{"gene":"LRP6","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2007,"finding":"Wnt treatment induces plasma membrane-associated LRP6 aggregates (signalosomes) that are phosphorylated and form ribosome-sized multiprotein complexes. Dishevelled (Dvl) is required for LRP6 phosphorylation and aggregation, and phospho-LRP6 aggregates contain caveolin but no common vesicular traffic markers. Phospho-LRP6 promotes Axin recruitment and beta-catenin stabilization.","method":"Live imaging of vertebrate cells, detergent solubilization, biochemical fractionation, dominant-negative Dvl experiments","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (live imaging, biochemical fractionation, genetic perturbation), widely replicated finding in the field","pmids":["17569865"],"is_preprint":false},{"year":2010,"finding":"LRP6 is phosphorylated at multiple conserved PPSPXS motifs by both proline-directed kinases (GSK3, PKA, Pftk1, GRK5/6) and non-proline-directed kinases (CK1 family). This phosphorylation is induced by Wnt ligand binding and by mitosis, and phospho-LRP6 promotes Axin and GSK3 recruitment to stabilize beta-catenin.","method":"Review synthesizing in vitro kinase assays, mutagenesis, and cell-based signaling assays from multiple studies","journal":"Cellular and Molecular Life Sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — based on multiple replicated in vitro kinase assays and mutagenesis studies across labs (review synthesis)","pmids":["20229235"],"is_preprint":false},{"year":2010,"finding":"In vitro reconstitution of the Fz8 CRD·Wnt3a·LRP6 signaling complex established that Wnt3a binds to LRP6 E3E4 (third and fourth beta-propeller domains), while Wnt9b binds to a distinct region (E1E2). Wnt3a and Wnt9b can bind LRP6 simultaneously. Dkk1 binds both E1E2 and E3E4 and competes with both Wnts, providing a mechanism for broad-spectrum Wnt inhibition.","method":"Insect cell expression/purification of soluble LRP6 extracellular domain fragments, binding affinity measurements, in vitro reconstitution of ternary complex","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — purified protein reconstitution with multiple LRP6 domain fragments and binding competition assays","pmids":["20093360"],"is_preprint":false},{"year":2006,"finding":"LRP6 is required for anthrax toxin internalization and lethality. LRP6 interacts at the cell surface with PA receptors TEM8/ATR and/or CMG2 to form a multicomponent complex that enables toxin endocytosis. Downregulation of LRP6 or expression of a dominant-negative LRP6 truncation, or antibodies against LRP6 extracellular domain, protected cells from anthrax toxin.","method":"siRNA knockdown, dominant-negative LRP6 expression, antibody blocking, fluorescence microscopy, biochemical co-immunoprecipitation","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (knockdown, dominant-negative, antibody, co-IP, microscopy) in one lab; contradicted by a subsequent paper (PMID:17335347)","pmids":["16564009"],"is_preprint":false},{"year":2007,"finding":"NEGATIVE RESULT: LRP5 and LRP6 are NOT required for protective antigen (PA)-mediated internalization or lethality of anthrax lethal toxin. Uptake was unaltered in cells and mice with targeted deletions of Lrp5 or Lrp6, and siRNA knockdown of LRP5/6 did not impair PA-mediated uptake in ANTXR-expressing CHO cells.","method":"Cells and mice with targeted Lrp5/Lrp6 deletions, siRNA knockdown, cytotoxicity assay","journal":"PLoS Pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout animals plus siRNA in cell lines, single lab contradicting prior Cell paper","pmids":["17335347"],"is_preprint":false},{"year":2009,"finding":"GRK5 and GRK6, membrane-associated kinases classically known for GPCR desensitization, directly phosphorylate the PPPSP motifs on LRP6 and activate Wnt/LRP6 signaling. Depletion of GRK5 markedly reduces Wnt3A-stimulated LRP6 phosphorylation in cells. In zebrafish, functional knockdown of GRK5 reduces Wnt signaling similarly to LRP6 knockdown.","method":"In vitro kinase assay, cell-based phosphorylation assays, siRNA depletion, zebrafish knockdown with beta-catenin/target gene readout","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro direct phosphorylation assay plus in vivo zebrafish epistasis, single lab but multiple orthogonal methods","pmids":["19801552"],"is_preprint":false},{"year":2006,"finding":"CKI-epsilon binds to LRP5 and LRP6 in vitro and in vivo and phosphorylates LRP6 at Ser1420 and Ser1430, which negatively regulates Wnt signaling. Mutation of these sites to alanine makes LRP6 a more potent activator of beta-catenin/Lef-1 and strengthens its interaction with Axin, suggesting a negative feedback mechanism.","method":"In vitro binding and kinase assays, co-immunoprecipitation, site-directed mutagenesis of LRP6, Lef-1 reporter assays","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, co-IP, and functional reporter assay in one study","pmids":["16513652"],"is_preprint":false},{"year":2011,"finding":"TMEM198, a seven-transmembrane protein, associates with LRP6 and recruits casein kinase family proteins via its cytoplasmic domain to phosphorylate LRP6 at key activation residues. TMEM198 is required for Wnt signaling and CK1-induced LRP6 phosphorylation in mammalian cells and for Wnt-mediated neural crest formation in Xenopus.","method":"Co-immunoprecipitation, LRP6 phosphorylation assays, siRNA knockdown in mammalian cells, Xenopus loss-of-function experiments","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, kinase phosphorylation assay, in vivo Xenopus epistasis, single lab","pmids":["21536646"],"is_preprint":false},{"year":2014,"finding":"Tyrosine kinases Src and Fer directly phosphorylate LRP6 at conserved tyrosine residues adjacent to PPSPXS motifs, negatively regulating Wnt/LRP6 signaling. Src reduces cell surface LRP6 levels and disrupts LRP6 signalosome formation. MEF cells lacking Src/Fer show enhanced Wnt signaling. CK1γ inhibits Fer-induced LRP6 tyrosine phosphorylation, suggesting CK1γ de-represses inhibitory tyrosine phosphorylation.","method":"Cell culture cDNA expression screen, co-immunoprecipitation, in vitro phosphorylation assays, MEF knockout cells, cell surface LRP6 measurements, signalosome imaging","journal":"EMBO Reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro phosphorylation, co-IP, knockout MEF epistasis, and cell surface assays in one study","pmids":["25391905"],"is_preprint":false},{"year":2014,"finding":"LRP6 endocytosis is regulated by a tyrosine-based signal in its cytoplasmic tail. LRP6 with defective tyrosine signal has increased cell surface distribution, increased localization to caveolae, increased phosphorylation, and enhanced Wnt/beta-catenin signaling. Clathrin-mediated endocytosis of LRP6 desensitizes signaling, while caveolae-mediated endocytosis promotes it. Wnt3a treatment redistributes LRP6 to lipid rafts.","method":"LRP6 tyrosine mutant analysis, cell surface distribution assays, caveolae inhibitor treatments, phosphorylation assays, Wnt reporter assays","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple endocytosis assays and LRP6 mutants in single lab","pmids":["25143377"],"is_preprint":false},{"year":2010,"finding":"Dkk1 stabilizes LRP6 protein with prolonged half-life and causes LRP6 accumulation at the cell surface and in endosomes, in contrast to its expected role as a Wnt inhibitor that promotes LRP6 internalization. Kremen2 co-expression abrogated Dkk1-induced LRP6 accumulation. Wnt3A treatment induces LRP6 down-regulation through caveolae-mediated endocytosis, and Dkk1 blocks this Wnt3A-induced LRP6 down-regulation.","method":"Conditioned medium/recombinant protein treatment, protein half-life assay, cell surface biotinylation, co-expression of Kremen2, caveolae endocytosis inhibitor","journal":"PLoS ONE","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays, single lab","pmids":["20543981"],"is_preprint":false},{"year":2011,"finding":"LRP6 forms a complex with LDL receptor (LDLR), clathrin, and ARH, and undergoes clathrin-mediated internalization after LDL stimulation. LRP6 knockdown severely impairs LDLR internalization and LDL uptake. The LRP6(R611C) mutation impairs LRP6 complex formation with LDLR/clathrin/ARH, and reduces LDLR and LRP6 internalization and LDL uptake.","method":"LRP6 overexpression and knockdown in CHO cells (LDLR-deficient and wild-type), co-immunoprecipitation of LRP6-LDLR-clathrin-ARH complex, LDL binding/uptake assays","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of multiprotein complex, functional LDL uptake assays, single lab","pmids":["22128165"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of a Drosophila WntD N-terminal domain fragment at 2.1 Å resolution reveals conformational plasticity compared to Xenopus Wnt8. Structure-based mutational analysis of mouse Wnt3a shows that the linker between N- and C-terminal domains is required for LRP6 binding.","method":"X-ray crystallography, structure-based mutagenesis of Wnt3a, LRP6 binding assays","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with functional mutagenesis to map LRP6 binding site on Wnt","pmids":["23791946"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structure of an affinity-matured XWnt8-Frizzled8-LRP6 ternary initiation complex reveals that canonical Wnts engage LRP6 E1E2 domain funnels through their N-termini and linker domains. Chimeric Wnts with modular linker grafts transferred LRP6 domain specificity between Wnts and enabled non-canonical Wnt5a to signal through the canonical pathway. Synthetic peptides comprising the linker domain acted as Wnt-specific antagonists.","method":"Cryo-EM structure determination, chimeric Wnt engineering, cell-based signaling assays, synthetic peptide antagonism","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure with multiple functional validations (chimeras, peptide antagonists, signaling assays)","pmids":["36893265"],"is_preprint":false},{"year":2020,"finding":"Crystal structure of the LRP6 E1E2-sclerostin (SOST) complex reveals two tandem interaction sites: the known LRP6 E1 domain interaction and an unexpected additional binding site between the C-terminus of SOST and the LRP6 E2 domain. The E2 interaction was confirmed by in vitro binding and cell-based signaling assays, and validated in vivo in Xenopus laevis embryos.","method":"X-ray crystallography, in vitro binding assays, cell-based Wnt signaling assays, Xenopus embryo functional validation","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with multiple orthogonal functional validations including in vivo","pmids":["33097721"],"is_preprint":false},{"year":2009,"finding":"LRP6 beta-propeller (BP) domains 1+2 form one cooperative folding unit and BP3+4 form another. BP12 and BP34 each independently bind Wnt3a, Dkk1, and the chaperone Mesd. Mesd blocks binding of both Wnt3a and Dkk1 to LRP6, enabling it to function as a Wnt signaling modulator.","method":"Recombinant LRP6 domain expression, folding/secretion assays with Mesd co-expression, ligand binding competition assays","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro protein biochemistry with purified domains, single lab","pmids":["19339249"],"is_preprint":false},{"year":2013,"finding":"Caveolin-1 (Cav-1) interacts with LRP6 in prostate cancer cells, and this interaction stimulates Wnt-β-catenin signaling and aerobic glycolysis. Cav-1 and LRP6 exert their effects on Akt and glycolytic activities (HK2, Glut3) by stimulating IGF-IR/IR signaling. LRP6 knockdown or Cav-1 knockdown reduces Akt-mTORC1 signaling and aerobic glycolysis.","method":"Co-immunoprecipitation, gene knockdown, chemical inhibition of Akt, glycolysis assays in prostate cancer cells","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional knockdown with multiple readouts, single lab","pmids":["23302227"],"is_preprint":false},{"year":2016,"finding":"LRP6 acts as a scaffold protein at cardiac intercalated discs, binding connexin 43 (Cx43) independently of Wnt/beta-catenin signaling. LRP6 deficiency impairs Cx43 trafficking from the ER to the Golgi apparatus, leading to lysosomal degradation of Cx43 and disruption of gap junction formation. Cardiac-specific Lrp6-knockout mice show reduced Cx43 gap junction plaques and lethal arrhythmias without abnormality in Wnt signaling.","method":"Co-immunoprecipitation, cardiomyocyte-specific conditional knockout, immunofluorescence of Cx43 localization, ER-to-Golgi trafficking assays, cardiac electrophysiology","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple methods (co-IP, conditional KO, trafficking assays, arrhythmia phenotype) with clear Wnt-independent mechanism demonstrated","pmids":["27250245"],"is_preprint":false},{"year":2014,"finding":"The LRP6(R611C) mutation triggers hepatic de novo lipogenesis, lipid/cholesterol biosynthesis, and apoB secretion through Sp1-dependent activation of IGF1, AKT, and both mTORC1 and mTORC2. In vivo administration of recombinant Wnt3a to LRP6(R611C) mice normalized lipogenic enzyme expression and restored plasma TG and LDL levels.","method":"LRP6(R611C) knock-in mouse model, primary hepatocyte culture, IGF1R antagonist/rapamycin/Wnt3a treatments, in vivo Wnt3a rescue","journal":"Cell Metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic and pharmacological interventions with in vivo rescue, single lab with multiple orthogonal methods","pmids":["24506864"],"is_preprint":false},{"year":2015,"finding":"Impaired LRP6 activity in LRP6(R611C) mice promotes loss of VSMC differentiation through enhanced non-canonical Wnt signaling, leading to diminished TCF7L2 and increased Sp1-dependent activation of PDGF signaling. Wnt3a administration improved LRP6 activity, led to TCF7L2-dependent VSMC differentiation, and rescued post-carotid-injury neointima formation.","method":"LRP6(R611C) knock-in mice, high-fat diet/LDLR-KO crosses, carotid injury model, Wnt3a in vivo administration, TCF7L2 and PDGF signaling analysis","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model with pharmacological rescue and multiple mechanistic readouts","pmids":["26489464"],"is_preprint":false},{"year":2013,"finding":"PTK7 physically interacts with LRP6 and stabilizes LRP6 protein levels, thereby maintaining high LRP6 to promote canonical Wnt/beta-catenin signaling. PTK7 morpholino depletion in Xenopus reduces LRP6 protein levels and inhibits Wnt/beta-catenin activity while phenocopying LRP6 depletion. High LRP6 levels maintained by PTK7 negatively regulate Wnt/PCP activity.","method":"Co-immunoprecipitation, morpholino knockdown in Xenopus, western blot for LRP6 protein levels, Wnt reporter assays","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus in vivo Xenopus epistasis, single lab","pmids":["24353057"],"is_preprint":false},{"year":2017,"finding":"GPR37, a Parkinson's disease-associated receptor, functions as an ER chaperone for LRP6, promoting maturation of LRP6's N-terminal beta-propellers. GPR37 protects LRP6 from ER-associated degradation (ERAD) via CHIP and VCP. GPR37 is required for Wnt/beta-catenin signaling and for Wnt-dependent neurogenesis in neural progenitor cells.","method":"Co-immunoprecipitation, GPR37 knockdown/knockout, LRP6 protein maturation and degradation assays (CHIP/VCP), neural progenitor cell Wnt signaling assays","journal":"EMBO Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ERAD machinery identification, functional knockdown in NPCs, single lab","pmids":["28341812"],"is_preprint":false},{"year":2020,"finding":"LRP6 deficiency in cardiomyocytes increases cell cycle activity and induces a regenerative response after myocardial infarction. The pro-proliferative effect of Lrp6 deficiency is mediated through the ING5/P21 signaling pathway. Lineage tracing showed newly formed cardiomyocytes derive from resident cardiomyocytes. AAV9-mediated miRNA knockdown of Lrp6 promoted cardiac repair in vivo.","method":"Cardiomyocyte-specific conditional knockout, genetic lineage tracing, ING5/P21 pathway analysis, AAV9 gene therapy in mice, hiPSC-derived cardiomyocyte assays","journal":"Cell Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with lineage tracing and pathway identification, single lab","pmids":["32973339"],"is_preprint":false},{"year":2014,"finding":"LRP6 dimerization through its LDLR domain is required for robust canonical Wnt pathway activation. Wnt ligand stimulation induces conformational change of Frizzled-LRP6 complex leading to hexamer formation with a core LDLR domain-mediated LRP6 homodimer stabilized by two Wnt3a-Frz8 pairs (Wnt3a-Frz8-LRP6-LRP6-Frz8-Wnt3a).","method":"Co-immunoprecipitation, Wnt reporter assays, LDLR domain mutant analysis, protein interaction studies","journal":"Cellular Signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical interaction studies with mutants and reporter assays, single lab","pmids":["24412751"],"is_preprint":false},{"year":2015,"finding":"N-cadherin restrains PTH-induced Lrp6/PTHR1 interaction. Ablation of N-cadherin gene in osteogenic cells increased Lrp6/PTHR1 interaction in response to PTH, enhancing PKA signaling and PKA-dependent beta-catenin C-terminus phosphorylation (which promotes transcriptional activity). Beta-catenin C-terminus phosphorylation was abolished by Lrp6 knockdown. Conditional Cdh2-deletion mice showed accentuated PTH anabolic effect on bone.","method":"Cdh2 conditional knockout in osteogenic cells, co-immunoprecipitation of Lrp6/PTHR1, LRP6 knockdown, PKA and beta-catenin phosphorylation assays, in vivo PTH bone mass measurements","journal":"Journal of Bone and Mineral Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of LRP6/PTHR1 complex plus conditional KO with functional readouts, single lab","pmids":["25088803"],"is_preprint":false},{"year":2019,"finding":"VSTM2A, a secreted protein, directly binds to LRP6 (E1-4 domain via its IgV domain) at the cell membrane, suppresses LRP6 phosphorylation in a time- and dose-dependent manner, and induces LRP6 endocytosis and lysosome-mediated degradation, thereby inactivating Wnt signaling in colorectal cancer cells.","method":"Mass spectrometry identification, co-immunoprecipitation, deletion/mutation mapping, LRP6 phosphorylation assays, lysosome inhibitor experiments, LRP6 endocytosis assays","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification + co-IP domain mapping + functional phosphorylation and trafficking assays, single lab","pmids":["31588233"],"is_preprint":false},{"year":2018,"finding":"Oxidized phospholipids (oxPLs) are direct ligands of LRP6 (but not the closely related LRP5). oxPL-LRP6 binding induces LRP6 endocytosis through a clathrin-mediated pathway in bone marrow mesenchymal stromal cells, decreasing osteogenic factor responses and diminishing osteoblast differentiation.","method":"LRP6 binding assays with purified oxPLs, LRP6 vs LRP5 specificity assays, clathrin inhibitor experiments, osteoblast differentiation assays","journal":"Bone Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ligand binding assays with functional endocytosis and differentiation readouts, single lab","pmids":["30038821"],"is_preprint":false},{"year":2012,"finding":"Cripto-1 binds to LRP5 and LRP6 co-receptors, facilitating Wnt3a binding to LRP5 and LRP6, and enhances Wnt3a/beta-catenin signaling including cytoplasmic beta-catenin stabilization and TCF transcriptional activation. Wnt3a also increases Cripto-1-stimulated migration, invasion, and colony formation in mammary epithelial cells.","method":"Co-immunoprecipitation of Cripto-1 with LRP5/LRP6, beta-catenin stabilization assays, TCF reporter assays, migration/invasion assays","journal":"Cellular Signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP binding plus functional signaling and cell assays, single lab","pmids":["23022962"],"is_preprint":false},{"year":2019,"finding":"GRP78 chaperones LRP6 folding and maturation in the ER. GRP78 knockdown leads to LRP6 misfolding and ER-associated degradation (ERAD), reducing mature LRP6 levels and inhibiting Wnt/HOXB9 signaling in hepatocellular carcinoma cells.","method":"GRP78 knockdown, LRP6 protein maturation/ERAD assays, Wnt signaling pathway analysis, HCC invasion/metastasis assays","journal":"Experimental Cell Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with LRP6 maturation and ERAD mechanistic readouts, single lab","pmids":["31310747"],"is_preprint":false},{"year":2023,"finding":"The deubiquitylase complex USP46/UAF1/WDR20 deubiquitylates LRP6. Wnt signaling promotes association between the USP46 complex and cell-surface LRP6. USP46 knockdown decreases steady-state LRP6 levels and increases ubiquitylated LRP6. USP46 complex overexpression blocks LRP6 ubiquitylation by the ubiquitin ligases RNF43 and ZNFR3. USP46 is essential for Wnt-dependent intestinal organoid viability.","method":"Co-immunoprecipitation, ubiquitylation assays, siRNA knockdown, CRISPR knockout in cells and zebrafish/Xenopus, size exclusion chromatography, intestinal organoid assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical ubiquitylation assays, co-IP, multiple genetic models (human cells, Xenopus, zebrafish, organoids)","pmids":["37798301"],"is_preprint":false},{"year":2020,"finding":"Proximity labeling (APEX2 fused to Lrp6) revealed that endosomal proteins, ESCRT machinery components, and Trk-fused gene (TFG) are recruited near LRP6 within 5 min of Wnt3a treatment. TFG depletion (siRNA or CRISPR) significantly reduced Wnt/beta-catenin signaling in cell culture, and TFG is required for Wnt-dependent embryonic patterning in Xenopus.","method":"APEX2 proximity biotinylation, mass spectrometry, siRNA knockdown, CRISPR knockout, Xenopus in vivo patterning assays","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity labeling with MS plus functional validation in cells and in vivo, single lab","pmids":["33299006"],"is_preprint":false},{"year":2021,"finding":"TMEM97 interacts with the LRP6 intracellular domain and enhances LRP6-mediated Wnt signaling in a CK1delta/epsilon-dependent manner. TMEM97 binding to LRP6 facilitates recruitment of CK1delta/epsilon to the LRP6 complex, resulting in LRP6 phosphorylation at Ser1490 and beta-catenin stabilization. TMEM97 knockout attenuates Wnt/beta-catenin signaling via reduced LRP6 phosphorylation.","method":"Co-immunoprecipitation, LRP6 phosphorylation assays, TMEM97 knockout in breast cancer cells, Wnt target gene expression analysis, xenograft tumor model","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with mechanistic phosphorylation assay plus functional KO studies, single lab","pmids":["34615853"],"is_preprint":false},{"year":2022,"finding":"SIK2, phosphorylated by CK1alpha, directly phosphorylates LRP6 in a SIK2 kinase activity-dependent manner, activating Wnt/beta-catenin signaling and maintaining breast cancer stemness. SIK2-mediated Wnt/beta-catenin activation induces IDH1 expression, causing metabolic reprogramming in breast cancer cells. SIK2 inhibitors block LRP6 phosphorylation and beta-catenin accumulation.","method":"Kinase activity assays, LRP6 phosphorylation assays, SIK2 knockdown/inhibitor treatment, BCSC proportion assays, IDH1 expression analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct kinase-substrate assay plus functional signaling readouts, single lab","pmids":["35277657"],"is_preprint":false},{"year":2019,"finding":"LRP6 ectodomain (LRP6N) directly binds CXCR4 and competitively prevents SDF-1 binding to CXCR4. LRP6N prevented SDF-1/CXCR4-induced breast cancer metastasis to lung in vivo. LRP6 knockdown activated SDF-1/CXCR4 signal transduction and promoted lung metastasis. A secreted form of LRP6N was detected in serum of mice and humans.","method":"Direct binding assays (LRP6N to CXCR4), competitive binding assays, LRP6 knockdown, in vivo breast cancer metastasis model, serum LRP6N detection","journal":"Clinical Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assays plus in vivo functional validation, single lab","pmids":["31010839"],"is_preprint":false},{"year":2015,"finding":"Calcipotriol (vitamin D analogue) inhibits Wnt/beta-catenin signaling in PDAC cells through a novel mechanism: transcriptional upregulation of LDLRAP1 (LDL receptor adaptor protein 1), which decreases LRP6 protein levels. Changes in LRP6 or LDLRAP1 expression directly alter Wnt reporter activity.","method":"Cell-based Wnt reporter assays, LRP6 protein level analysis with calcipotriol, LDLRAP1 overexpression/knockdown experiments, PDAC cell growth assays","journal":"Molecular Cancer Research","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — cell-based assays showing LDLRAP1-LRP6 connection, single lab, mechanism of LDLRAP1-induced LRP6 reduction not fully defined at molecular level","pmids":["26224368"],"is_preprint":false},{"year":2013,"finding":"Syndecan-4 (SDC4) and fibronectin inhibit Wnt/beta-catenin signaling at the cell membrane level through regulation of LRP6. Epistatic and biochemical experiments placed this inhibition at the LRP6 level. SDC4 modulates the ability of R-spondin 3 to potentiate Wnt/beta-catenin signaling through LRP6.","method":"Gain- and loss-of-function in mammalian cell lines and Xenopus embryos, epistasis analysis, co-immunoprecipitation","journal":"International Journal of Biochemistry & Cell Biology","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — epistasis and co-IP but biochemical mechanism of SDC4-LRP6 interaction not fully resolved in abstract","pmids":["24275095"],"is_preprint":false},{"year":2024,"finding":"ATP6AP2 promotes LRP6/beta-catenin and N-cadherin/beta-catenin protein complex distribution at the cell membrane in osteoblasts, preventing their degradation. ATP6AP2 conditional knockout in osteoblast-lineage cells reduced LRP6 and N-cadherin levels in BMSCs and OBs (but not osteocytes), impairing beta-catenin signaling and trabecular bone formation.","method":"Conditional knockout mice, proteomic analysis, cell surface fractionation, co-immunoprecipitation, beta-catenin signaling assays","journal":"Bone Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with proteomic and biochemical mechanistic follow-up, single lab","pmids":["38811544"],"is_preprint":false},{"year":2023,"finding":"The AD-linked LRP6-Val variant has reduced Wnt signaling. Wnt7a stimulates formation of the LRP6-Frizzled-5 complex, but this complex does not form when LRP6-Val is present. Lrp6-val knock-in mice develop normally but neurons do not respond to Wnt7a, exhibit age-dependent structural and functional synaptic defects, and show exacerbated synapse loss around amyloid plaques in an AD mouse model.","method":"CRISPR knock-in mice, LRP6-Frizzled-5 co-immunoprecipitation assays, Wnt7a signaling assays in neurons, synapse structural/functional analysis, NL-G-F AD model crossing","journal":"Science Advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR knock-in with multiple orthogonal functional analyses (receptor complex formation, signaling, synaptic morphology, electrophysiology, AD model)","pmids":["36638182"],"is_preprint":false},{"year":2008,"finding":"LRP6 forms a complex with anthrax toxin receptors (ATRs/ANTXRs) at the cell surface. This ATR-LRP6 interaction is bidirectional: ATRs control LRP6 protein levels (RNAi against ATRs decreased LRP6 levels and reduced Wnt signaling), while LRP6 plays a role in anthrax toxin endocytosis (toxin binding triggers LRP6 tyrosine phosphorylation, redistribution into detergent-resistant domains, and LRP6 endocytosis; LRP6 RNAi strongly delayed toxin endocytosis).","method":"Co-immunoprecipitation, siRNA against ATRs and LRP6, Wnt signaling reporter assays, LRP6 tyrosine phosphorylation analysis, detergent-resistant domain fractionation, toxin endocytosis assays","journal":"Cellular Microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with bidirectional siRNA studies and biochemical fractionation, single lab","pmids":["18717822"],"is_preprint":false},{"year":2022,"finding":"Ninjurin1 (Ninj1) forms an assembly with LRP6 through its extracellular N-terminal domain and recruits Frizzled2 and downstream signaling mediators, resulting in ligand-independent activation of the LRP6/beta-catenin signaling pathway in lung cancer cells.","method":"Co-immunoprecipitation, domain mapping of Ninj1-LRP6 interaction, Wnt reporter assays, functional gain/loss of Ninj1 expression","journal":"Journal of Experimental & Clinical Cancer Research","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — co-IP with reporter assays, mechanistic details limited in abstract, single lab","pmids":["35395804"],"is_preprint":false}],"current_model":"LRP6 is a single-pass transmembrane Wnt co-receptor that, upon Wnt binding together with Frizzled, clusters into membrane signalosomes where it is phosphorylated at PPSPXS motifs by multiple kinases (CK1 family, GSK3, GRK5/6, SIK2) to recruit Axin and stabilize beta-catenin, while being negatively regulated by Src/Fer-mediated tyrosine phosphorylation, modulated in abundance by the deubiquitylase USP46 complex (counteracting RNF43/ZNRF3-mediated ubiquitylation) and ER chaperones (GPR37, GRP78), and additionally functioning as a scaffold for cardiac Cx43 gap junction trafficking, an endocytic regulator of the LDL receptor, a direct receptor for oxidized phospholipids, and a CXCR4 competitor—all mechanistically established by structural studies, reconstitution experiments, genetic epistasis, and cell biology."},"narrative":{"mechanistic_narrative":"LRP6 is a single-pass transmembrane Wnt co-receptor that, upon Wnt binding together with Frizzled, clusters into phosphorylated plasma-membrane signalosomes that recruit Axin and GSK3 to stabilize beta-catenin [PMID:17569865, PMID:20229235]. Structurally, the LRP6 ectodomain presents tandem beta-propeller folding units (E1E2 and E3E4) that bind distinct Wnt ligands at separate sites—Wnt3a engaging E3E4 and other Wnts E1E2—while the broad-spectrum antagonist Dkk1 and the antagonist sclerostin (SOST) occupy these surfaces to block signaling [PMID:20093360, PMID:33097721, PMID:19339249]; cryo-EM of a Wnt-Frizzled-LRP6 ternary complex shows canonical Wnts engaging the E1E2 funnels through their N-terminal linker domains, with LDLR-domain-mediated LRP6 homodimerization driving a hexameric initiation assembly required for robust pathway activation [PMID:36893265, PMID:24412751]. Signalosome activation depends on phosphorylation of conserved cytoplasmic PPSPXS motifs by a battery of kinases including CK1 family, GSK3, GRK5/6, and SIK2, with the activity controlled by adaptors and scaffolds such as TMEM198 and TMEM97 that recruit casein kinases to the receptor [PMID:20229235, PMID:19801552, PMID:21536646, PMID:34615853, PMID:35277657]; conversely, CK1-epsilon phosphorylation at Ser1420/Ser1430 and Src/Fer-mediated tyrosine phosphorylation provide negative feedback that limits signalosome formation and surface receptor levels [PMID:16513652, PMID:25391905]. Receptor abundance and trafficking are further set by ER chaperones GPR37 and GRP78 that promote LRP6 maturation and protect it from ER-associated degradation [PMID:28341812, PMID:31310747], by the USP46/UAF1/WDR20 deubiquitylase complex that counteracts RNF43/ZNRF3-mediated ubiquitylation at the cell surface [PMID:37798301], and by tyrosine-signal-dependent partitioning between desensitizing clathrin and signaling-promoting caveolar endocytic routes [PMID:25143377]. Beyond canonical Wnt signaling, LRP6 acts as a Wnt-independent scaffold for connexin 43 trafficking at cardiac intercalated discs, the loss of which causes lethal arrhythmias [PMID:27250245], regulates LDL receptor internalization through a complex with clathrin and ARH [PMID:22128165], and the LRP6(R611C) hypomorphic mutation drives hepatic lipogenesis and loss of vascular smooth muscle cell differentiation, both rescuable by Wnt3a [PMID:24506864, PMID:26489464]. An AD-linked LRP6-Val variant fails to form the Wnt7a-dependent LRP6-Frizzled5 complex and produces age-dependent synaptic defects in knock-in mice [PMID:36638182].","teleology":[{"year":2006,"claim":"Establishing that LRP6 phosphorylation is the regulatory switch for Wnt signaling required identifying the kinases acting on its cytoplasmic motifs and whether they activate or restrain the pathway.","evidence":"In vitro binding/kinase assays, co-IP, site-directed mutagenesis, and Lef-1 reporter assays for CKI-epsilon on LRP6 Ser1420/1430","pmids":["16513652"],"confidence":"High","gaps":["Did not resolve how this negative feedback is integrated with activating phosphorylation in vivo","Stoichiometry and kinetics of multi-site phosphorylation unaddressed"]},{"year":2007,"claim":"How LRP6 transduces a Wnt signal at the membrane was unknown; this showed Wnt induces phosphorylated LRP6 aggregates (signalosomes) that recruit Axin to stabilize beta-catenin.","evidence":"Live imaging, detergent solubilization/fractionation, and dominant-negative Dvl in vertebrate cells","pmids":["17569865"],"confidence":"High","gaps":["Molecular architecture of the signalosome not resolved","Role of caveolin in aggregate function unclear"]},{"year":2010,"claim":"The kinase logic and ligand-binding architecture of LRP6 were defined: multiple proline-directed and CK1-family kinases phosphorylate PPSPXS motifs, and distinct ectodomain regions bind different Wnts and Dkk1.","evidence":"Review synthesis of kinase/mutagenesis studies plus in vitro reconstitution of the Fz8-Wnt3a-LRP6 ternary complex with binding-competition assays","pmids":["20229235","20093360"],"confidence":"High","gaps":["High-resolution structure of the active complex still lacking at this stage","How simultaneous Wnt binding affects signaling output not tested"]},{"year":2009,"claim":"Identifying GRK5/6 as direct activating kinases and characterizing the cooperative beta-propeller folding units extended the kinase repertoire and clarified ectodomain modularity.","evidence":"In vitro kinase assays, siRNA depletion, zebrafish epistasis (GRK5/6); recombinant domain folding/ligand-binding assays with Mesd chaperone","pmids":["19801552","19339249"],"confidence":"High","gaps":["GRK5/6 work single-lab biochemistry combined with in vivo (Medium-rationale domain study)","How Mesd-controlled folding is coupled to surface delivery unclear"]},{"year":2011,"claim":"Whether kinase recruitment to LRP6 is actively scaffolded was unknown; TMEM198 was shown to bridge casein kinases to LRP6 for activating phosphorylation.","evidence":"Reciprocal co-IP, phosphorylation assays, siRNA, and Xenopus loss-of-function","pmids":["21536646"],"confidence":"High","gaps":["Whether TMEM198 acts within the signalosome or upstream unclear","Direct CK1-TMEM198 contact not structurally mapped"]},{"year":2014,"claim":"The negative regulatory layer was defined: Src/Fer tyrosine phosphorylation restrains signalosome formation, while a tyrosine-based endocytic signal partitions LRP6 between desensitizing clathrin and signaling caveolar routes; LDLR-domain dimerization was shown to be required for robust activation.","evidence":"cDNA screen, in vitro phosphorylation, knockout MEFs, surface/endocytosis assays, and LDLR-domain mutant interaction studies","pmids":["25391905","25143377","24412751"],"confidence":"High","gaps":["Endocytosis and dimerization studies are single-lab (Medium)","Cross-talk between tyrosine phosphorylation and trafficking partitioning not fully resolved"]},{"year":2014,"claim":"The pathological consequences of attenuated LRP6 activity in metabolism and vasculature were established through the R611C hypomorph, linking LRP6 to lipogenesis and VSMC differentiation via Wnt-rescuable mechanisms.","evidence":"LRP6(R611C) knock-in mice, primary hepatocytes, carotid injury model, and in vivo Wnt3a rescue","pmids":["24506864","26489464"],"confidence":"High","gaps":["Mechanistic link between receptor hypomorphism and Sp1/IGF1 axis incompletely defined","Single-lab models"]},{"year":2016,"claim":"A Wnt-independent function for LRP6 was demonstrated: it scaffolds connexin 43 ER-to-Golgi trafficking at cardiac intercalated discs, with loss causing lethal arrhythmias.","evidence":"Co-IP, cardiomyocyte-specific conditional knockout, Cx43 trafficking imaging, and cardiac electrophysiology","pmids":["27250245"],"confidence":"High","gaps":["Structural basis of LRP6-Cx43 interaction not defined","Whether this scaffolding generalizes beyond cardiomyocytes unknown"]},{"year":2017,"claim":"Control of LRP6 biogenesis was extended to ER quality control, with GPR37 (and later GRP78) acting as chaperones protecting LRP6 from ERAD to license Wnt signaling.","evidence":"Co-IP, GPR37 knockdown/knockout, LRP6 maturation/degradation assays (CHIP/VCP), NPC Wnt assays; GRP78 knockdown/ERAD assays in HCC","pmids":["28341812","31310747"],"confidence":"Medium","gaps":["Whether GPR37 and GRP78 act sequentially or redundantly unknown","Single-lab studies"]},{"year":2020,"claim":"High-resolution structure and proximity proteomics refined the activation mechanism: the Wnt-Frizzled-LRP6 initiation complex engages E1E2 via Wnt linker domains, and rapid Wnt-induced recruitment of ESCRT/endosomal machinery including TFG supports signaling.","evidence":"Cryo-EM with chimeric Wnt engineering and peptide antagonists; APEX2 proximity labeling with MS and Xenopus validation; SOST-E1E2 crystal structure","pmids":["36893265","33299006","33097721"],"confidence":"High","gaps":["How endosomal recruitment couples mechanistically to beta-catenin stabilization not fully resolved","TFG study single-lab (Medium)"]},{"year":2023,"claim":"The ubiquitin/deubiquitin balance setting surface LRP6 levels was defined, with USP46/UAF1/WDR20 counteracting RNF43/ZNRF3, and a disease-linked LRP6-Val variant was shown to disrupt Wnt7a-dependent receptor complex assembly and synaptic maintenance.","evidence":"Ubiquitylation assays, co-IP, multi-organism genetics, and organoid assays (USP46); CRISPR knock-in mice, LRP6-Frizzled5 co-IP, and synaptic/AD-model analysis (LRP6-Val)","pmids":["37798301","36638182"],"confidence":"High","gaps":["How Wnt promotes USP46-LRP6 association mechanistically unresolved","Causal chain from LRP6-Val synapse loss to AD pathology not established"]},{"year":null,"claim":"How LRP6's distinct roles—canonical Wnt signalosome receptor, Wnt-independent trafficking scaffold, LDLR endocytic partner, oxPL/CXCR4-binding ectodomain—are physically and spatially segregated within a single receptor remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model integrating Wnt-dependent and Wnt-independent functions","Tissue-specific determinants of which LRP6 function dominates undefined","Several non-canonical interactions rest on single-lab co-IP evidence"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[2,13,14,26]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,17,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[11,33]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,9,23,25]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[21,28,17]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[10,30,9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,13]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[9,11,30]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[21,28,29]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[19,37]}],"complexes":["Wnt-Frizzled-LRP6 signalosome","USP46/UAF1/WDR20 deubiquitylase complex","LRP6-LDLR-clathrin-ARH complex"],"partners":["FZD8","AXIN1","DKK1","SOST","GPR37","USP46","GJA1","PTK7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75581","full_name":"Low-density lipoprotein receptor-related protein 6","aliases":[],"length_aa":1613,"mass_kda":180.4,"function":"Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalosomes (PubMed:11357136, PubMed:11448771, PubMed:15778503, PubMed:16341017, PubMed:16513652, PubMed:17326769, PubMed:17400545, PubMed:19107203, PubMed:19293931, PubMed:19801552, PubMed:28341812, PubMed:34896607). Cell-surface coreceptor of Wnt/beta-catenin signaling, which plays a pivotal role in various processes including retinal angiogenesis and bone formation (PubMed:11357136, PubMed:11448771, PubMed:15778503, PubMed:16341017, PubMed:16513652, PubMed:17326769, PubMed:17400545, PubMed:19107203, PubMed:19293931, PubMed:19801552, PubMed:28341812, PubMed:34896607). The Wnt-induced Fzd/LRP6 coreceptor complex recruits DVL1 polymers to the plasma membrane which, in turn, recruits the AXIN1/GSK3B-complex to the cell surface promoting the formation of signalosomes and inhibiting AXIN1/GSK3-mediated phosphorylation and destruction of beta-catenin (PubMed:16513652). Required for posterior patterning of the epiblast during gastrulation (By similarity)","subcellular_location":"Cell membrane; Endoplasmic reticulum; Membrane raft","url":"https://www.uniprot.org/uniprotkb/O75581/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LRP6","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"EDF1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LRP6","total_profiled":1310},"omim":[{"mim_id":"621449","title":"OSTEOPETROSIS, AUTOSOMAL DOMINANT 4; OPTA4","url":"https://www.omim.org/entry/621449"},{"mim_id":"621268","title":"EXUDATIVE VITREORETINOPATHY 8; EVR8","url":"https://www.omim.org/entry/621268"},{"mim_id":"620559","title":"CYCLIN Y-LIKE 1; CCNYL1","url":"https://www.omim.org/entry/620559"},{"mim_id":"619959","title":"ACCES SYNDROME; ACCES","url":"https://www.omim.org/entry/619959"},{"mim_id":"618957","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 27; ANKRD27","url":"https://www.omim.org/entry/618957"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LRP6"},"hgnc":{"alias_symbol":["ADCAD2"],"prev_symbol":[]},"alphafold":{"accession":"O75581","domains":[{"cath_id":"2.120.10.30","chopping":"26-310","consensus_level":"medium","plddt":90.4257,"start":26,"end":310},{"cath_id":"2.120.10.30","chopping":"330-596","consensus_level":"high","plddt":90.0255,"start":330,"end":596},{"cath_id":"2.120.10.30","chopping":"631-930","consensus_level":"high","plddt":92.0601,"start":631,"end":930},{"cath_id":"2.120.10.30","chopping":"937-1206","consensus_level":"high","plddt":90.9793,"start":937,"end":1206},{"cath_id":"4.10.400.10","chopping":"1249-1286","consensus_level":"medium","plddt":70.1982,"start":1249,"end":1286},{"cath_id":"-","chopping":"1293-1344","consensus_level":"medium","plddt":72.6625,"start":1293,"end":1344}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75581","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75581-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75581-F1-predicted_aligned_error_v6.png","plddt_mean":79.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LRP6","jax_strain_url":"https://www.jax.org/strain/search?query=LRP6"},"sequence":{"accession":"O75581","fasta_url":"https://rest.uniprot.org/uniprotkb/O75581.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75581/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75581"}},"corpus_meta":[{"pmid":"17569865","id":"PMC_17569865","title":"Wnt 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Dishevelled (Dvl) is required for LRP6 phosphorylation and aggregation, and phospho-LRP6 aggregates contain caveolin but no common vesicular traffic markers. Phospho-LRP6 promotes Axin recruitment and beta-catenin stabilization.\",\n      \"method\": \"Live imaging of vertebrate cells, detergent solubilization, biochemical fractionation, dominant-negative Dvl experiments\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (live imaging, biochemical fractionation, genetic perturbation), widely replicated finding in the field\",\n      \"pmids\": [\"17569865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LRP6 is phosphorylated at multiple conserved PPSPXS motifs by both proline-directed kinases (GSK3, PKA, Pftk1, GRK5/6) and non-proline-directed kinases (CK1 family). This phosphorylation is induced by Wnt ligand binding and by mitosis, and phospho-LRP6 promotes Axin and GSK3 recruitment to stabilize beta-catenin.\",\n      \"method\": \"Review synthesizing in vitro kinase assays, mutagenesis, and cell-based signaling assays from multiple studies\",\n      \"journal\": \"Cellular and Molecular Life Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — based on multiple replicated in vitro kinase assays and mutagenesis studies across labs (review synthesis)\",\n      \"pmids\": [\"20229235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In vitro reconstitution of the Fz8 CRD·Wnt3a·LRP6 signaling complex established that Wnt3a binds to LRP6 E3E4 (third and fourth beta-propeller domains), while Wnt9b binds to a distinct region (E1E2). Wnt3a and Wnt9b can bind LRP6 simultaneously. Dkk1 binds both E1E2 and E3E4 and competes with both Wnts, providing a mechanism for broad-spectrum Wnt inhibition.\",\n      \"method\": \"Insect cell expression/purification of soluble LRP6 extracellular domain fragments, binding affinity measurements, in vitro reconstitution of ternary complex\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — purified protein reconstitution with multiple LRP6 domain fragments and binding competition assays\",\n      \"pmids\": [\"20093360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"LRP6 is required for anthrax toxin internalization and lethality. LRP6 interacts at the cell surface with PA receptors TEM8/ATR and/or CMG2 to form a multicomponent complex that enables toxin endocytosis. Downregulation of LRP6 or expression of a dominant-negative LRP6 truncation, or antibodies against LRP6 extracellular domain, protected cells from anthrax toxin.\",\n      \"method\": \"siRNA knockdown, dominant-negative LRP6 expression, antibody blocking, fluorescence microscopy, biochemical co-immunoprecipitation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (knockdown, dominant-negative, antibody, co-IP, microscopy) in one lab; contradicted by a subsequent paper (PMID:17335347)\",\n      \"pmids\": [\"16564009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NEGATIVE RESULT: LRP5 and LRP6 are NOT required for protective antigen (PA)-mediated internalization or lethality of anthrax lethal toxin. Uptake was unaltered in cells and mice with targeted deletions of Lrp5 or Lrp6, and siRNA knockdown of LRP5/6 did not impair PA-mediated uptake in ANTXR-expressing CHO cells.\",\n      \"method\": \"Cells and mice with targeted Lrp5/Lrp6 deletions, siRNA knockdown, cytotoxicity assay\",\n      \"journal\": \"PLoS Pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout animals plus siRNA in cell lines, single lab contradicting prior Cell paper\",\n      \"pmids\": [\"17335347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"GRK5 and GRK6, membrane-associated kinases classically known for GPCR desensitization, directly phosphorylate the PPPSP motifs on LRP6 and activate Wnt/LRP6 signaling. Depletion of GRK5 markedly reduces Wnt3A-stimulated LRP6 phosphorylation in cells. In zebrafish, functional knockdown of GRK5 reduces Wnt signaling similarly to LRP6 knockdown.\",\n      \"method\": \"In vitro kinase assay, cell-based phosphorylation assays, siRNA depletion, zebrafish knockdown with beta-catenin/target gene readout\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro direct phosphorylation assay plus in vivo zebrafish epistasis, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"19801552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CKI-epsilon binds to LRP5 and LRP6 in vitro and in vivo and phosphorylates LRP6 at Ser1420 and Ser1430, which negatively regulates Wnt signaling. Mutation of these sites to alanine makes LRP6 a more potent activator of beta-catenin/Lef-1 and strengthens its interaction with Axin, suggesting a negative feedback mechanism.\",\n      \"method\": \"In vitro binding and kinase assays, co-immunoprecipitation, site-directed mutagenesis of LRP6, Lef-1 reporter assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, co-IP, and functional reporter assay in one study\",\n      \"pmids\": [\"16513652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TMEM198, a seven-transmembrane protein, associates with LRP6 and recruits casein kinase family proteins via its cytoplasmic domain to phosphorylate LRP6 at key activation residues. TMEM198 is required for Wnt signaling and CK1-induced LRP6 phosphorylation in mammalian cells and for Wnt-mediated neural crest formation in Xenopus.\",\n      \"method\": \"Co-immunoprecipitation, LRP6 phosphorylation assays, siRNA knockdown in mammalian cells, Xenopus loss-of-function experiments\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, kinase phosphorylation assay, in vivo Xenopus epistasis, single lab\",\n      \"pmids\": [\"21536646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Tyrosine kinases Src and Fer directly phosphorylate LRP6 at conserved tyrosine residues adjacent to PPSPXS motifs, negatively regulating Wnt/LRP6 signaling. Src reduces cell surface LRP6 levels and disrupts LRP6 signalosome formation. MEF cells lacking Src/Fer show enhanced Wnt signaling. CK1γ inhibits Fer-induced LRP6 tyrosine phosphorylation, suggesting CK1γ de-represses inhibitory tyrosine phosphorylation.\",\n      \"method\": \"Cell culture cDNA expression screen, co-immunoprecipitation, in vitro phosphorylation assays, MEF knockout cells, cell surface LRP6 measurements, signalosome imaging\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphorylation, co-IP, knockout MEF epistasis, and cell surface assays in one study\",\n      \"pmids\": [\"25391905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LRP6 endocytosis is regulated by a tyrosine-based signal in its cytoplasmic tail. LRP6 with defective tyrosine signal has increased cell surface distribution, increased localization to caveolae, increased phosphorylation, and enhanced Wnt/beta-catenin signaling. Clathrin-mediated endocytosis of LRP6 desensitizes signaling, while caveolae-mediated endocytosis promotes it. Wnt3a treatment redistributes LRP6 to lipid rafts.\",\n      \"method\": \"LRP6 tyrosine mutant analysis, cell surface distribution assays, caveolae inhibitor treatments, phosphorylation assays, Wnt reporter assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple endocytosis assays and LRP6 mutants in single lab\",\n      \"pmids\": [\"25143377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Dkk1 stabilizes LRP6 protein with prolonged half-life and causes LRP6 accumulation at the cell surface and in endosomes, in contrast to its expected role as a Wnt inhibitor that promotes LRP6 internalization. Kremen2 co-expression abrogated Dkk1-induced LRP6 accumulation. Wnt3A treatment induces LRP6 down-regulation through caveolae-mediated endocytosis, and Dkk1 blocks this Wnt3A-induced LRP6 down-regulation.\",\n      \"method\": \"Conditioned medium/recombinant protein treatment, protein half-life assay, cell surface biotinylation, co-expression of Kremen2, caveolae endocytosis inhibitor\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays, single lab\",\n      \"pmids\": [\"20543981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LRP6 forms a complex with LDL receptor (LDLR), clathrin, and ARH, and undergoes clathrin-mediated internalization after LDL stimulation. LRP6 knockdown severely impairs LDLR internalization and LDL uptake. The LRP6(R611C) mutation impairs LRP6 complex formation with LDLR/clathrin/ARH, and reduces LDLR and LRP6 internalization and LDL uptake.\",\n      \"method\": \"LRP6 overexpression and knockdown in CHO cells (LDLR-deficient and wild-type), co-immunoprecipitation of LRP6-LDLR-clathrin-ARH complex, LDL binding/uptake assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of multiprotein complex, functional LDL uptake assays, single lab\",\n      \"pmids\": [\"22128165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of a Drosophila WntD N-terminal domain fragment at 2.1 Å resolution reveals conformational plasticity compared to Xenopus Wnt8. Structure-based mutational analysis of mouse Wnt3a shows that the linker between N- and C-terminal domains is required for LRP6 binding.\",\n      \"method\": \"X-ray crystallography, structure-based mutagenesis of Wnt3a, LRP6 binding assays\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with functional mutagenesis to map LRP6 binding site on Wnt\",\n      \"pmids\": [\"23791946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structure of an affinity-matured XWnt8-Frizzled8-LRP6 ternary initiation complex reveals that canonical Wnts engage LRP6 E1E2 domain funnels through their N-termini and linker domains. Chimeric Wnts with modular linker grafts transferred LRP6 domain specificity between Wnts and enabled non-canonical Wnt5a to signal through the canonical pathway. Synthetic peptides comprising the linker domain acted as Wnt-specific antagonists.\",\n      \"method\": \"Cryo-EM structure determination, chimeric Wnt engineering, cell-based signaling assays, synthetic peptide antagonism\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure with multiple functional validations (chimeras, peptide antagonists, signaling assays)\",\n      \"pmids\": [\"36893265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of the LRP6 E1E2-sclerostin (SOST) complex reveals two tandem interaction sites: the known LRP6 E1 domain interaction and an unexpected additional binding site between the C-terminus of SOST and the LRP6 E2 domain. The E2 interaction was confirmed by in vitro binding and cell-based signaling assays, and validated in vivo in Xenopus laevis embryos.\",\n      \"method\": \"X-ray crystallography, in vitro binding assays, cell-based Wnt signaling assays, Xenopus embryo functional validation\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with multiple orthogonal functional validations including in vivo\",\n      \"pmids\": [\"33097721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LRP6 beta-propeller (BP) domains 1+2 form one cooperative folding unit and BP3+4 form another. BP12 and BP34 each independently bind Wnt3a, Dkk1, and the chaperone Mesd. Mesd blocks binding of both Wnt3a and Dkk1 to LRP6, enabling it to function as a Wnt signaling modulator.\",\n      \"method\": \"Recombinant LRP6 domain expression, folding/secretion assays with Mesd co-expression, ligand binding competition assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro protein biochemistry with purified domains, single lab\",\n      \"pmids\": [\"19339249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Caveolin-1 (Cav-1) interacts with LRP6 in prostate cancer cells, and this interaction stimulates Wnt-β-catenin signaling and aerobic glycolysis. Cav-1 and LRP6 exert their effects on Akt and glycolytic activities (HK2, Glut3) by stimulating IGF-IR/IR signaling. LRP6 knockdown or Cav-1 knockdown reduces Akt-mTORC1 signaling and aerobic glycolysis.\",\n      \"method\": \"Co-immunoprecipitation, gene knockdown, chemical inhibition of Akt, glycolysis assays in prostate cancer cells\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional knockdown with multiple readouts, single lab\",\n      \"pmids\": [\"23302227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LRP6 acts as a scaffold protein at cardiac intercalated discs, binding connexin 43 (Cx43) independently of Wnt/beta-catenin signaling. LRP6 deficiency impairs Cx43 trafficking from the ER to the Golgi apparatus, leading to lysosomal degradation of Cx43 and disruption of gap junction formation. Cardiac-specific Lrp6-knockout mice show reduced Cx43 gap junction plaques and lethal arrhythmias without abnormality in Wnt signaling.\",\n      \"method\": \"Co-immunoprecipitation, cardiomyocyte-specific conditional knockout, immunofluorescence of Cx43 localization, ER-to-Golgi trafficking assays, cardiac electrophysiology\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple methods (co-IP, conditional KO, trafficking assays, arrhythmia phenotype) with clear Wnt-independent mechanism demonstrated\",\n      \"pmids\": [\"27250245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The LRP6(R611C) mutation triggers hepatic de novo lipogenesis, lipid/cholesterol biosynthesis, and apoB secretion through Sp1-dependent activation of IGF1, AKT, and both mTORC1 and mTORC2. In vivo administration of recombinant Wnt3a to LRP6(R611C) mice normalized lipogenic enzyme expression and restored plasma TG and LDL levels.\",\n      \"method\": \"LRP6(R611C) knock-in mouse model, primary hepatocyte culture, IGF1R antagonist/rapamycin/Wnt3a treatments, in vivo Wnt3a rescue\",\n      \"journal\": \"Cell Metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic and pharmacological interventions with in vivo rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24506864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Impaired LRP6 activity in LRP6(R611C) mice promotes loss of VSMC differentiation through enhanced non-canonical Wnt signaling, leading to diminished TCF7L2 and increased Sp1-dependent activation of PDGF signaling. Wnt3a administration improved LRP6 activity, led to TCF7L2-dependent VSMC differentiation, and rescued post-carotid-injury neointima formation.\",\n      \"method\": \"LRP6(R611C) knock-in mice, high-fat diet/LDLR-KO crosses, carotid injury model, Wnt3a in vivo administration, TCF7L2 and PDGF signaling analysis\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model with pharmacological rescue and multiple mechanistic readouts\",\n      \"pmids\": [\"26489464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PTK7 physically interacts with LRP6 and stabilizes LRP6 protein levels, thereby maintaining high LRP6 to promote canonical Wnt/beta-catenin signaling. PTK7 morpholino depletion in Xenopus reduces LRP6 protein levels and inhibits Wnt/beta-catenin activity while phenocopying LRP6 depletion. High LRP6 levels maintained by PTK7 negatively regulate Wnt/PCP activity.\",\n      \"method\": \"Co-immunoprecipitation, morpholino knockdown in Xenopus, western blot for LRP6 protein levels, Wnt reporter assays\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus in vivo Xenopus epistasis, single lab\",\n      \"pmids\": [\"24353057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GPR37, a Parkinson's disease-associated receptor, functions as an ER chaperone for LRP6, promoting maturation of LRP6's N-terminal beta-propellers. GPR37 protects LRP6 from ER-associated degradation (ERAD) via CHIP and VCP. GPR37 is required for Wnt/beta-catenin signaling and for Wnt-dependent neurogenesis in neural progenitor cells.\",\n      \"method\": \"Co-immunoprecipitation, GPR37 knockdown/knockout, LRP6 protein maturation and degradation assays (CHIP/VCP), neural progenitor cell Wnt signaling assays\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ERAD machinery identification, functional knockdown in NPCs, single lab\",\n      \"pmids\": [\"28341812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LRP6 deficiency in cardiomyocytes increases cell cycle activity and induces a regenerative response after myocardial infarction. The pro-proliferative effect of Lrp6 deficiency is mediated through the ING5/P21 signaling pathway. Lineage tracing showed newly formed cardiomyocytes derive from resident cardiomyocytes. AAV9-mediated miRNA knockdown of Lrp6 promoted cardiac repair in vivo.\",\n      \"method\": \"Cardiomyocyte-specific conditional knockout, genetic lineage tracing, ING5/P21 pathway analysis, AAV9 gene therapy in mice, hiPSC-derived cardiomyocyte assays\",\n      \"journal\": \"Cell Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with lineage tracing and pathway identification, single lab\",\n      \"pmids\": [\"32973339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LRP6 dimerization through its LDLR domain is required for robust canonical Wnt pathway activation. Wnt ligand stimulation induces conformational change of Frizzled-LRP6 complex leading to hexamer formation with a core LDLR domain-mediated LRP6 homodimer stabilized by two Wnt3a-Frz8 pairs (Wnt3a-Frz8-LRP6-LRP6-Frz8-Wnt3a).\",\n      \"method\": \"Co-immunoprecipitation, Wnt reporter assays, LDLR domain mutant analysis, protein interaction studies\",\n      \"journal\": \"Cellular Signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical interaction studies with mutants and reporter assays, single lab\",\n      \"pmids\": [\"24412751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"N-cadherin restrains PTH-induced Lrp6/PTHR1 interaction. Ablation of N-cadherin gene in osteogenic cells increased Lrp6/PTHR1 interaction in response to PTH, enhancing PKA signaling and PKA-dependent beta-catenin C-terminus phosphorylation (which promotes transcriptional activity). Beta-catenin C-terminus phosphorylation was abolished by Lrp6 knockdown. Conditional Cdh2-deletion mice showed accentuated PTH anabolic effect on bone.\",\n      \"method\": \"Cdh2 conditional knockout in osteogenic cells, co-immunoprecipitation of Lrp6/PTHR1, LRP6 knockdown, PKA and beta-catenin phosphorylation assays, in vivo PTH bone mass measurements\",\n      \"journal\": \"Journal of Bone and Mineral Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of LRP6/PTHR1 complex plus conditional KO with functional readouts, single lab\",\n      \"pmids\": [\"25088803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VSTM2A, a secreted protein, directly binds to LRP6 (E1-4 domain via its IgV domain) at the cell membrane, suppresses LRP6 phosphorylation in a time- and dose-dependent manner, and induces LRP6 endocytosis and lysosome-mediated degradation, thereby inactivating Wnt signaling in colorectal cancer cells.\",\n      \"method\": \"Mass spectrometry identification, co-immunoprecipitation, deletion/mutation mapping, LRP6 phosphorylation assays, lysosome inhibitor experiments, LRP6 endocytosis assays\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification + co-IP domain mapping + functional phosphorylation and trafficking assays, single lab\",\n      \"pmids\": [\"31588233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Oxidized phospholipids (oxPLs) are direct ligands of LRP6 (but not the closely related LRP5). oxPL-LRP6 binding induces LRP6 endocytosis through a clathrin-mediated pathway in bone marrow mesenchymal stromal cells, decreasing osteogenic factor responses and diminishing osteoblast differentiation.\",\n      \"method\": \"LRP6 binding assays with purified oxPLs, LRP6 vs LRP5 specificity assays, clathrin inhibitor experiments, osteoblast differentiation assays\",\n      \"journal\": \"Bone Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ligand binding assays with functional endocytosis and differentiation readouts, single lab\",\n      \"pmids\": [\"30038821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cripto-1 binds to LRP5 and LRP6 co-receptors, facilitating Wnt3a binding to LRP5 and LRP6, and enhances Wnt3a/beta-catenin signaling including cytoplasmic beta-catenin stabilization and TCF transcriptional activation. Wnt3a also increases Cripto-1-stimulated migration, invasion, and colony formation in mammary epithelial cells.\",\n      \"method\": \"Co-immunoprecipitation of Cripto-1 with LRP5/LRP6, beta-catenin stabilization assays, TCF reporter assays, migration/invasion assays\",\n      \"journal\": \"Cellular Signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP binding plus functional signaling and cell assays, single lab\",\n      \"pmids\": [\"23022962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GRP78 chaperones LRP6 folding and maturation in the ER. GRP78 knockdown leads to LRP6 misfolding and ER-associated degradation (ERAD), reducing mature LRP6 levels and inhibiting Wnt/HOXB9 signaling in hepatocellular carcinoma cells.\",\n      \"method\": \"GRP78 knockdown, LRP6 protein maturation/ERAD assays, Wnt signaling pathway analysis, HCC invasion/metastasis assays\",\n      \"journal\": \"Experimental Cell Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with LRP6 maturation and ERAD mechanistic readouts, single lab\",\n      \"pmids\": [\"31310747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The deubiquitylase complex USP46/UAF1/WDR20 deubiquitylates LRP6. Wnt signaling promotes association between the USP46 complex and cell-surface LRP6. USP46 knockdown decreases steady-state LRP6 levels and increases ubiquitylated LRP6. USP46 complex overexpression blocks LRP6 ubiquitylation by the ubiquitin ligases RNF43 and ZNFR3. USP46 is essential for Wnt-dependent intestinal organoid viability.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assays, siRNA knockdown, CRISPR knockout in cells and zebrafish/Xenopus, size exclusion chromatography, intestinal organoid assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical ubiquitylation assays, co-IP, multiple genetic models (human cells, Xenopus, zebrafish, organoids)\",\n      \"pmids\": [\"37798301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Proximity labeling (APEX2 fused to Lrp6) revealed that endosomal proteins, ESCRT machinery components, and Trk-fused gene (TFG) are recruited near LRP6 within 5 min of Wnt3a treatment. TFG depletion (siRNA or CRISPR) significantly reduced Wnt/beta-catenin signaling in cell culture, and TFG is required for Wnt-dependent embryonic patterning in Xenopus.\",\n      \"method\": \"APEX2 proximity biotinylation, mass spectrometry, siRNA knockdown, CRISPR knockout, Xenopus in vivo patterning assays\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling with MS plus functional validation in cells and in vivo, single lab\",\n      \"pmids\": [\"33299006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TMEM97 interacts with the LRP6 intracellular domain and enhances LRP6-mediated Wnt signaling in a CK1delta/epsilon-dependent manner. TMEM97 binding to LRP6 facilitates recruitment of CK1delta/epsilon to the LRP6 complex, resulting in LRP6 phosphorylation at Ser1490 and beta-catenin stabilization. TMEM97 knockout attenuates Wnt/beta-catenin signaling via reduced LRP6 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, LRP6 phosphorylation assays, TMEM97 knockout in breast cancer cells, Wnt target gene expression analysis, xenograft tumor model\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with mechanistic phosphorylation assay plus functional KO studies, single lab\",\n      \"pmids\": [\"34615853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIK2, phosphorylated by CK1alpha, directly phosphorylates LRP6 in a SIK2 kinase activity-dependent manner, activating Wnt/beta-catenin signaling and maintaining breast cancer stemness. SIK2-mediated Wnt/beta-catenin activation induces IDH1 expression, causing metabolic reprogramming in breast cancer cells. SIK2 inhibitors block LRP6 phosphorylation and beta-catenin accumulation.\",\n      \"method\": \"Kinase activity assays, LRP6 phosphorylation assays, SIK2 knockdown/inhibitor treatment, BCSC proportion assays, IDH1 expression analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct kinase-substrate assay plus functional signaling readouts, single lab\",\n      \"pmids\": [\"35277657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LRP6 ectodomain (LRP6N) directly binds CXCR4 and competitively prevents SDF-1 binding to CXCR4. LRP6N prevented SDF-1/CXCR4-induced breast cancer metastasis to lung in vivo. LRP6 knockdown activated SDF-1/CXCR4 signal transduction and promoted lung metastasis. A secreted form of LRP6N was detected in serum of mice and humans.\",\n      \"method\": \"Direct binding assays (LRP6N to CXCR4), competitive binding assays, LRP6 knockdown, in vivo breast cancer metastasis model, serum LRP6N detection\",\n      \"journal\": \"Clinical Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assays plus in vivo functional validation, single lab\",\n      \"pmids\": [\"31010839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Calcipotriol (vitamin D analogue) inhibits Wnt/beta-catenin signaling in PDAC cells through a novel mechanism: transcriptional upregulation of LDLRAP1 (LDL receptor adaptor protein 1), which decreases LRP6 protein levels. Changes in LRP6 or LDLRAP1 expression directly alter Wnt reporter activity.\",\n      \"method\": \"Cell-based Wnt reporter assays, LRP6 protein level analysis with calcipotriol, LDLRAP1 overexpression/knockdown experiments, PDAC cell growth assays\",\n      \"journal\": \"Molecular Cancer Research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cell-based assays showing LDLRAP1-LRP6 connection, single lab, mechanism of LDLRAP1-induced LRP6 reduction not fully defined at molecular level\",\n      \"pmids\": [\"26224368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Syndecan-4 (SDC4) and fibronectin inhibit Wnt/beta-catenin signaling at the cell membrane level through regulation of LRP6. Epistatic and biochemical experiments placed this inhibition at the LRP6 level. SDC4 modulates the ability of R-spondin 3 to potentiate Wnt/beta-catenin signaling through LRP6.\",\n      \"method\": \"Gain- and loss-of-function in mammalian cell lines and Xenopus embryos, epistasis analysis, co-immunoprecipitation\",\n      \"journal\": \"International Journal of Biochemistry & Cell Biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — epistasis and co-IP but biochemical mechanism of SDC4-LRP6 interaction not fully resolved in abstract\",\n      \"pmids\": [\"24275095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATP6AP2 promotes LRP6/beta-catenin and N-cadherin/beta-catenin protein complex distribution at the cell membrane in osteoblasts, preventing their degradation. ATP6AP2 conditional knockout in osteoblast-lineage cells reduced LRP6 and N-cadherin levels in BMSCs and OBs (but not osteocytes), impairing beta-catenin signaling and trabecular bone formation.\",\n      \"method\": \"Conditional knockout mice, proteomic analysis, cell surface fractionation, co-immunoprecipitation, beta-catenin signaling assays\",\n      \"journal\": \"Bone Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with proteomic and biochemical mechanistic follow-up, single lab\",\n      \"pmids\": [\"38811544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The AD-linked LRP6-Val variant has reduced Wnt signaling. Wnt7a stimulates formation of the LRP6-Frizzled-5 complex, but this complex does not form when LRP6-Val is present. Lrp6-val knock-in mice develop normally but neurons do not respond to Wnt7a, exhibit age-dependent structural and functional synaptic defects, and show exacerbated synapse loss around amyloid plaques in an AD mouse model.\",\n      \"method\": \"CRISPR knock-in mice, LRP6-Frizzled-5 co-immunoprecipitation assays, Wnt7a signaling assays in neurons, synapse structural/functional analysis, NL-G-F AD model crossing\",\n      \"journal\": \"Science Advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR knock-in with multiple orthogonal functional analyses (receptor complex formation, signaling, synaptic morphology, electrophysiology, AD model)\",\n      \"pmids\": [\"36638182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LRP6 forms a complex with anthrax toxin receptors (ATRs/ANTXRs) at the cell surface. This ATR-LRP6 interaction is bidirectional: ATRs control LRP6 protein levels (RNAi against ATRs decreased LRP6 levels and reduced Wnt signaling), while LRP6 plays a role in anthrax toxin endocytosis (toxin binding triggers LRP6 tyrosine phosphorylation, redistribution into detergent-resistant domains, and LRP6 endocytosis; LRP6 RNAi strongly delayed toxin endocytosis).\",\n      \"method\": \"Co-immunoprecipitation, siRNA against ATRs and LRP6, Wnt signaling reporter assays, LRP6 tyrosine phosphorylation analysis, detergent-resistant domain fractionation, toxin endocytosis assays\",\n      \"journal\": \"Cellular Microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with bidirectional siRNA studies and biochemical fractionation, single lab\",\n      \"pmids\": [\"18717822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Ninjurin1 (Ninj1) forms an assembly with LRP6 through its extracellular N-terminal domain and recruits Frizzled2 and downstream signaling mediators, resulting in ligand-independent activation of the LRP6/beta-catenin signaling pathway in lung cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping of Ninj1-LRP6 interaction, Wnt reporter assays, functional gain/loss of Ninj1 expression\",\n      \"journal\": \"Journal of Experimental & Clinical Cancer Research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP with reporter assays, mechanistic details limited in abstract, single lab\",\n      \"pmids\": [\"35395804\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LRP6 is a single-pass transmembrane Wnt co-receptor that, upon Wnt binding together with Frizzled, clusters into membrane signalosomes where it is phosphorylated at PPSPXS motifs by multiple kinases (CK1 family, GSK3, GRK5/6, SIK2) to recruit Axin and stabilize beta-catenin, while being negatively regulated by Src/Fer-mediated tyrosine phosphorylation, modulated in abundance by the deubiquitylase USP46 complex (counteracting RNF43/ZNRF3-mediated ubiquitylation) and ER chaperones (GPR37, GRP78), and additionally functioning as a scaffold for cardiac Cx43 gap junction trafficking, an endocytic regulator of the LDL receptor, a direct receptor for oxidized phospholipids, and a CXCR4 competitor—all mechanistically established by structural studies, reconstitution experiments, genetic epistasis, and cell biology.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LRP6 is a single-pass transmembrane Wnt co-receptor that, upon Wnt binding together with Frizzled, clusters into phosphorylated plasma-membrane signalosomes that recruit Axin and GSK3 to stabilize beta-catenin [#0, #1]. Structurally, the LRP6 ectodomain presents tandem beta-propeller folding units (E1E2 and E3E4) that bind distinct Wnt ligands at separate sites—Wnt3a engaging E3E4 and other Wnts E1E2—while the broad-spectrum antagonist Dkk1 and the antagonist sclerostin (SOST) occupy these surfaces to block signaling [#2, #14, #15]; cryo-EM of a Wnt-Frizzled-LRP6 ternary complex shows canonical Wnts engaging the E1E2 funnels through their N-terminal linker domains, with LDLR-domain-mediated LRP6 homodimerization driving a hexameric initiation assembly required for robust pathway activation [#13, #23]. Signalosome activation depends on phosphorylation of conserved cytoplasmic PPSPXS motifs by a battery of kinases including CK1 family, GSK3, GRK5/6, and SIK2, with the activity controlled by adaptors and scaffolds such as TMEM198 and TMEM97 that recruit casein kinases to the receptor [#1, #5, #7, #31, #32]; conversely, CK1-epsilon phosphorylation at Ser1420/Ser1430 and Src/Fer-mediated tyrosine phosphorylation provide negative feedback that limits signalosome formation and surface receptor levels [#6, #8]. Receptor abundance and trafficking are further set by ER chaperones GPR37 and GRP78 that promote LRP6 maturation and protect it from ER-associated degradation [#21, #28], by the USP46/UAF1/WDR20 deubiquitylase complex that counteracts RNF43/ZNRF3-mediated ubiquitylation at the cell surface [#29], and by tyrosine-signal-dependent partitioning between desensitizing clathrin and signaling-promoting caveolar endocytic routes [#9]. Beyond canonical Wnt signaling, LRP6 acts as a Wnt-independent scaffold for connexin 43 trafficking at cardiac intercalated discs, the loss of which causes lethal arrhythmias [#17], regulates LDL receptor internalization through a complex with clathrin and ARH [#11], and the LRP6(R611C) hypomorphic mutation drives hepatic lipogenesis and loss of vascular smooth muscle cell differentiation, both rescuable by Wnt3a [#18, #19]. An AD-linked LRP6-Val variant fails to form the Wnt7a-dependent LRP6-Frizzled5 complex and produces age-dependent synaptic defects in knock-in mice [#37].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing that LRP6 phosphorylation is the regulatory switch for Wnt signaling required identifying the kinases acting on its cytoplasmic motifs and whether they activate or restrain the pathway.\",\n      \"evidence\": \"In vitro binding/kinase assays, co-IP, site-directed mutagenesis, and Lef-1 reporter assays for CKI-epsilon on LRP6 Ser1420/1430\",\n      \"pmids\": [\"16513652\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how this negative feedback is integrated with activating phosphorylation in vivo\", \"Stoichiometry and kinetics of multi-site phosphorylation unaddressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"How LRP6 transduces a Wnt signal at the membrane was unknown; this showed Wnt induces phosphorylated LRP6 aggregates (signalosomes) that recruit Axin to stabilize beta-catenin.\",\n      \"evidence\": \"Live imaging, detergent solubilization/fractionation, and dominant-negative Dvl in vertebrate cells\",\n      \"pmids\": [\"17569865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular architecture of the signalosome not resolved\", \"Role of caveolin in aggregate function unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The kinase logic and ligand-binding architecture of LRP6 were defined: multiple proline-directed and CK1-family kinases phosphorylate PPSPXS motifs, and distinct ectodomain regions bind different Wnts and Dkk1.\",\n      \"evidence\": \"Review synthesis of kinase/mutagenesis studies plus in vitro reconstitution of the Fz8-Wnt3a-LRP6 ternary complex with binding-competition assays\",\n      \"pmids\": [\"20229235\", \"20093360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the active complex still lacking at this stage\", \"How simultaneous Wnt binding affects signaling output not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying GRK5/6 as direct activating kinases and characterizing the cooperative beta-propeller folding units extended the kinase repertoire and clarified ectodomain modularity.\",\n      \"evidence\": \"In vitro kinase assays, siRNA depletion, zebrafish epistasis (GRK5/6); recombinant domain folding/ligand-binding assays with Mesd chaperone\",\n      \"pmids\": [\"19801552\", \"19339249\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GRK5/6 work single-lab biochemistry combined with in vivo (Medium-rationale domain study)\", \"How Mesd-controlled folding is coupled to surface delivery unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Whether kinase recruitment to LRP6 is actively scaffolded was unknown; TMEM198 was shown to bridge casein kinases to LRP6 for activating phosphorylation.\",\n      \"evidence\": \"Reciprocal co-IP, phosphorylation assays, siRNA, and Xenopus loss-of-function\",\n      \"pmids\": [\"21536646\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TMEM198 acts within the signalosome or upstream unclear\", \"Direct CK1-TMEM198 contact not structurally mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The negative regulatory layer was defined: Src/Fer tyrosine phosphorylation restrains signalosome formation, while a tyrosine-based endocytic signal partitions LRP6 between desensitizing clathrin and signaling caveolar routes; LDLR-domain dimerization was shown to be required for robust activation.\",\n      \"evidence\": \"cDNA screen, in vitro phosphorylation, knockout MEFs, surface/endocytosis assays, and LDLR-domain mutant interaction studies\",\n      \"pmids\": [\"25391905\", \"25143377\", \"24412751\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endocytosis and dimerization studies are single-lab (Medium)\", \"Cross-talk between tyrosine phosphorylation and trafficking partitioning not fully resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The pathological consequences of attenuated LRP6 activity in metabolism and vasculature were established through the R611C hypomorph, linking LRP6 to lipogenesis and VSMC differentiation via Wnt-rescuable mechanisms.\",\n      \"evidence\": \"LRP6(R611C) knock-in mice, primary hepatocytes, carotid injury model, and in vivo Wnt3a rescue\",\n      \"pmids\": [\"24506864\", \"26489464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between receptor hypomorphism and Sp1/IGF1 axis incompletely defined\", \"Single-lab models\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A Wnt-independent function for LRP6 was demonstrated: it scaffolds connexin 43 ER-to-Golgi trafficking at cardiac intercalated discs, with loss causing lethal arrhythmias.\",\n      \"evidence\": \"Co-IP, cardiomyocyte-specific conditional knockout, Cx43 trafficking imaging, and cardiac electrophysiology\",\n      \"pmids\": [\"27250245\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of LRP6-Cx43 interaction not defined\", \"Whether this scaffolding generalizes beyond cardiomyocytes unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Control of LRP6 biogenesis was extended to ER quality control, with GPR37 (and later GRP78) acting as chaperones protecting LRP6 from ERAD to license Wnt signaling.\",\n      \"evidence\": \"Co-IP, GPR37 knockdown/knockout, LRP6 maturation/degradation assays (CHIP/VCP), NPC Wnt assays; GRP78 knockdown/ERAD assays in HCC\",\n      \"pmids\": [\"28341812\", \"31310747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GPR37 and GRP78 act sequentially or redundantly unknown\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"High-resolution structure and proximity proteomics refined the activation mechanism: the Wnt-Frizzled-LRP6 initiation complex engages E1E2 via Wnt linker domains, and rapid Wnt-induced recruitment of ESCRT/endosomal machinery including TFG supports signaling.\",\n      \"evidence\": \"Cryo-EM with chimeric Wnt engineering and peptide antagonists; APEX2 proximity labeling with MS and Xenopus validation; SOST-E1E2 crystal structure\",\n      \"pmids\": [\"36893265\", \"33299006\", \"33097721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How endosomal recruitment couples mechanistically to beta-catenin stabilization not fully resolved\", \"TFG study single-lab (Medium)\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The ubiquitin/deubiquitin balance setting surface LRP6 levels was defined, with USP46/UAF1/WDR20 counteracting RNF43/ZNRF3, and a disease-linked LRP6-Val variant was shown to disrupt Wnt7a-dependent receptor complex assembly and synaptic maintenance.\",\n      \"evidence\": \"Ubiquitylation assays, co-IP, multi-organism genetics, and organoid assays (USP46); CRISPR knock-in mice, LRP6-Frizzled5 co-IP, and synaptic/AD-model analysis (LRP6-Val)\",\n      \"pmids\": [\"37798301\", \"36638182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Wnt promotes USP46-LRP6 association mechanistically unresolved\", \"Causal chain from LRP6-Val synapse loss to AD pathology not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LRP6's distinct roles—canonical Wnt signalosome receptor, Wnt-independent trafficking scaffold, LDLR endocytic partner, oxPL/CXCR4-binding ectodomain—are physically and spatially segregated within a single receptor remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model integrating Wnt-dependent and Wnt-independent functions\", \"Tissue-specific determinants of which LRP6 function dominates undefined\", \"Several non-canonical interactions rest on single-lab co-IP evidence\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [2, 13, 14, 26]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 17, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [11, 33]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 9, 23, 25]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [21, 28, 17]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [10, 30, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 13]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [9, 11, 30]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [21, 28, 29]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [19, 37]}\n    ],\n    \"complexes\": [\n      \"Wnt-Frizzled-LRP6 signalosome\",\n      \"USP46/UAF1/WDR20 deubiquitylase complex\",\n      \"LRP6-LDLR-clathrin-ARH complex\"\n    ],\n    \"partners\": [\n      \"FZD8\",\n      \"AXIN1\",\n      \"DKK1\",\n      \"SOST\",\n      \"GPR37\",\n      \"USP46\",\n      \"GJA1\",\n      \"PTK7\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}