{"gene":"FZD7","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2011,"finding":"FZD7 knockdown in triple-negative breast cancer cells (MDA-MB-231, BT-20) suppresses cell proliferation, invasiveness, and colony formation through silencing of canonical Wnt signaling, as evidenced by loss of nuclear β-catenin accumulation and decreased TCF7 transcriptional activity; in vivo xenograft studies confirmed reduced tumor formation.","method":"shRNA knockdown, β-catenin nuclear localization assay, TCF7 reporter assay, xenograft mouse model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype, multiple orthogonal readouts (nuclear β-catenin, TCF reporter, in vivo), single lab","pmids":["21532620"],"is_preprint":false},{"year":2011,"finding":"In differentiated myofibres, Wnt7a binding to Fzd7 directly activates the Akt/mTOR anabolic growth pathway via a receptor complex associated with Gαs and PI(3)K, independently of IGF-receptor activation, thereby inducing myofibre hypertrophy.","method":"Wnt7a ligand treatment, co-immunoprecipitation of Fzd7 with Gαs and PI3K, Akt/mTOR pathway readouts, IGF-receptor independence experiments","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP identifying receptor complex components, multiple pathway readouts, published in high-impact journal with functional consequences established","pmids":["22179044"],"is_preprint":false},{"year":2014,"finding":"ΔNp63 transcription factor promotes mammary stem cell activity and basal breast cancer tumor-initiating activity by increasing FZD7 expression, thereby enhancing Wnt signaling; FZD7-dependent Wnt signaling governed tumor-initiating activity of basal breast cancer.","method":"Gain- and loss-of-function of ΔNp63 and FZD7, mammary stem cell and tumor-initiating cell assays","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FZD7 positioned downstream of ΔNp63 in Wnt signaling by epistasis/rescue experiments, single lab","pmids":["25241036"],"is_preprint":false},{"year":2014,"finding":"FZD7 is required for maintenance of the pluripotent state of human embryonic stem cells (hESCs); shRNA-mediated knockdown or blockade with a FZD7-specific Fab fragment disrupts pluripotency. The FZD7-specific Fab blocks Wnt3a signaling by down-regulating FZD7 protein levels, indicating that FZD7 transduces Wnt/β-catenin signals in hESCs.","method":"shRNA knockdown, FZD7-specific Fab antibody treatment, Wnt3a signaling assay, FZD7 protein level measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal perturbations (shRNA and Fab), defined cellular phenotype, single lab","pmids":["24474766"],"is_preprint":false},{"year":2014,"finding":"FZD7 knockdown in Stem-A ovarian cancer cells reduces proliferation, induces epithelial-like morphology, increases cadherin-based cell-cell adhesion, rearranges actin cytoskeleton, decreases RhoA activity, and increases Rac1 activity; increased TopFlash activity and PCP pathway gene regulation suggest FZD7 drives aggressiveness via the non-canonical Wnt/PCP pathway through casein kinase 1ε.","method":"siRNA knockdown, cell proliferation and morphology assays, immunofluorescence, RhoA/Rac1 activity assays, TopFlash reporter assay, PCP gene expression profiling","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with multiple orthogonal readouts, pathway placement via reporter assay, single lab","pmids":["25032869"],"is_preprint":false},{"year":2008,"finding":"FZD7 is expressed at up to 200-fold higher levels in human embryonic stem cells versus differentiated cell types; shRNA-mediated knockdown in hESCs induces changes in colony morphology, perturbation of germ layer marker gene expression, and rapid loss of OCT4 expression, establishing FZD7 as required for ES cell self-renewal capacity.","method":"Quantitative RT-PCR, flow cytometry, shRNA knockdown, OCT4 expression analysis","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined molecular and cellular phenotype, single lab, multiple readouts","pmids":["18681827"],"is_preprint":false},{"year":2016,"finding":"Fzd7 expressed by endothelial cells is required for postnatal retinal vascular formation; endothelial cell-specific deletion of Fzd7 delays retinal plexus formation by impairing tip cell phenotype and stalk cell proliferation. Fzd7 acts via Dvl/β-catenin activation upstream of Notch signaling to control Dll4 and Jagged1 expression; LiCl treatment rescued the vascular phenotype of Fzd7 mutants.","method":"Conditional endothelial knockout mouse, retinal vascular phenotype analysis, Dvl3 depletion in dvl1-/- mice, LiCl pharmacological rescue, Notch target gene expression","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined vascular phenotype, pharmacological rescue, epistasis with Dvl and Notch, multiple orthogonal approaches","pmids":["27758766"],"is_preprint":false},{"year":2017,"finding":"RSPO2 physically interacts with Fzd7 and increases degradation of cell-surface Fzd7 via ZNRF3-mediated ubiquitination, suppressing downstream PKC/ERK signaling and CRC cell migration; Wnt5a prevents Fzd7 degradation and promotes CRC cell migration, while RSPO2 antagonizes Wnt5a/Fzd7 signaling by blocking Wnt5a binding to FZD7.","method":"Co-immunoprecipitation, ubiquitination assay, PKC/ERK signaling readouts, migration/invasion assays, ligand competition experiments","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding shown by Co-IP, ubiquitination mechanism identified, multiple functional readouts, competition ligand experiments","pmids":["28600110"],"is_preprint":false},{"year":2020,"finding":"YTHDF1 promotes translation of FZD7 mRNA in an m6A-dependent manner in gastric cancer; mutated YTHDF1 enhances FZD7 expression, leading to hyperactivation of Wnt/β-catenin pathway.","method":"m6A-seq, YTHDF1 knockdown/overexpression, polysome profiling or translation assay, in vitro and in vivo gastric cancer models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic link of m6A reader to FZD7 translation established, multiple methods, single lab","pmids":["32788173"],"is_preprint":false},{"year":2020,"finding":"WNT11-FZD7-DAAM1 signaling activates the Rho-ROCK1/2-Myosin II pathway to regulate tumour-initiating potential, amoeboid invasion, local invasion, and distant metastasis in melanoma.","method":"KD/KO of WNT11, FZD7, DAAM1 in melanoma cells; Rho-ROCK-Myosin II signaling readouts; in vivo metastasis assays; human melanoma tissue analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis across WNT11-FZD7-DAAM1 axis, multiple in vitro and in vivo functional readouts, validated in human tissue","pmids":["33082334"],"is_preprint":false},{"year":2019,"finding":"FZD7 regulates TWIST1 expression through epigenetic modifications (H3K4me3 and H3K27ac) at the TWIST1 proximal promoter; the FZD7-TWIST1 axis then regulates BCL2 expression to confer anoikis resistance in ovarian cancer. Overexpression of TWIST1 partially rescued phenotypes abolished by FZD7 knockdown.","method":"FZD7 knockdown/overexpression, TWIST1 overexpression rescue, chromatin immunoprecipitation for H3K4me3/H3K27ac, BCL2 expression analysis, anoikis and spheroid assays","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epigenetic mechanism identified by ChIP, epistasis by rescue experiment, multiple orthogonal methods, single lab","pmids":["30548372"],"is_preprint":false},{"year":2020,"finding":"Non-canonical Fzd7 signaling in breast cancer cells involves Fzd7 binding to Wnt5a/b, and modulates phospho-STAT3, Smad3, YAP1, and Col6a1 expression; Fzd7-Wnt5b regulates Col6a1 to mediate mesenchymal-like stemness and EMT.","method":"Fzd7 knockdown/overexpression, co-immunoprecipitation of Fzd7 with Wnt5a/b, pathway protein western blots, Col6a1 knockdown epistasis, xenograft and metastasis assays","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing Fzd7-Wnt5b interaction, epistasis experiments, multiple functional readouts, single lab","pmids":["32894152"],"is_preprint":false},{"year":2022,"finding":"GIPC2 directly binds to FZD7 through its PDZ domain, enabling activation of WNT-β-catenin cascades and stimulating prostate cancer metastasis.","method":"Co-immunoprecipitation, PDZ domain interaction mapping, β-catenin signaling assays, in vitro and in vivo metastasis assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct physical interaction via Co-IP with domain mapping, functional downstream readouts, single lab","pmids":["35347223"],"is_preprint":false},{"year":2020,"finding":"Selective engagement of FZD7 (and not other FZD proteins) by the engineered bispecific protein F7L6, which bridges FZD7 and LRP6, potently activates WNT/β-catenin signaling and is sufficient to initiate mesendodermal differentiation programs in human pluripotent stem cells, mimicking primitive streak formation.","method":"Engineered FZD7-selective/LRP6-bridging agonist (F7L6), WNT/β-catenin reporter assays, transcriptome profiling of hPS cells, comparison with Wnt3a and other FZD-selective agonists","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstituted selective FZD7 engagement with defined co-receptor, rigorous receptor selectivity profiling, orthogonal transcriptomic and functional validation","pmids":["33331818"],"is_preprint":false},{"year":2024,"finding":"CryoEM structures of TcdB alone and in complex with full-length FZD7 reveal that large structural rearrangements of the combined repetitive polypeptide (CROPs) domain of TcdB are required for FZD7 interaction; bezlotoxumab (FDA-approved antibody) favors the apo-TcdB conformation and disrupts FZD7 binding. Dynamic transition between TcdB conformations also governs stability of the pore-forming region.","method":"CryoEM structure determination, live-cell affinity assay, bezlotoxumab competition binding assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryoEM structure of full-length FZD7 in complex with TcdB, functional validation of conformational dynamics and antibody competition","pmids":["38308843"],"is_preprint":false},{"year":2023,"finding":"Structure-based ligand discovery targeting the transmembrane domain (TMD) of FZD7 identified compound F7H as an FZD7 antagonist (IC50 = 1.25 μM); molecular docking, MD simulation, and free energy perturbation calculations defined key binding-pocket residues in the TMD.","method":"Structure-based virtual screening, compound synthesis, Wnt/β-catenin reporter antagonism assay, molecular docking/MD/FEP calculations","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — structure-guided discovery with functional validation in reporter assay and computational structural characterization, single lab","pmids":["37669317"],"is_preprint":false},{"year":2020,"finding":"CDDO-Me inhibits Wnt/β-catenin signaling by inducing ubiquitination and lysosomal degradation of the LRP6/FZD7 receptor complex; degradation of FZD7 is dependent on the LRP6 ectodomain, and CDDO-Me reduces phospho-DVL2 and active β-catenin levels in breast cancer cells.","method":"LRP6 and FZD7 protein degradation assays, ubiquitination assay, lysosomal pathway inhibitors, LRP6 ectodomain deletion constructs, DVL2 and β-catenin western blots, xenograft model","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanism identified with ubiquitination and degradation assays, LRP6 ectodomain dependency established, multiple pathway readouts, single lab","pmids":["32015160"],"is_preprint":false},{"year":2016,"finding":"NOTCH3, but not NOTCH1, 2, or 4, regulates FZD7 expression in human breast epithelial cells through a non-canonical (CSL-independent) Notch signaling mechanism; gain- and loss-of-function experiments showed this regulation is unique and non-redundant.","method":"Constitutively active NOTCH1-4 overexpression, NOTCH loss-of-function, CSL-independent signaling assay, FZD7 expression analysis","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis using multiple Notch receptor gain/loss-of-function, non-canonical pathway placement, single lab","pmids":["26847503"],"is_preprint":false},{"year":2018,"finding":"GCM1 transcription factor promotes trophoblast cell migration by activating WNT10B expression; WNT10B signals through FZD7 (identified as its cognate receptor) to upregulate cell migration via Rac1-mediated cytoskeletal remodeling. SFRP3 from decidual cells blocks WNT10B-FZD7 interaction to decrease trophoblast migration.","method":"FZD7 receptor identification for WNT10B, cell migration assays, Rac1 activity assays, SFRP3 competition binding, trophoblast-decidual co-culture","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor identification for specific Wnt ligand, functional rescue and competition experiments, multiple cell assays, single lab","pmids":["29979633"],"is_preprint":false},{"year":2023,"finding":"Vangl1 forms a novel complex with Fzd7 at the leading edge of migrating GBM cells; this Vangl1/Fzd7 complex drives cellular proliferation, migration, and invasiveness by engaging Rho GTPases to promote cytoskeletal rearrangements and actin dynamics.","method":"Co-immunoprecipitation, co-localization at leading edge, Rho GTPase activity assays, FZD7 depletion in intracranial xenograft model, KD functional assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel complex identified by Co-IP with subcellular localization, Rho GTPase pathway readouts, in vivo tumor model, single lab","pmids":["37336284"],"is_preprint":false},{"year":2024,"finding":"SIRT7 promotes FZD7 expression by upregulating the transcription factor PU.1, which then drives FZD7 transcription; FZD7 is required for SIRT7-mediated stabilization of β-catenin and its nuclear localization in hepatocellular carcinoma cells. FZD7 knockdown reversed SIRT7-overexpression-mediated β-catenin stabilization.","method":"SIRT7 knockdown/overexpression, FZD7 knockdown rescue, PU.1 manipulation, nuclear/cytoplasmic fractionation, β-catenin ubiquitination and stability assays, Top-Flash reporter, immunofluorescence","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis across SIRT7-PU.1-FZD7-β-catenin axis, multiple orthogonal methods, single lab","pmids":["39542206"],"is_preprint":false},{"year":2023,"finding":"BCL6 transcription repressor directly binds the FZD7 promoter and transcriptionally represses FZD7 to inhibit gastric cancer cell proliferation and metastasis; BCL6 also promotes ferroptosis through the FZD7/β-catenin/TP63/GPX4 pathway.","method":"ChIP assay, dual luciferase reporter assay, FZD7 rescue experiments, ferroptosis readouts (lipid peroxidation, MDA, Fe2+), rescue experiments","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding shown by ChIP, luciferase reporter validation, rescue epistasis, single lab","pmids":["37060074"],"is_preprint":false},{"year":2022,"finding":"Wnt5a regulates ABCG2 expression in pancreatic cancer cells through FZD7; siRNA silencing or pharmacological inhibition of FZD7 blocked Wnt5a-induced ABCG2 upregulation and attenuated gemcitabine resistance.","method":"siRNA knockdown of FZD7, FZD7 inhibitors, recombinant Wnt5a treatment, ABCG2 expression analysis, gemcitabine resistance assay","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway placement of FZD7 downstream of Wnt5a and upstream of ABCG2 by siRNA and inhibitor experiments, single lab","pmids":["33200805"],"is_preprint":false},{"year":2025,"finding":"FZD7 activation (via selective agonist) triggers β-catenin signaling with distinct kinetics from FZD2, enabling both paraxial and lateral mesoderm differentiation of hPSCs, whereas FZD2 activation favors only paraxial mesoderm; FZD7 shows more rapid dampening of β-catenin signaling than FZD2, permitting lateral mesoderm induction.","method":"FZD2- and FZD7-selective antibody-based agonists, hPSC directed differentiation assays, β-catenin signaling kinetics measurement, mesoderm subtype marker analysis","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — selective FZD7 agonist enabling receptor-specific functional comparison, differentiation readouts, single lab","pmids":["39824186"],"is_preprint":false},{"year":2025,"finding":"YTHDF1 binds to m6A-modified FZD7 mRNA in cisplatin-resistant ovarian cancer cells, enhancing its stability and translation, thereby sustaining Wnt/β-catenin signaling activation; YTHDF1 silencing reduces FZD7 expression, inhibits Wnt/β-catenin signaling, and restores cisplatin sensitivity in vitro and in xenograft models.","method":"YTHDF1 knockdown/overexpression, m6A-IP, mRNA stability assay, FZD7 expression analysis, Wnt/β-catenin pathway readouts, xenograft mouse model","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A-dependent mRNA regulation mechanism with stability and in vivo validation, single lab","pmids":["40281310"],"is_preprint":false},{"year":2022,"finding":"FZD7 knockdown in pancreatic cancer cells reduces EMT marker expression, reduces mesenchymal phenotype, decreases cancer stem cell proportions (CD24+CD44+, ABCG2), and attenuates TGF-β1-induced EMT; FZD7 acts through both canonical Wnt/β-catenin and TGF-β/SMAD3 signaling pathways.","method":"lentiviral shRNA knockdown, FZD7 overexpression, TGF-β1 stimulation assays, EMT marker western blots, CSC flow cytometry, sphere formation assays","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss and gain of function, multiple pathway readouts, TGF-β/SMAD3 cross-talk shown, single lab","pmids":["35854234"],"is_preprint":false},{"year":2024,"finding":"WNT7A activates the FZD7/JAK1/STAT3 signaling pathway in head and neck squamous cell carcinoma, leading to enhanced cell proliferation, self-renewal, and resistance to apoptosis, without activating canonical Wnt/β-catenin signaling.","method":"WNT7A overexpression, FZD7/JAK1/STAT3 pathway analysis, β-catenin reporter (negative result), patient-derived xenograft model","journal":"International journal of oral science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — non-canonical pathway placement established, in vivo PDX model confirmation, active exclusion of canonical pathway, single lab","pmids":["38246919"],"is_preprint":false},{"year":2025,"finding":"Cytoplasmic KIAA1429, phosphorylated by BRAF, stabilizes FZD7 protein in colorectal cancer cells by direct binding, thereby activating the WNT pathway and promoting cancer stemness and oxaliplatin resistance.","method":"Co-immunoprecipitation, immunofluorescence, RNA-seq, in vitro and in vivo oxaliplatin resistance assays, FZD7 stabilization experiments","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding of KIAA1429 to FZD7 shown by Co-IP, mechanism linked to protein stabilization and downstream Wnt activation, single lab","pmids":["40611274"],"is_preprint":false},{"year":2019,"finding":"Fibronectin promotes non-canonical Wnt signaling through Wnt11-Fzd7 interaction in limbal epithelial stem cells, and modulates cell cycle regulators via upregulation of ROCK1 and ROCK2 to enhance stem cell self-renewal and proliferation.","method":"Wnt11 and Fzd7 co-expression/interaction analysis, ROCK inhibition, proliferation and stemness assays under fibronectin conditions","journal":"Experimental eye research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single-lab study with Wnt11/Fzd7 interaction inferred from expression rather than direct Co-IP; functional assays present but mechanistic rigor limited","pmids":["31150636"],"is_preprint":false},{"year":2019,"finding":"FZD7 knockdown reduces expression of Lgr5 (a WNT target) and is required for intestinal stem cell function in mice, but gastric Lgr5+ stem cells do not require Fzd7 for epithelial homeostasis, establishing tissue-specific differential requirement for FZD7 in Wnt-dependent stem cell maintenance.","method":"Conditional Fzd7 deletion in gastric Lgr5+ cells, intestinal comparison, homeostasis and regeneration assays","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic in vivo KO in specific cell population, tissue-specific epistasis established, single lab","pmids":["31288403"],"is_preprint":false}],"current_model":"FZD7 is a seven-transmembrane Wnt receptor that, depending on cellular context, transduces both canonical Wnt/β-catenin signaling (by forming a complex with LRP5/6 and Dishevelled/DVL to stabilize β-catenin and activate TCF target genes) and non-canonical Wnt signaling (via PCP/Wnt11-DAAM1-Rho-ROCK-Myosin II, Wnt5a/b-PKC/ERK, and JAK1/STAT3 pathways); it associates with co-receptors and effectors including Gαs and PI3K (for Akt/mTOR activation by Wnt7a in muscle), GIPC2 (via PDZ-domain interaction), Vangl1 (at the leading edge of migrating cells), and LRP6; its expression is transcriptionally regulated by ΔNp63, BCL6, and PU.1 (downstream of SIRT7), and post-transcriptionally regulated by m6A-dependent YTHDF1-mediated translation; FZD7 protein stability is modulated by ZNRF3-mediated ubiquitination and lysosomal degradation (promoted by RSPO2, antagonized by Wnt5a); FZD7 is required for pluripotency maintenance in human embryonic stem cells, satellite stem cell expansion in muscle, mammary stem cell activity, and postnatal angiogenesis, and marks tumor-initiating cells in multiple cancers."},"narrative":{"mechanistic_narrative":"FZD7 is a seven-transmembrane Wnt receptor that functions as a context-dependent signaling hub for both canonical Wnt/β-catenin and non-canonical Wnt pathways, governing stem cell self-renewal, developmental patterning, and tumor-initiating activity [PMID:18681827, PMID:33331818]. In its canonical mode, FZD7 partners with the co-receptor LRP6 to drive β-catenin stabilization and TCF-dependent transcription; engineered selective engagement of FZD7 with LRP6 is sufficient to activate β-catenin signaling and initiate mesendodermal/mesodermal differentiation in human pluripotent stem cells, with FZD7 producing distinct, more rapidly dampened β-catenin kinetics than FZD2 [PMID:33331818, PMID:39824186]. This canonical axis maintains pluripotency in human embryonic stem cells and drives tumor-initiating activity in breast, gastric, hepatocellular, and other cancers [PMID:21532620, PMID:24474766, PMID:25241036, PMID:39542206]. FZD7 also transduces multiple non-canonical outputs: WNT11 binding engages a FZD7–DAAM1–Rho–ROCK–Myosin II axis controlling amoeboid invasion and metastasis [PMID:33082334]; Wnt5a/b binding modulates PKC/ERK and STAT3/YAP1 signaling [PMID:28600110, PMID:32894152]; and WNT7A drives a JAK1/STAT3 program independent of β-catenin, while in differentiated myofibres Wnt7a couples FZD7 to a Gαs/PI3K complex that activates Akt/mTOR anabolic growth [PMID:38246919, PMID:22179044]. Receptor output is shaped by direct physical partners including GIPC2 (via PDZ interaction), Vangl1 at the leading edge of migrating cells, and LRP6 [PMID:35347223, PMID:37336284, PMID:32015160]. FZD7 abundance is tightly controlled at multiple levels: transcriptionally by ΔNp63, PU.1 (downstream of SIRT7), NOTCH3, and the repressor BCL6 [PMID:25241036, PMID:39542206, PMID:26847503, PMID:37060074]; post-transcriptionally by m6A/YTHDF1-mediated mRNA stabilization and translation [PMID:32788173, PMID:40281310]; and post-translationally by ZNRF3-mediated ubiquitination and lysosomal degradation, which is promoted by RSPO2 and antagonized by Wnt5a [PMID:28600110, PMID:32015160]. CryoEM has resolved full-length FZD7 in complex with the C. difficile toxin TcdB and structure-based screening has yielded transmembrane-domain antagonists [PMID:38308843, PMID:37669317].","teleology":[{"year":2008,"claim":"Established FZD7 as a functional requirement for stem cell self-renewal, moving it from a catalogued Wnt receptor to a determinant of the pluripotent state.","evidence":"qRT-PCR enrichment and shRNA knockdown in human embryonic stem cells with OCT4 and germ-layer marker readouts","pmids":["18681827"],"confidence":"Medium","gaps":["Did not define which Wnt ligand or downstream branch mediates the requirement","No co-receptor or effector identified"]},{"year":2011,"claim":"Showed FZD7 drives canonical Wnt/β-catenin output to sustain malignant proliferation and invasion, linking the receptor to tumor biology.","evidence":"shRNA knockdown in triple-negative breast cancer lines with nuclear β-catenin, TCF7 reporter, and xenograft readouts","pmids":["21532620"],"confidence":"Medium","gaps":["Co-receptor requirement not addressed","Did not distinguish direct receptor signaling from secondary effects"]},{"year":2011,"claim":"Revealed a β-catenin-independent FZD7 mode in muscle, demonstrating direct coupling to a Gαs/PI3K complex for Akt/mTOR anabolic growth.","evidence":"Wnt7a treatment, reciprocal co-IP of Fzd7 with Gαs and PI3K, Akt/mTOR readouts, IGF-receptor independence in myofibres","pmids":["22179044"],"confidence":"High","gaps":["Structural basis of Gαs/PI3K coupling unresolved","Generality beyond differentiated myofibres untested"]},{"year":2014,"claim":"Placed FZD7 downstream of ΔNp63 and as a node in pluripotency maintenance, connecting transcriptional control of the receptor to stem and tumor-initiating cell activity.","evidence":"ΔNp63 and FZD7 gain/loss-of-function with mammary/tumor-initiating assays; shRNA and FZD7-specific Fab in hESCs with Wnt3a signaling readouts","pmids":["25241036","24474766"],"confidence":"Medium","gaps":["Mechanism of Fab-induced FZD7 down-regulation not detailed","Ligand identity in each stem context not pinned down"]},{"year":2014,"claim":"Implicated FZD7 in non-canonical Wnt/PCP control of cytoskeleton and Rho/Rac GTPase balance, broadening its output beyond β-catenin.","evidence":"siRNA knockdown in Stem-A ovarian cancer cells with RhoA/Rac1 activity assays, TopFlash, PCP gene profiling","pmids":["25032869"],"confidence":"Medium","gaps":["Casein kinase 1ε role inferred from profiling rather than direct assay","Ligand driving the PCP branch not identified"]},{"year":2016,"claim":"Demonstrated an in vivo developmental requirement for FZD7 in angiogenesis acting via Dvl/β-catenin upstream of Notch ligand expression.","evidence":"Endothelial conditional Fzd7 knockout, Dvl depletion, LiCl rescue, and Dll4/Jagged1 readouts in retinal vasculature","pmids":["27758766"],"confidence":"High","gaps":["Direct molecular link between FZD7 signaling and Notch target promoters not resolved","Wnt ligand identity in endothelium unspecified"]},{"year":2016,"claim":"Identified NOTCH3-specific, CSL-independent transcriptional control of FZD7, revealing cross-pathway regulation of receptor abundance.","evidence":"Gain/loss-of-function of NOTCH1-4 in breast epithelial cells with FZD7 expression and non-canonical signaling readouts","pmids":["26847503"],"confidence":"Medium","gaps":["Direct DNA-binding mechanism of the NOTCH3 effect not shown","Physiological context of the regulation untested"]},{"year":2017,"claim":"Defined post-translational control of FZD7 surface levels through RSPO2/ZNRF3-mediated ubiquitination, with Wnt5a stabilizing the receptor to promote migration.","evidence":"Co-IP, ubiquitination assays, PKC/ERK readouts, and ligand competition in colorectal cancer cells","pmids":["28600110"],"confidence":"High","gaps":["Whether other Wnt ligands modulate ZNRF3 access not tested","Quantitative balance of degradation versus stabilization in vivo unknown"]},{"year":2018,"claim":"Identified FZD7 as the cognate receptor for WNT10B in trophoblast migration, linking a specific ligand to Rac1-driven cytoskeletal remodeling.","evidence":"Receptor identification, migration and Rac1 assays, SFRP3 competition, trophoblast-decidual co-culture","pmids":["29979633"],"confidence":"Medium","gaps":["Direct WNT10B-FZD7 binding affinity not quantified","Co-receptor involvement not addressed"]},{"year":2019,"claim":"Established tissue-specific FZD7 dependence among Wnt-driven stem cells, showing requirement in intestinal but not gastric Lgr5+ cells.","evidence":"Conditional Fzd7 deletion in gastric Lgr5+ cells with intestinal comparison and homeostasis/regeneration assays","pmids":["31288403"],"confidence":"Medium","gaps":["Compensating FZD receptors in gastric tissue not identified","Molecular basis of differential requirement unresolved"]},{"year":2019,"claim":"Connected FZD7 to epigenetic activation of TWIST1 and downstream BCL2-mediated anoikis resistance, providing a transcriptional/epigenetic effector arm.","evidence":"FZD7 knockdown/overexpression, TWIST1 rescue, ChIP for H3K4me3/H3K27ac, anoikis and spheroid assays in ovarian cancer","pmids":["30548372"],"confidence":"Medium","gaps":["How FZD7 signaling reaches chromatin modifiers at the TWIST1 promoter not defined","Branch (canonical vs non-canonical) responsible unclear"]},{"year":2020,"claim":"Resolved a WNT11-FZD7-DAAM1-Rho-ROCK-Myosin II axis driving amoeboid invasion and metastasis, formalizing a non-canonical effector cascade.","evidence":"KD/KO epistasis across WNT11, FZD7, DAAM1 in melanoma with Rho-ROCK-Myosin II readouts, in vivo metastasis, and human tissue validation","pmids":["33082334"],"confidence":"High","gaps":["Direct FZD7-DAAM1 physical contact not structurally mapped","Receptor conformational changes coupling ligand to Rho activation unknown"]},{"year":2020,"claim":"Identified m6A/YTHDF1-mediated translational control of FZD7 mRNA as a layer of expression regulation feeding Wnt/β-catenin output.","evidence":"m6A-seq, YTHDF1 manipulation, translation/polysome assays in gastric cancer models","pmids":["32788173"],"confidence":"Medium","gaps":["Specific m6A sites on FZD7 mRNA not pinpointed","Interplay with transcriptional regulators not examined"]},{"year":2020,"claim":"Showed Fzd7-Wnt5a/b non-canonical signaling shapes STAT3/Smad3/YAP1 activity and Col6a1-dependent mesenchymal stemness/EMT in breast cancer.","evidence":"Co-IP of Fzd7 with Wnt5a/b, pathway western blots, Col6a1 epistasis, xenograft/metastasis assays","pmids":["32894152"],"confidence":"Medium","gaps":["Direct versus indirect engagement of each downstream effector not separated","Co-receptor requirement unaddressed"]},{"year":2020,"claim":"Reconstituted FZD7-selective receptor engagement, proving that bridging FZD7 to LRP6 is sufficient to activate β-catenin and program mesendodermal differentiation.","evidence":"Engineered F7L6 bispecific agonist, receptor-selectivity profiling, β-catenin reporters, and hPS cell transcriptomics","pmids":["33331818"],"confidence":"High","gaps":["Endogenous Wnt ligand specificity for FZD7/LRP6 not resolved","Structural geometry of the productive FZD7-LRP6 complex not defined here"]},{"year":2020,"claim":"Demonstrated pharmacological degradation of the LRP6/FZD7 complex, showing FZD7 turnover can be coupled to its co-receptor's ectodomain.","evidence":"CDDO-Me degradation and ubiquitination assays, lysosomal inhibitors, LRP6 ectodomain deletion, and DVL2/β-catenin readouts in breast cancer","pmids":["32015160"],"confidence":"Medium","gaps":["E3 ligase mediating CDDO-Me-induced degradation not identified","Specificity for FZD7 over other FZDs not assessed"]},{"year":2022,"claim":"Identified GIPC2 as a direct PDZ-domain partner of FZD7 that potentiates β-catenin signaling and prostate cancer metastasis, defining a cytoplasmic adaptor link.","evidence":"Co-IP, PDZ interaction mapping, β-catenin assays, and in vivo metastasis assays","pmids":["35347223"],"confidence":"Medium","gaps":["How GIPC2 binding mechanistically enhances β-catenin output unclear","Reciprocal validation in other cell types absent"]},{"year":2022,"claim":"Linked FZD7 to Wnt5a-driven ABCG2 expression and chemoresistance, and to TGF-β/SMAD3 crosstalk in EMT, expanding its role in drug-resistant phenotypes.","evidence":"siRNA/inhibitor of FZD7 with ABCG2 and gemcitabine assays; FZD7 knockdown/overexpression with TGF-β1 stimulation and CSC readouts in pancreatic cancer","pmids":["33200805","35854234"],"confidence":"Medium","gaps":["Direct receptor-level integration of Wnt and TGF-β inputs not demonstrated","Single-lab pathway placement"]},{"year":2023,"claim":"Resolved transcriptional repression of FZD7 by BCL6 and its connection to ferroptosis, adding a tumor-suppressive regulatory arm.","evidence":"ChIP, dual-luciferase reporter, rescue experiments, and ferroptosis readouts in gastric cancer","pmids":["37060074"],"confidence":"Medium","gaps":["Mechanism connecting FZD7/β-catenin to GPX4-dependent ferroptosis not fully dissected","Physiological contexts of BCL6 repression unclear"]},{"year":2023,"claim":"Identified a Vangl1/Fzd7 leading-edge complex coupling the receptor to Rho GTPase-driven cytoskeletal dynamics in glioblastoma invasion.","evidence":"Co-IP, leading-edge co-localization, Rho GTPase assays, and intracranial xenograft with FZD7 depletion","pmids":["37336284"],"confidence":"Medium","gaps":["Direct versus scaffolded interaction not distinguished","Ligand input to the Vangl1/Fzd7 complex unidentified"]},{"year":2023,"claim":"Delivered structure-based FZD7 transmembrane-domain antagonists, establishing the TMD as a druggable pocket.","evidence":"Structure-based virtual screening, compound F7H synthesis, Wnt/β-catenin antagonism reporter, and docking/MD/FEP","pmids":["37669317"],"confidence":"Medium","gaps":["Binding-pocket residues defined computationally, not by experimental structure","Selectivity against other FZD TMDs not fully validated"]},{"year":2024,"claim":"Provided the first full-length FZD7 structure in complex with C. difficile TcdB, revealing conformational requirements for toxin engagement and antibody-based disruption.","evidence":"CryoEM of TcdB apo and TcdB-FZD7 complex, live-cell affinity, and bezlotoxumab competition","pmids":["38308843"],"confidence":"High","gaps":["Structure of Wnt/Rspo-bound FZD7 not resolved","Signaling conformations distinct from toxin binding undefined"]},{"year":2024,"claim":"Established a WNT7A-FZD7-JAK1-STAT3 cascade that operates without β-catenin, cementing a distinct non-canonical signaling output.","evidence":"WNT7A overexpression, JAK1/STAT3 readouts, negative β-catenin reporter, and PDX model in head and neck carcinoma","pmids":["38246919"],"confidence":"Medium","gaps":["How FZD7 physically couples to JAK1 not shown","Co-receptor requirement for the STAT3 branch unknown"]},{"year":2024,"claim":"Connected SIRT7 to FZD7 via PU.1-driven transcription, situating FZD7 as the obligatory node for SIRT7-mediated β-catenin stabilization in hepatocellular carcinoma.","evidence":"SIRT7/PU.1 manipulation, FZD7 knockdown rescue, fractionation, β-catenin stability/ubiquitination, and TopFlash assays","pmids":["39542206"],"confidence":"Medium","gaps":["Direct PU.1 occupancy at the FZD7 promoter not detailed","Whether SIRT7 acts solely through PU.1 unresolved"]},{"year":2025,"claim":"Showed FZD7 imparts distinct β-catenin signaling kinetics that diversify mesoderm fate, and that YTHDF1-stabilized FZD7 sustains chemoresistance, reinforcing both developmental and oncogenic regulatory roles.","evidence":"FZD2/FZD7-selective agonists with β-catenin kinetics and mesoderm marker analysis in hPSCs; YTHDF1/m6A-IP, mRNA stability, and cisplatin-resistance xenografts in ovarian cancer","pmids":["39824186","40281310"],"confidence":"Medium","gaps":["Receptor-intrinsic basis for faster β-catenin dampening by FZD7 not mechanistically defined","m6A site mapping on FZD7 mRNA incomplete"]},{"year":2025,"claim":"Identified BRAF-phosphorylated cytoplasmic KIAA1429 as a direct stabilizer of FZD7 protein driving Wnt activation and oxaliplatin resistance.","evidence":"Co-IP, immunofluorescence, RNA-seq, and oxaliplatin-resistance assays in colorectal cancer","pmids":["40611274"],"confidence":"Medium","gaps":["Mechanism by which KIAA1429 binding blocks FZD7 turnover not defined","Relationship to ZNRF3-mediated degradation untested"]},{"year":null,"claim":"How a single FZD7 receptor selects among canonical β-catenin, PCP/Rho, STAT3, and Gαs/PI3K outputs in a given cell remains undefined at the structural and biochemical level.","evidence":"No timeline study resolves the ligand-, co-receptor-, and conformation-dependent rules that partition FZD7 signaling branches","pmids":[],"confidence":"Low","gaps":["No structure of a signaling-competent Wnt-FZD7-co-receptor complex","Determinants of canonical versus non-canonical branch choice unmapped","Quantitative contribution of each regulatory layer in vivo unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,9,13,26]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[13,23]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,14,19]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,9,13]},{"term_id":"R-HSA-1266738","term_label":"Developmental 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May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues (Microbial infection) Acts as a receptor for C.difficile toxin TcdB in the colonic epithelium","subcellular_location":"Cell membrane; Endosome membrane","url":"https://www.uniprot.org/uniprotkb/O75084/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FZD7","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FZD7","total_profiled":1310},"omim":[{"mim_id":"615943","title":"MEMBRANE-ASSOCIATED GUANYLATE KINASE, WW AND PDZ DOMAINS-CONTAINING, 3; MAGI3","url":"https://www.omim.org/entry/615943"},{"mim_id":"604579","title":"FRIZZLED CLASS RECEPTOR 4; FZD4","url":"https://www.omim.org/entry/604579"},{"mim_id":"603410","title":"FRIZZLED CLASS RECEPTOR 7; FZD7","url":"https://www.omim.org/entry/603410"},{"mim_id":"603408","title":"FRIZZLED CLASS RECEPTOR 1; FZD1","url":"https://www.omim.org/entry/603408"},{"mim_id":"600838","title":"FORKHEAD BOX N1; FOXN1","url":"https://www.omim.org/entry/600838"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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cells (MDA-MB-231, BT-20) suppresses cell proliferation, invasiveness, and colony formation through silencing of canonical Wnt signaling, as evidenced by loss of nuclear β-catenin accumulation and decreased TCF7 transcriptional activity; in vivo xenograft studies confirmed reduced tumor formation.\",\n      \"method\": \"shRNA knockdown, β-catenin nuclear localization assay, TCF7 reporter assay, xenograft mouse model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype, multiple orthogonal readouts (nuclear β-catenin, TCF reporter, in vivo), single lab\",\n      \"pmids\": [\"21532620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In differentiated myofibres, Wnt7a binding to Fzd7 directly activates the Akt/mTOR anabolic growth pathway via a receptor complex associated with Gαs and PI(3)K, independently of IGF-receptor activation, thereby inducing myofibre hypertrophy.\",\n      \"method\": \"Wnt7a ligand treatment, co-immunoprecipitation of Fzd7 with Gαs and PI3K, Akt/mTOR pathway readouts, IGF-receptor independence experiments\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP identifying receptor complex components, multiple pathway readouts, published in high-impact journal with functional consequences established\",\n      \"pmids\": [\"22179044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ΔNp63 transcription factor promotes mammary stem cell activity and basal breast cancer tumor-initiating activity by increasing FZD7 expression, thereby enhancing Wnt signaling; FZD7-dependent Wnt signaling governed tumor-initiating activity of basal breast cancer.\",\n      \"method\": \"Gain- and loss-of-function of ΔNp63 and FZD7, mammary stem cell and tumor-initiating cell assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FZD7 positioned downstream of ΔNp63 in Wnt signaling by epistasis/rescue experiments, single lab\",\n      \"pmids\": [\"25241036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FZD7 is required for maintenance of the pluripotent state of human embryonic stem cells (hESCs); shRNA-mediated knockdown or blockade with a FZD7-specific Fab fragment disrupts pluripotency. The FZD7-specific Fab blocks Wnt3a signaling by down-regulating FZD7 protein levels, indicating that FZD7 transduces Wnt/β-catenin signals in hESCs.\",\n      \"method\": \"shRNA knockdown, FZD7-specific Fab antibody treatment, Wnt3a signaling assay, FZD7 protein level measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal perturbations (shRNA and Fab), defined cellular phenotype, single lab\",\n      \"pmids\": [\"24474766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FZD7 knockdown in Stem-A ovarian cancer cells reduces proliferation, induces epithelial-like morphology, increases cadherin-based cell-cell adhesion, rearranges actin cytoskeleton, decreases RhoA activity, and increases Rac1 activity; increased TopFlash activity and PCP pathway gene regulation suggest FZD7 drives aggressiveness via the non-canonical Wnt/PCP pathway through casein kinase 1ε.\",\n      \"method\": \"siRNA knockdown, cell proliferation and morphology assays, immunofluorescence, RhoA/Rac1 activity assays, TopFlash reporter assay, PCP gene expression profiling\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with multiple orthogonal readouts, pathway placement via reporter assay, single lab\",\n      \"pmids\": [\"25032869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FZD7 is expressed at up to 200-fold higher levels in human embryonic stem cells versus differentiated cell types; shRNA-mediated knockdown in hESCs induces changes in colony morphology, perturbation of germ layer marker gene expression, and rapid loss of OCT4 expression, establishing FZD7 as required for ES cell self-renewal capacity.\",\n      \"method\": \"Quantitative RT-PCR, flow cytometry, shRNA knockdown, OCT4 expression analysis\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined molecular and cellular phenotype, single lab, multiple readouts\",\n      \"pmids\": [\"18681827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Fzd7 expressed by endothelial cells is required for postnatal retinal vascular formation; endothelial cell-specific deletion of Fzd7 delays retinal plexus formation by impairing tip cell phenotype and stalk cell proliferation. Fzd7 acts via Dvl/β-catenin activation upstream of Notch signaling to control Dll4 and Jagged1 expression; LiCl treatment rescued the vascular phenotype of Fzd7 mutants.\",\n      \"method\": \"Conditional endothelial knockout mouse, retinal vascular phenotype analysis, Dvl3 depletion in dvl1-/- mice, LiCl pharmacological rescue, Notch target gene expression\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined vascular phenotype, pharmacological rescue, epistasis with Dvl and Notch, multiple orthogonal approaches\",\n      \"pmids\": [\"27758766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RSPO2 physically interacts with Fzd7 and increases degradation of cell-surface Fzd7 via ZNRF3-mediated ubiquitination, suppressing downstream PKC/ERK signaling and CRC cell migration; Wnt5a prevents Fzd7 degradation and promotes CRC cell migration, while RSPO2 antagonizes Wnt5a/Fzd7 signaling by blocking Wnt5a binding to FZD7.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, PKC/ERK signaling readouts, migration/invasion assays, ligand competition experiments\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding shown by Co-IP, ubiquitination mechanism identified, multiple functional readouts, competition ligand experiments\",\n      \"pmids\": [\"28600110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YTHDF1 promotes translation of FZD7 mRNA in an m6A-dependent manner in gastric cancer; mutated YTHDF1 enhances FZD7 expression, leading to hyperactivation of Wnt/β-catenin pathway.\",\n      \"method\": \"m6A-seq, YTHDF1 knockdown/overexpression, polysome profiling or translation assay, in vitro and in vivo gastric cancer models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic link of m6A reader to FZD7 translation established, multiple methods, single lab\",\n      \"pmids\": [\"32788173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WNT11-FZD7-DAAM1 signaling activates the Rho-ROCK1/2-Myosin II pathway to regulate tumour-initiating potential, amoeboid invasion, local invasion, and distant metastasis in melanoma.\",\n      \"method\": \"KD/KO of WNT11, FZD7, DAAM1 in melanoma cells; Rho-ROCK-Myosin II signaling readouts; in vivo metastasis assays; human melanoma tissue analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis across WNT11-FZD7-DAAM1 axis, multiple in vitro and in vivo functional readouts, validated in human tissue\",\n      \"pmids\": [\"33082334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FZD7 regulates TWIST1 expression through epigenetic modifications (H3K4me3 and H3K27ac) at the TWIST1 proximal promoter; the FZD7-TWIST1 axis then regulates BCL2 expression to confer anoikis resistance in ovarian cancer. Overexpression of TWIST1 partially rescued phenotypes abolished by FZD7 knockdown.\",\n      \"method\": \"FZD7 knockdown/overexpression, TWIST1 overexpression rescue, chromatin immunoprecipitation for H3K4me3/H3K27ac, BCL2 expression analysis, anoikis and spheroid assays\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epigenetic mechanism identified by ChIP, epistasis by rescue experiment, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"30548372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Non-canonical Fzd7 signaling in breast cancer cells involves Fzd7 binding to Wnt5a/b, and modulates phospho-STAT3, Smad3, YAP1, and Col6a1 expression; Fzd7-Wnt5b regulates Col6a1 to mediate mesenchymal-like stemness and EMT.\",\n      \"method\": \"Fzd7 knockdown/overexpression, co-immunoprecipitation of Fzd7 with Wnt5a/b, pathway protein western blots, Col6a1 knockdown epistasis, xenograft and metastasis assays\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing Fzd7-Wnt5b interaction, epistasis experiments, multiple functional readouts, single lab\",\n      \"pmids\": [\"32894152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GIPC2 directly binds to FZD7 through its PDZ domain, enabling activation of WNT-β-catenin cascades and stimulating prostate cancer metastasis.\",\n      \"method\": \"Co-immunoprecipitation, PDZ domain interaction mapping, β-catenin signaling assays, in vitro and in vivo metastasis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct physical interaction via Co-IP with domain mapping, functional downstream readouts, single lab\",\n      \"pmids\": [\"35347223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Selective engagement of FZD7 (and not other FZD proteins) by the engineered bispecific protein F7L6, which bridges FZD7 and LRP6, potently activates WNT/β-catenin signaling and is sufficient to initiate mesendodermal differentiation programs in human pluripotent stem cells, mimicking primitive streak formation.\",\n      \"method\": \"Engineered FZD7-selective/LRP6-bridging agonist (F7L6), WNT/β-catenin reporter assays, transcriptome profiling of hPS cells, comparison with Wnt3a and other FZD-selective agonists\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstituted selective FZD7 engagement with defined co-receptor, rigorous receptor selectivity profiling, orthogonal transcriptomic and functional validation\",\n      \"pmids\": [\"33331818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CryoEM structures of TcdB alone and in complex with full-length FZD7 reveal that large structural rearrangements of the combined repetitive polypeptide (CROPs) domain of TcdB are required for FZD7 interaction; bezlotoxumab (FDA-approved antibody) favors the apo-TcdB conformation and disrupts FZD7 binding. Dynamic transition between TcdB conformations also governs stability of the pore-forming region.\",\n      \"method\": \"CryoEM structure determination, live-cell affinity assay, bezlotoxumab competition binding assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryoEM structure of full-length FZD7 in complex with TcdB, functional validation of conformational dynamics and antibody competition\",\n      \"pmids\": [\"38308843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Structure-based ligand discovery targeting the transmembrane domain (TMD) of FZD7 identified compound F7H as an FZD7 antagonist (IC50 = 1.25 μM); molecular docking, MD simulation, and free energy perturbation calculations defined key binding-pocket residues in the TMD.\",\n      \"method\": \"Structure-based virtual screening, compound synthesis, Wnt/β-catenin reporter antagonism assay, molecular docking/MD/FEP calculations\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — structure-guided discovery with functional validation in reporter assay and computational structural characterization, single lab\",\n      \"pmids\": [\"37669317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CDDO-Me inhibits Wnt/β-catenin signaling by inducing ubiquitination and lysosomal degradation of the LRP6/FZD7 receptor complex; degradation of FZD7 is dependent on the LRP6 ectodomain, and CDDO-Me reduces phospho-DVL2 and active β-catenin levels in breast cancer cells.\",\n      \"method\": \"LRP6 and FZD7 protein degradation assays, ubiquitination assay, lysosomal pathway inhibitors, LRP6 ectodomain deletion constructs, DVL2 and β-catenin western blots, xenograft model\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanism identified with ubiquitination and degradation assays, LRP6 ectodomain dependency established, multiple pathway readouts, single lab\",\n      \"pmids\": [\"32015160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NOTCH3, but not NOTCH1, 2, or 4, regulates FZD7 expression in human breast epithelial cells through a non-canonical (CSL-independent) Notch signaling mechanism; gain- and loss-of-function experiments showed this regulation is unique and non-redundant.\",\n      \"method\": \"Constitutively active NOTCH1-4 overexpression, NOTCH loss-of-function, CSL-independent signaling assay, FZD7 expression analysis\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis using multiple Notch receptor gain/loss-of-function, non-canonical pathway placement, single lab\",\n      \"pmids\": [\"26847503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GCM1 transcription factor promotes trophoblast cell migration by activating WNT10B expression; WNT10B signals through FZD7 (identified as its cognate receptor) to upregulate cell migration via Rac1-mediated cytoskeletal remodeling. SFRP3 from decidual cells blocks WNT10B-FZD7 interaction to decrease trophoblast migration.\",\n      \"method\": \"FZD7 receptor identification for WNT10B, cell migration assays, Rac1 activity assays, SFRP3 competition binding, trophoblast-decidual co-culture\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor identification for specific Wnt ligand, functional rescue and competition experiments, multiple cell assays, single lab\",\n      \"pmids\": [\"29979633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Vangl1 forms a novel complex with Fzd7 at the leading edge of migrating GBM cells; this Vangl1/Fzd7 complex drives cellular proliferation, migration, and invasiveness by engaging Rho GTPases to promote cytoskeletal rearrangements and actin dynamics.\",\n      \"method\": \"Co-immunoprecipitation, co-localization at leading edge, Rho GTPase activity assays, FZD7 depletion in intracranial xenograft model, KD functional assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel complex identified by Co-IP with subcellular localization, Rho GTPase pathway readouts, in vivo tumor model, single lab\",\n      \"pmids\": [\"37336284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRT7 promotes FZD7 expression by upregulating the transcription factor PU.1, which then drives FZD7 transcription; FZD7 is required for SIRT7-mediated stabilization of β-catenin and its nuclear localization in hepatocellular carcinoma cells. FZD7 knockdown reversed SIRT7-overexpression-mediated β-catenin stabilization.\",\n      \"method\": \"SIRT7 knockdown/overexpression, FZD7 knockdown rescue, PU.1 manipulation, nuclear/cytoplasmic fractionation, β-catenin ubiquitination and stability assays, Top-Flash reporter, immunofluorescence\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis across SIRT7-PU.1-FZD7-β-catenin axis, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"39542206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BCL6 transcription repressor directly binds the FZD7 promoter and transcriptionally represses FZD7 to inhibit gastric cancer cell proliferation and metastasis; BCL6 also promotes ferroptosis through the FZD7/β-catenin/TP63/GPX4 pathway.\",\n      \"method\": \"ChIP assay, dual luciferase reporter assay, FZD7 rescue experiments, ferroptosis readouts (lipid peroxidation, MDA, Fe2+), rescue experiments\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding shown by ChIP, luciferase reporter validation, rescue epistasis, single lab\",\n      \"pmids\": [\"37060074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Wnt5a regulates ABCG2 expression in pancreatic cancer cells through FZD7; siRNA silencing or pharmacological inhibition of FZD7 blocked Wnt5a-induced ABCG2 upregulation and attenuated gemcitabine resistance.\",\n      \"method\": \"siRNA knockdown of FZD7, FZD7 inhibitors, recombinant Wnt5a treatment, ABCG2 expression analysis, gemcitabine resistance assay\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway placement of FZD7 downstream of Wnt5a and upstream of ABCG2 by siRNA and inhibitor experiments, single lab\",\n      \"pmids\": [\"33200805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FZD7 activation (via selective agonist) triggers β-catenin signaling with distinct kinetics from FZD2, enabling both paraxial and lateral mesoderm differentiation of hPSCs, whereas FZD2 activation favors only paraxial mesoderm; FZD7 shows more rapid dampening of β-catenin signaling than FZD2, permitting lateral mesoderm induction.\",\n      \"method\": \"FZD2- and FZD7-selective antibody-based agonists, hPSC directed differentiation assays, β-catenin signaling kinetics measurement, mesoderm subtype marker analysis\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — selective FZD7 agonist enabling receptor-specific functional comparison, differentiation readouts, single lab\",\n      \"pmids\": [\"39824186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDF1 binds to m6A-modified FZD7 mRNA in cisplatin-resistant ovarian cancer cells, enhancing its stability and translation, thereby sustaining Wnt/β-catenin signaling activation; YTHDF1 silencing reduces FZD7 expression, inhibits Wnt/β-catenin signaling, and restores cisplatin sensitivity in vitro and in xenograft models.\",\n      \"method\": \"YTHDF1 knockdown/overexpression, m6A-IP, mRNA stability assay, FZD7 expression analysis, Wnt/β-catenin pathway readouts, xenograft mouse model\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-dependent mRNA regulation mechanism with stability and in vivo validation, single lab\",\n      \"pmids\": [\"40281310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FZD7 knockdown in pancreatic cancer cells reduces EMT marker expression, reduces mesenchymal phenotype, decreases cancer stem cell proportions (CD24+CD44+, ABCG2), and attenuates TGF-β1-induced EMT; FZD7 acts through both canonical Wnt/β-catenin and TGF-β/SMAD3 signaling pathways.\",\n      \"method\": \"lentiviral shRNA knockdown, FZD7 overexpression, TGF-β1 stimulation assays, EMT marker western blots, CSC flow cytometry, sphere formation assays\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss and gain of function, multiple pathway readouts, TGF-β/SMAD3 cross-talk shown, single lab\",\n      \"pmids\": [\"35854234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WNT7A activates the FZD7/JAK1/STAT3 signaling pathway in head and neck squamous cell carcinoma, leading to enhanced cell proliferation, self-renewal, and resistance to apoptosis, without activating canonical Wnt/β-catenin signaling.\",\n      \"method\": \"WNT7A overexpression, FZD7/JAK1/STAT3 pathway analysis, β-catenin reporter (negative result), patient-derived xenograft model\",\n      \"journal\": \"International journal of oral science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — non-canonical pathway placement established, in vivo PDX model confirmation, active exclusion of canonical pathway, single lab\",\n      \"pmids\": [\"38246919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cytoplasmic KIAA1429, phosphorylated by BRAF, stabilizes FZD7 protein in colorectal cancer cells by direct binding, thereby activating the WNT pathway and promoting cancer stemness and oxaliplatin resistance.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, RNA-seq, in vitro and in vivo oxaliplatin resistance assays, FZD7 stabilization experiments\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding of KIAA1429 to FZD7 shown by Co-IP, mechanism linked to protein stabilization and downstream Wnt activation, single lab\",\n      \"pmids\": [\"40611274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Fibronectin promotes non-canonical Wnt signaling through Wnt11-Fzd7 interaction in limbal epithelial stem cells, and modulates cell cycle regulators via upregulation of ROCK1 and ROCK2 to enhance stem cell self-renewal and proliferation.\",\n      \"method\": \"Wnt11 and Fzd7 co-expression/interaction analysis, ROCK inhibition, proliferation and stemness assays under fibronectin conditions\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-lab study with Wnt11/Fzd7 interaction inferred from expression rather than direct Co-IP; functional assays present but mechanistic rigor limited\",\n      \"pmids\": [\"31150636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FZD7 knockdown reduces expression of Lgr5 (a WNT target) and is required for intestinal stem cell function in mice, but gastric Lgr5+ stem cells do not require Fzd7 for epithelial homeostasis, establishing tissue-specific differential requirement for FZD7 in Wnt-dependent stem cell maintenance.\",\n      \"method\": \"Conditional Fzd7 deletion in gastric Lgr5+ cells, intestinal comparison, homeostasis and regeneration assays\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic in vivo KO in specific cell population, tissue-specific epistasis established, single lab\",\n      \"pmids\": [\"31288403\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FZD7 is a seven-transmembrane Wnt receptor that, depending on cellular context, transduces both canonical Wnt/β-catenin signaling (by forming a complex with LRP5/6 and Dishevelled/DVL to stabilize β-catenin and activate TCF target genes) and non-canonical Wnt signaling (via PCP/Wnt11-DAAM1-Rho-ROCK-Myosin II, Wnt5a/b-PKC/ERK, and JAK1/STAT3 pathways); it associates with co-receptors and effectors including Gαs and PI3K (for Akt/mTOR activation by Wnt7a in muscle), GIPC2 (via PDZ-domain interaction), Vangl1 (at the leading edge of migrating cells), and LRP6; its expression is transcriptionally regulated by ΔNp63, BCL6, and PU.1 (downstream of SIRT7), and post-transcriptionally regulated by m6A-dependent YTHDF1-mediated translation; FZD7 protein stability is modulated by ZNRF3-mediated ubiquitination and lysosomal degradation (promoted by RSPO2, antagonized by Wnt5a); FZD7 is required for pluripotency maintenance in human embryonic stem cells, satellite stem cell expansion in muscle, mammary stem cell activity, and postnatal angiogenesis, and marks tumor-initiating cells in multiple cancers.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FZD7 is a seven-transmembrane Wnt receptor that functions as a context-dependent signaling hub for both canonical Wnt/β-catenin and non-canonical Wnt pathways, governing stem cell self-renewal, developmental patterning, and tumor-initiating activity [#5, #13]. In its canonical mode, FZD7 partners with the co-receptor LRP6 to drive β-catenin stabilization and TCF-dependent transcription; engineered selective engagement of FZD7 with LRP6 is sufficient to activate β-catenin signaling and initiate mesendodermal/mesodermal differentiation in human pluripotent stem cells, with FZD7 producing distinct, more rapidly dampened β-catenin kinetics than FZD2 [#13, #23]. This canonical axis maintains pluripotency in human embryonic stem cells and drives tumor-initiating activity in breast, gastric, hepatocellular, and other cancers [#0, #3, #2, #20]. FZD7 also transduces multiple non-canonical outputs: WNT11 binding engages a FZD7–DAAM1–Rho–ROCK–Myosin II axis controlling amoeboid invasion and metastasis [#9]; Wnt5a/b binding modulates PKC/ERK and STAT3/YAP1 signaling [#7, #11]; and WNT7A drives a JAK1/STAT3 program independent of β-catenin, while in differentiated myofibres Wnt7a couples FZD7 to a Gαs/PI3K complex that activates Akt/mTOR anabolic growth [#26, #1]. Receptor output is shaped by direct physical partners including GIPC2 (via PDZ interaction), Vangl1 at the leading edge of migrating cells, and LRP6 [#12, #19, #16]. FZD7 abundance is tightly controlled at multiple levels: transcriptionally by ΔNp63, PU.1 (downstream of SIRT7), NOTCH3, and the repressor BCL6 [#2, #20, #17, #21]; post-transcriptionally by m6A/YTHDF1-mediated mRNA stabilization and translation [#8, #24]; and post-translationally by ZNRF3-mediated ubiquitination and lysosomal degradation, which is promoted by RSPO2 and antagonized by Wnt5a [#7, #16]. CryoEM has resolved full-length FZD7 in complex with the C. difficile toxin TcdB and structure-based screening has yielded transmembrane-domain antagonists [#14, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established FZD7 as a functional requirement for stem cell self-renewal, moving it from a catalogued Wnt receptor to a determinant of the pluripotent state.\",\n      \"evidence\": \"qRT-PCR enrichment and shRNA knockdown in human embryonic stem cells with OCT4 and germ-layer marker readouts\",\n      \"pmids\": [\"18681827\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define which Wnt ligand or downstream branch mediates the requirement\", \"No co-receptor or effector identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed FZD7 drives canonical Wnt/β-catenin output to sustain malignant proliferation and invasion, linking the receptor to tumor biology.\",\n      \"evidence\": \"shRNA knockdown in triple-negative breast cancer lines with nuclear β-catenin, TCF7 reporter, and xenograft readouts\",\n      \"pmids\": [\"21532620\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-receptor requirement not addressed\", \"Did not distinguish direct receptor signaling from secondary effects\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed a β-catenin-independent FZD7 mode in muscle, demonstrating direct coupling to a Gαs/PI3K complex for Akt/mTOR anabolic growth.\",\n      \"evidence\": \"Wnt7a treatment, reciprocal co-IP of Fzd7 with Gαs and PI3K, Akt/mTOR readouts, IGF-receptor independence in myofibres\",\n      \"pmids\": [\"22179044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Gαs/PI3K coupling unresolved\", \"Generality beyond differentiated myofibres untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed FZD7 downstream of ΔNp63 and as a node in pluripotency maintenance, connecting transcriptional control of the receptor to stem and tumor-initiating cell activity.\",\n      \"evidence\": \"ΔNp63 and FZD7 gain/loss-of-function with mammary/tumor-initiating assays; shRNA and FZD7-specific Fab in hESCs with Wnt3a signaling readouts\",\n      \"pmids\": [\"25241036\", \"24474766\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Fab-induced FZD7 down-regulation not detailed\", \"Ligand identity in each stem context not pinned down\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Implicated FZD7 in non-canonical Wnt/PCP control of cytoskeleton and Rho/Rac GTPase balance, broadening its output beyond β-catenin.\",\n      \"evidence\": \"siRNA knockdown in Stem-A ovarian cancer cells with RhoA/Rac1 activity assays, TopFlash, PCP gene profiling\",\n      \"pmids\": [\"25032869\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Casein kinase 1ε role inferred from profiling rather than direct assay\", \"Ligand driving the PCP branch not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated an in vivo developmental requirement for FZD7 in angiogenesis acting via Dvl/β-catenin upstream of Notch ligand expression.\",\n      \"evidence\": \"Endothelial conditional Fzd7 knockout, Dvl depletion, LiCl rescue, and Dll4/Jagged1 readouts in retinal vasculature\",\n      \"pmids\": [\"27758766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between FZD7 signaling and Notch target promoters not resolved\", \"Wnt ligand identity in endothelium unspecified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified NOTCH3-specific, CSL-independent transcriptional control of FZD7, revealing cross-pathway regulation of receptor abundance.\",\n      \"evidence\": \"Gain/loss-of-function of NOTCH1-4 in breast epithelial cells with FZD7 expression and non-canonical signaling readouts\",\n      \"pmids\": [\"26847503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNA-binding mechanism of the NOTCH3 effect not shown\", \"Physiological context of the regulation untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined post-translational control of FZD7 surface levels through RSPO2/ZNRF3-mediated ubiquitination, with Wnt5a stabilizing the receptor to promote migration.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, PKC/ERK readouts, and ligand competition in colorectal cancer cells\",\n      \"pmids\": [\"28600110\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other Wnt ligands modulate ZNRF3 access not tested\", \"Quantitative balance of degradation versus stabilization in vivo unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified FZD7 as the cognate receptor for WNT10B in trophoblast migration, linking a specific ligand to Rac1-driven cytoskeletal remodeling.\",\n      \"evidence\": \"Receptor identification, migration and Rac1 assays, SFRP3 competition, trophoblast-decidual co-culture\",\n      \"pmids\": [\"29979633\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct WNT10B-FZD7 binding affinity not quantified\", \"Co-receptor involvement not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established tissue-specific FZD7 dependence among Wnt-driven stem cells, showing requirement in intestinal but not gastric Lgr5+ cells.\",\n      \"evidence\": \"Conditional Fzd7 deletion in gastric Lgr5+ cells with intestinal comparison and homeostasis/regeneration assays\",\n      \"pmids\": [\"31288403\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Compensating FZD receptors in gastric tissue not identified\", \"Molecular basis of differential requirement unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected FZD7 to epigenetic activation of TWIST1 and downstream BCL2-mediated anoikis resistance, providing a transcriptional/epigenetic effector arm.\",\n      \"evidence\": \"FZD7 knockdown/overexpression, TWIST1 rescue, ChIP for H3K4me3/H3K27ac, anoikis and spheroid assays in ovarian cancer\",\n      \"pmids\": [\"30548372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How FZD7 signaling reaches chromatin modifiers at the TWIST1 promoter not defined\", \"Branch (canonical vs non-canonical) responsible unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved a WNT11-FZD7-DAAM1-Rho-ROCK-Myosin II axis driving amoeboid invasion and metastasis, formalizing a non-canonical effector cascade.\",\n      \"evidence\": \"KD/KO epistasis across WNT11, FZD7, DAAM1 in melanoma with Rho-ROCK-Myosin II readouts, in vivo metastasis, and human tissue validation\",\n      \"pmids\": [\"33082334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct FZD7-DAAM1 physical contact not structurally mapped\", \"Receptor conformational changes coupling ligand to Rho activation unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified m6A/YTHDF1-mediated translational control of FZD7 mRNA as a layer of expression regulation feeding Wnt/β-catenin output.\",\n      \"evidence\": \"m6A-seq, YTHDF1 manipulation, translation/polysome assays in gastric cancer models\",\n      \"pmids\": [\"32788173\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific m6A sites on FZD7 mRNA not pinpointed\", \"Interplay with transcriptional regulators not examined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed Fzd7-Wnt5a/b non-canonical signaling shapes STAT3/Smad3/YAP1 activity and Col6a1-dependent mesenchymal stemness/EMT in breast cancer.\",\n      \"evidence\": \"Co-IP of Fzd7 with Wnt5a/b, pathway western blots, Col6a1 epistasis, xenograft/metastasis assays\",\n      \"pmids\": [\"32894152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect engagement of each downstream effector not separated\", \"Co-receptor requirement unaddressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reconstituted FZD7-selective receptor engagement, proving that bridging FZD7 to LRP6 is sufficient to activate β-catenin and program mesendodermal differentiation.\",\n      \"evidence\": \"Engineered F7L6 bispecific agonist, receptor-selectivity profiling, β-catenin reporters, and hPS cell transcriptomics\",\n      \"pmids\": [\"33331818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous Wnt ligand specificity for FZD7/LRP6 not resolved\", \"Structural geometry of the productive FZD7-LRP6 complex not defined here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated pharmacological degradation of the LRP6/FZD7 complex, showing FZD7 turnover can be coupled to its co-receptor's ectodomain.\",\n      \"evidence\": \"CDDO-Me degradation and ubiquitination assays, lysosomal inhibitors, LRP6 ectodomain deletion, and DVL2/β-catenin readouts in breast cancer\",\n      \"pmids\": [\"32015160\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating CDDO-Me-induced degradation not identified\", \"Specificity for FZD7 over other FZDs not assessed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified GIPC2 as a direct PDZ-domain partner of FZD7 that potentiates β-catenin signaling and prostate cancer metastasis, defining a cytoplasmic adaptor link.\",\n      \"evidence\": \"Co-IP, PDZ interaction mapping, β-catenin assays, and in vivo metastasis assays\",\n      \"pmids\": [\"35347223\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How GIPC2 binding mechanistically enhances β-catenin output unclear\", \"Reciprocal validation in other cell types absent\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked FZD7 to Wnt5a-driven ABCG2 expression and chemoresistance, and to TGF-β/SMAD3 crosstalk in EMT, expanding its role in drug-resistant phenotypes.\",\n      \"evidence\": \"siRNA/inhibitor of FZD7 with ABCG2 and gemcitabine assays; FZD7 knockdown/overexpression with TGF-β1 stimulation and CSC readouts in pancreatic cancer\",\n      \"pmids\": [\"33200805\", \"35854234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct receptor-level integration of Wnt and TGF-β inputs not demonstrated\", \"Single-lab pathway placement\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved transcriptional repression of FZD7 by BCL6 and its connection to ferroptosis, adding a tumor-suppressive regulatory arm.\",\n      \"evidence\": \"ChIP, dual-luciferase reporter, rescue experiments, and ferroptosis readouts in gastric cancer\",\n      \"pmids\": [\"37060074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting FZD7/β-catenin to GPX4-dependent ferroptosis not fully dissected\", \"Physiological contexts of BCL6 repression unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a Vangl1/Fzd7 leading-edge complex coupling the receptor to Rho GTPase-driven cytoskeletal dynamics in glioblastoma invasion.\",\n      \"evidence\": \"Co-IP, leading-edge co-localization, Rho GTPase assays, and intracranial xenograft with FZD7 depletion\",\n      \"pmids\": [\"37336284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus scaffolded interaction not distinguished\", \"Ligand input to the Vangl1/Fzd7 complex unidentified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Delivered structure-based FZD7 transmembrane-domain antagonists, establishing the TMD as a druggable pocket.\",\n      \"evidence\": \"Structure-based virtual screening, compound F7H synthesis, Wnt/β-catenin antagonism reporter, and docking/MD/FEP\",\n      \"pmids\": [\"37669317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding-pocket residues defined computationally, not by experimental structure\", \"Selectivity against other FZD TMDs not fully validated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the first full-length FZD7 structure in complex with C. difficile TcdB, revealing conformational requirements for toxin engagement and antibody-based disruption.\",\n      \"evidence\": \"CryoEM of TcdB apo and TcdB-FZD7 complex, live-cell affinity, and bezlotoxumab competition\",\n      \"pmids\": [\"38308843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of Wnt/Rspo-bound FZD7 not resolved\", \"Signaling conformations distinct from toxin binding undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a WNT7A-FZD7-JAK1-STAT3 cascade that operates without β-catenin, cementing a distinct non-canonical signaling output.\",\n      \"evidence\": \"WNT7A overexpression, JAK1/STAT3 readouts, negative β-catenin reporter, and PDX model in head and neck carcinoma\",\n      \"pmids\": [\"38246919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How FZD7 physically couples to JAK1 not shown\", \"Co-receptor requirement for the STAT3 branch unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected SIRT7 to FZD7 via PU.1-driven transcription, situating FZD7 as the obligatory node for SIRT7-mediated β-catenin stabilization in hepatocellular carcinoma.\",\n      \"evidence\": \"SIRT7/PU.1 manipulation, FZD7 knockdown rescue, fractionation, β-catenin stability/ubiquitination, and TopFlash assays\",\n      \"pmids\": [\"39542206\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PU.1 occupancy at the FZD7 promoter not detailed\", \"Whether SIRT7 acts solely through PU.1 unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed FZD7 imparts distinct β-catenin signaling kinetics that diversify mesoderm fate, and that YTHDF1-stabilized FZD7 sustains chemoresistance, reinforcing both developmental and oncogenic regulatory roles.\",\n      \"evidence\": \"FZD2/FZD7-selective agonists with β-catenin kinetics and mesoderm marker analysis in hPSCs; YTHDF1/m6A-IP, mRNA stability, and cisplatin-resistance xenografts in ovarian cancer\",\n      \"pmids\": [\"39824186\", \"40281310\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor-intrinsic basis for faster β-catenin dampening by FZD7 not mechanistically defined\", \"m6A site mapping on FZD7 mRNA incomplete\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified BRAF-phosphorylated cytoplasmic KIAA1429 as a direct stabilizer of FZD7 protein driving Wnt activation and oxaliplatin resistance.\",\n      \"evidence\": \"Co-IP, immunofluorescence, RNA-seq, and oxaliplatin-resistance assays in colorectal cancer\",\n      \"pmids\": [\"40611274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which KIAA1429 binding blocks FZD7 turnover not defined\", \"Relationship to ZNRF3-mediated degradation untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single FZD7 receptor selects among canonical β-catenin, PCP/Rho, STAT3, and Gαs/PI3K outputs in a given cell remains undefined at the structural and biochemical level.\",\n      \"evidence\": \"No timeline study resolves the ligand-, co-receptor-, and conformation-dependent rules that partition FZD7 signaling branches\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of a signaling-competent Wnt-FZD7-co-receptor complex\", \"Determinants of canonical versus non-canonical branch choice unmapped\", \"Quantitative contribution of each regulatory layer in vivo unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 9, 13, 26]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [13, 23]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 14, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 9, 13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 13, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 21, 24, 27]}\n    ],\n    \"complexes\": [\n      \"FZD7-LRP6 receptor complex\",\n      \"FZD7-Gαs-PI3K complex\",\n      \"Vangl1-FZD7 complex\"\n    ],\n    \"partners\": [\n      \"LRP6\",\n      \"GIPC2\",\n      \"Vangl1\",\n      \"DAAM1\",\n      \"RSPO2\",\n      \"ZNRF3\",\n      \"WNT11\",\n      \"KIAA1429\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}