab\",\n      \"pmids\": [\"38707304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Wnt specifically induces FZD5 (and FZD8) endocytosis and degradation in a ZNRF3/RNF43-dependent manner; ZNRF3/RNF43 selectively target FZD5/8 for degradation upon Wnt stimulation; Wnt promotes physical interaction between FZD5 and RNF43; RSPO1 specifically stabilizes FZD5/8 by antagonizing ZNRF3/RNF43; DVL promotes ligand-independent FZD endocytosis but is dispensable for Wnt-induced FZD5/8 degradation.\",\n      \"method\": \"Endocytosis and degradation assays (cell-based), Co-immunoprecipitation (FZD5-RNF43 interaction), ZNRF3/RNF43 knockout and knockdown, RSPO1 treatment, DVL loss-of-function\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic (KO, KD) and biochemical (Co-IP, degradation assays) approaches with specificity controls (FZD selectivity), consistent results across peer-reviewed publication\",\n      \"pmids\": [\"41070826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In drug-resistant renal cell carcinoma, miR-124 targets FZD5; Wnt-5a dose-dependently activates FZD5 to stimulate p-PKCα/βII and p-CaMKII; FZD5 silencing reversed PKC/CaMKII activation and suppressed P-glycoprotein expression, demonstrating that FZD5/PKC signaling mediates multi-drug resistance.\",\n      \"method\": \"miR-124 mimic transfection, FZD5 siRNA, Western blot for p-PKCα/βII and p-CaMKII, IC50 assay, flow cytometry apoptosis\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, partial mechanistic dissection, mainly downstream protein phosphorylation assays without full pathway reconstitution\",\n      \"pmids\": [\"25861751\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FZD5 is a seven-transmembrane class F GPCR Wnt receptor that forms ligand-specific receptor complexes (e.g., FZD5·LRP6) with WNT ligands including WNT5A, WNT7A, and WNT7B; upon WNT-5A binding it undergoes conformational change and couples to Gαq to activate downstream Ca2+/PKC, NFκB, and β-catenin signaling cascades; Wnt stimulation specifically induces FZD5 endocytosis and lysosomal degradation through ZNRF3/RNF43-dependent ubiquitination (antagonized by RSPO1), while CVAK104 independently promotes basal FZD5 lysosomal degradation via a Dishevelled-interacting mechanism; FZD5 is essential for yolk sac and placental angiogenesis, chorionic branching morphogenesis (via a Gcm1 positive feedback loop and β-catenin-dependent junction remodeling), neural anterior-posterior patterning, and stem cell self-renewal, and its expression is regulated at the transcriptional level by POU/SP1 factors and DNMT3A-mediated promoter methylation, and at the post-transcriptional level by m6A-dependent YTHDF1-driven translation and lncRNA HIDEN/IMP1-mediated mRNA stabilization.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FZD5 is a class F seven-transmembrane GPCR that serves as a ligand-specific WNT receptor controlling endothelial growth, trophoblast morphogenesis, neural patterning, and stem cell self-renewal [#0, #4, #20]. It binds WNT ligands directly through its extracellular cysteine-rich domain, including a nanomolar-affinity interaction with WNT7A and surface-plasmon-resonance-measured binding of WNT5A [#3, #10], and assembles ligand-specific complexes with the co-receptor LRP6/LRP5 to stabilize beta-catenin and drive TCF/LEF transcription [#1, #16, #20]. Upon WNT-5A stimulation FZD5 undergoes a GPCR-like conformational change and couples to Galphaq, activating intracellular Ca2+ release and PKC/CaMKII signaling as well as NFkB-driven transcription [#8, #5, #18]. Through these branches FZD5 sustains endothelial proliferation and angiogenesis [#0, #5, #9], drives chorionic branching via a Gcm1 positive-feedback loop coupled to junctional remodeling [#4], and is the selective WNT receptor required for proliferation of RNF43-mutant pancreatic tumors [#7]. FZD5 abundance is set by ZNRF3/RNF43-dependent endocytosis and lysosomal degradation upon WNT stimulation (antagonized by RSPO1) and by CVAK104-mediated basal lysosomal turnover [#22, #2], and its expression is further controlled transcriptionally by DNMT3A promoter methylation and post-transcriptionally by m6A/YTHDF1 translation and lncRNA HIDEN/IMP1 mRNA stabilization [#21, #11, #17]. A heterozygous frameshift mutation producing a secreted, dominant-negative truncated FZD5 causes coloboma and microphthalmia [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established FZD5 as a developmentally essential WNT receptor by showing its loss is embryonic-lethal due to a specific angiogenic-proliferation defect, the first in vivo proof it transduces WNT signals.\",\n      \"evidence\": \"Knockout mouse with BrdU proliferation assay plus Xenopus ectopic-axis synergy with WNT2/5A/10B\",\n      \"pmids\": [\"11092808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the downstream signaling branch responsible for the proliferation defect\", \"Ligand-receptor binding not demonstrated biochemically\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the receptor architecture by showing FZD5 partners with LRP6 to transduce a specific WNT ligand into canonical beta-catenin/TCF signaling.\",\n      \"evidence\": \"TCF/LEF reporter, beta-catenin stability assay and Dickkopf antagonism in PC12 cells\",\n      \"pmids\": [\"12857724\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell type\", \"Direct WNT7A-FZD5 physical binding not shown here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Provided direct biochemical proof of ligand engagement, showing WNT7A binds the FZD5 cysteine-rich domain at nanomolar affinity.\",\n      \"evidence\": \"ELISA-based purified-protein binding assay and split-eGFP complementation in cells\",\n      \"pmids\": [\"18230341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab/paper\", \"No structural model of the complex\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed that FZD5 surface levels are actively controlled by trafficking, identifying CVAK104 as a selective regulator routing FZD5 to lysosomal degradation and thereby tuning WNT signaling output.\",\n      \"evidence\": \"Co-IP with FZD1/FZD4 selectivity controls, dominant-negative Rab5, RNAi, lysosomal inhibitors and beta-catenin reporter\",\n      \"pmids\": [\"19643732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship to ligand-induced degradation pathway not addressed\", \"Mechanism of CVAK104 substrate selectivity unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed FZD5 in a developmental morphogenetic circuit, showing it forms a Gcm1 positive-feedback loop and drives cell-junction disassembly to initiate chorionic branching.\",\n      \"evidence\": \"Global and trophoblast-specific KO mice, trophoblast stem cell lines, tetraploid aggregation, immunofluorescence and Western blot\",\n      \"pmids\": [\"23610556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How beta-catenin signaling selectively downregulates junctional proteins not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected FZD5 to non-canonical Ca2+/NFkB signaling in angiogenesis, showing monocyte-derived WNT5A drives tissue-factor expression in endothelium.\",\n      \"evidence\": \"Paracrine co-culture, Ca2+ release, NFkB reporter, tube formation and in vivo microvessel assays\",\n      \"pmids\": [\"25240054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"G-protein coupling not directly demonstrated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated a Mendelian disease mechanism: a secreted, transmembrane-less FZD5 fragment acts as a dominant-negative WNT decoy causing ocular coloboma/microphthalmia.\",\n      \"evidence\": \"Cell secretion assay, canonical/non-canonical reporters, zebrafish overexpression, mouse Fz5/Fz8 compound KO\",\n      \"pmids\": [\"26908622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Penetrance and human population frequency not addressed in mechanism studies\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified FZD5 as a uniquely targetable WNT receptor in RNF43-mutant cancer, showing functional specificity not explained by expression level among the ten FZD receptors.\",\n      \"evidence\": \"Genome-wide CRISPR-Cas9 dropout screens, anti-FZD5 antibody panel, xenografts and patient-derived organoids\",\n      \"pmids\": [\"27869803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FZD5 functional uniqueness undefined\", \"Ligand identity in this context not specified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the proximal signaling mechanism, showing FZD5 behaves as a Galphaq-coupled GPCR undergoing WNT-5A-induced conformational change.\",\n      \"evidence\": \"Dual-color FRAP and RET-based assays with live-cell conformational imaging\",\n      \"pmids\": [\"30514810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the active conformation not solved\", \"Which downstream branch each G protein selects not fully mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Dissected the angiogenic effector branch, showing FZD5 signals through PKC and Ets1 to control endothelial cycle and pro-angiogenic gene expression independently of canonical Wnt, Ca2+/NFAT, and PCP/JNK.\",\n      \"evidence\": \"siRNA knockdown, cell cycle and migration assays, 3D collagen tube formation, inhibitor-panel pathway dissection\",\n      \"pmids\": [\"29845518\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand driving this branch not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Quantified WNT5A receptor preference, showing FZD5 binds WNT5A more strongly than RYK and is required for WNT5A's anti-proliferative effect in prostate cancer.\",\n      \"evidence\": \"Surface plasmon resonance and FZD5/RYK/FZD8 siRNA with proliferation/apoptosis readouts\",\n      \"pmids\": [\"29930766\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Division of labor between FZD5 and RYK in cells not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed post-transcriptional control of FZD5, with m6A-dependent YTHDF1 boosting FZD5 translation to drive WNT/beta-catenin oncogenesis.\",\n      \"evidence\": \"Ribosome profiling/multi-omics, m6A analysis, YTHDF1 perturbation, in vitro and in vivo assays in HCC\",\n      \"pmids\": [\"33230473\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Site-level m6A marks on FZD5 mRNA not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked FZD5 to a proliferative/DNA-repair program, identifying FOXM1 as a downstream effector and WNT7B as the relevant ligand in TNBC.\",\n      \"evidence\": \"FZD5 loss/gain-of-function with FOXM1 rescue, cell cycle and DNA damage repair assays\",\n      \"pmids\": [\"33311446\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How FZD5 signaling activates FOXM1 mechanistically not defined\", \"WNT7B-FZD5 binding not biochemically shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended FZD5's role to stem cell maintenance, showing it restrains senescence in mesenchymal stem cells via non-canonical WNT and WNT5A.\",\n      \"evidence\": \"siRNA knockdown, overexpression, WNT5A treatment with senescence and proliferation assays\",\n      \"pmids\": [\"33338299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific non-canonical effectors not delineated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined an EMT-suppressive function and its transcriptional regulation, mapping a PKC-ELF3-ZEB1 axis downstream and SNAI2/TEAD1 as upstream repressors of FZD5.\",\n      \"evidence\": \"ChIP-PCR, siRNA, PKC inhibitor, luciferase reporter and EMT marker analysis in gastric cancer\",\n      \"pmids\": [\"33618713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"WNT7B/LRP5 partnership stated as putative\", \"Context-dependence vs pro-tumor roles unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed receptor-tyrosine-kinase crosstalk, showing WNT5A/WNT11-FZD5 signaling cooperates with EGFR to drive cardiac fibrosis.\",\n      \"evidence\": \"TAC mouse model, bidirectional siRNA of WNT5A/WNT11/EGFR/FZD5, Masson staining and signaling Western blots\",\n      \"pmids\": [\"34564708\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular nature of FZD5-EGFR interaction not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirmed a WNT5A-FZD5-LRP5 canonical self-renewal axis in endometrial stem-like cells using antibody neutralization.\",\n      \"evidence\": \"Anti-FZD5 neutralizing antibody, gene silencing, co-culture, TCF/LEF reporter and DKK1 inhibition\",\n      \"pmids\": [\"35295855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of WNT5A driving canonical signaling here vs non-canonical elsewhere not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established lncRNA-mediated mRNA stabilization as another control layer, with HIDEN-IMP1 stabilizing FZD5 mRNA to sustain WNT-dependent endoderm differentiation.\",\n      \"evidence\": \"shRNA/promoter deletion, RIP of IMP1-FZD5 mRNA, mRNA stability assay, WNT agonist rescue in human PSCs\",\n      \"pmids\": [\"37095549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IMP1 binding site on FZD5 mRNA not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a secreted modulator, SFRP2, that binds FZD5 to promote Ca2+/CaMKII-Mek-Erk signaling and fibrosis in diabetic kidney disease.\",\n      \"evidence\": \"snRNA-seq, Co-IP of Sfrp2-Fzd5, Ca2+ measurement, perturbation and in vivo diabetic model\",\n      \"pmids\": [\"37951508\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SFRP2 acts as agonist vs ligand-presenting factor unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a hormonally regulated WNT7A-FZD5 axis maintaining fallopian tube stem cell self-renewal via canonical WNT signaling.\",\n      \"evidence\": \"Organoids, endogenous WNT reporter, single-cell and bulk transcriptomics, loss-of-function\",\n      \"pmids\": [\"37917586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct WNT7A-FZD5 binding in this system not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated FZD5's role in neural anterior-posterior patterning and its therapeutic targetability via selective FZD5/LRP6 clustering to generate dopaminergic neurons.\",\n      \"evidence\": \"Flow-cytometry receptor profiling and tetravalent FZD5/LRP6 bispecific antibody driving hPSC differentiation in vitro and in vivo\",\n      \"pmids\": [\"38358799\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous WNT ligand for anterior FZD5 expression not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed epigenetic transcriptional control, with DNMT3A binding the FZD5 promoter and silencing it via methylation, loss of which drives aberrant FZD5 in NSCLC.\",\n      \"evidence\": \"ChIP, methylation-specific PCR, DNMT3A overexpression in mouse, FZD5 siLNA in cells and in vivo\",\n      \"pmids\": [\"38707304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific methylated CpGs not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the ligand-induced degradation mechanism, showing WNT triggers ZNRF3/RNF43-dependent FZD5/8 endocytosis and degradation, antagonized by RSPO1 and distinct from DVL-driven basal endocytosis.\",\n      \"evidence\": \"Endocytosis/degradation assays, FZD5-RNF43 Co-IP, ZNRF3/RNF43 KO/KD, RSPO1 treatment, DVL loss-of-function\",\n      \"pmids\": [\"41070826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitination sites on FZD5 not mapped\", \"Relationship to CVAK104-mediated turnover not reconciled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single receptor selects among canonical beta-catenin, Galphaq/Ca2+/PKC, and NFkB outputs in different tissues, and what determines its ligand- and context-specific functional uniqueness among FZD receptors.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of an active FZD5-ligand-coreceptor complex\", \"Rules governing branch selection across cell types unknown\", \"Pro- versus anti-tumor context determinants undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [8, 0]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [3, 10]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [8, 20, 2]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [2, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 8, 22]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 4, 20]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 22]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [\n      \"FZD5-LRP6 receptor complex\",\n      \"FZD5-LRP5 receptor complex\"\n    ],\n    \"partners\": [\n      \"LRP6\",\n      \"LRP5\",\n      \"WNT5A\",\n      \"WNT7A\",\n      \"WNT7B\",\n      \"RNF43\",\n      \"CVAK104\",\n      \"SFRP2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}