{"gene":"FBXW2","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1999,"finding":"Mouse Fwd2 (FBXW2 ortholog) interacts with SKP1 through its F-box domain in vivo, and also interacts with CUL1 through SKP1, forming an SCF(Fwd2) ubiquitin ligase complex. FBXW2 localizes to the cytoplasm.","method":"Co-immunoprecipitation, immunofluorescence staining","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP demonstrating SKP1 and CUL1 interactions, with localization data; single lab, two orthogonal methods","pmids":["10585767"],"is_preprint":false},{"year":2005,"finding":"FBXW2 (FBW2) is the substrate-recognition subunit of SCF(FBW2) E3 ligase that targets human GCMa (hGCMa/GCM1) for ubiquitin-proteasomal degradation in a phosphorylation-dependent manner. SKP1 and CUL1 associate with hGCMa in vivo. RNAi knockdown of FBW2 reduced hGCMa ubiquitination and increased its protein stability.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, RNA interference knockdown with pulse-chase stability assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ubiquitination assay, RNAi/stability), replicated concept in subsequent papers","pmids":["15640526"],"is_preprint":false},{"year":2008,"finding":"UBE2D2 is the E2 ubiquitin-conjugating enzyme required for SCF(FBXW2)-mediated ubiquitination of GCM1. UBE2D2 enzyme activity is required for GCM1 ubiquitination and for its association with the SCF(FBXW2) complex. Knockdown of UBE2D2 suppressed FBXW2-mediated GCM1 ubiquitination and prolonged GCM1 half-life.","method":"In vitro ubiquitination assay with a panel of E2 proteins, RNA interference knockdown, in vivo ubiquitination assay, protein half-life assay","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution assay identifying specific E2, validated by RNAi and in vivo ubiquitination; single lab with multiple orthogonal methods","pmids":["18703417"],"is_preprint":false},{"year":2013,"finding":"RACK1 interacts with FBXW2 via WD repeats (in both proteins) and competes with GCM1 for FBXW2 binding, thereby preventing GCM1 ubiquitination and stabilizing GCM1. RACK1 knockdown destabilizes GCM1 and reduces expression of the GCM1 target gene HTRA4, leading to decreased placental cell migration and invasion.","method":"Tandem-affinity purification coupled with MS, Co-immunoprecipitation, RNA interference knockdown, ubiquitination assay, cell migration/invasion assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TAP-MS identification of interaction, validated by Co-IP and functional knockdown; single lab with multiple orthogonal methods","pmids":["23651062"],"is_preprint":false},{"year":2017,"finding":"FBXW2 is a substrate of β-TrCP1, which promotes FBXW2 ubiquitylation and shortens its half-life. FBXW2 in turn acts as an E3 ligase for SKP2, promoting SKP2 ubiquitylation and degradation. This forms a β-TrCP1-FBXW2-SKP2 oncogene–tumor suppressor–oncogene cascade controlling lung cancer cell growth.","method":"Co-immunoprecipitation, ubiquitination assay, protein half-life assay (cycloheximide chase), gain- and loss-of-function experiments in cell lines and in vivo","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, half-life assay, in vivo models; multiple orthogonal methods in single rigorous study","pmids":["28090088"],"is_preprint":false},{"year":2019,"finding":"FBXW2 is an E3 ligase for β-catenin. FBXW2 binds to β-catenin upon EGF-AKT1-mediated phosphorylation of β-catenin at Ser552, promoting its ubiquitylation and degradation. FBXW2 overexpression reduces β-catenin levels and protein half-life; FBXW2 knockdown increases them. Functionally, FBXW2 inhibits lung cancer cell migration and invasion by blocking β-catenin-driven MMP transactivation.","method":"Co-immunoprecipitation, ubiquitination assay, protein half-life assay (cycloheximide chase), gain- and loss-of-function in vitro and in vivo lung cancer models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, half-life assay, in vivo models, phosphorylation-dependent binding established; multiple orthogonal methods","pmids":["30918250"],"is_preprint":false},{"year":2019,"finding":"MSX2 is a substrate of FBXW2 E3 ligase. FBXW2 binds MSX2 and promotes its ubiquitylation and degradation, shortening its protein half-life. VRK2 kinase, induced by hypoxia, facilitates MSX2-FBXW2 binding and FBXW2-mediated MSX2 ubiquitylation and degradation, leading to SOX2 induction via derepression. This establishes a negative FBXW2-MSX2-SOX2 cascade regulating stem cell property and drug resistance.","method":"Co-immunoprecipitation, ubiquitination assay, protein half-life assay, gain- and loss-of-function in vitro and in vivo models, tumor sphere formation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, half-life assay, kinase identification, in vivo models; multiple orthogonal methods in single rigorous study","pmids":["31548378"],"is_preprint":false},{"year":2020,"finding":"KSRP (KH-type splicing regulatory protein) is a ubiquitin substrate of SCF(FBXW2). FBXW2 targets KSRP for degradation in macrophages, and the C-terminus (P3) of FBXW2 competitively inhibits this function. Myeloid-specific FBXW2 knockout reduces proinflammatory responses, implicating FBXW2 as a pro-inflammatory mediator through KSRP degradation.","method":"Co-immunoprecipitation, ubiquitination assay, myeloid-specific knockout mouse models, gain- and loss-of-function experiments","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo knockout model; single lab with multiple methods","pmids":["33101872"],"is_preprint":false},{"year":2021,"finding":"NF-κB p65 is a substrate of FBXW2. FBXW2 directly binds p65 and promotes its ubiquitination and degradation. p300-mediated acetylation of p65 blocks FBXW2-induced p65 ubiquitination. FBXW2-p65 axis regulates SOX2-induced stemness in breast cancer, and FBXW2-induced p65 degradation was confirmed in FBXW2-knockout mice.","method":"Co-immunoprecipitation, ubiquitination assay, gain- and loss-of-function in vitro and in vivo, FBXW2-knockout mice","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, knockout mouse validation, in vivo tumor models; multiple orthogonal methods","pmids":["34465889"],"is_preprint":false},{"year":2022,"finding":"FBXW2 is an E3 ligase for EGFR in prostate cancer. FBXW2 binds EGFR via its consensus degron motif (TSNNST), promoting EGFR ubiquitylation and degradation, shortening EGFR protein half-life. A dominant-negative FBXW2 mutant fails to degrade EGFR, confirming the mechanism.","method":"Co-immunoprecipitation, ubiquitination assay, protein half-life assay (cycloheximide chase), dominant-negative mutant analysis, gain- and loss-of-function in vitro and in vivo","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, dominant-negative mutant, half-life assay; single lab with multiple orthogonal methods","pmids":["35499593"],"is_preprint":false},{"year":2023,"finding":"Moesin is a substrate of FBXW2 E3 ligase. FBXW2 promotes proteasomal degradation of Moesin. AKT phosphorylates Moesin at Thr-558, preventing FBXW2-mediated degradation by weakening the FBXW2-Moesin association. Accumulated Moesin in turn prevents FBXW2-mediated degradation of SKP2 by promoting non-degradable polyubiquitination of SKP2, establishing an AKT-Moesin-SKP2 oncogenic axis.","method":"Co-immunoprecipitation, ubiquitination assay, kinase assay, gain- and loss-of-function in vitro and in vivo","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, kinase assay; single lab with multiple orthogonal methods","pmids":["37736741"],"is_preprint":false},{"year":2025,"finding":"WASL (WASP-like actin nucleation-promoting factor) is a direct substrate of FBXW2. FBXW2 physically interacts with WASL and promotes its ubiquitination-dependent proteasomal degradation in gastric cancer cells. Ectopic WASL expression abrogates FBXW2-mediated tumor suppression. FOXP2 transcription factor directly binds the FBXW2 promoter to repress its transcription.","method":"Label-free quantitative proteomics, Co-immunoprecipitation, ubiquitination assay, chromatin immunoprecipitation-PCR, DNA pull-down, gain- and loss-of-function in vitro and in vivo","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, ChIP-PCR, proteomics; single lab with multiple orthogonal methods","pmids":["40721413"],"is_preprint":false},{"year":2025,"finding":"FBXW2 binds β-catenin and facilitates its ubiquitination in gastric cancer, leading to enhanced nuclear translocation of β-catenin upon FBXW2 knockdown. FBXW2 knockdown also reduced GSK3β and Axin2 levels.","method":"Co-immunoprecipitation, ubiquitination assay, Western blotting, shRNA knockdown","journal":"International journal of medical sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and ubiquitination assay; single lab, largely confirmatory of prior β-catenin finding","pmids":["40225854"],"is_preprint":false}],"current_model":"FBXW2 functions as the substrate-recognition subunit of the SCF(FBXW2) E3 ubiquitin ligase complex (together with SKP1 and CUL1, using UBE2D2 as the E2 enzyme) and promotes ubiquitin-proteasomal degradation of multiple substrates including SKP2, β-catenin (upon AKT1-mediated Ser552 phosphorylation), GCM1/GCMa (phosphorylation-dependent), MSX2 (VRK2-facilitated), NF-κB p65 (blocked by p300 acetylation), EGFR (via a TSNNST degron motif), Moesin (blocked by AKT-mediated Thr-558 phosphorylation), KSRP, and WASL; FBXW2 is itself targeted for degradation by β-TrCP1, forming a β-TrCP1–FBXW2–SKP2 oncogene–tumor suppressor–oncogene cascade, and its transcription is repressed by FOXP2 in gastric cancer."},"narrative":{"mechanistic_narrative":"FBXW2 is the substrate-recognition subunit of an SCF(FBXW2) E3 ubiquitin ligase that assembles with SKP1 and CUL1 and directs ubiquitin-proteasomal degradation of a broad set of substrates, positioning it as a tumor suppressor across multiple cancer types [PMID:10585767, PMID:15640526, PMID:28090088]. Substrate recognition is frequently gated by phosphorylation: it degrades GCM1/GCMa in a phosphorylation-dependent manner using UBE2D2 as the cognate E2 [PMID:15640526, PMID:18703417], engages β-catenin only after EGF-AKT1-driven Ser552 phosphorylation to block β-catenin-driven MMP transactivation and tumor cell invasion [PMID:30918250], and binds MSX2 in a manner facilitated by hypoxia-induced VRK2, thereby controlling a downstream SOX2/stemness program [PMID:31548378]. FBXW2 also targets EGFR through a defined TSNNST degron [PMID:35499593], and degrades SKP2, NF-κB p65 (an activity blocked by p300-mediated p65 acetylation), Moesin (blocked by AKT-mediated Thr-558 phosphorylation), KSRP, and WASL, linking it to growth control, inflammation, and stemness [PMID:28090088, PMID:34465889, PMID:37736741, PMID:33101872, PMID:40721413]. FBXW2 itself is regulated at the protein level by β-TrCP1-mediated ubiquitylation, forming a β-TrCP1–FBXW2–SKP2 cascade, and at the transcriptional level by FOXP2-mediated promoter repression [PMID:28090088, PMID:40721413]. Its activity is further tuned by competitors such as RACK1, which displaces GCM1 from FBXW2 to stabilize it [PMID:23651062].","teleology":[{"year":1999,"claim":"Established that the FBXW2 ortholog is a bona fide F-box protein that nucleates an SCF complex, defining its core biochemical identity before any substrate was known.","evidence":"Co-immunoprecipitation showing SKP1 (via F-box) and CUL1 (via SKP1) binding, with cytoplasmic immunofluorescence localization in mouse cells","pmids":["10585767"],"confidence":"Medium","gaps":["No substrate identified at this stage","E2 enzyme and catalytic output not defined"]},{"year":2005,"claim":"Identified the first FBXW2 substrate, GCM1/GCMa, showing FBXW2 functions as a phosphorylation-dependent degradation receptor within the SCF complex.","evidence":"Co-IP, in vivo ubiquitination assay, and RNAi knockdown with pulse-chase stability assay in human cells","pmids":["15640526"],"confidence":"High","gaps":["Specific phosphodegron residues on GCM1 not mapped","E2 enzyme not identified"]},{"year":2008,"claim":"Defined UBE2D2 as the E2 conjugating enzyme that powers SCF(FBXW2) ubiquitination, completing the enzymatic core of the ligase.","evidence":"In vitro ubiquitination with an E2 panel, RNAi knockdown, in vivo ubiquitination and half-life assays","pmids":["18703417"],"confidence":"High","gaps":["Whether UBE2D2 serves all FBXW2 substrates not tested","Chain linkage type not characterized"]},{"year":2013,"claim":"Showed FBXW2 substrate targeting can be antagonized by competitive WD-repeat binding, revealing a layer of regulation over substrate access.","evidence":"TAP-MS, Co-IP, RNAi, ubiquitination and migration/invasion assays demonstrating RACK1 competes with GCM1 for FBXW2","pmids":["23651062"],"confidence":"Medium","gaps":["Structural basis of RACK1-FBXW2 competition not resolved","Generality of competitive antagonism for other substrates unknown"]},{"year":2017,"claim":"Placed FBXW2 in a regulatory cascade, showing it is both a substrate of β-TrCP1 and an E3 ligase for the oncoprotein SKP2, establishing its tumor-suppressor role in lung cancer.","evidence":"Reciprocal Co-IP, ubiquitination assay, cycloheximide-chase half-life assay, and in vivo gain/loss-of-function lung cancer models","pmids":["28090088"],"confidence":"High","gaps":["SKP2 degron on FBXW2 recognition not mapped","Inputs controlling β-TrCP1 targeting of FBXW2 unclear"]},{"year":2019,"claim":"Expanded the substrate repertoire to β-catenin and MSX2 and demonstrated that upstream kinases (AKT1, VRK2) gate substrate recognition, linking FBXW2 to invasion and stemness programs.","evidence":"Co-IP, ubiquitination, half-life assays, and in vivo models; phosphorylation-dependent binding (AKT1-Ser552 on β-catenin; hypoxia/VRK2 on MSX2)","pmids":["30918250","31548378"],"confidence":"High","gaps":["Whether β-catenin and MSX2 degrons share a consensus motif unresolved","Cross-talk between the two cascades not examined"]},{"year":2020,"claim":"Extended FBXW2 function beyond cancer into innate immunity by identifying KSRP as a substrate driving proinflammatory macrophage responses.","evidence":"Co-IP, ubiquitination assay, and myeloid-specific knockout mouse models","pmids":["33101872"],"confidence":"Medium","gaps":["KSRP degron not mapped","Reciprocal validation in human cells limited"]},{"year":2021,"claim":"Identified NF-κB p65 as an FBXW2 substrate and showed acetylation can override ubiquitination, revealing post-translational competition controlling stemness signaling.","evidence":"Reciprocal Co-IP, ubiquitination assay, FBXW2-knockout mice, and in vivo breast cancer tumor models; p300 acetylation blocks p65 ubiquitination","pmids":["34465889"],"confidence":"High","gaps":["Which p65 lysines are acetyl/ubiquitin-competing not fully defined","Interplay with canonical NF-κB degradation pathways unclear"]},{"year":2022,"claim":"Defined an explicit TSNNST degron in EGFR recognized by FBXW2, providing the first sequence-level motif for FBXW2 substrate engagement.","evidence":"Co-IP, ubiquitination assay, cycloheximide-chase half-life assay, and dominant-negative FBXW2 mutant analysis in prostate cancer models","pmids":["35499593"],"confidence":"Medium","gaps":["Whether the TSNNST motif is shared by other FBXW2 substrates not tested","Single-lab finding"]},{"year":2023,"claim":"Showed Moesin is an FBXW2 substrate whose AKT-phosphorylated form not only escapes degradation but feeds back to block FBXW2-mediated SKP2 turnover, defining an AKT-Moesin-SKP2 oncogenic axis.","evidence":"Co-IP, ubiquitination assay, kinase assay, and in vivo gain/loss-of-function studies; AKT Thr-558 phosphorylation weakens FBXW2-Moesin binding","pmids":["37736741"],"confidence":"Medium","gaps":["Mechanism of Moesin-driven non-degradable SKP2 polyubiquitination not detailed","Single-lab finding"]},{"year":2025,"claim":"Identified WASL as a substrate and FOXP2 as a transcriptional repressor of FBXW2, adding transcriptional control to its regulation in gastric cancer.","evidence":"Label-free proteomics, Co-IP, ubiquitination assay, ChIP-PCR and DNA pull-down with in vivo models","pmids":["40721413"],"confidence":"Medium","gaps":["WASL degron not mapped","Breadth of FOXP2-FBXW2 regulation beyond gastric cancer unknown"]},{"year":null,"claim":"It remains unresolved whether the diverse FBXW2 substrates share a unifying degron logic and how the multiple phosphorylation/acetylation switches are coordinated within a cell.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of FBXW2 substrate recognition","No systematic comparison of degron motifs across substrates","Physiological substrate hierarchy in normal tissues undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,4,5,6,8,9,10,11]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[1,4,5,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,4,5,6,8,9,10,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,5,6,8,9,11]}],"complexes":["SCF(FBXW2) E3 ubiquitin ligase"],"partners":["SKP1","CUL1","UBE2D2","RACK1","SKP2","CTNNB1","EGFR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UKT8","full_name":"F-box/WD repeat-containing protein 2","aliases":["F-box and WD-40 domain-containing protein 2","Protein MD6"],"length_aa":454,"mass_kda":51.5,"function":"Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9UKT8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBXW2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FBXW2","total_profiled":1310},"omim":[{"mim_id":"618171","title":"KINESIN FAMILY MEMBER 16B; KIF16B","url":"https://www.omim.org/entry/618171"},{"mim_id":"609071","title":"F-BOX AND WD40 DOMAIN PROTEIN 2; FBXW2","url":"https://www.omim.org/entry/609071"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FBXW2"},"hgnc":{"alias_symbol":["FBW2","Md6","Fwd2"],"prev_symbol":[]},"alphafold":{"accession":"Q9UKT8","domains":[{"cath_id":"1.20.1280.50","chopping":"51-135","consensus_level":"medium","plddt":77.9119,"start":51,"end":135},{"cath_id":"2.130.10.10","chopping":"138-449","consensus_level":"medium","plddt":92.7005,"start":138,"end":449}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKT8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKT8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKT8-F1-predicted_aligned_error_v6.png","plddt_mean":89.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBXW2","jax_strain_url":"https://www.jax.org/strain/search?query=FBXW2"},"sequence":{"accession":"Q9UKT8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UKT8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UKT8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKT8"}},"corpus_meta":[{"pmid":"34465889","id":"PMC_34465889","title":"Ubiquitination of NF-κB p65 by FBXW2 suppresses breast cancer stemness, tumorigenesis, and paclitaxel resistance.","date":"2021","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/34465889","citation_count":98,"is_preprint":false},{"pmid":"30918250","id":"PMC_30918250","title":"FBXW2 suppresses migration and invasion of lung cancer cells via promoting β-catenin ubiquitylation and degradation.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30918250","citation_count":91,"is_preprint":false},{"pmid":"31548378","id":"PMC_31548378","title":"The FBXW2-MSX2-SOX2 axis regulates stem cell property and drug resistance of cancer cells.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/31548378","citation_count":89,"is_preprint":false},{"pmid":"28090088","id":"PMC_28090088","title":"The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28090088","citation_count":76,"is_preprint":false},{"pmid":"15640526","id":"PMC_15640526","title":"FBW2 targets GCMa to the ubiquitin-proteasome degradation system.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15640526","citation_count":45,"is_preprint":false},{"pmid":"35499593","id":"PMC_35499593","title":"FBXW2 inhibits prostate cancer proliferation and metastasis via promoting EGFR ubiquitylation and degradation.","date":"2022","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/35499593","citation_count":26,"is_preprint":false},{"pmid":"31782573","id":"PMC_31782573","title":"Gartanin is a novel NEDDylation inhibitor for induction of Skp2 degradation, FBXW2 expression, and autophagy.","date":"2019","source":"Molecular 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discovery","url":"https://pubmed.ncbi.nlm.nih.gov/40721413","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11242,"output_tokens":3817,"usd":0.045491,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11350,"output_tokens":3902,"usd":0.07715,"stage2_stop_reason":"end_turn"},"total_usd":0.122641,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"Mouse Fwd2 (FBXW2 ortholog) interacts with SKP1 through its F-box domain in vivo, and also interacts with CUL1 through SKP1, forming an SCF(Fwd2) ubiquitin ligase complex. FBXW2 localizes to the cytoplasm.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence staining\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP demonstrating SKP1 and CUL1 interactions, with localization data; single lab, two orthogonal methods\",\n      \"pmids\": [\"10585767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FBXW2 (FBW2) is the substrate-recognition subunit of SCF(FBW2) E3 ligase that targets human GCMa (hGCMa/GCM1) for ubiquitin-proteasomal degradation in a phosphorylation-dependent manner. SKP1 and CUL1 associate with hGCMa in vivo. RNAi knockdown of FBW2 reduced hGCMa ubiquitination and increased its protein stability.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, RNA interference knockdown with pulse-chase stability assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ubiquitination assay, RNAi/stability), replicated concept in subsequent papers\",\n      \"pmids\": [\"15640526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"UBE2D2 is the E2 ubiquitin-conjugating enzyme required for SCF(FBXW2)-mediated ubiquitination of GCM1. UBE2D2 enzyme activity is required for GCM1 ubiquitination and for its association with the SCF(FBXW2) complex. Knockdown of UBE2D2 suppressed FBXW2-mediated GCM1 ubiquitination and prolonged GCM1 half-life.\",\n      \"method\": \"In vitro ubiquitination assay with a panel of E2 proteins, RNA interference knockdown, in vivo ubiquitination assay, protein half-life assay\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution assay identifying specific E2, validated by RNAi and in vivo ubiquitination; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18703417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RACK1 interacts with FBXW2 via WD repeats (in both proteins) and competes with GCM1 for FBXW2 binding, thereby preventing GCM1 ubiquitination and stabilizing GCM1. RACK1 knockdown destabilizes GCM1 and reduces expression of the GCM1 target gene HTRA4, leading to decreased placental cell migration and invasion.\",\n      \"method\": \"Tandem-affinity purification coupled with MS, Co-immunoprecipitation, RNA interference knockdown, ubiquitination assay, cell migration/invasion assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TAP-MS identification of interaction, validated by Co-IP and functional knockdown; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23651062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FBXW2 is a substrate of β-TrCP1, which promotes FBXW2 ubiquitylation and shortens its half-life. FBXW2 in turn acts as an E3 ligase for SKP2, promoting SKP2 ubiquitylation and degradation. This forms a β-TrCP1-FBXW2-SKP2 oncogene–tumor suppressor–oncogene cascade controlling lung cancer cell growth.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, protein half-life assay (cycloheximide chase), gain- and loss-of-function experiments in cell lines and in vivo\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, half-life assay, in vivo models; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"28090088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FBXW2 is an E3 ligase for β-catenin. FBXW2 binds to β-catenin upon EGF-AKT1-mediated phosphorylation of β-catenin at Ser552, promoting its ubiquitylation and degradation. FBXW2 overexpression reduces β-catenin levels and protein half-life; FBXW2 knockdown increases them. Functionally, FBXW2 inhibits lung cancer cell migration and invasion by blocking β-catenin-driven MMP transactivation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, protein half-life assay (cycloheximide chase), gain- and loss-of-function in vitro and in vivo lung cancer models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, half-life assay, in vivo models, phosphorylation-dependent binding established; multiple orthogonal methods\",\n      \"pmids\": [\"30918250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MSX2 is a substrate of FBXW2 E3 ligase. FBXW2 binds MSX2 and promotes its ubiquitylation and degradation, shortening its protein half-life. VRK2 kinase, induced by hypoxia, facilitates MSX2-FBXW2 binding and FBXW2-mediated MSX2 ubiquitylation and degradation, leading to SOX2 induction via derepression. This establishes a negative FBXW2-MSX2-SOX2 cascade regulating stem cell property and drug resistance.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, protein half-life assay, gain- and loss-of-function in vitro and in vivo models, tumor sphere formation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, half-life assay, kinase identification, in vivo models; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"31548378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KSRP (KH-type splicing regulatory protein) is a ubiquitin substrate of SCF(FBXW2). FBXW2 targets KSRP for degradation in macrophages, and the C-terminus (P3) of FBXW2 competitively inhibits this function. Myeloid-specific FBXW2 knockout reduces proinflammatory responses, implicating FBXW2 as a pro-inflammatory mediator through KSRP degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, myeloid-specific knockout mouse models, gain- and loss-of-function experiments\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo knockout model; single lab with multiple methods\",\n      \"pmids\": [\"33101872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NF-κB p65 is a substrate of FBXW2. FBXW2 directly binds p65 and promotes its ubiquitination and degradation. p300-mediated acetylation of p65 blocks FBXW2-induced p65 ubiquitination. FBXW2-p65 axis regulates SOX2-induced stemness in breast cancer, and FBXW2-induced p65 degradation was confirmed in FBXW2-knockout mice.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, gain- and loss-of-function in vitro and in vivo, FBXW2-knockout mice\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, knockout mouse validation, in vivo tumor models; multiple orthogonal methods\",\n      \"pmids\": [\"34465889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FBXW2 is an E3 ligase for EGFR in prostate cancer. FBXW2 binds EGFR via its consensus degron motif (TSNNST), promoting EGFR ubiquitylation and degradation, shortening EGFR protein half-life. A dominant-negative FBXW2 mutant fails to degrade EGFR, confirming the mechanism.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, protein half-life assay (cycloheximide chase), dominant-negative mutant analysis, gain- and loss-of-function in vitro and in vivo\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, dominant-negative mutant, half-life assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35499593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Moesin is a substrate of FBXW2 E3 ligase. FBXW2 promotes proteasomal degradation of Moesin. AKT phosphorylates Moesin at Thr-558, preventing FBXW2-mediated degradation by weakening the FBXW2-Moesin association. Accumulated Moesin in turn prevents FBXW2-mediated degradation of SKP2 by promoting non-degradable polyubiquitination of SKP2, establishing an AKT-Moesin-SKP2 oncogenic axis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, kinase assay, gain- and loss-of-function in vitro and in vivo\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, kinase assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37736741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"WASL (WASP-like actin nucleation-promoting factor) is a direct substrate of FBXW2. FBXW2 physically interacts with WASL and promotes its ubiquitination-dependent proteasomal degradation in gastric cancer cells. Ectopic WASL expression abrogates FBXW2-mediated tumor suppression. FOXP2 transcription factor directly binds the FBXW2 promoter to repress its transcription.\",\n      \"method\": \"Label-free quantitative proteomics, Co-immunoprecipitation, ubiquitination assay, chromatin immunoprecipitation-PCR, DNA pull-down, gain- and loss-of-function in vitro and in vivo\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, ChIP-PCR, proteomics; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40721413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXW2 binds β-catenin and facilitates its ubiquitination in gastric cancer, leading to enhanced nuclear translocation of β-catenin upon FBXW2 knockdown. FBXW2 knockdown also reduced GSK3β and Axin2 levels.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Western blotting, shRNA knockdown\",\n      \"journal\": \"International journal of medical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and ubiquitination assay; single lab, largely confirmatory of prior β-catenin finding\",\n      \"pmids\": [\"40225854\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXW2 functions as the substrate-recognition subunit of the SCF(FBXW2) E3 ubiquitin ligase complex (together with SKP1 and CUL1, using UBE2D2 as the E2 enzyme) and promotes ubiquitin-proteasomal degradation of multiple substrates including SKP2, β-catenin (upon AKT1-mediated Ser552 phosphorylation), GCM1/GCMa (phosphorylation-dependent), MSX2 (VRK2-facilitated), NF-κB p65 (blocked by p300 acetylation), EGFR (via a TSNNST degron motif), Moesin (blocked by AKT-mediated Thr-558 phosphorylation), KSRP, and WASL; FBXW2 is itself targeted for degradation by β-TrCP1, forming a β-TrCP1–FBXW2–SKP2 oncogene–tumor suppressor–oncogene cascade, and its transcription is repressed by FOXP2 in gastric cancer.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FBXW2 is the substrate-recognition subunit of an SCF(FBXW2) E3 ubiquitin ligase that assembles with SKP1 and CUL1 and directs ubiquitin-proteasomal degradation of a broad set of substrates, positioning it as a tumor suppressor across multiple cancer types [#0, #1, #4]. Substrate recognition is frequently gated by phosphorylation: it degrades GCM1/GCMa in a phosphorylation-dependent manner using UBE2D2 as the cognate E2 [#1, #2], engages \\u03b2-catenin only after EGF-AKT1-driven Ser552 phosphorylation to block \\u03b2-catenin-driven MMP transactivation and tumor cell invasion [#5], and binds MSX2 in a manner facilitated by hypoxia-induced VRK2, thereby controlling a downstream SOX2/stemness program [#6]. FBXW2 also targets EGFR through a defined TSNNST degron [#9], and degrades SKP2, NF-\\u03baB p65 (an activity blocked by p300-mediated p65 acetylation), Moesin (blocked by AKT-mediated Thr-558 phosphorylation), KSRP, and WASL, linking it to growth control, inflammation, and stemness [#4, #8, #10, #7, #11]. FBXW2 itself is regulated at the protein level by \\u03b2-TrCP1-mediated ubiquitylation, forming a \\u03b2-TrCP1\\u2013FBXW2\\u2013SKP2 cascade, and at the transcriptional level by FOXP2-mediated promoter repression [#4, #11]. Its activity is further tuned by competitors such as RACK1, which displaces GCM1 from FBXW2 to stabilize it [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that the FBXW2 ortholog is a bona fide F-box protein that nucleates an SCF complex, defining its core biochemical identity before any substrate was known.\",\n      \"evidence\": \"Co-immunoprecipitation showing SKP1 (via F-box) and CUL1 (via SKP1) binding, with cytoplasmic immunofluorescence localization in mouse cells\",\n      \"pmids\": [\"10585767\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No substrate identified at this stage\", \"E2 enzyme and catalytic output not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified the first FBXW2 substrate, GCM1/GCMa, showing FBXW2 functions as a phosphorylation-dependent degradation receptor within the SCF complex.\",\n      \"evidence\": \"Co-IP, in vivo ubiquitination assay, and RNAi knockdown with pulse-chase stability assay in human cells\",\n      \"pmids\": [\"15640526\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Specific phosphodegron residues on GCM1 not mapped\", \"E2 enzyme not identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined UBE2D2 as the E2 conjugating enzyme that powers SCF(FBXW2) ubiquitination, completing the enzymatic core of the ligase.\",\n      \"evidence\": \"In vitro ubiquitination with an E2 panel, RNAi knockdown, in vivo ubiquitination and half-life assays\",\n      \"pmids\": [\"18703417\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether UBE2D2 serves all FBXW2 substrates not tested\", \"Chain linkage type not characterized\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed FBXW2 substrate targeting can be antagonized by competitive WD-repeat binding, revealing a layer of regulation over substrate access.\",\n      \"evidence\": \"TAP-MS, Co-IP, RNAi, ubiquitination and migration/invasion assays demonstrating RACK1 competes with GCM1 for FBXW2\",\n      \"pmids\": [\"23651062\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of RACK1-FBXW2 competition not resolved\", \"Generality of competitive antagonism for other substrates unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed FBXW2 in a regulatory cascade, showing it is both a substrate of \\u03b2-TrCP1 and an E3 ligase for the oncoprotein SKP2, establishing its tumor-suppressor role in lung cancer.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assay, cycloheximide-chase half-life assay, and in vivo gain/loss-of-function lung cancer models\",\n      \"pmids\": [\"28090088\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"SKP2 degron on FBXW2 recognition not mapped\", \"Inputs controlling \\u03b2-TrCP1 targeting of FBXW2 unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Expanded the substrate repertoire to \\u03b2-catenin and MSX2 and demonstrated that upstream kinases (AKT1, VRK2) gate substrate recognition, linking FBXW2 to invasion and stemness programs.\",\n      \"evidence\": \"Co-IP, ubiquitination, half-life assays, and in vivo models; phosphorylation-dependent binding (AKT1-Ser552 on \\u03b2-catenin; hypoxia/VRK2 on MSX2)\",\n      \"pmids\": [\"30918250\", \"31548378\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether \\u03b2-catenin and MSX2 degrons share a consensus motif unresolved\", \"Cross-talk between the two cascades not examined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended FBXW2 function beyond cancer into innate immunity by identifying KSRP as a substrate driving proinflammatory macrophage responses.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, and myeloid-specific knockout mouse models\",\n      \"pmids\": [\"33101872\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"KSRP degron not mapped\", \"Reciprocal validation in human cells limited\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified NF-\\u03baB p65 as an FBXW2 substrate and showed acetylation can override ubiquitination, revealing post-translational competition controlling stemness signaling.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assay, FBXW2-knockout mice, and in vivo breast cancer tumor models; p300 acetylation blocks p65 ubiquitination\",\n      \"pmids\": [\"34465889\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Which p65 lysines are acetyl/ubiquitin-competing not fully defined\", \"Interplay with canonical NF-\\u03baB degradation pathways unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined an explicit TSNNST degron in EGFR recognized by FBXW2, providing the first sequence-level motif for FBXW2 substrate engagement.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, cycloheximide-chase half-life assay, and dominant-negative FBXW2 mutant analysis in prostate cancer models\",\n      \"pmids\": [\"35499593\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether the TSNNST motif is shared by other FBXW2 substrates not tested\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed Moesin is an FBXW2 substrate whose AKT-phosphorylated form not only escapes degradation but feeds back to block FBXW2-mediated SKP2 turnover, defining an AKT-Moesin-SKP2 oncogenic axis.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, kinase assay, and in vivo gain/loss-of-function studies; AKT Thr-558 phosphorylation weakens FBXW2-Moesin binding\",\n      \"pmids\": [\"37736741\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism of Moesin-driven non-degradable SKP2 polyubiquitination not detailed\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified WASL as a substrate and FOXP2 as a transcriptional repressor of FBXW2, adding transcriptional control to its regulation in gastric cancer.\",\n      \"evidence\": \"Label-free proteomics, Co-IP, ubiquitination assay, ChIP-PCR and DNA pull-down with in vivo models\",\n      \"pmids\": [\"40721413\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"WASL degron not mapped\", \"Breadth of FOXP2-FBXW2 regulation beyond gastric cancer unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether the diverse FBXW2 substrates share a unifying degron logic and how the multiple phosphorylation/acetylation switches are coordinated within a cell.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of FBXW2 substrate recognition\", \"No systematic comparison of degron motifs across substrates\", \"Physiological substrate hierarchy in normal tissues undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 4, 5, 6, 8, 9, 10, 11]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [1, 4, 5, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 4, 5, 6, 8, 9, 10, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5, 6, 8, 9, 11]}\n    ],\n    \"complexes\": [\"SCF(FBXW2) E3 ubiquitin ligase\"],\n    \"partners\": [\"SKP1\", \"CUL1\", \"UBE2D2\", \"RACK1\", \"SKP2\", \"CTNNB1\", \"EGFR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}