{"gene":"CTNNB1","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":1997,"finding":"The crystal structure of the armadillo repeat region of beta-catenin (12 copies of a 42-aa repeat) was determined, revealing a superhelix of helices with a long, positively charged groove. The acidic binding regions of cadherins, TCFs, and APC were proposed to interact with this groove, explaining how a single domain mediates multiple protein interactions.","method":"X-ray crystallography (3D structure of protease-resistant armadillo repeat fragment)","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional mapping of binding groove, foundational structural study widely replicated in the field","pmids":["9298899"],"is_preprint":false},{"year":1996,"finding":"Drosophila Armadillo (beta-catenin ortholog) is required for adherens junction assembly in vivo. Loss of Armadillo (armXP33 allele) prevents adherens junction assembly, causes epithelial cells to lose adhesion, round up, adopt mesenchymal character, lose polarity, and blocks gastrulation morphogenesis.","method":"Genetic loss-of-function (intermediate mutant allele armXP33) with morphological and biochemical analysis in Drosophila embryos","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean in vivo loss-of-function with defined cellular phenotypes (loss of adhesion, polarity, morphogenesis), multiple orthogonal readouts","pmids":["8698810"],"is_preprint":false},{"year":1997,"finding":"Armadillo/beta-catenin binds directly to TCF/LEF-family HMG-box transcription factors in the nucleus, forming bipartite transcription factors that activate Wingless/Wnt-responsive target genes in both Drosophila and vertebrates.","method":"Review synthesizing direct binding experiments and genetic data (Co-IP, reporter assays in Drosophila and vertebrate systems)","journal":"Current opinion in genetics & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — synthesis of binding and epistasis data from multiple labs, but this paper is a review (primary data cited therein)","pmids":["9309175"],"is_preprint":false},{"year":2003,"finding":"CK2 phosphorylates beta-catenin primarily at Thr393 within the armadillo repeat domain (where APC and Axin bind). This phosphorylation promotes proteasome resistance, increases beta-catenin protein levels, and enhances co-transcriptional activity, making CK2 a positive regulator of Wnt signaling.","method":"Pharmacological inhibition and dominant-negative CK2 expression; site-directed mutagenesis of Thr393; cotranscriptional reporter assays; proteasome inhibitor rescue; in vitro phosphorylation mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro phosphorylation assay, mutagenesis of specific residue (T393), functional reporter assays, proteasome-dependence experiments; single lab but multiple orthogonal methods","pmids":["12700239"],"is_preprint":false},{"year":2004,"finding":"Nuclear localization of beta-catenin is necessary for Wnt/Wingless pathway activation. Membrane-tethered beta-catenin is insufficient to activate transcription; only nuclear beta-catenin drives target gene expression. Two novel missense loss-of-function alleles that retain protein stability but cannot transduce signal were identified.","method":"Genetic epistasis in Drosophila: transgenic constructs with truncations/tethering; signaling-null condition defined; Chibby as C-terminus-specific negative regulator used to test membrane vs. nuclear function","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple transgenic constructs, functional readouts, epistasis, and identification of novel loss-of-function alleles; single lab but multiple orthogonal genetic approaches","pmids":["15024404"],"is_preprint":false},{"year":2006,"finding":"Parafibromin (human) / Hyrax (Drosophila), a component of the PAF1 complex, is required for Wnt/Wg target gene transcription and binds directly to the C-terminal region of beta-catenin/Armadillo. Recruitment of Pygopus to beta-catenin/Armadillo is required for the transactivation potential of Parafibromin/Hyrax. This provides a mechanism by which the nuclear Wnt signaling complex directly engages the PAF1 complex to control transcriptional initiation and elongation.","method":"Drosophila genetic screens (Hyrax identified as Wnt pathway component); direct binding assays (Parafibromin/Hyrax binds C-terminal region of beta-catenin/Armadillo); human ortholog validated; epistasis with Pygopus","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic identification + direct binding assays + human ortholog validation + epistasis with Pygopus, published in Cell with multiple orthogonal approaches","pmids":["16630820"],"is_preprint":false},{"year":2006,"finding":"In Drosophila epidermis, asymmetric distribution and phosphorylation of Armadillo/beta-catenin at the cell membrane is required for proper planar cell polarity; interference with Arm phosphorylation leads to polarity defects, revealing a polarity-signaling role for junctional/membrane Arm.","method":"Drosophila genetics (Wg/Hh pathway manipulation); immunostaining for Arm distribution and phosphorylation; cuticle polarity phenotype analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic and phosphorylation analyses in Drosophila, single lab with multiple readouts","pmids":["17183721"],"is_preprint":false},{"year":2009,"finding":"The caspase DrICE (Drosophila caspase-3 homolog) cleaves Armadillo/beta-catenin at a DQVD motif in the N-terminal domain during apoptosis, generating a stable membrane-associated fragment. This cleavage contributes to DE-cadherin removal from the plasma membrane during apoptotic adherens junction disassembly.","method":"In vitro caspase cleavage assays; site-directed mutagenesis of DQVD cleavage site; in vivo validation in Drosophila embryo apoptosis; immunostaining for Arm and DE-cadherin","journal":"BMC developmental biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of caspase cleavage, mutagenesis of cleavage site, and in vivo validation; single lab with multiple orthogonal methods","pmids":["19232093"],"is_preprint":false},{"year":2013,"finding":"In Drosophila, Brain tumor (Brat) specifies intermediate neural progenitor (INP) identity through attenuating Armadillo/beta-catenin activity via the Wnt destruction complex. Increasing Arm activity in immature INPs exacerbates supernumerary neuroblast formation in brat mutants, while reducing Arm activity suppresses it, establishing epistatic placement of Arm downstream of Brat-dependent INP specification.","method":"Drosophila genetics: brat mutants, Arm gain/loss-of-function in INPs, epistasis analysis; neuroblast counting phenotype","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic epistasis in Drosophila with quantitative phenotypic readout; single lab","pmids":["24257623"],"is_preprint":false},{"year":2014,"finding":"Kinesin-II subunit Klp64D (Drosophila Kif3A homolog) directly binds to the Arm repeat domain of Armadillo/beta-catenin and recruits Dishevelled in the presence of Arm. Loss of Klp64D causes aberrant Arm accumulation in vesicular/Golgi structures, indicating that Kinesin-II regulates intracellular trafficking of Arm for Wingless signaling. Human KIF3A also binds beta-catenin and rescues klp64D RNAi phenotypes.","method":"Drosophila genetics (klp64D mutations, RNAi); direct binding assays (Klp64D binds Arm repeat domain); subcellular fractionation/immunostaining of Arm/Golgi; human KIF3A rescue experiment","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct binding assay, genetic epistasis, localization experiment with functional consequence, human ortholog cross-validation; single lab with multiple orthogonal methods","pmids":["25063455"],"is_preprint":false},{"year":2015,"finding":"Muscle beta-catenin/Ctnnb1 acts as a transcriptional regulator (not via its cell-adhesion function) to drive expression of Slit2 as a retrograde signal for presynaptic differentiation at the neuromuscular junction. Ctnnb1 mutant lacking the transactivation domain fails to rescue presynaptic deficits; Slit2 transgenic expression in muscle rescues presynaptic defects caused by Ctnnb1 mutation; Slit2-coated beads induce synaptophysin puncta in spinal cord axons.","method":"In vivo transgenic mouse rescue experiments (transactivation-domain deleted Ctnnb1); Slit2 muscle-specific transgenic rescue; Slit2 bead assay in spinal cord explants","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function rescue with domain-specific constructs, identification of downstream retrograde factor (Slit2), bead assay for functional validation; single lab with multiple orthogonal in vivo methods","pmids":["26159615"],"is_preprint":false},{"year":2019,"finding":"ACLY (ATP-citrate lyase) stabilizes CTNNB1/beta-catenin protein by direct interaction, and the ACLY-CTNNB1 complex promotes CTNNB1 translocation from cytoplasm to nucleus, subsequently increasing CTNNB1 transcriptional activity and colon cancer cell migration and invasion.","method":"Co-immunoprecipitation (ACLY-CTNNB1 interaction); Western blot (CTNNB1 stabilization); migration/invasion assays in ACLY-deficient cell lines; in vivo mouse colon metastasis model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP for interaction, functional assays in KO cell lines and in vivo; multiple methods but interaction evidence is limited to Co-IP","pmids":["31511060"],"is_preprint":false},{"year":2019,"finding":"TRAF6 drives selective autophagic degradation of CTNNB1/beta-catenin by interacting with LC3B through its LIR motif and catalyzing K63-linked polyubiquitination of LC3B; K63-ubiquitinated LC3B promotes the LC3B-ATG7 complex and directs CTNNB1 recognition for autophagic degradation. GSK3B phosphorylates TRAF6 at Thr266, triggering K48-linked polyubiquitination and degradation of TRAF6, thereby relieving CTNNB1 from autophagic degradation.","method":"Co-IP (TRAF6-LC3B, LC3B-ATG7); ubiquitination assays (K63-LC3B, K48-TRAF6); site-directed mutagenesis (LIR motif, Thr266); autophagy flux assays; GSK3B kinase assay; in vivo xenograft","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple biochemical reconstitution experiments, ubiquitination assays, mutagenesis, and in vivo validation; single lab but comprehensive mechanistic dissection","pmids":["30806153"],"is_preprint":false},{"year":2017,"finding":"CTNNB1 mutations in exon 3 (affecting GSK3beta phosphorylation sites) increase beta-catenin stability by inhibiting ubiquitination, thereby activating the Wnt signaling pathway and promoting cell proliferation in adamantinomatous craniopharyngioma. A novel CTNNB1 mutation (transversion + in-frame deletion in exon 3) was functionally validated to confer increased beta-catenin stability.","method":"Whole-genome sequencing; ubiquitination assay; Wnt reporter (TOPFlash); CCK8 and colony formation proliferation assays in ACP primary cells","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay + TOPFlash reporter + proliferation assay for functional validation of novel mutation; single lab","pmids":["34922552"],"is_preprint":false},{"year":2017,"finding":"GLUT3 (glucose transporter) is a direct TCF4/beta-catenin target gene in hepatoblastoma, mechanistically linking CTNNB1 mutation to metabolic reprogramming (glycolysis) in this tumor type.","method":"RNA sequencing; functional analyses in hepatoblastoma cell lines; reporter assays demonstrating direct TCF4/beta-catenin transcriptional regulation of GLUT3","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq plus functional reporter assay establishing GLUT3 as a direct beta-catenin target; single lab","pmids":["28923827"],"is_preprint":false},{"year":2020,"finding":"Beta-catenin in mature adipocytes regulates transcription of Saa3 (serum amyloid A3) through the beta-catenin-TCF complex; Saa3 activates macrophages to secrete Pdgf-aa, which promotes proliferation of Pdgfralpha+ preadipocytes, establishing a beta-catenin/Saa3/macrophage axis mediating mature adipocyte-preadipocyte cross-talk and fat expansion.","method":"Adipocyte-specific beta-catenin knockout mice (high-fat diet); ChIP/reporter assays for beta-catenin-TCF binding to Saa3 promoter; macrophage conditioned medium experiments; Pdgfralpha+ preadipocyte proliferation assays; whole-exome sequencing in obese subjects","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO with defined phenotype, ChIP/reporter validation of direct target (Saa3), functional cross-talk experiments; single lab but multiple orthogonal methods","pmids":["31934629"],"is_preprint":false},{"year":2020,"finding":"Nitric oxide (NO) mediates VEGFA-induced vascular permeability by targeting CTNNB1/beta-catenin at endothelial junctions. In autophagy-deficient (atg7 KO) uteri, decreased CTNNB1 at endothelial junctions is associated with increased vascular permeability; NOS inhibitor treatment reduces extravasation, confirming NO/CTNNB1-dependent endothelial junction regulation.","method":"Conditional Atg7 knockout (Amhr2-Cre); Western blot/immunostaining for CTNNB1 at endothelial junctions; NOS inhibitor treatment; vascular permeability assay","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization and pharmacological rescue experiments; functional link between NO, CTNNB1, and permeability established but primarily in a tissue context without direct CTNNB1 mutagenesis","pmids":["32579471"],"is_preprint":false},{"year":1996,"finding":"The human CTNNB1 gene comprises 16 exons spanning 23.2 kb. A major transcription initiation site was mapped 214 nt upstream of the ATG. The 5'-flanking region is GC-rich with a TATA box and binding sites for NF-kappaB, SP1, AP2, and EGR1. A 437-bp fragment and a 6-kb fragment containing the 5'-flanking region and exon 1 showed promoter activity in a reporter assay.","method":"Genomic cloning, restriction mapping, sequencing; transcription initiation mapping; promoter-reporter transfection assay in mouse epithelial cells","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genomic/promoter characterization with functional reporter validation; single lab","pmids":["8838805"],"is_preprint":false},{"year":2022,"finding":"Two CTNNB1 missense variants found in patients with NEDSDV (neurodevelopmental disorder) act as dominant negative regulators of WNT signaling, as demonstrated by TOPFlash reporter assay, establishing a functional mechanism for these pathogenic variants.","method":"TOPFlash WNT reporter assay for functional assessment of CTNNB1 missense variants from patient cohort","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional reporter assay (TOPFlash) validating dominant-negative effect; single method, single study","pmids":["36083290"],"is_preprint":false},{"year":2018,"finding":"LKB1 (STK11) signaling is activated downstream of oncogenic CTNNB1/beta-catenin in HCC: forced oncogenic activation of beta-catenin in human HCC cells induces post-transcriptional accumulation of LKB1 protein, and LKB1 in turn positively regulates beta-catenin signaling (metabolic zonation in liver). Lkb1 deletion impairs hepatic metabolic zonation downstream of beta-catenin, revealing a positive reciprocal cross-talk.","method":"Oncogenic beta-catenin overexpression in HCC cells (post-transcriptional LKB1 accumulation); beta-catenin siRNA knockdown (loss of LKB1 signature); conditional Lkb1 KO mice (impaired metabolic zonation); hierarchical clustering of human HCC datasets","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function experiments in vitro and in vivo mouse model; single lab with multiple methods","pmids":["30566242"],"is_preprint":false},{"year":2017,"finding":"CRISPR-Cas9 knockout of CTNNB1 in HEK 293T cells reduces cell adhesion and inhibits proliferation, decreases expression of CCND1, CCNE1 (cyclin D1, E1), N-Cadherin, and GSK3-beta, while increasing gamma-catenin, demonstrating that beta-catenin is required for Wnt/beta-catenin-driven cell cycle gene expression and cell adhesion.","method":"CRISPR-Cas9 knockout; Western blot; qPCR; MTT proliferation assay; flow cytometry apoptosis assay","journal":"Biotechnology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KO with defined phenotype (proliferation, adhesion) and downstream target expression; single lab, single study","pmids":["29249062"],"is_preprint":false}],"current_model":"CTNNB1/beta-catenin is a dual-function protein: its 12-armadillo-repeat domain forms a positively charged groove that mediates binding to cadherins (cell adhesion), APC, Axin, TCF/LEF transcription factors, and other partners; in the absence of Wnt signaling, it is phosphorylated by the GSK3beta/CK1 destruction complex at exon-3-encoded serine/threonine residues (S33, S37, T41, S45), ubiquitinated, and degraded by the proteasome, whereas Wnt activation or exon-3 mutations block this degradation, allowing beta-catenin to accumulate, translocate to the nucleus, and—by binding TCF/LEF and recruiting the PAF1 complex via Parafibromin—activate transcription of target genes including Cyclin D1, MYC, AXIN2, GLUT3, and Saa3; CK2-mediated phosphorylation at Thr393 provides an additional positive regulatory mechanism promoting proteasome resistance; selective autophagy via TRAF6/LC3B provides an alternative degradation route; and in specific contexts (muscle, adipocytes, neuromuscular junction) nuclear beta-catenin-TCF transcriptional activity drives tissue-specific retrograde signaling (Slit2) and paracrine cross-talk (Saa3/macrophage axis)."},"narrative":{"mechanistic_narrative":"CTNNB1/beta-catenin is a dual-function protein that couples cell-cell adhesion to Wnt-responsive transcription, with its central 12-armadillo-repeat domain forming a long, positively charged groove that serves as a common docking surface for cadherins, TCF/LEF transcription factors, and the APC/Axin destruction machinery [PMID:9298899]. At adherens junctions its adhesion role is essential for epithelial integrity: loss of the Drosophila ortholog Armadillo blocks junction assembly and causes cells to lose adhesion, polarity, and morphogenetic competence [PMID:8698810], and the protein is removed from junctions during apoptosis by caspase (DrICE) cleavage at an N-terminal DQVD motif that drives cadherin disassembly [PMID:19232093]. In its signaling role, nuclear beta-catenin—and nuclear localization specifically, not membrane-tethered protein, is required for pathway output [PMID:15024404]—binds TCF/LEF HMG-box factors to form bipartite transcriptional activators [PMID:9309175] and recruits the PAF1-complex subunit Parafibromin/Hyrax via its C-terminus, with Pygopus, to drive target-gene transcription [PMID:16630820]. Pathway output is set by protein stability: phosphorylation of exon-3-encoded GSK3beta sites targets beta-catenin for ubiquitination and degradation, and exon-3 mutations that block this stabilize the protein and constitutively activate Wnt signaling and proliferation [PMID:34922552]; CK2 phosphorylation at Thr393 within the armadillo domain confers proteasome resistance as a positive regulatory input [PMID:12700239]; and an alternative TRAF6/LC3B-dependent selective-autophagy route degrades beta-catenin, itself relieved by GSK3B-driven TRAF6 turnover [PMID:30806153]. Through TCF-dependent transcription beta-catenin drives context-specific programs: cell-cycle genes such as CCND1/CCNE1 and adhesion genes in proliferating cells [PMID:29249062], GLUT3-linked glycolytic reprogramming in tumors [PMID:28923827], Slit2 as a retrograde signal for presynaptic differentiation at the neuromuscular junction [PMID:26159615], and a Saa3/macrophage paracrine axis governing adipose expansion [PMID:31934629]. Dominant-negative CTNNB1 missense variants that impair Wnt reporter activity cause a neurodevelopmental disorder (NEDSDV) [PMID:36083290].","teleology":[{"year":1996,"claim":"Defining the in vivo adhesion requirement established beta-catenin as essential for adherens junction assembly and epithelial organization, distinguishing it from a purely signaling factor.","evidence":"Genetic loss-of-function of the Armadillo ortholog in Drosophila embryos with morphological/biochemical readout","pmids":["8698810"],"confidence":"High","gaps":["Does not separate the adhesion role from the later-defined transcriptional role at the molecular level","Drosophila ortholog rather than human CTNNB1"]},{"year":1997,"claim":"The armadillo-repeat crystal structure answered how a single protein binds multiple partners, revealing a positively charged groove as a shared docking surface for cadherins, TCFs, and APC.","evidence":"X-ray crystallography of the protease-resistant armadillo repeat fragment with functional mapping","pmids":["9298899"],"confidence":"High","gaps":["Binding-groove interactions inferred structurally rather than co-crystallized for all partners","No structure of the N-terminal regulatory/phosphodegron region"]},{"year":1997,"claim":"Direct binding to TCF/LEF HMG-box factors established beta-catenin as a transcriptional co-activator forming bipartite Wnt-responsive transcription factors.","evidence":"Synthesis of Co-IP and reporter data from Drosophila and vertebrate systems (review)","pmids":["9309175"],"confidence":"Medium","gaps":["Primary data summarized in a review","Does not define which co-activators are recruited downstream of TCF binding"]},{"year":2003,"claim":"Identification of CK2 phosphorylation at Thr393 revealed a positive stability input acting within the armadillo domain, separate from the GSK3 destruction pathway.","evidence":"In vitro phosphorylation mapping, Thr393 mutagenesis, reporter and proteasome-rescue assays","pmids":["12700239"],"confidence":"High","gaps":["Single lab","How Thr393 phosphorylation mechanistically blocks degradation not resolved"]},{"year":2004,"claim":"Compartment-resolution experiments demonstrated that nuclear localization, not mere protein stabilization, is required for transcriptional output, separating signaling from membrane functions.","evidence":"Drosophila genetic epistasis with truncation/tethering constructs and signaling-null alleles","pmids":["15024404"],"confidence":"High","gaps":["Mechanism of nuclear import/retention not defined","Drosophila ortholog"]},{"year":2006,"claim":"Parafibromin/Hyrax recruitment linked nuclear beta-catenin directly to the PAF1 complex, providing a mechanism connecting the Wnt transcription complex to initiation/elongation machinery.","evidence":"Drosophila genetic screen, direct C-terminal binding assays, Pygopus epistasis, human ortholog validation","pmids":["16630820"],"confidence":"High","gaps":["How PAF1 recruitment is regulated context-dependently not addressed","Stoichiometry of the nuclear complex unresolved"]},{"year":2006,"claim":"Membrane-localized phosphorylated Armadillo was shown to contribute to planar cell polarity, extending beta-catenin's junctional role beyond static adhesion.","evidence":"Drosophila genetics, phospho-specific immunostaining, cuticle polarity phenotypes","pmids":["17183721"],"confidence":"Medium","gaps":["Phosphosites mediating polarity not molecularly defined","Drosophila context only"]},{"year":2009,"claim":"Caspase cleavage at an N-terminal DQVD motif explained how beta-catenin is processed during apoptosis to drive cadherin removal and junction disassembly.","evidence":"In vitro DrICE cleavage, cleavage-site mutagenesis, in vivo Drosophila apoptosis validation","pmids":["19232093"],"confidence":"High","gaps":["Functional fate of the stable membrane fragment unresolved","Conservation of cleavage in mammalian CTNNB1 not tested here"]},{"year":2013,"claim":"Epistatic placement of Armadillo downstream of Brat defined a developmental setting where attenuating beta-catenin activity specifies neural progenitor identity.","evidence":"Drosophila brat mutants with Arm gain/loss-of-function and neuroblast counting","pmids":["24257623"],"confidence":"Medium","gaps":["Direct transcriptional targets in INPs not identified","Drosophila ortholog"]},{"year":2014,"claim":"Kinesin-II (Klp64D/KIF3A) binding to the armadillo domain revealed a trafficking mechanism controlling beta-catenin subcellular distribution for Wingless signaling.","evidence":"Direct binding assay, Drosophila genetics, Golgi localization, human KIF3A rescue","pmids":["25063455"],"confidence":"High","gaps":["How trafficking is coupled to signaling state not resolved","Single lab"]},{"year":2017,"claim":"CRISPR knockout in human cells confirmed beta-catenin is required for cell-cycle gene expression (CCND1/CCNE1) and adhesion, linking loss-of-function directly to proliferation and adhesion phenotypes.","evidence":"CRISPR-Cas9 KO in HEK293T with Western blot, qPCR, proliferation and apoptosis assays","pmids":["29249062"],"confidence":"Medium","gaps":["Single cell line","Direct versus indirect target effects not distinguished"]},{"year":2017,"claim":"Functional validation of exon-3 mutations established that escape from GSK3beta-directed ubiquitination stabilizes beta-catenin and constitutively activates Wnt-driven proliferation in tumors.","evidence":"Whole-genome sequencing, ubiquitination assay, TOPFlash reporter, proliferation assays in craniopharyngioma cells","pmids":["34922552"],"confidence":"Medium","gaps":["Single tumor type","Destruction-complex assembly steps not dissected here"]},{"year":2017,"claim":"Identification of GLUT3 as a direct TCF4/beta-catenin target connected CTNNB1 mutation to glycolytic metabolic reprogramming in hepatoblastoma.","evidence":"RNA-seq with reporter assays in hepatoblastoma cell lines","pmids":["28923827"],"confidence":"Medium","gaps":["Single tumor context","In vivo contribution of GLUT3 induction not quantified"]},{"year":2018,"claim":"Reciprocal cross-talk with LKB1 was defined, showing oncogenic beta-catenin post-transcriptionally accumulates LKB1, which in turn supports beta-catenin signaling and hepatic metabolic zonation.","evidence":"Gain/loss of beta-catenin in HCC cells, conditional Lkb1 KO mice, human HCC dataset clustering","pmids":["30566242"],"confidence":"Medium","gaps":["Molecular basis of post-transcriptional LKB1 accumulation unknown","Single lab"]},{"year":2019,"claim":"Discovery of a TRAF6/LC3B selective-autophagy route established a proteasome-independent degradation pathway for beta-catenin, gated by GSK3B-driven TRAF6 turnover.","evidence":"Co-IP, K63/K48 ubiquitination assays, LIR/Thr266 mutagenesis, autophagy flux, GSK3B kinase assay, xenograft","pmids":["30806153"],"confidence":"High","gaps":["Relative contribution of autophagic versus proteasomal degradation in vivo unquantified","Single lab"]},{"year":2019,"claim":"ACLY was shown to stabilize beta-catenin and promote its nuclear translocation, linking a metabolic enzyme to beta-catenin-driven colon cancer invasion.","evidence":"Co-IP, Western blot, migration/invasion assays in ACLY-deficient cells, mouse metastasis model","pmids":["31511060"],"confidence":"Medium","gaps":["Interaction rests on single Co-IP without reciprocal validation","Mechanism of stabilization not defined"]},{"year":2020,"claim":"The beta-catenin/Saa3/macrophage axis defined a tissue-specific transcriptional output mediating mature adipocyte-preadipocyte cross-talk during fat expansion.","evidence":"Adipocyte-specific beta-catenin KO mice, ChIP/reporter on Saa3 promoter, macrophage conditioned-medium and preadipocyte proliferation assays","pmids":["31934629"],"confidence":"High","gaps":["Upstream signal activating adipocyte beta-catenin not defined","Human relevance from exome data correlative"]},{"year":2020,"claim":"NO was implicated in regulating junctional CTNNB1 to control VEGFA-induced endothelial permeability, tying beta-catenin to vascular barrier function.","evidence":"Conditional Atg7 KO, junctional CTNNB1 immunostaining, NOS inhibitor rescue, permeability assays","pmids":["32579471"],"confidence":"Medium","gaps":["No direct CTNNB1 mutagenesis","Mechanism by which NO targets CTNNB1 not resolved"]},{"year":2022,"claim":"Functional testing of patient missense variants established a dominant-negative loss of Wnt signaling as the mechanism underlying a CTNNB1-associated neurodevelopmental disorder.","evidence":"TOPFlash WNT reporter assay on patient-derived missense variants","pmids":["36083290"],"confidence":"Medium","gaps":["Single reporter assay","Cellular/developmental consequences in neurons not modeled"]},{"year":null,"claim":"How the competing inputs—GSK3-destruction-complex phosphodegron control, CK2-mediated stabilization, kinesin-dependent trafficking, and TRAF6/autophagic degradation—are integrated to set nuclear beta-catenin levels in a given cell type remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No quantitative model balancing the multiple degradation/stabilization routes","Tissue-specific selection of distinct transcriptional programs (Slit2 vs Saa3 vs GLUT3) mechanistically unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,5,10,14,15]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,20]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,5,11]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,6,7,16]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,4,5,13]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[1,7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,14,15,20]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[12]}],"complexes":["beta-catenin/TCF-LEF transcription complex","adherens junction","Wnt destruction complex (substrate)","PAF1 complex (via Parafibromin)"],"partners":["TCF/LEF","APC","AXIN","PARAFIBROMIN","PYGOPUS","KIF3A","TRAF6","ACLY"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35222","full_name":"Catenin beta-1","aliases":["Beta-catenin"],"length_aa":781,"mass_kda":85.5,"function":"Key downstream component of the canonical Wnt signaling pathway (PubMed:17524503, PubMed:18077326, PubMed:18086858, PubMed:18957423, PubMed:21262353, PubMed:22155184, PubMed:22647378, PubMed:22699938). In the absence of Wnt, forms a complex with AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC and its subsequent degradation by the proteasome (PubMed:17524503, PubMed:18077326, PubMed:18086858, PubMed:18957423, PubMed:21262353, PubMed:22155184, PubMed:22647378, PubMed:22699938). In the presence of Wnt ligand, CTNNB1 is not ubiquitinated and accumulates in the nucleus, where it acts as a coactivator for transcription factors of the TCF/LEF family, leading to activate Wnt responsive genes (PubMed:17524503, PubMed:18077326, PubMed:18086858, PubMed:18957423, PubMed:21262353, PubMed:22155184, PubMed:22647378, PubMed:22699938). Also acts as a coactivator for other transcription factors, such as NR5A2 (PubMed:22187462). Promotes epithelial to mesenchymal transition/mesenchymal to epithelial transition (EMT/MET) via driving transcription of CTNNB1/TCF-target genes (PubMed:29910125). Involved in the regulation of cell adhesion, as component of an E-cadherin:catenin adhesion complex (By similarity). Acts as a negative regulator of centrosome cohesion (PubMed:18086858). Involved in the CDK2/PTPN6/CTNNB1/CEACAM1 pathway of insulin internalization (PubMed:21262353). Blocks anoikis of malignant kidney and intestinal epithelial cells and promotes their anchorage-independent growth by down-regulating DAPK2 (PubMed:18957423). Disrupts PML function and PML-NB formation by inhibiting RANBP2-mediated sumoylation of PML (PubMed:22155184). Promotes neurogenesis by maintaining sympathetic neuroblasts within the cell cycle (By similarity). Involved in chondrocyte differentiation via interaction with SOX9: SOX9-binding competes with the binding sites of TCF/LEF within CTNNB1, thereby inhibiting the Wnt signaling (By similarity). Acts as a positive regulator of odontoblast differentiation during mesenchymal tooth germ formation, via promoting the transcription of differentiation factors such as LEF1, BMP2 and BMP4 (By similarity). Activity is repressed in a MSX1-mediated manner at the bell stage of mesenchymal tooth germ formation which prevents premature differentiation of odontoblasts (By similarity)","subcellular_location":"Cytoplasm; Nucleus; Cytoplasm, cytoskeleton; Cell junction, adherens junction; Cell junction; Cell membrane; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, spindle pole; Synapse; Cytoplasm, cytoskeleton, cilium basal body","url":"https://www.uniprot.org/uniprotkb/P35222/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CTNNB1","classification":"Not 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pathology","url":"https://pubmed.ncbi.nlm.nih.gov/36206446","citation_count":24,"is_preprint":false},{"pmid":"35921500","id":"PMC_35921500","title":"Differential requirement of Hippo cascade during CTNNB1 or AXIN1 mutation-driven hepatocarcinogenesis.","date":"2022","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/35921500","citation_count":23,"is_preprint":false},{"pmid":"22086512","id":"PMC_22086512","title":"PROP1 and CTNNB1 expression in adamantinomatous craniopharyngiomas with or without β-catenin mutations.","date":"2011","source":"Clinics (Sao Paulo, Brazil)","url":"https://pubmed.ncbi.nlm.nih.gov/22086512","citation_count":23,"is_preprint":false},{"pmid":"32579471","id":"PMC_32579471","title":"An autophagic deficit in the uterine vessel microenvironment provokes hyperpermeability through deregulated VEGFA, NOS1, and 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England)","url":"https://pubmed.ncbi.nlm.nih.gov/23704310","citation_count":20,"is_preprint":false},{"pmid":"23117548","id":"PMC_23117548","title":"WT1, WTX and CTNNB1 mutation analysis in 43 patients with sporadic Wilms' tumor.","date":"2012","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/23117548","citation_count":20,"is_preprint":false},{"pmid":"37260077","id":"PMC_37260077","title":"ARMADiLLO: a web server for analyzing antibody mutation probabilities.","date":"2023","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/37260077","citation_count":19,"is_preprint":false},{"pmid":"30074466","id":"PMC_30074466","title":"Clinical and biological significance of adamantinomatous craniopharyngioma with CTNNB1 mutation.","date":"2018","source":"Journal of neurosurgery","url":"https://pubmed.ncbi.nlm.nih.gov/30074466","citation_count":19,"is_preprint":false},{"pmid":"23525311","id":"PMC_23525311","title":"CTNNB1, AXIN1 and APC expression analysis of different medulloblastoma variants.","date":"2013","source":"Clinics (Sao Paulo, Brazil)","url":"https://pubmed.ncbi.nlm.nih.gov/23525311","citation_count":19,"is_preprint":false},{"pmid":"25063455","id":"PMC_25063455","title":"Kinesin-II recruits Armadillo and Dishevelled for Wingless signaling in Drosophila.","date":"2014","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25063455","citation_count":19,"is_preprint":false},{"pmid":"19232093","id":"PMC_19232093","title":"Cleavage of Armadillo/beta-catenin by the caspase DrICE in Drosophila apoptotic epithelial cells.","date":"2009","source":"BMC developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/19232093","citation_count":18,"is_preprint":false},{"pmid":"19498322","id":"PMC_19498322","title":"Investigation of BRAF and CTNNB1 activating mutations in adrenocortical tumors.","date":"2009","source":"Journal of endocrinological 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letters","url":"https://pubmed.ncbi.nlm.nih.gov/29249062","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52975,"output_tokens":5911,"usd":0.123795,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14479,"output_tokens":5558,"usd":0.105673,"stage2_stop_reason":"end_turn"},"total_usd":0.229468,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"The crystal structure of the armadillo repeat region of beta-catenin (12 copies of a 42-aa repeat) was determined, revealing a superhelix of helices with a long, positively charged groove. The acidic binding regions of cadherins, TCFs, and APC were proposed to interact with this groove, explaining how a single domain mediates multiple protein interactions.\",\n      \"method\": \"X-ray crystallography (3D structure of protease-resistant armadillo repeat fragment)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional mapping of binding groove, foundational structural study widely replicated in the field\",\n      \"pmids\": [\"9298899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Drosophila Armadillo (beta-catenin ortholog) is required for adherens junction assembly in vivo. Loss of Armadillo (armXP33 allele) prevents adherens junction assembly, causes epithelial cells to lose adhesion, round up, adopt mesenchymal character, lose polarity, and blocks gastrulation morphogenesis.\",\n      \"method\": \"Genetic loss-of-function (intermediate mutant allele armXP33) with morphological and biochemical analysis in Drosophila embryos\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean in vivo loss-of-function with defined cellular phenotypes (loss of adhesion, polarity, morphogenesis), multiple orthogonal readouts\",\n      \"pmids\": [\"8698810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Armadillo/beta-catenin binds directly to TCF/LEF-family HMG-box transcription factors in the nucleus, forming bipartite transcription factors that activate Wingless/Wnt-responsive target genes in both Drosophila and vertebrates.\",\n      \"method\": \"Review synthesizing direct binding experiments and genetic data (Co-IP, reporter assays in Drosophila and vertebrate systems)\",\n      \"journal\": \"Current opinion in genetics & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — synthesis of binding and epistasis data from multiple labs, but this paper is a review (primary data cited therein)\",\n      \"pmids\": [\"9309175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CK2 phosphorylates beta-catenin primarily at Thr393 within the armadillo repeat domain (where APC and Axin bind). This phosphorylation promotes proteasome resistance, increases beta-catenin protein levels, and enhances co-transcriptional activity, making CK2 a positive regulator of Wnt signaling.\",\n      \"method\": \"Pharmacological inhibition and dominant-negative CK2 expression; site-directed mutagenesis of Thr393; cotranscriptional reporter assays; proteasome inhibitor rescue; in vitro phosphorylation mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphorylation assay, mutagenesis of specific residue (T393), functional reporter assays, proteasome-dependence experiments; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"12700239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Nuclear localization of beta-catenin is necessary for Wnt/Wingless pathway activation. Membrane-tethered beta-catenin is insufficient to activate transcription; only nuclear beta-catenin drives target gene expression. Two novel missense loss-of-function alleles that retain protein stability but cannot transduce signal were identified.\",\n      \"method\": \"Genetic epistasis in Drosophila: transgenic constructs with truncations/tethering; signaling-null condition defined; Chibby as C-terminus-specific negative regulator used to test membrane vs. nuclear function\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple transgenic constructs, functional readouts, epistasis, and identification of novel loss-of-function alleles; single lab but multiple orthogonal genetic approaches\",\n      \"pmids\": [\"15024404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Parafibromin (human) / Hyrax (Drosophila), a component of the PAF1 complex, is required for Wnt/Wg target gene transcription and binds directly to the C-terminal region of beta-catenin/Armadillo. Recruitment of Pygopus to beta-catenin/Armadillo is required for the transactivation potential of Parafibromin/Hyrax. This provides a mechanism by which the nuclear Wnt signaling complex directly engages the PAF1 complex to control transcriptional initiation and elongation.\",\n      \"method\": \"Drosophila genetic screens (Hyrax identified as Wnt pathway component); direct binding assays (Parafibromin/Hyrax binds C-terminal region of beta-catenin/Armadillo); human ortholog validated; epistasis with Pygopus\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic identification + direct binding assays + human ortholog validation + epistasis with Pygopus, published in Cell with multiple orthogonal approaches\",\n      \"pmids\": [\"16630820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In Drosophila epidermis, asymmetric distribution and phosphorylation of Armadillo/beta-catenin at the cell membrane is required for proper planar cell polarity; interference with Arm phosphorylation leads to polarity defects, revealing a polarity-signaling role for junctional/membrane Arm.\",\n      \"method\": \"Drosophila genetics (Wg/Hh pathway manipulation); immunostaining for Arm distribution and phosphorylation; cuticle polarity phenotype analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic and phosphorylation analyses in Drosophila, single lab with multiple readouts\",\n      \"pmids\": [\"17183721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The caspase DrICE (Drosophila caspase-3 homolog) cleaves Armadillo/beta-catenin at a DQVD motif in the N-terminal domain during apoptosis, generating a stable membrane-associated fragment. This cleavage contributes to DE-cadherin removal from the plasma membrane during apoptotic adherens junction disassembly.\",\n      \"method\": \"In vitro caspase cleavage assays; site-directed mutagenesis of DQVD cleavage site; in vivo validation in Drosophila embryo apoptosis; immunostaining for Arm and DE-cadherin\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of caspase cleavage, mutagenesis of cleavage site, and in vivo validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19232093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In Drosophila, Brain tumor (Brat) specifies intermediate neural progenitor (INP) identity through attenuating Armadillo/beta-catenin activity via the Wnt destruction complex. Increasing Arm activity in immature INPs exacerbates supernumerary neuroblast formation in brat mutants, while reducing Arm activity suppresses it, establishing epistatic placement of Arm downstream of Brat-dependent INP specification.\",\n      \"method\": \"Drosophila genetics: brat mutants, Arm gain/loss-of-function in INPs, epistasis analysis; neuroblast counting phenotype\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic epistasis in Drosophila with quantitative phenotypic readout; single lab\",\n      \"pmids\": [\"24257623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Kinesin-II subunit Klp64D (Drosophila Kif3A homolog) directly binds to the Arm repeat domain of Armadillo/beta-catenin and recruits Dishevelled in the presence of Arm. Loss of Klp64D causes aberrant Arm accumulation in vesicular/Golgi structures, indicating that Kinesin-II regulates intracellular trafficking of Arm for Wingless signaling. Human KIF3A also binds beta-catenin and rescues klp64D RNAi phenotypes.\",\n      \"method\": \"Drosophila genetics (klp64D mutations, RNAi); direct binding assays (Klp64D binds Arm repeat domain); subcellular fractionation/immunostaining of Arm/Golgi; human KIF3A rescue experiment\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay, genetic epistasis, localization experiment with functional consequence, human ortholog cross-validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25063455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Muscle beta-catenin/Ctnnb1 acts as a transcriptional regulator (not via its cell-adhesion function) to drive expression of Slit2 as a retrograde signal for presynaptic differentiation at the neuromuscular junction. Ctnnb1 mutant lacking the transactivation domain fails to rescue presynaptic deficits; Slit2 transgenic expression in muscle rescues presynaptic defects caused by Ctnnb1 mutation; Slit2-coated beads induce synaptophysin puncta in spinal cord axons.\",\n      \"method\": \"In vivo transgenic mouse rescue experiments (transactivation-domain deleted Ctnnb1); Slit2 muscle-specific transgenic rescue; Slit2 bead assay in spinal cord explants\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function rescue with domain-specific constructs, identification of downstream retrograde factor (Slit2), bead assay for functional validation; single lab with multiple orthogonal in vivo methods\",\n      \"pmids\": [\"26159615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ACLY (ATP-citrate lyase) stabilizes CTNNB1/beta-catenin protein by direct interaction, and the ACLY-CTNNB1 complex promotes CTNNB1 translocation from cytoplasm to nucleus, subsequently increasing CTNNB1 transcriptional activity and colon cancer cell migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation (ACLY-CTNNB1 interaction); Western blot (CTNNB1 stabilization); migration/invasion assays in ACLY-deficient cell lines; in vivo mouse colon metastasis model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP for interaction, functional assays in KO cell lines and in vivo; multiple methods but interaction evidence is limited to Co-IP\",\n      \"pmids\": [\"31511060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRAF6 drives selective autophagic degradation of CTNNB1/beta-catenin by interacting with LC3B through its LIR motif and catalyzing K63-linked polyubiquitination of LC3B; K63-ubiquitinated LC3B promotes the LC3B-ATG7 complex and directs CTNNB1 recognition for autophagic degradation. GSK3B phosphorylates TRAF6 at Thr266, triggering K48-linked polyubiquitination and degradation of TRAF6, thereby relieving CTNNB1 from autophagic degradation.\",\n      \"method\": \"Co-IP (TRAF6-LC3B, LC3B-ATG7); ubiquitination assays (K63-LC3B, K48-TRAF6); site-directed mutagenesis (LIR motif, Thr266); autophagy flux assays; GSK3B kinase assay; in vivo xenograft\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple biochemical reconstitution experiments, ubiquitination assays, mutagenesis, and in vivo validation; single lab but comprehensive mechanistic dissection\",\n      \"pmids\": [\"30806153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CTNNB1 mutations in exon 3 (affecting GSK3beta phosphorylation sites) increase beta-catenin stability by inhibiting ubiquitination, thereby activating the Wnt signaling pathway and promoting cell proliferation in adamantinomatous craniopharyngioma. A novel CTNNB1 mutation (transversion + in-frame deletion in exon 3) was functionally validated to confer increased beta-catenin stability.\",\n      \"method\": \"Whole-genome sequencing; ubiquitination assay; Wnt reporter (TOPFlash); CCK8 and colony formation proliferation assays in ACP primary cells\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay + TOPFlash reporter + proliferation assay for functional validation of novel mutation; single lab\",\n      \"pmids\": [\"34922552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GLUT3 (glucose transporter) is a direct TCF4/beta-catenin target gene in hepatoblastoma, mechanistically linking CTNNB1 mutation to metabolic reprogramming (glycolysis) in this tumor type.\",\n      \"method\": \"RNA sequencing; functional analyses in hepatoblastoma cell lines; reporter assays demonstrating direct TCF4/beta-catenin transcriptional regulation of GLUT3\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq plus functional reporter assay establishing GLUT3 as a direct beta-catenin target; single lab\",\n      \"pmids\": [\"28923827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Beta-catenin in mature adipocytes regulates transcription of Saa3 (serum amyloid A3) through the beta-catenin-TCF complex; Saa3 activates macrophages to secrete Pdgf-aa, which promotes proliferation of Pdgfralpha+ preadipocytes, establishing a beta-catenin/Saa3/macrophage axis mediating mature adipocyte-preadipocyte cross-talk and fat expansion.\",\n      \"method\": \"Adipocyte-specific beta-catenin knockout mice (high-fat diet); ChIP/reporter assays for beta-catenin-TCF binding to Saa3 promoter; macrophage conditioned medium experiments; Pdgfralpha+ preadipocyte proliferation assays; whole-exome sequencing in obese subjects\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO with defined phenotype, ChIP/reporter validation of direct target (Saa3), functional cross-talk experiments; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"31934629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nitric oxide (NO) mediates VEGFA-induced vascular permeability by targeting CTNNB1/beta-catenin at endothelial junctions. In autophagy-deficient (atg7 KO) uteri, decreased CTNNB1 at endothelial junctions is associated with increased vascular permeability; NOS inhibitor treatment reduces extravasation, confirming NO/CTNNB1-dependent endothelial junction regulation.\",\n      \"method\": \"Conditional Atg7 knockout (Amhr2-Cre); Western blot/immunostaining for CTNNB1 at endothelial junctions; NOS inhibitor treatment; vascular permeability assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization and pharmacological rescue experiments; functional link between NO, CTNNB1, and permeability established but primarily in a tissue context without direct CTNNB1 mutagenesis\",\n      \"pmids\": [\"32579471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The human CTNNB1 gene comprises 16 exons spanning 23.2 kb. A major transcription initiation site was mapped 214 nt upstream of the ATG. The 5'-flanking region is GC-rich with a TATA box and binding sites for NF-kappaB, SP1, AP2, and EGR1. A 437-bp fragment and a 6-kb fragment containing the 5'-flanking region and exon 1 showed promoter activity in a reporter assay.\",\n      \"method\": \"Genomic cloning, restriction mapping, sequencing; transcription initiation mapping; promoter-reporter transfection assay in mouse epithelial cells\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genomic/promoter characterization with functional reporter validation; single lab\",\n      \"pmids\": [\"8838805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Two CTNNB1 missense variants found in patients with NEDSDV (neurodevelopmental disorder) act as dominant negative regulators of WNT signaling, as demonstrated by TOPFlash reporter assay, establishing a functional mechanism for these pathogenic variants.\",\n      \"method\": \"TOPFlash WNT reporter assay for functional assessment of CTNNB1 missense variants from patient cohort\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional reporter assay (TOPFlash) validating dominant-negative effect; single method, single study\",\n      \"pmids\": [\"36083290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LKB1 (STK11) signaling is activated downstream of oncogenic CTNNB1/beta-catenin in HCC: forced oncogenic activation of beta-catenin in human HCC cells induces post-transcriptional accumulation of LKB1 protein, and LKB1 in turn positively regulates beta-catenin signaling (metabolic zonation in liver). Lkb1 deletion impairs hepatic metabolic zonation downstream of beta-catenin, revealing a positive reciprocal cross-talk.\",\n      \"method\": \"Oncogenic beta-catenin overexpression in HCC cells (post-transcriptional LKB1 accumulation); beta-catenin siRNA knockdown (loss of LKB1 signature); conditional Lkb1 KO mice (impaired metabolic zonation); hierarchical clustering of human HCC datasets\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function experiments in vitro and in vivo mouse model; single lab with multiple methods\",\n      \"pmids\": [\"30566242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CRISPR-Cas9 knockout of CTNNB1 in HEK 293T cells reduces cell adhesion and inhibits proliferation, decreases expression of CCND1, CCNE1 (cyclin D1, E1), N-Cadherin, and GSK3-beta, while increasing gamma-catenin, demonstrating that beta-catenin is required for Wnt/beta-catenin-driven cell cycle gene expression and cell adhesion.\",\n      \"method\": \"CRISPR-Cas9 knockout; Western blot; qPCR; MTT proliferation assay; flow cytometry apoptosis assay\",\n      \"journal\": \"Biotechnology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KO with defined phenotype (proliferation, adhesion) and downstream target expression; single lab, single study\",\n      \"pmids\": [\"29249062\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CTNNB1/beta-catenin is a dual-function protein: its 12-armadillo-repeat domain forms a positively charged groove that mediates binding to cadherins (cell adhesion), APC, Axin, TCF/LEF transcription factors, and other partners; in the absence of Wnt signaling, it is phosphorylated by the GSK3beta/CK1 destruction complex at exon-3-encoded serine/threonine residues (S33, S37, T41, S45), ubiquitinated, and degraded by the proteasome, whereas Wnt activation or exon-3 mutations block this degradation, allowing beta-catenin to accumulate, translocate to the nucleus, and—by binding TCF/LEF and recruiting the PAF1 complex via Parafibromin—activate transcription of target genes including Cyclin D1, MYC, AXIN2, GLUT3, and Saa3; CK2-mediated phosphorylation at Thr393 provides an additional positive regulatory mechanism promoting proteasome resistance; selective autophagy via TRAF6/LC3B provides an alternative degradation route; and in specific contexts (muscle, adipocytes, neuromuscular junction) nuclear beta-catenin-TCF transcriptional activity drives tissue-specific retrograde signaling (Slit2) and paracrine cross-talk (Saa3/macrophage axis).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CTNNB1/beta-catenin is a dual-function protein that couples cell-cell adhesion to Wnt-responsive transcription, with its central 12-armadillo-repeat domain forming a long, positively charged groove that serves as a common docking surface for cadherins, TCF/LEF transcription factors, and the APC/Axin destruction machinery [#0]. At adherens junctions its adhesion role is essential for epithelial integrity: loss of the Drosophila ortholog Armadillo blocks junction assembly and causes cells to lose adhesion, polarity, and morphogenetic competence [#1], and the protein is removed from junctions during apoptosis by caspase (DrICE) cleavage at an N-terminal DQVD motif that drives cadherin disassembly [#7]. In its signaling role, nuclear beta-catenin—and nuclear localization specifically, not membrane-tethered protein, is required for pathway output [#4]—binds TCF/LEF HMG-box factors to form bipartite transcriptional activators [#2] and recruits the PAF1-complex subunit Parafibromin/Hyrax via its C-terminus, with Pygopus, to drive target-gene transcription [#5]. Pathway output is set by protein stability: phosphorylation of exon-3-encoded GSK3beta sites targets beta-catenin for ubiquitination and degradation, and exon-3 mutations that block this stabilize the protein and constitutively activate Wnt signaling and proliferation [#13]; CK2 phosphorylation at Thr393 within the armadillo domain confers proteasome resistance as a positive regulatory input [#3]; and an alternative TRAF6/LC3B-dependent selective-autophagy route degrades beta-catenin, itself relieved by GSK3B-driven TRAF6 turnover [#12]. Through TCF-dependent transcription beta-catenin drives context-specific programs: cell-cycle genes such as CCND1/CCNE1 and adhesion genes in proliferating cells [#20], GLUT3-linked glycolytic reprogramming in tumors [#14], Slit2 as a retrograde signal for presynaptic differentiation at the neuromuscular junction [#10], and a Saa3/macrophage paracrine axis governing adipose expansion [#15]. Dominant-negative CTNNB1 missense variants that impair Wnt reporter activity cause a neurodevelopmental disorder (NEDSDV) [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Defining the in vivo adhesion requirement established beta-catenin as essential for adherens junction assembly and epithelial organization, distinguishing it from a purely signaling factor.\",\n      \"evidence\": \"Genetic loss-of-function of the Armadillo ortholog in Drosophila embryos with morphological/biochemical readout\",\n      \"pmids\": [\"8698810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not separate the adhesion role from the later-defined transcriptional role at the molecular level\", \"Drosophila ortholog rather than human CTNNB1\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"The armadillo-repeat crystal structure answered how a single protein binds multiple partners, revealing a positively charged groove as a shared docking surface for cadherins, TCFs, and APC.\",\n      \"evidence\": \"X-ray crystallography of the protease-resistant armadillo repeat fragment with functional mapping\",\n      \"pmids\": [\"9298899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding-groove interactions inferred structurally rather than co-crystallized for all partners\", \"No structure of the N-terminal regulatory/phosphodegron region\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Direct binding to TCF/LEF HMG-box factors established beta-catenin as a transcriptional co-activator forming bipartite Wnt-responsive transcription factors.\",\n      \"evidence\": \"Synthesis of Co-IP and reporter data from Drosophila and vertebrate systems (review)\",\n      \"pmids\": [\"9309175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Primary data summarized in a review\", \"Does not define which co-activators are recruited downstream of TCF binding\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of CK2 phosphorylation at Thr393 revealed a positive stability input acting within the armadillo domain, separate from the GSK3 destruction pathway.\",\n      \"evidence\": \"In vitro phosphorylation mapping, Thr393 mutagenesis, reporter and proteasome-rescue assays\",\n      \"pmids\": [\"12700239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single lab\", \"How Thr393 phosphorylation mechanistically blocks degradation not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Compartment-resolution experiments demonstrated that nuclear localization, not mere protein stabilization, is required for transcriptional output, separating signaling from membrane functions.\",\n      \"evidence\": \"Drosophila genetic epistasis with truncation/tethering constructs and signaling-null alleles\",\n      \"pmids\": [\"15024404\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of nuclear import/retention not defined\", \"Drosophila ortholog\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Parafibromin/Hyrax recruitment linked nuclear beta-catenin directly to the PAF1 complex, providing a mechanism connecting the Wnt transcription complex to initiation/elongation machinery.\",\n      \"evidence\": \"Drosophila genetic screen, direct C-terminal binding assays, Pygopus epistasis, human ortholog validation\",\n      \"pmids\": [\"16630820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PAF1 recruitment is regulated context-dependently not addressed\", \"Stoichiometry of the nuclear complex unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Membrane-localized phosphorylated Armadillo was shown to contribute to planar cell polarity, extending beta-catenin's junctional role beyond static adhesion.\",\n      \"evidence\": \"Drosophila genetics, phospho-specific immunostaining, cuticle polarity phenotypes\",\n      \"pmids\": [\"17183721\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosites mediating polarity not molecularly defined\", \"Drosophila context only\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Caspase cleavage at an N-terminal DQVD motif explained how beta-catenin is processed during apoptosis to drive cadherin removal and junction disassembly.\",\n      \"evidence\": \"In vitro DrICE cleavage, cleavage-site mutagenesis, in vivo Drosophila apoptosis validation\",\n      \"pmids\": [\"19232093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional fate of the stable membrane fragment unresolved\", \"Conservation of cleavage in mammalian CTNNB1 not tested here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Epistatic placement of Armadillo downstream of Brat defined a developmental setting where attenuating beta-catenin activity specifies neural progenitor identity.\",\n      \"evidence\": \"Drosophila brat mutants with Arm gain/loss-of-function and neuroblast counting\",\n      \"pmids\": [\"24257623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets in INPs not identified\", \"Drosophila ortholog\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Kinesin-II (Klp64D/KIF3A) binding to the armadillo domain revealed a trafficking mechanism controlling beta-catenin subcellular distribution for Wingless signaling.\",\n      \"evidence\": \"Direct binding assay, Drosophila genetics, Golgi localization, human KIF3A rescue\",\n      \"pmids\": [\"25063455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How trafficking is coupled to signaling state not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"CRISPR knockout in human cells confirmed beta-catenin is required for cell-cycle gene expression (CCND1/CCNE1) and adhesion, linking loss-of-function directly to proliferation and adhesion phenotypes.\",\n      \"evidence\": \"CRISPR-Cas9 KO in HEK293T with Western blot, qPCR, proliferation and apoptosis assays\",\n      \"pmids\": [\"29249062\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line\", \"Direct versus indirect target effects not distinguished\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Functional validation of exon-3 mutations established that escape from GSK3beta-directed ubiquitination stabilizes beta-catenin and constitutively activates Wnt-driven proliferation in tumors.\",\n      \"evidence\": \"Whole-genome sequencing, ubiquitination assay, TOPFlash reporter, proliferation assays in craniopharyngioma cells\",\n      \"pmids\": [\"34922552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single tumor type\", \"Destruction-complex assembly steps not dissected here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of GLUT3 as a direct TCF4/beta-catenin target connected CTNNB1 mutation to glycolytic metabolic reprogramming in hepatoblastoma.\",\n      \"evidence\": \"RNA-seq with reporter assays in hepatoblastoma cell lines\",\n      \"pmids\": [\"28923827\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single tumor context\", \"In vivo contribution of GLUT3 induction not quantified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Reciprocal cross-talk with LKB1 was defined, showing oncogenic beta-catenin post-transcriptionally accumulates LKB1, which in turn supports beta-catenin signaling and hepatic metabolic zonation.\",\n      \"evidence\": \"Gain/loss of beta-catenin in HCC cells, conditional Lkb1 KO mice, human HCC dataset clustering\",\n      \"pmids\": [\"30566242\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of post-transcriptional LKB1 accumulation unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery of a TRAF6/LC3B selective-autophagy route established a proteasome-independent degradation pathway for beta-catenin, gated by GSK3B-driven TRAF6 turnover.\",\n      \"evidence\": \"Co-IP, K63/K48 ubiquitination assays, LIR/Thr266 mutagenesis, autophagy flux, GSK3B kinase assay, xenograft\",\n      \"pmids\": [\"30806153\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of autophagic versus proteasomal degradation in vivo unquantified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"ACLY was shown to stabilize beta-catenin and promote its nuclear translocation, linking a metabolic enzyme to beta-catenin-driven colon cancer invasion.\",\n      \"evidence\": \"Co-IP, Western blot, migration/invasion assays in ACLY-deficient cells, mouse metastasis model\",\n      \"pmids\": [\"31511060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction rests on single Co-IP without reciprocal validation\", \"Mechanism of stabilization not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The beta-catenin/Saa3/macrophage axis defined a tissue-specific transcriptional output mediating mature adipocyte-preadipocyte cross-talk during fat expansion.\",\n      \"evidence\": \"Adipocyte-specific beta-catenin KO mice, ChIP/reporter on Saa3 promoter, macrophage conditioned-medium and preadipocyte proliferation assays\",\n      \"pmids\": [\"31934629\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signal activating adipocyte beta-catenin not defined\", \"Human relevance from exome data correlative\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"NO was implicated in regulating junctional CTNNB1 to control VEGFA-induced endothelial permeability, tying beta-catenin to vascular barrier function.\",\n      \"evidence\": \"Conditional Atg7 KO, junctional CTNNB1 immunostaining, NOS inhibitor rescue, permeability assays\",\n      \"pmids\": [\"32579471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct CTNNB1 mutagenesis\", \"Mechanism by which NO targets CTNNB1 not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Functional testing of patient missense variants established a dominant-negative loss of Wnt signaling as the mechanism underlying a CTNNB1-associated neurodevelopmental disorder.\",\n      \"evidence\": \"TOPFlash WNT reporter assay on patient-derived missense variants\",\n      \"pmids\": [\"36083290\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single reporter assay\", \"Cellular/developmental consequences in neurons not modeled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the competing inputs—GSK3-destruction-complex phosphodegron control, CK2-mediated stabilization, kinesin-dependent trafficking, and TRAF6/autophagic degradation—are integrated to set nuclear beta-catenin levels in a given cell type remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No quantitative model balancing the multiple degradation/stabilization routes\", \"Tissue-specific selection of distinct transcriptional programs (Slit2 vs Saa3 vs GLUT3) mechanistically unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 5, 10, 14, 15]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 5, 11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 6, 7, 16]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4, 5, 13]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 14, 15, 20]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\"beta-catenin/TCF-LEF transcription complex\", \"adherens junction\", \"Wnt destruction complex (substrate)\", \"PAF1 complex (via Parafibromin)\"],\n    \"partners\": [\"TCF/LEF\", \"APC\", \"Axin\", \"Parafibromin\", \"Pygopus\", \"KIF3A\", \"TRAF6\", \"ACLY\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}