{"gene":"FZD7","run_date":"2026-04-28T17:46:04","timeline":{"discoveries":[{"year":2011,"finding":"FZD7 knockdown in TNBC cells suppresses canonical Wnt signaling, evidenced by loss of nuclear β-catenin accumulation and decreased TCF7 transcriptional activity, establishing FZD7 as a required receptor for canonical Wnt/β-catenin pathway activation in triple-negative breast cancer.","method":"shRNA knockdown, β-catenin nuclear localization assay, TCF7 reporter assay, xenograft tumor model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KD, reporter assay, in vivo xenograft) in a highly-cited paper","pmids":["21532620"],"is_preprint":false},{"year":2011,"finding":"Wnt7a binds Fzd7 and directly activates the Akt/mTOR anabolic growth pathway in differentiated myofibers through a complex containing Gαs and PI(3)K, independent of IGF-receptor activation, demonstrating a non-canonical Wnt7a-Fzd7 signaling axis distinct from its planar cell polarity role in satellite stem cells.","method":"Co-immunoprecipitation (Fzd7 complex with Gαs and PI(3)K), Wnt7a treatment of myotubes, PI3K inhibitor, KO/KD with Akt/mTOR readout","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical complex identification with functional validation, highly cited, multiple orthogonal methods","pmids":["22179044"],"is_preprint":false},{"year":2014,"finding":"ΔNp63 transcription factor promotes mammary stem cell activity and basal breast cancer tumor-initiating ability by directly enhancing Fzd7 expression, thereby increasing Wnt signaling.","method":"Gain/loss-of-function of ΔNp63, Fzd7 expression analysis, mammary stem cell activity assays, tumor-initiating cell assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple functional readouts, highly-cited paper, mechanistic link from transcription factor to receptor established","pmids":["25241036"],"is_preprint":false},{"year":2014,"finding":"FZD7 is required for maintenance of the pluripotent state in human embryonic stem cells; a FZD7-specific Fab antibody blocks Wnt3a signaling by downregulating FZD7 protein levels, and shRNA-mediated knockdown disrupts the pluripotent state, demonstrating that hESCs require endogenous WNT/β-catenin signaling through FZD7.","method":"shRNA knockdown, FZD7-specific Fab antibody blocking, Wnt3a treatment, pluripotency marker analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KD, blocking antibody, Wnt3a rescue), rigorous functional readouts","pmids":["24474766"],"is_preprint":false},{"year":2008,"finding":"FZD7 is highly expressed in human embryonic stem cells, and shRNA-mediated knockdown induces colony morphology changes and rapid loss of OCT4 expression, identifying FZD7 as a component of hESC self-renewal signaling.","method":"shRNA knockdown, quantitative RT-PCR, flow cytometry, morphological analysis","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype, single lab","pmids":["18681827"],"is_preprint":false},{"year":2014,"finding":"FZD7 knockdown in Stem-A ovarian cancer cells causes actin cytoskeletal rearrangement via reciprocal regulation of RhoA and Rac1 (reduced RhoA activity, increased Rac1 activity), changes in phospho-myosin light chain distribution, and increased TopFlash reporter activity, establishing FZD7 involvement in the non-canonical Wnt/PCP pathway through casein kinase 1ε.","method":"siRNA knockdown, RhoA/Rac1 activity assays, phospho-MLC immunofluorescence, TopFlash reporter assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — multiple mechanistic readouts (Rho GTPase activity, cytoskeletal imaging, reporter assay), single lab","pmids":["25032869"],"is_preprint":false},{"year":2016,"finding":"Fzd7 expressed by endothelial cells controls postnatal angiogenesis via activation of Dvl/β-catenin signaling, acting upstream of Notch signaling to regulate Dll4 and Jagged1 expression; endothelial-specific deletion of fzd7 (fzd7ECKO) delays retinal plexus formation due to impaired tip cell phenotype and decreased stalk cell proliferation, rescued by LiCl treatment.","method":"Conditional endothelial KO (fzd7ECKO mice), retinal vascular imaging, LiCl pharmacological rescue, Dvl1/3 double KO comparison","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with defined vascular phenotype, genetic and pharmacological rescue establishing pathway position","pmids":["27758766"],"is_preprint":false},{"year":2017,"finding":"RSPO2 physically interacts with Fzd7 and promotes ZNRF3-mediated ubiquitination and degradation of cell-surface Fzd7, suppressing downstream PKC/ERK signaling; Wnt5a prevents Fzd7 degradation, and RSPO2 antagonizes Wnt5a-driven noncanonical Wnt signaling by blocking Wnt5a binding to Fzd7.","method":"Co-immunoprecipitation, ubiquitination assay, ZNRF3 involvement, PKC/ERK signaling readout, Wnt5a competitive binding","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical interaction (Co-IP, ubiquitination), pathway mechanism with competitive ligand binding, multiple methods","pmids":["28600110"],"is_preprint":false},{"year":2020,"finding":"YTHDF1 promotes translation of FZD7 mRNA in an m6A-dependent manner, leading to hyperactivation of the Wnt/β-catenin pathway; mutated YTHDF1 further enhances FZD7 expression and gastric carcinogenesis.","method":"YTHDF1 knockdown/overexpression, m6A methylation analysis, FZD7 protein translation assay, Wnt/β-catenin pathway readout, in vitro and in vivo tumor models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — m6A-dependent translational regulation established with multiple orthogonal methods, highly cited","pmids":["32788173"],"is_preprint":false},{"year":2021,"finding":"circACTN4 recruits Y-box binding protein 1 (YBX1) to stimulate FZD7 transcription in intrahepatic cholangiocarcinoma, identified via RNA pulldown, mass spectrometry, ChIP, RIP, EMSA, and luciferase reporter assays.","method":"RNA pulldown, mass spectrometry, chromatin immunoprecipitation (ChIP), RNA-binding protein immunoprecipitation (RIP), EMSA, luciferase reporter assay","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal biochemical methods establishing transcriptional mechanism, highly cited","pmids":["34509526"],"is_preprint":false},{"year":2020,"finding":"WNT11-FZD7-DAAM1 signaling activates Rho-ROCK1/2-Myosin II and plays a crucial role in amoeboid melanoma invasion, tumor-initiating potential, and distant metastasis formation.","method":"KD of WNT11/FZD7/DAAM1, Rho-ROCK-Myosin II pathway readout, invasion assays, in vivo metastasis models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — clean loss-of-function with pathway placement (WNT11→FZD7→DAAM1→Rho-ROCK-MYO), multiple readouts, in vivo validation","pmids":["33082334"],"is_preprint":false},{"year":2020,"finding":"Fzd7 in breast cancer cells interacts with Wnt5a/b to modulate phosphorylated STAT3, Smad3, and YAP1; Fzd7-Wnt5b signaling upregulates Col6a1, which mediates Fzd7-Wnt5b-induced mesenchymal-like stemness, establishing a non-canonical Wnt pathway role for Fzd7 in EMT and stemness.","method":"Co-IP (Fzd7 with Wnt5a/b), KD of Fzd7/Wnt5b/Col6a1, immunofluorescence, mammosphere formation, xenograft, lung metastasis assay","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP binding partner identified, multiple functional readouts, single lab","pmids":["32894152"],"is_preprint":false},{"year":2022,"finding":"GIPC2 directly binds the WNT co-receptor Fzd7 through its PDZ domain, enabling activation of WNT-β-catenin cascades and stimulating prostate cancer metastasis.","method":"Co-immunoprecipitation, PDZ domain binding assay, GIPC2 KD with WNT-β-catenin readout, in vitro and in vivo metastasis assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP identifies binding partner and PDZ domain interaction, functional KD with pathway readout","pmids":["35347223"],"is_preprint":false},{"year":2019,"finding":"FZD7 regulates TWIST1 expression through epigenetic modifications of H3K4me3 and H3K27ac at the TWIST1 proximal promoter; the FZD7-TWIST1 axis controls BCL2 expression to confer anoikis resistance in ovarian cancer cells.","method":"FZD7 KD, chromatin histone modification analysis (H3K4me3/H3K27ac at TWIST1 promoter), TWIST1 overexpression rescue, BCL2 expression assay, anoikis resistance assays","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 — epigenetic mechanism established with ChIP-like analysis; multiple functional readouts in single lab","pmids":["30548372"],"is_preprint":false},{"year":2016,"finding":"Notch3, but not Notch1, 2, or 4, uniquely regulates FZD7 expression in human breast epithelial cells through a non-canonical (CSL-independent) Notch signaling mechanism.","method":"Gain and loss-of-function of NOTCH1-4, FZD7 expression analysis, CSL-independence assay","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 2 — clear genetic specificity (only NOTCH3 affects FZD7), CSL-independence established, single lab","pmids":["26847503"],"is_preprint":false},{"year":2018,"finding":"GCM1 transcription factor promotes trophoblast cell migration through transcriptional activation of WNT10B; WNT10B then signals through FZD7 as its cognate receptor to upregulate Rac1-mediated cytoskeletal remodeling and cell migration; SFRP3 from decidual cells blocks WNT10B-FZD7 interaction to suppress migration.","method":"GCM1 target gene identification, WNT10B-FZD7 interaction (co-immunoprecipitation/functional blocking), Rac1 activity assay, SFRP3 competitive binding, trophoblast migration assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2-3 — receptor-ligand interaction identified, competitive inhibition by SFRP3 established, functional migration readout","pmids":["29979633"],"is_preprint":false},{"year":2020,"finding":"Selective engagement of FZD7 and LRP6 by engineered bispecific antibody F7L6 is sufficient to potently activate WNT/β-catenin signaling and drive mesendodermal differentiation of human pluripotent stem cells, demonstrating that FZD7 specifically can transduce canonical Wnt signals.","method":"Engineered FZD7-specific scFv bispecific agonist (F7L6), WNT/β-catenin reporter assay, transcriptional profiling of hPS cell differentiation, comparison to Wnt3a","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — tool protein with defined specificity used to dissect receptor-specific signaling, multiple orthogonal readouts","pmids":["33331818"],"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; the ectodomain of LRP6 is required for CDDO-Me-induced FZD7 degradation, revealing LRP6-dependent regulation of FZD7 protein stability.","method":"Ubiquitination assay, lysosomal pathway inhibitor, LRP6 ectodomain deletion constructs, FZD7 and LRP6 protein stability assays, Wnt target gene readout","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical mechanism (ubiquitination, lysosomal degradation) established with domain-specificity experiments","pmids":["32015160"],"is_preprint":false},{"year":2023,"finding":"BCL6 directly binds and transcriptionally represses FZD7, reducing Wnt/β-catenin signaling and promoting ferroptosis via the FZD7/β-catenin/TP63/GPX4 pathway in gastric cancer.","method":"ChIP assay (BCL6 binding to FZD7 promoter), dual luciferase reporter assay, rescue experiments, ferroptosis markers (lipid peroxidation, MDA, Fe2+), GPX4 expression","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and luciferase confirm direct transcriptional repression of FZD7, pathway dissected by rescue experiments","pmids":["37060074"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of Clostridioides difficile toxin B (TcdB) alone and in complex with full-length FZD7 reveal that large structural rearrangements of the combined repetitive polypeptide (CROPs) domain are required for FZD7 binding; bezlotoxumab (FDA-approved antibody) favors the apo-TcdB conformation and disrupts FZD7 binding.","method":"Cryo-EM structure determination of TcdB-FZD7 complex, live-cell binding assay, bezlotoxumab competition assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with full-length FZD7 plus functional validation, defines receptor interaction mechanism","pmids":["38308843"],"is_preprint":false},{"year":2023,"finding":"Vangl1 and Fzd7 form a complex at the leading edge of migrating GBM cells, promoting actin cytoskeletal rearrangements, Rho GTPase engagement, and tumor cell proliferation, migration, and invasiveness via non-canonical Wnt/PCP signaling.","method":"Co-immunoprecipitation (Vangl1/Fzd7 complex), KD of FZD7 and Vangl1, Rho GTPase assays, actin dynamics imaging, intracranial xenograft model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP identifies novel complex, in vivo and in vitro phenotype with pathway placement","pmids":["37336284"],"is_preprint":false},{"year":2023,"finding":"Structure-based ligand discovery targeting the transmembrane domain (TMD) of FZD7 identified compound F7H as an antagonist (IC50 = 1.25 μM); molecular docking, MD simulation, and FEP calculations defined the binding pocket and key residue interactions.","method":"Virtual screening, molecular docking, molecular dynamics simulation, free energy perturbation, functional Wnt antagonism assay","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1-3 — structural modeling with functional validation of binding pocket, single study","pmids":["37669317"],"is_preprint":false},{"year":2024,"finding":"SIRT7 promotes FZD7 expression via transcription factor PU.1 upregulation, and FZD7 is essential for SIRT7-mediated β-catenin stabilization (preventing its association with the destruction complex) and activation of canonical Wnt signaling in hepatocellular carcinoma.","method":"SIRT7/PU.1/FZD7 KD, nuclear cytosol fractionation, β-catenin ubiquitination/stability assay, TopFlash reporter, ChIP-PCR for PU.1 at FZD7 promoter","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — pathway hierarchy established (SIRT7→PU.1→FZD7→β-catenin) with biochemical readouts, single lab","pmids":["39542206"],"is_preprint":false},{"year":2025,"finding":"FZD7 and FZD2 activate β-catenin signaling with different kinetics in hPSCs; FZD7 activation promotes both paraxial and lateral mesoderm differentiation while FZD2 favors only paraxial mesoderm, demonstrating non-redundant roles of these closely related FZD receptors in mesoderm specification.","method":"Selective FZD7- and FZD2-specific antibody-based agonists, β-catenin signaling kinetics measurement, directed differentiation of hPSCs, transcriptional profiling of mesoderm subtypes","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — subtype-selective tools established non-redundancy with multiple differentiation readouts","pmids":["39824186"],"is_preprint":false},{"year":2024,"finding":"WNT7A activates FZD7 to stimulate the JAK1/STAT3 signaling pathway (not the canonical Wnt-β-catenin pathway) in head and neck squamous cell carcinoma, promoting cell proliferation, self-renewal, and resistance to apoptosis.","method":"WNT7A overexpression, β-catenin pathway reporter (negative), FZD7/JAK1/STAT3 pathway analysis, PDX tumor model","journal":"International journal of oral science","confidence":"Medium","confidence_rationale":"Tier 2-3 — pathway placement established, in vivo PDX validation, but limited biochemical detail on FZD7-JAK1 interaction","pmids":["38246919"],"is_preprint":false},{"year":2022,"finding":"FZD7 silencing in pancreatic cancer attenuates TGF-β1-induced EMT and reduces stemness markers (ABCG2, CD24, CD44), demonstrating that FZD7 participates in both canonical Wnt and TGF-β/SMAD3 signaling to drive EMT and cancer stem cell properties.","method":"shRNA FZD7 silencing, TGF-β1 stimulation, EMT marker Western blot, sphere formation, flow cytometry for CD24/CD44, β-catenin activation assay","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional KD with multiple pathway readouts, single lab","pmids":["35854234"],"is_preprint":false},{"year":2020,"finding":"Wnt5a upregulates ABCG2 expression through FZD7 in pancreatic cancer cells, and FZD7 silencing or inhibition abolishes Wnt5a-induced ABCG2 upregulation and gemcitabine resistance, placing FZD7 as the essential receptor for Wnt5a-driven drug resistance.","method":"Recombinant Wnt5a treatment, siRNA FZD7 silencing, FZD7 inhibitor, ABCG2 expression assay, gemcitabine resistance assay","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — epistasis established (Wnt5a→FZD7→ABCG2), functional drug resistance readout, single lab","pmids":["33200805"],"is_preprint":false},{"year":2019,"finding":"Fibronectin promotes limbal epithelial stem cell self-renewal by facilitating Wnt11-Fzd7 interaction and activating the non-canonical Wnt11/Fzd7/ROCK pathway to modulate cell cycle regulators.","method":"Fibronectin treatment, Wnt11/Fzd7 co-expression and interaction analysis, ROCK1/2 activity assay, cell cycle analysis, stemness assays","journal":"Experimental eye research","confidence":"Low","confidence_rationale":"Tier 3 — interaction inferred functionally without direct biochemical pulldown of Fzd7-Wnt11 complex","pmids":["31150636"],"is_preprint":false},{"year":2016,"finding":"FZD7 overexpression in glioma activates TAZ (transcriptional coactivator with PDZ-binding motif), and TAZ is required for FZD7-driven glioma cell proliferation, placing TAZ as a downstream effector of FZD7 signaling.","method":"FZD7 overexpression/KD, TAZ activity assay, TAZ KD rescue experiment, xenograft proliferation assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 — genetic epistasis (TAZ KD blocks FZD7 effect) with in vivo validation, single lab","pmids":["27852064"],"is_preprint":false},{"year":2025,"finding":"KIAA1429 phosphorylation by BRAF drives its cytoplasmic accumulation, where it binds and stabilizes FZD7, leading to WNT pathway activation, enhanced cancer stemness and oxaliplatin resistance in colorectal cancer.","method":"Co-immunoprecipitation (KIAA1429-FZD7), IP-MS, immunofluorescence (nuclear/cytoplasmic distribution), FZD7 stability assay, in vitro and in vivo drug resistance experiments","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP confirms direct KIAA1429-FZD7 interaction, mechanistic pathway established with domain specificity","pmids":["40611274"],"is_preprint":false}],"current_model":"FZD7 is a seven-transmembrane Frizzled receptor that transduces both canonical Wnt/β-catenin signaling (via a complex with LRP5/6, Gαs, PI3K, and Dvl proteins) and non-canonical Wnt pathways (PCP via Vangl1/DAAM1/Rho-ROCK-Myosin II; non-canonical via Wnt5a/STAT3/TAZ); its expression is regulated by transcription factors including ΔNp63 and BCL6, by NOTCH3-mediated non-canonical Notch signaling, and post-transcriptionally by m6A readers (YTHDF1) and multiple miRNAs; FZD7 protein stability is controlled by ZNRF3-mediated ubiquitination and lysosomal degradation dependent on the LRP6 ectodomain; and its selective activation is sufficient to drive mesendodermal differentiation of pluripotent stem cells and maintain stem cell self-renewal, while cryo-EM structural studies reveal that FZD7 is exploited by C. difficile TcdB through conformational rearrangements of the toxin's CROPs domain."},"narrative":{"teleology":[{"year":2008,"claim":"Establishing that FZD7 is functionally important in human embryonic stem cells answered whether Frizzled receptors play active roles in pluripotency maintenance, rather than being passive markers of undifferentiated cells.","evidence":"shRNA knockdown of FZD7 in hESCs with OCT4 loss and morphology change","pmids":["18681827"],"confidence":"Medium","gaps":["Downstream pathway (canonical vs. non-canonical) not resolved","No rescue experiment to confirm specificity","Mechanism linking FZD7 to OCT4 expression unknown"]},{"year":2011,"claim":"Demonstrating that FZD7 is the receptor required for canonical Wnt/β-catenin signaling in triple-negative breast cancer, and independently that Wnt7a–Fzd7 activates Akt/mTOR via a Gαs–PI3K complex in myofibers, established FZD7 as a bifunctional receptor capable of engaging distinct intracellular signaling cascades depending on ligand and cell context.","evidence":"shRNA knockdown with β-catenin/TCF reporter in TNBC (PMID:21532620); Co-IP of Fzd7–Gαs–PI3K complex with Akt/mTOR readout in myotubes (PMID:22179044)","pmids":["21532620","22179044"],"confidence":"High","gaps":["Whether Gαs–PI3K complex forms in non-muscle contexts unknown","Structural basis for ligand-selective pathway activation not determined"]},{"year":2014,"claim":"Identifying ΔNp63 as a direct transcriptional activator of FZD7 in mammary stem cells, and showing that FZD7-specific antibody blockade disrupts hESC pluripotency, established how FZD7 expression is controlled and confirmed its non-redundant receptor function in stem cell biology.","evidence":"ΔNp63 gain/loss-of-function with FZD7 expression and mammary stem cell assays (PMID:25241036); FZD7-specific Fab blocking antibody and shRNA in hESCs (PMID:24474766); FZD7 KD with RhoA/Rac1 activity assays in ovarian cancer (PMID:25032869)","pmids":["25241036","24474766","25032869"],"confidence":"High","gaps":["Whether ΔNp63 regulation of FZD7 operates in non-mammary stem cells unknown","How FZD7 simultaneously regulates canonical and PCP outputs in the same cell not resolved"]},{"year":2016,"claim":"Conditional endothelial deletion of Fzd7 and identification of Notch3-specific and TAZ-dependent FZD7 signaling expanded the receptor's known physiological roles to angiogenesis and glioma, and revealed additional upstream regulators and downstream effectors.","evidence":"fzd7ECKO mice with retinal angiogenesis defects rescued by LiCl (PMID:27758766); NOTCH3-specific, CSL-independent FZD7 regulation (PMID:26847503); TAZ epistasis in glioma (PMID:27852064)","pmids":["27758766","26847503","27852064"],"confidence":"High","gaps":["Mechanism of CSL-independent Notch3 regulation of FZD7 promoter not defined","Direct physical interaction between FZD7 signaling and TAZ not biochemically demonstrated"]},{"year":2017,"claim":"Showing that RSPO2 promotes ZNRF3-mediated ubiquitination and lysosomal degradation of FZD7 while Wnt5a protects it from degradation answered how FZD7 surface levels are post-translationally controlled and how R-spondin modulates non-canonical signaling.","evidence":"Co-IP and ubiquitination assays of RSPO2–ZNRF3–FZD7; Wnt5a competition for FZD7 binding","pmids":["28600110"],"confidence":"High","gaps":["Whether other E3 ligases besides ZNRF3 target FZD7 unknown","Structural basis of RSPO2–FZD7 interaction not resolved"]},{"year":2020,"claim":"Multiple studies converged to define the full scope of FZD7 non-canonical signaling, showing WNT11–FZD7–DAAM1–Rho-ROCK-Myosin II drives melanoma invasion, Wnt5a–FZD7 activates STAT3/YAP1/Col6a1 in breast cancer stemness, and that selective FZD7–LRP6 bispecific agonists drive mesendodermal differentiation, thereby resolving ligand-specific pathway outputs.","evidence":"KD of WNT11/FZD7/DAAM1 with Rho-ROCK readout and metastasis models (PMID:33082334); Co-IP of Fzd7–Wnt5b with STAT3/YAP1 readout (PMID:32894152); F7L6 bispecific antibody with hPSC differentiation (PMID:33331818)","pmids":["33082334","32894152","33331818"],"confidence":"High","gaps":["Structural basis for how FZD7 selects between DAAM1-PCP and Dvl-β-catenin outputs unknown","Whether STAT3 activation is direct or through intermediary kinases not fully resolved"]},{"year":2020,"claim":"Discovery that YTHDF1 promotes FZD7 mRNA translation in an m6A-dependent manner, and that LRP6 ectodomain is required for CDDO-Me-induced FZD7 degradation, established both translational and post-translational layers of FZD7 regulation.","evidence":"YTHDF1 KD/OE with m6A analysis and FZD7 protein readout in gastric cancer (PMID:32788173); LRP6 ectodomain deletion with FZD7 ubiquitination/stability assay (PMID:32015160)","pmids":["32788173","32015160"],"confidence":"High","gaps":["Identity of the m6A writer depositing marks on FZD7 mRNA not determined","Whether LRP6-dependent degradation operates in normal (non-pharmacological) contexts unclear"]},{"year":2021,"claim":"Identification of circACTN4/YBX1-driven transcriptional activation of FZD7 in cholangiocarcinoma added a circular RNA regulatory axis to the growing inventory of FZD7 transcriptional controls.","evidence":"RNA pulldown, mass spectrometry, ChIP, RIP, EMSA, and luciferase reporter identifying circACTN4–YBX1–FZD7 promoter axis","pmids":["34509526"],"confidence":"High","gaps":["Whether circACTN4-YBX1 regulation of FZD7 operates outside cholangiocarcinoma unknown","Relative contribution of this axis versus ΔNp63 or BCL6 in the same cell type not assessed"]},{"year":2023,"claim":"Demonstrating that Vangl1–Fzd7 complex formation at the leading edge of glioblastoma cells drives PCP-mediated invasion, and that BCL6 directly represses FZD7 transcription to promote ferroptosis, further defined tissue-specific regulatory and effector circuits.","evidence":"Co-IP of Vangl1–Fzd7 with Rho GTPase and intracranial xenograft (PMID:37336284); ChIP of BCL6 at FZD7 promoter with ferroptosis markers (PMID:37060074)","pmids":["37336284","37060074"],"confidence":"Medium","gaps":["How Vangl1–Fzd7 complex is spatially restricted to leading edge not mechanistically defined","Whether BCL6-mediated FZD7 repression occurs in non-gastric tissues unknown","Single-lab studies for each finding"]},{"year":2024,"claim":"Cryo-EM structures of full-length FZD7 in complex with C. difficile TcdB revealed that CROPs domain rearrangement is essential for toxin–receptor engagement, providing the first high-resolution structural view of full-length FZD7 in a receptor complex and explaining bezlotoxumab's mechanism of action.","evidence":"Cryo-EM of TcdB–FZD7 complex, live-cell binding assay, bezlotoxumab competition","pmids":["38308843"],"confidence":"High","gaps":["No structure of FZD7 in complex with a Wnt ligand or Dvl","Whether CROPs rearrangement mimics any aspect of physiological FZD7 activation unknown"]},{"year":2025,"claim":"Receptor-selective agonists demonstrated that FZD7 and FZD2 activate β-catenin with different kinetics and specify distinct mesoderm subtypes, and BRAF-phosphorylated KIAA1429 stabilizes FZD7 protein to drive Wnt activation, revealing non-redundancy among closely related FZDs and a new post-translational stabilization mechanism.","evidence":"FZD7- vs FZD2-selective antibody agonists with hPSC mesoderm differentiation (PMID:39824186); Co-IP of KIAA1429–FZD7 with FZD7 stability assay in CRC (PMID:40611274)","pmids":["39824186","40611274"],"confidence":"Medium","gaps":["Structural basis for differential FZD7 vs FZD2 signaling kinetics unknown","Whether KIAA1429 stabilization of FZD7 is m6A-dependent or independent not resolved","Single-lab findings awaiting independent replication"]},{"year":null,"claim":"A high-resolution structure of FZD7 bound to a native Wnt ligand and intracellular transducer (Dvl or G protein) is needed to explain how a single receptor selects between canonical β-catenin, PCP, and Gαs/PI3K signaling outputs in a ligand-dependent manner.","evidence":"","pmids":[],"confidence":"High","gaps":["No Wnt–FZD7–effector ternary complex structure exists","Molecular determinants of pathway selectivity at the receptor level remain undefined","In vivo requirement for FZD7 in adult tissue homeostasis beyond angiogenesis not systematically addressed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,3,6,10,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,10,20]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,16,17,19,20]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,3,6,7,8,10,16,22]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[16,23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,10,11,25,29]}],"complexes":["FZD7–LRP6 Wnt signalosome","FZD7–Gαs–PI3K complex","FZD7–Vangl1 PCP complex"],"partners":["LRP6","DAAM1","VANGL1","ZNRF3","RSPO2","GIPC2","KIAA1429","DVL1"],"other_free_text":[]},"mechanistic_narrative":"FZD7 is a seven-transmembrane Frizzled family receptor that serves as a central hub for both canonical Wnt/β-catenin and non-canonical Wnt signaling, governing stem cell self-renewal, differentiation, cell polarity, and cytoskeletal dynamics across diverse tissue contexts. In canonical signaling, FZD7 partners with LRP6 to transduce Wnt3a and other ligands, stabilizing β-catenin and activating TCF-dependent transcription; selective FZD7–LRP6 engagement is sufficient to drive mesendodermal differentiation of human pluripotent stem cells and is required for maintaining the pluripotent state [PMID:33331818, PMID:24474766, PMID:21532620]. In non-canonical pathways, FZD7 engages Wnt11 or Wnt5a to activate PCP effectors (Vangl1, DAAM1, Rho-ROCK-Myosin II) controlling cell migration and invasion, and independently signals through Gαs/PI3K/Akt or JAK1/STAT3 axes depending on cellular context [PMID:33082334, PMID:22179044, PMID:38246919, PMID:37336284]. FZD7 protein levels are regulated transcriptionally by ΔNp63, BCL6, Notch3, and PU.1, post-transcriptionally by the m6A reader YTHDF1, and post-translationally by ZNRF3-mediated ubiquitination and lysosomal degradation that depends on the LRP6 ectodomain [PMID:25241036, PMID:37060074, PMID:32788173, PMID:28600110, PMID:32015160]."},"prefetch_data":{"uniprot":{"accession":"O75084","full_name":"Frizzled-7","aliases":["FzE3"],"length_aa":574,"mass_kda":63.6,"function":"Receptor for Wnt proteins. Most frizzled receptors are coupled to the beta-catenin canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. 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and decreased TCF7 transcriptional activity, establishing FZD7 as a required receptor for canonical Wnt/β-catenin pathway activation in triple-negative breast cancer.\",\n      \"method\": \"shRNA knockdown, β-catenin nuclear localization assay, TCF7 reporter assay, xenograft tumor model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD, reporter assay, in vivo xenograft) in a highly-cited paper\",\n      \"pmids\": [\"21532620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Wnt7a binds Fzd7 and directly activates the Akt/mTOR anabolic growth pathway in differentiated myofibers through a complex containing Gαs and PI(3)K, independent of IGF-receptor activation, demonstrating a non-canonical Wnt7a-Fzd7 signaling axis distinct from its planar cell polarity role in satellite stem cells.\",\n      \"method\": \"Co-immunoprecipitation (Fzd7 complex with Gαs and PI(3)K), Wnt7a treatment of myotubes, PI3K inhibitor, KO/KD with Akt/mTOR readout\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical complex identification with functional validation, highly cited, multiple orthogonal methods\",\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 ability by directly enhancing Fzd7 expression, thereby increasing Wnt signaling.\",\n      \"method\": \"Gain/loss-of-function of ΔNp63, Fzd7 expression analysis, mammary stem cell activity assays, tumor-initiating cell assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional readouts, highly-cited paper, mechanistic link from transcription factor to receptor established\",\n      \"pmids\": [\"25241036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FZD7 is required for maintenance of the pluripotent state in human embryonic stem cells; a FZD7-specific Fab antibody blocks Wnt3a signaling by downregulating FZD7 protein levels, and shRNA-mediated knockdown disrupts the pluripotent state, demonstrating that hESCs require endogenous WNT/β-catenin signaling through FZD7.\",\n      \"method\": \"shRNA knockdown, FZD7-specific Fab antibody blocking, Wnt3a treatment, pluripotency marker analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD, blocking antibody, Wnt3a rescue), rigorous functional readouts\",\n      \"pmids\": [\"24474766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FZD7 is highly expressed in human embryonic stem cells, and shRNA-mediated knockdown induces colony morphology changes and rapid loss of OCT4 expression, identifying FZD7 as a component of hESC self-renewal signaling.\",\n      \"method\": \"shRNA knockdown, quantitative RT-PCR, flow cytometry, morphological analysis\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype, single lab\",\n      \"pmids\": [\"18681827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FZD7 knockdown in Stem-A ovarian cancer cells causes actin cytoskeletal rearrangement via reciprocal regulation of RhoA and Rac1 (reduced RhoA activity, increased Rac1 activity), changes in phospho-myosin light chain distribution, and increased TopFlash reporter activity, establishing FZD7 involvement in the non-canonical Wnt/PCP pathway through casein kinase 1ε.\",\n      \"method\": \"siRNA knockdown, RhoA/Rac1 activity assays, phospho-MLC immunofluorescence, TopFlash reporter assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple mechanistic readouts (Rho GTPase activity, cytoskeletal imaging, reporter assay), single lab\",\n      \"pmids\": [\"25032869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Fzd7 expressed by endothelial cells controls postnatal angiogenesis via activation of Dvl/β-catenin signaling, acting upstream of Notch signaling to regulate Dll4 and Jagged1 expression; endothelial-specific deletion of fzd7 (fzd7ECKO) delays retinal plexus formation due to impaired tip cell phenotype and decreased stalk cell proliferation, rescued by LiCl treatment.\",\n      \"method\": \"Conditional endothelial KO (fzd7ECKO mice), retinal vascular imaging, LiCl pharmacological rescue, Dvl1/3 double KO comparison\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with defined vascular phenotype, genetic and pharmacological rescue establishing pathway position\",\n      \"pmids\": [\"27758766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RSPO2 physically interacts with Fzd7 and promotes ZNRF3-mediated ubiquitination and degradation of cell-surface Fzd7, suppressing downstream PKC/ERK signaling; Wnt5a prevents Fzd7 degradation, and RSPO2 antagonizes Wnt5a-driven noncanonical Wnt signaling by blocking Wnt5a binding to Fzd7.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, ZNRF3 involvement, PKC/ERK signaling readout, Wnt5a competitive binding\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical interaction (Co-IP, ubiquitination), pathway mechanism with competitive ligand binding, multiple methods\",\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, leading to hyperactivation of the Wnt/β-catenin pathway; mutated YTHDF1 further enhances FZD7 expression and gastric carcinogenesis.\",\n      \"method\": \"YTHDF1 knockdown/overexpression, m6A methylation analysis, FZD7 protein translation assay, Wnt/β-catenin pathway readout, in vitro and in vivo tumor models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — m6A-dependent translational regulation established with multiple orthogonal methods, highly cited\",\n      \"pmids\": [\"32788173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"circACTN4 recruits Y-box binding protein 1 (YBX1) to stimulate FZD7 transcription in intrahepatic cholangiocarcinoma, identified via RNA pulldown, mass spectrometry, ChIP, RIP, EMSA, and luciferase reporter assays.\",\n      \"method\": \"RNA pulldown, mass spectrometry, chromatin immunoprecipitation (ChIP), RNA-binding protein immunoprecipitation (RIP), EMSA, luciferase reporter assay\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical methods establishing transcriptional mechanism, highly cited\",\n      \"pmids\": [\"34509526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WNT11-FZD7-DAAM1 signaling activates Rho-ROCK1/2-Myosin II and plays a crucial role in amoeboid melanoma invasion, tumor-initiating potential, and distant metastasis formation.\",\n      \"method\": \"KD of WNT11/FZD7/DAAM1, Rho-ROCK-Myosin II pathway readout, invasion assays, in vivo metastasis models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with pathway placement (WNT11→FZD7→DAAM1→Rho-ROCK-MYO), multiple readouts, in vivo validation\",\n      \"pmids\": [\"33082334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Fzd7 in breast cancer cells interacts with Wnt5a/b to modulate phosphorylated STAT3, Smad3, and YAP1; Fzd7-Wnt5b signaling upregulates Col6a1, which mediates Fzd7-Wnt5b-induced mesenchymal-like stemness, establishing a non-canonical Wnt pathway role for Fzd7 in EMT and stemness.\",\n      \"method\": \"Co-IP (Fzd7 with Wnt5a/b), KD of Fzd7/Wnt5b/Col6a1, immunofluorescence, mammosphere formation, xenograft, lung metastasis assay\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP binding partner identified, multiple functional readouts, single lab\",\n      \"pmids\": [\"32894152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GIPC2 directly binds the WNT co-receptor Fzd7 through its PDZ domain, enabling activation of WNT-β-catenin cascades and stimulating prostate cancer metastasis.\",\n      \"method\": \"Co-immunoprecipitation, PDZ domain binding assay, GIPC2 KD with WNT-β-catenin readout, in vitro and in vivo metastasis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP identifies binding partner and PDZ domain interaction, functional KD with pathway readout\",\n      \"pmids\": [\"35347223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FZD7 regulates TWIST1 expression through epigenetic modifications of H3K4me3 and H3K27ac at the TWIST1 proximal promoter; the FZD7-TWIST1 axis controls BCL2 expression to confer anoikis resistance in ovarian cancer cells.\",\n      \"method\": \"FZD7 KD, chromatin histone modification analysis (H3K4me3/H3K27ac at TWIST1 promoter), TWIST1 overexpression rescue, BCL2 expression assay, anoikis resistance assays\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — epigenetic mechanism established with ChIP-like analysis; multiple functional readouts in single lab\",\n      \"pmids\": [\"30548372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Notch3, but not Notch1, 2, or 4, uniquely regulates FZD7 expression in human breast epithelial cells through a non-canonical (CSL-independent) Notch signaling mechanism.\",\n      \"method\": \"Gain and loss-of-function of NOTCH1-4, FZD7 expression analysis, CSL-independence assay\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clear genetic specificity (only NOTCH3 affects FZD7), CSL-independence established, single lab\",\n      \"pmids\": [\"26847503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GCM1 transcription factor promotes trophoblast cell migration through transcriptional activation of WNT10B; WNT10B then signals through FZD7 as its cognate receptor to upregulate Rac1-mediated cytoskeletal remodeling and cell migration; SFRP3 from decidual cells blocks WNT10B-FZD7 interaction to suppress migration.\",\n      \"method\": \"GCM1 target gene identification, WNT10B-FZD7 interaction (co-immunoprecipitation/functional blocking), Rac1 activity assay, SFRP3 competitive binding, trophoblast migration assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — receptor-ligand interaction identified, competitive inhibition by SFRP3 established, functional migration readout\",\n      \"pmids\": [\"29979633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Selective engagement of FZD7 and LRP6 by engineered bispecific antibody F7L6 is sufficient to potently activate WNT/β-catenin signaling and drive mesendodermal differentiation of human pluripotent stem cells, demonstrating that FZD7 specifically can transduce canonical Wnt signals.\",\n      \"method\": \"Engineered FZD7-specific scFv bispecific agonist (F7L6), WNT/β-catenin reporter assay, transcriptional profiling of hPS cell differentiation, comparison to Wnt3a\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — tool protein with defined specificity used to dissect receptor-specific signaling, multiple orthogonal readouts\",\n      \"pmids\": [\"33331818\"],\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; the ectodomain of LRP6 is required for CDDO-Me-induced FZD7 degradation, revealing LRP6-dependent regulation of FZD7 protein stability.\",\n      \"method\": \"Ubiquitination assay, lysosomal pathway inhibitor, LRP6 ectodomain deletion constructs, FZD7 and LRP6 protein stability assays, Wnt target gene readout\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical mechanism (ubiquitination, lysosomal degradation) established with domain-specificity experiments\",\n      \"pmids\": [\"32015160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BCL6 directly binds and transcriptionally represses FZD7, reducing Wnt/β-catenin signaling and promoting ferroptosis via the FZD7/β-catenin/TP63/GPX4 pathway in gastric cancer.\",\n      \"method\": \"ChIP assay (BCL6 binding to FZD7 promoter), dual luciferase reporter assay, rescue experiments, ferroptosis markers (lipid peroxidation, MDA, Fe2+), GPX4 expression\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and luciferase confirm direct transcriptional repression of FZD7, pathway dissected by rescue experiments\",\n      \"pmids\": [\"37060074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of Clostridioides difficile toxin B (TcdB) alone and in complex with full-length FZD7 reveal that large structural rearrangements of the combined repetitive polypeptide (CROPs) domain are required for FZD7 binding; bezlotoxumab (FDA-approved antibody) favors the apo-TcdB conformation and disrupts FZD7 binding.\",\n      \"method\": \"Cryo-EM structure determination of TcdB-FZD7 complex, live-cell binding assay, bezlotoxumab competition assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with full-length FZD7 plus functional validation, defines receptor interaction mechanism\",\n      \"pmids\": [\"38308843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Vangl1 and Fzd7 form a complex at the leading edge of migrating GBM cells, promoting actin cytoskeletal rearrangements, Rho GTPase engagement, and tumor cell proliferation, migration, and invasiveness via non-canonical Wnt/PCP signaling.\",\n      \"method\": \"Co-immunoprecipitation (Vangl1/Fzd7 complex), KD of FZD7 and Vangl1, Rho GTPase assays, actin dynamics imaging, intracranial xenograft model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP identifies novel complex, in vivo and in vitro phenotype with pathway placement\",\n      \"pmids\": [\"37336284\"],\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 antagonist (IC50 = 1.25 μM); molecular docking, MD simulation, and FEP calculations defined the binding pocket and key residue interactions.\",\n      \"method\": \"Virtual screening, molecular docking, molecular dynamics simulation, free energy perturbation, functional Wnt antagonism assay\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-3 — structural modeling with functional validation of binding pocket, single study\",\n      \"pmids\": [\"37669317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRT7 promotes FZD7 expression via transcription factor PU.1 upregulation, and FZD7 is essential for SIRT7-mediated β-catenin stabilization (preventing its association with the destruction complex) and activation of canonical Wnt signaling in hepatocellular carcinoma.\",\n      \"method\": \"SIRT7/PU.1/FZD7 KD, nuclear cytosol fractionation, β-catenin ubiquitination/stability assay, TopFlash reporter, ChIP-PCR for PU.1 at FZD7 promoter\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway hierarchy established (SIRT7→PU.1→FZD7→β-catenin) with biochemical readouts, single lab\",\n      \"pmids\": [\"39542206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FZD7 and FZD2 activate β-catenin signaling with different kinetics in hPSCs; FZD7 activation promotes both paraxial and lateral mesoderm differentiation while FZD2 favors only paraxial mesoderm, demonstrating non-redundant roles of these closely related FZD receptors in mesoderm specification.\",\n      \"method\": \"Selective FZD7- and FZD2-specific antibody-based agonists, β-catenin signaling kinetics measurement, directed differentiation of hPSCs, transcriptional profiling of mesoderm subtypes\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — subtype-selective tools established non-redundancy with multiple differentiation readouts\",\n      \"pmids\": [\"39824186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WNT7A activates FZD7 to stimulate the JAK1/STAT3 signaling pathway (not the canonical Wnt-β-catenin pathway) in head and neck squamous cell carcinoma, promoting cell proliferation, self-renewal, and resistance to apoptosis.\",\n      \"method\": \"WNT7A overexpression, β-catenin pathway reporter (negative), FZD7/JAK1/STAT3 pathway analysis, PDX tumor model\",\n      \"journal\": \"International journal of oral science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pathway placement established, in vivo PDX validation, but limited biochemical detail on FZD7-JAK1 interaction\",\n      \"pmids\": [\"38246919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FZD7 silencing in pancreatic cancer attenuates TGF-β1-induced EMT and reduces stemness markers (ABCG2, CD24, CD44), demonstrating that FZD7 participates in both canonical Wnt and TGF-β/SMAD3 signaling to drive EMT and cancer stem cell properties.\",\n      \"method\": \"shRNA FZD7 silencing, TGF-β1 stimulation, EMT marker Western blot, sphere formation, flow cytometry for CD24/CD44, β-catenin activation assay\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional KD with multiple pathway readouts, single lab\",\n      \"pmids\": [\"35854234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Wnt5a upregulates ABCG2 expression through FZD7 in pancreatic cancer cells, and FZD7 silencing or inhibition abolishes Wnt5a-induced ABCG2 upregulation and gemcitabine resistance, placing FZD7 as the essential receptor for Wnt5a-driven drug resistance.\",\n      \"method\": \"Recombinant Wnt5a treatment, siRNA FZD7 silencing, FZD7 inhibitor, ABCG2 expression assay, gemcitabine resistance assay\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — epistasis established (Wnt5a→FZD7→ABCG2), functional drug resistance readout, single lab\",\n      \"pmids\": [\"33200805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Fibronectin promotes limbal epithelial stem cell self-renewal by facilitating Wnt11-Fzd7 interaction and activating the non-canonical Wnt11/Fzd7/ROCK pathway to modulate cell cycle regulators.\",\n      \"method\": \"Fibronectin treatment, Wnt11/Fzd7 co-expression and interaction analysis, ROCK1/2 activity assay, cell cycle analysis, stemness assays\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — interaction inferred functionally without direct biochemical pulldown of Fzd7-Wnt11 complex\",\n      \"pmids\": [\"31150636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FZD7 overexpression in glioma activates TAZ (transcriptional coactivator with PDZ-binding motif), and TAZ is required for FZD7-driven glioma cell proliferation, placing TAZ as a downstream effector of FZD7 signaling.\",\n      \"method\": \"FZD7 overexpression/KD, TAZ activity assay, TAZ KD rescue experiment, xenograft proliferation assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — genetic epistasis (TAZ KD blocks FZD7 effect) with in vivo validation, single lab\",\n      \"pmids\": [\"27852064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KIAA1429 phosphorylation by BRAF drives its cytoplasmic accumulation, where it binds and stabilizes FZD7, leading to WNT pathway activation, enhanced cancer stemness and oxaliplatin resistance in colorectal cancer.\",\n      \"method\": \"Co-immunoprecipitation (KIAA1429-FZD7), IP-MS, immunofluorescence (nuclear/cytoplasmic distribution), FZD7 stability assay, in vitro and in vivo drug resistance experiments\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP confirms direct KIAA1429-FZD7 interaction, mechanistic pathway established with domain specificity\",\n      \"pmids\": [\"40611274\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FZD7 is a seven-transmembrane Frizzled receptor that transduces both canonical Wnt/β-catenin signaling (via a complex with LRP5/6, Gαs, PI3K, and Dvl proteins) and non-canonical Wnt pathways (PCP via Vangl1/DAAM1/Rho-ROCK-Myosin II; non-canonical via Wnt5a/STAT3/TAZ); its expression is regulated by transcription factors including ΔNp63 and BCL6, by NOTCH3-mediated non-canonical Notch signaling, and post-transcriptionally by m6A readers (YTHDF1) and multiple miRNAs; FZD7 protein stability is controlled by ZNRF3-mediated ubiquitination and lysosomal degradation dependent on the LRP6 ectodomain; and its selective activation is sufficient to drive mesendodermal differentiation of pluripotent stem cells and maintain stem cell self-renewal, while cryo-EM structural studies reveal that FZD7 is exploited by C. difficile TcdB through conformational rearrangements of the toxin's CROPs domain.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FZD7 is a seven-transmembrane Frizzled family receptor that serves as a central hub for both canonical Wnt/β-catenin and non-canonical Wnt signaling, governing stem cell self-renewal, differentiation, cell polarity, and cytoskeletal dynamics across diverse tissue contexts. In canonical signaling, FZD7 partners with LRP6 to transduce Wnt3a and other ligands, stabilizing β-catenin and activating TCF-dependent transcription; selective FZD7–LRP6 engagement is sufficient to drive mesendodermal differentiation of human pluripotent stem cells and is required for maintaining the pluripotent state [PMID:33331818, PMID:24474766, PMID:21532620]. In non-canonical pathways, FZD7 engages Wnt11 or Wnt5a to activate PCP effectors (Vangl1, DAAM1, Rho-ROCK-Myosin II) controlling cell migration and invasion, and independently signals through Gαs/PI3K/Akt or JAK1/STAT3 axes depending on cellular context [PMID:33082334, PMID:22179044, PMID:38246919, PMID:37336284]. FZD7 protein levels are regulated transcriptionally by ΔNp63, BCL6, Notch3, and PU.1, post-transcriptionally by the m6A reader YTHDF1, and post-translationally by ZNRF3-mediated ubiquitination and lysosomal degradation that depends on the LRP6 ectodomain [PMID:25241036, PMID:37060074, PMID:32788173, PMID:28600110, PMID:32015160].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing that FZD7 is functionally important in human embryonic stem cells answered whether Frizzled receptors play active roles in pluripotency maintenance, rather than being passive markers of undifferentiated cells.\",\n      \"evidence\": \"shRNA knockdown of FZD7 in hESCs with OCT4 loss and morphology change\",\n      \"pmids\": [\"18681827\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream pathway (canonical vs. non-canonical) not resolved\", \"No rescue experiment to confirm specificity\", \"Mechanism linking FZD7 to OCT4 expression unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that FZD7 is the receptor required for canonical Wnt/β-catenin signaling in triple-negative breast cancer, and independently that Wnt7a–Fzd7 activates Akt/mTOR via a Gαs–PI3K complex in myofibers, established FZD7 as a bifunctional receptor capable of engaging distinct intracellular signaling cascades depending on ligand and cell context.\",\n      \"evidence\": \"shRNA knockdown with β-catenin/TCF reporter in TNBC (PMID:21532620); Co-IP of Fzd7–Gαs–PI3K complex with Akt/mTOR readout in myotubes (PMID:22179044)\",\n      \"pmids\": [\"21532620\", \"22179044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Gαs–PI3K complex forms in non-muscle contexts unknown\", \"Structural basis for ligand-selective pathway activation not determined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying ΔNp63 as a direct transcriptional activator of FZD7 in mammary stem cells, and showing that FZD7-specific antibody blockade disrupts hESC pluripotency, established how FZD7 expression is controlled and confirmed its non-redundant receptor function in stem cell biology.\",\n      \"evidence\": \"ΔNp63 gain/loss-of-function with FZD7 expression and mammary stem cell assays (PMID:25241036); FZD7-specific Fab blocking antibody and shRNA in hESCs (PMID:24474766); FZD7 KD with RhoA/Rac1 activity assays in ovarian cancer (PMID:25032869)\",\n      \"pmids\": [\"25241036\", \"24474766\", \"25032869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ΔNp63 regulation of FZD7 operates in non-mammary stem cells unknown\", \"How FZD7 simultaneously regulates canonical and PCP outputs in the same cell not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Conditional endothelial deletion of Fzd7 and identification of Notch3-specific and TAZ-dependent FZD7 signaling expanded the receptor's known physiological roles to angiogenesis and glioma, and revealed additional upstream regulators and downstream effectors.\",\n      \"evidence\": \"fzd7ECKO mice with retinal angiogenesis defects rescued by LiCl (PMID:27758766); NOTCH3-specific, CSL-independent FZD7 regulation (PMID:26847503); TAZ epistasis in glioma (PMID:27852064)\",\n      \"pmids\": [\"27758766\", \"26847503\", \"27852064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of CSL-independent Notch3 regulation of FZD7 promoter not defined\", \"Direct physical interaction between FZD7 signaling and TAZ not biochemically demonstrated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showing that RSPO2 promotes ZNRF3-mediated ubiquitination and lysosomal degradation of FZD7 while Wnt5a protects it from degradation answered how FZD7 surface levels are post-translationally controlled and how R-spondin modulates non-canonical signaling.\",\n      \"evidence\": \"Co-IP and ubiquitination assays of RSPO2–ZNRF3–FZD7; Wnt5a competition for FZD7 binding\",\n      \"pmids\": [\"28600110\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other E3 ligases besides ZNRF3 target FZD7 unknown\", \"Structural basis of RSPO2–FZD7 interaction not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Multiple studies converged to define the full scope of FZD7 non-canonical signaling, showing WNT11–FZD7–DAAM1–Rho-ROCK-Myosin II drives melanoma invasion, Wnt5a–FZD7 activates STAT3/YAP1/Col6a1 in breast cancer stemness, and that selective FZD7–LRP6 bispecific agonists drive mesendodermal differentiation, thereby resolving ligand-specific pathway outputs.\",\n      \"evidence\": \"KD of WNT11/FZD7/DAAM1 with Rho-ROCK readout and metastasis models (PMID:33082334); Co-IP of Fzd7–Wnt5b with STAT3/YAP1 readout (PMID:32894152); F7L6 bispecific antibody with hPSC differentiation (PMID:33331818)\",\n      \"pmids\": [\"33082334\", \"32894152\", \"33331818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for how FZD7 selects between DAAM1-PCP and Dvl-β-catenin outputs unknown\", \"Whether STAT3 activation is direct or through intermediary kinases not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery that YTHDF1 promotes FZD7 mRNA translation in an m6A-dependent manner, and that LRP6 ectodomain is required for CDDO-Me-induced FZD7 degradation, established both translational and post-translational layers of FZD7 regulation.\",\n      \"evidence\": \"YTHDF1 KD/OE with m6A analysis and FZD7 protein readout in gastric cancer (PMID:32788173); LRP6 ectodomain deletion with FZD7 ubiquitination/stability assay (PMID:32015160)\",\n      \"pmids\": [\"32788173\", \"32015160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the m6A writer depositing marks on FZD7 mRNA not determined\", \"Whether LRP6-dependent degradation operates in normal (non-pharmacological) contexts unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of circACTN4/YBX1-driven transcriptional activation of FZD7 in cholangiocarcinoma added a circular RNA regulatory axis to the growing inventory of FZD7 transcriptional controls.\",\n      \"evidence\": \"RNA pulldown, mass spectrometry, ChIP, RIP, EMSA, and luciferase reporter identifying circACTN4–YBX1–FZD7 promoter axis\",\n      \"pmids\": [\"34509526\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether circACTN4-YBX1 regulation of FZD7 operates outside cholangiocarcinoma unknown\", \"Relative contribution of this axis versus ΔNp63 or BCL6 in the same cell type not assessed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that Vangl1–Fzd7 complex formation at the leading edge of glioblastoma cells drives PCP-mediated invasion, and that BCL6 directly represses FZD7 transcription to promote ferroptosis, further defined tissue-specific regulatory and effector circuits.\",\n      \"evidence\": \"Co-IP of Vangl1–Fzd7 with Rho GTPase and intracranial xenograft (PMID:37336284); ChIP of BCL6 at FZD7 promoter with ferroptosis markers (PMID:37060074)\",\n      \"pmids\": [\"37336284\", \"37060074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How Vangl1–Fzd7 complex is spatially restricted to leading edge not mechanistically defined\", \"Whether BCL6-mediated FZD7 repression occurs in non-gastric tissues unknown\", \"Single-lab studies for each finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cryo-EM structures of full-length FZD7 in complex with C. difficile TcdB revealed that CROPs domain rearrangement is essential for toxin–receptor engagement, providing the first high-resolution structural view of full-length FZD7 in a receptor complex and explaining bezlotoxumab's mechanism of action.\",\n      \"evidence\": \"Cryo-EM of TcdB–FZD7 complex, live-cell binding assay, bezlotoxumab competition\",\n      \"pmids\": [\"38308843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of FZD7 in complex with a Wnt ligand or Dvl\", \"Whether CROPs rearrangement mimics any aspect of physiological FZD7 activation unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Receptor-selective agonists demonstrated that FZD7 and FZD2 activate β-catenin with different kinetics and specify distinct mesoderm subtypes, and BRAF-phosphorylated KIAA1429 stabilizes FZD7 protein to drive Wnt activation, revealing non-redundancy among closely related FZDs and a new post-translational stabilization mechanism.\",\n      \"evidence\": \"FZD7- vs FZD2-selective antibody agonists with hPSC mesoderm differentiation (PMID:39824186); Co-IP of KIAA1429–FZD7 with FZD7 stability assay in CRC (PMID:40611274)\",\n      \"pmids\": [\"39824186\", \"40611274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for differential FZD7 vs FZD2 signaling kinetics unknown\", \"Whether KIAA1429 stabilization of FZD7 is m6A-dependent or independent not resolved\", \"Single-lab findings awaiting independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structure of FZD7 bound to a native Wnt ligand and intracellular transducer (Dvl or G protein) is needed to explain how a single receptor selects between canonical β-catenin, PCP, and Gαs/PI3K signaling outputs in a ligand-dependent manner.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No Wnt–FZD7–effector ternary complex structure exists\", \"Molecular determinants of pathway selectivity at the receptor level remain undefined\", \"In vivo requirement for FZD7 in adult tissue homeostasis beyond angiogenesis not systematically addressed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 3, 6, 10, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 10, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 16, 17, 19, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 3, 6, 7, 8, 10, 16, 22]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [16, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 10, 11, 25, 29]}\n    ],\n    \"complexes\": [\n      \"FZD7–LRP6 Wnt signalosome\",\n      \"FZD7–Gαs–PI3K complex\",\n      \"FZD7–Vangl1 PCP complex\"\n    ],\n    \"partners\": [\n      \"LRP6\",\n      \"DAAM1\",\n      \"VANGL1\",\n      \"ZNRF3\",\n      \"RSPO2\",\n      \"GIPC2\",\n      \"KIAA1429\",\n      \"DVL1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}