{"gene":"FBXO46","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2018,"finding":"FBXO46 forms an SCF E3 ubiquitin ligase complex (SCF^FBXO46) that recognizes an RXXR motif at the C-terminus of FBXO31 to direct its polyubiquitination and proteasomal degradation, thereby maintaining basal FBXO31 levels and preventing premature cellular senescence under unstressed conditions.","method":"Molecular docking, mutational studies, co-immunoprecipitation, ubiquitination assays, FBXO46 depletion with senescence readout","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (molecular docking, mutagenesis of recognition motif, ubiquitination assay, KD phenotype) in a single focused study","pmids":["30171069"],"is_preprint":false},{"year":2018,"finding":"Following DNA damage, ATM kinase phosphorylates FBXO46 at Ser-21/Ser-67, leading to FBXO46 degradation via FBXO31, establishing a negative feedback loop that abrogates FBXO46-mediated FBXO31 degradation and allows FBXO31 accumulation for genomic stability maintenance.","method":"Phosphorylation site mapping, ATM inhibitor/activator experiments, mutational studies, ubiquitination and degradation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — specific phosphorylation sites identified by mutagenesis, functional consequences demonstrated with multiple orthogonal assays in a single rigorous study","pmids":["30171069"],"is_preprint":false},{"year":2024,"finding":"FBXO46 directly binds to Mdm2 and inhibits its auto-ubiquitination and degradation, thereby stabilizing Mdm2 and promoting Mdm2-mediated ubiquitination and degradation of p53, resulting in enhanced cell proliferation and G1/S cell cycle progression.","method":"Co-immunoprecipitation (direct binding), ubiquitination assays (auto-ubiquitination inhibition), p53 degradation assays, cell proliferation and cell cycle analysis upon FBXO46 manipulation","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — single lab, direct binding and functional ubiquitination assays shown but no mutagenesis or structural validation reported in abstract","pmids":["39548735"],"is_preprint":false}],"current_model":"FBXO46 is an F-box protein that functions as the substrate-recognition subunit of an SCF E3 ubiquitin ligase complex: it targets FBXO31 for polyubiquitination and proteasomal degradation (via an RXXR motif) to prevent premature senescence under normal conditions, and it stabilizes Mdm2 by inhibiting its auto-ubiquitination, thereby suppressing p53 activity to promote cell cycle progression; following DNA damage, ATM phosphorylates FBXO46 causing its own degradation through FBXO31 in a negative feedback loop that restores FBXO31 levels for genomic stability."},"narrative":{"mechanistic_narrative":"FBXO46 is an F-box protein that serves as the substrate-recognition subunit of an SCF E3 ubiquitin ligase complex (SCF^FBXO46), coupling its activity to cell cycle progression, senescence control, and the DNA-damage response [PMID:30171069, PMID:39548735]. Under unstressed conditions it recognizes an RXXR motif at the C-terminus of FBXO31 to direct FBXO31 polyubiquitination and proteasomal degradation, holding FBXO31 at basal levels and thereby preventing premature cellular senescence [PMID:30171069]. FBXO46 also directly binds Mdm2 and blocks its auto-ubiquitination, stabilizing Mdm2 so that it can ubiquitinate and degrade p53, which enhances proliferation and G1/S progression [PMID:39548735]. Following DNA damage, ATM kinase phosphorylates FBXO46 at Ser-21 and Ser-67, triggering FBXO46 degradation through FBXO31 in a negative-feedback loop that relieves FBXO31 degradation and permits FBXO31 accumulation for genomic stability [PMID:30171069].","teleology":[{"year":2018,"claim":"Established FBXO46 as a functional SCF substrate-recognition subunit and identified its first substrate, defining how basal FBXO31 levels are set to restrain senescence.","evidence":"Molecular docking, RXXR-motif mutagenesis, co-IP, ubiquitination assays, and FBXO46 depletion with senescence readout in cells","pmids":["30171069"],"confidence":"High","gaps":["Full SCF complex composition (Skp1/Cul1/Rbx1 with FBXO46) not enumerated in the finding","No structural model of the FBXO46–FBXO31 interface beyond docking","Physiological contexts in which FBXO31-driven senescence is engaged not mapped"]},{"year":2018,"claim":"Resolved how the DNA-damage response reverses FBXO46 activity, showing ATM phosphorylation converts FBXO46 into a degradation substrate to create a self-limiting feedback loop.","evidence":"Phosphorylation-site mapping, ATM inhibitor/activator experiments, phospho-site mutagenesis, and degradation/ubiquitination assays","pmids":["30171069"],"confidence":"High","gaps":["Whether ATM phosphorylation acts as a degron recognized by FBXO31 directly is not detailed","Quantitative kinetics of the feedback loop after damage not established","Other kinases or DNA-damage inputs converging on FBXO46 not tested"]},{"year":2024,"claim":"Extended FBXO46 function beyond substrate degradation to substrate stabilization, showing it protects Mdm2 to suppress p53 and drive proliferation.","evidence":"Co-IP for direct binding, Mdm2 auto-ubiquitination inhibition assays, p53 degradation assays, and cell proliferation/cycle analysis upon FBXO46 manipulation","pmids":["39548735"],"confidence":"Medium","gaps":["No mutagenesis or structural validation of the FBXO46–Mdm2 interaction reported","Whether Mdm2 stabilization requires the SCF complex or is an F-box-independent activity is unclear","Single-lab finding without reciprocal or in vivo confirmation"]},{"year":null,"claim":"How FBXO46's two opposing activities—SCF-mediated FBXO31 degradation versus Mdm2 stabilization—are integrated within the same cell and which dominates in a given physiological or stress state remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No study reconciles the senescence/genomic-stability axis with the Mdm2–p53 proliferation axis","Broader substrate repertoire of SCF^FBXO46 unknown","In vivo and disease relevance not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1]}],"complexes":["SCF^FBXO46"],"partners":["FBXO31","MDM2","ATM","TP53"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6PJ61","full_name":"F-box only protein 46","aliases":["F-box only protein 34-like"],"length_aa":603,"mass_kda":64.6,"function":"Substrate-recognition component of the SCF(FBXO46) protein ligase complex, which mediates the ubiquitination and degradation of target proteins (PubMed:30171069). In absence of stress, the SCF(FBXO46) complex catalyzes ubiquitination and degradation of MTOR-phosphorylated FBXO31 (PubMed:30171069)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q6PJ61/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBXO46","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FBXO46","total_profiled":1310},"omim":[{"mim_id":"609117","title":"F-BOX ONLY PROTEIN 46; FBXO46","url":"https://www.omim.org/entry/609117"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FBXO46"},"hgnc":{"alias_symbol":["20D7-FC4","Fbx46"],"prev_symbol":["FBXO34L"]},"alphafold":{"accession":"Q6PJ61","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PJ61","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PJ61-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PJ61-F1-predicted_aligned_error_v6.png","plddt_mean":44.84},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBXO46","jax_strain_url":"https://www.jax.org/strain/search?query=FBXO46"},"sequence":{"accession":"Q6PJ61","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6PJ61.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6PJ61/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PJ61"}},"corpus_meta":[{"pmid":"34461747","id":"PMC_34461747","title":"Genome-Wide Association Meta-Analysis Supports Genes Involved in Valve and Cardiac Development to Associate With Mitral Valve Prolapse.","date":"2021","source":"Circulation. Genomic and precision medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34461747","citation_count":16,"is_preprint":false},{"pmid":"30171069","id":"PMC_30171069","title":"The SCFFBXO46 ubiquitin ligase complex mediates degradation of the tumor suppressor FBXO31 and thereby prevents premature cellular senescence.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30171069","citation_count":12,"is_preprint":false},{"pmid":"39548735","id":"PMC_39548735","title":"FBXO46 negatively regulates p53 activity by stabilizing Mdm2.","date":"2024","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/39548735","citation_count":1,"is_preprint":false},{"pmid":"39754775","id":"PMC_39754775","title":"PPA1, TRIM68 and FBXO46: Potential Therapeutic Targets for Triple Negative Breast Cancer.","date":"2025","source":"Current protein & peptide science","url":"https://pubmed.ncbi.nlm.nih.gov/39754775","citation_count":1,"is_preprint":false},{"pmid":"42017308","id":"PMC_42017308","title":"Genetic Architecture of Trans-Laminar Cribrosa Pressure Difference and Primary Open-Angle Glaucoma.","date":"2026","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/42017308","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4952,"output_tokens":911,"usd":0.014261,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7375,"output_tokens":1824,"usd":0.041238,"stage2_stop_reason":"end_turn"},"total_usd":0.055499,"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\": 2018,\n      \"finding\": \"FBXO46 forms an SCF E3 ubiquitin ligase complex (SCF^FBXO46) that recognizes an RXXR motif at the C-terminus of FBXO31 to direct its polyubiquitination and proteasomal degradation, thereby maintaining basal FBXO31 levels and preventing premature cellular senescence under unstressed conditions.\",\n      \"method\": \"Molecular docking, mutational studies, co-immunoprecipitation, ubiquitination assays, FBXO46 depletion with senescence readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (molecular docking, mutagenesis of recognition motif, ubiquitination assay, KD phenotype) in a single focused study\",\n      \"pmids\": [\"30171069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Following DNA damage, ATM kinase phosphorylates FBXO46 at Ser-21/Ser-67, leading to FBXO46 degradation via FBXO31, establishing a negative feedback loop that abrogates FBXO46-mediated FBXO31 degradation and allows FBXO31 accumulation for genomic stability maintenance.\",\n      \"method\": \"Phosphorylation site mapping, ATM inhibitor/activator experiments, mutational studies, ubiquitination and degradation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — specific phosphorylation sites identified by mutagenesis, functional consequences demonstrated with multiple orthogonal assays in a single rigorous study\",\n      \"pmids\": [\"30171069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBXO46 directly binds to Mdm2 and inhibits its auto-ubiquitination and degradation, thereby stabilizing Mdm2 and promoting Mdm2-mediated ubiquitination and degradation of p53, resulting in enhanced cell proliferation and G1/S cell cycle progression.\",\n      \"method\": \"Co-immunoprecipitation (direct binding), ubiquitination assays (auto-ubiquitination inhibition), p53 degradation assays, cell proliferation and cell cycle analysis upon FBXO46 manipulation\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — single lab, direct binding and functional ubiquitination assays shown but no mutagenesis or structural validation reported in abstract\",\n      \"pmids\": [\"39548735\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXO46 is an F-box protein that functions as the substrate-recognition subunit of an SCF E3 ubiquitin ligase complex: it targets FBXO31 for polyubiquitination and proteasomal degradation (via an RXXR motif) to prevent premature senescence under normal conditions, and it stabilizes Mdm2 by inhibiting its auto-ubiquitination, thereby suppressing p53 activity to promote cell cycle progression; following DNA damage, ATM phosphorylates FBXO46 causing its own degradation through FBXO31 in a negative feedback loop that restores FBXO31 levels for genomic stability.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FBXO46 is an F-box protein that serves as the substrate-recognition subunit of an SCF E3 ubiquitin ligase complex (SCF^FBXO46), coupling its activity to cell cycle progression, senescence control, and the DNA-damage response [#0, #2]. Under unstressed conditions it recognizes an RXXR motif at the C-terminus of FBXO31 to direct FBXO31 polyubiquitination and proteasomal degradation, holding FBXO31 at basal levels and thereby preventing premature cellular senescence [#0]. FBXO46 also directly binds Mdm2 and blocks its auto-ubiquitination, stabilizing Mdm2 so that it can ubiquitinate and degrade p53, which enhances proliferation and G1/S progression [#2]. Following DNA damage, ATM kinase phosphorylates FBXO46 at Ser-21 and Ser-67, triggering FBXO46 degradation through FBXO31 in a negative-feedback loop that relieves FBXO31 degradation and permits FBXO31 accumulation for genomic stability [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established FBXO46 as a functional SCF substrate-recognition subunit and identified its first substrate, defining how basal FBXO31 levels are set to restrain senescence.\",\n      \"evidence\": \"Molecular docking, RXXR-motif mutagenesis, co-IP, ubiquitination assays, and FBXO46 depletion with senescence readout in cells\",\n      \"pmids\": [\"30171069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full SCF complex composition (Skp1/Cul1/Rbx1 with FBXO46) not enumerated in the finding\",\n        \"No structural model of the FBXO46\\u2013FBXO31 interface beyond docking\",\n        \"Physiological contexts in which FBXO31-driven senescence is engaged not mapped\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved how the DNA-damage response reverses FBXO46 activity, showing ATM phosphorylation converts FBXO46 into a degradation substrate to create a self-limiting feedback loop.\",\n      \"evidence\": \"Phosphorylation-site mapping, ATM inhibitor/activator experiments, phospho-site mutagenesis, and degradation/ubiquitination assays\",\n      \"pmids\": [\"30171069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ATM phosphorylation acts as a degron recognized by FBXO31 directly is not detailed\",\n        \"Quantitative kinetics of the feedback loop after damage not established\",\n        \"Other kinases or DNA-damage inputs converging on FBXO46 not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended FBXO46 function beyond substrate degradation to substrate stabilization, showing it protects Mdm2 to suppress p53 and drive proliferation.\",\n      \"evidence\": \"Co-IP for direct binding, Mdm2 auto-ubiquitination inhibition assays, p53 degradation assays, and cell proliferation/cycle analysis upon FBXO46 manipulation\",\n      \"pmids\": [\"39548735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No mutagenesis or structural validation of the FBXO46\\u2013Mdm2 interaction reported\",\n        \"Whether Mdm2 stabilization requires the SCF complex or is an F-box-independent activity is unclear\",\n        \"Single-lab finding without reciprocal or in vivo confirmation\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FBXO46's two opposing activities\\u2014SCF-mediated FBXO31 degradation versus Mdm2 stabilization\\u2014are integrated within the same cell and which dominates in a given physiological or stress state remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No study reconciles the senescence/genomic-stability axis with the Mdm2\\u2013p53 proliferation axis\",\n        \"Broader substrate repertoire of SCF^FBXO46 unknown\",\n        \"In vivo and disease relevance not established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"SCF^FBXO46\"],\n    \"partners\": [\"FBXO31\", \"MDM2\", \"ATM\", \"TP53\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}