{"gene":"FBXW11","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2016,"finding":"FBXW11 serves as the F-box substrate recognition subunit of the SCF(FBXW11) E3 ubiquitin ligase complex that mediates proteasomal degradation of PKR (protein kinase R) during Rift Valley fever virus (RVFV) infection. The viral NSs protein recruits PKR to the SCF(FBXW11) complex by binding FBXW11 via a six-amino-acid degron sequence (DDGFVE) and recruiting PKR through an alternate binding site. siRNA knockdown of FBXW11 or MLN4924 treatment blocked PKR degradation, activating PKR and suppressing RVFV replication.","method":"siRNA knockdown, small-molecule inhibitor (MLN4924), degron mutant viruses, co-immunoprecipitation","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional evidence from multiple orthogonal approaches (siRNA, inhibitor, viral degron mutants) replicated across two independent labs (PMID:26837067 and PMID:27122577)","pmids":["26837067","27122577"],"is_preprint":false},{"year":2016,"finding":"Both FBXW11 and β-TRCP1 (FBXW1) F-box proteins are required for full NSs-mediated PKR degradation; maximal PKR protection required simultaneous knockdown of both paralogs. NSs was found to interact with both FBXW11 and β-TRCP1.","method":"siRNA screen of ~70 human F-box proteins, co-immunoprecipitation, PKR phosphorylation assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide siRNA screen plus Co-IP, single lab, orthogonal validation by eIF2α phosphorylation","pmids":["27122577"],"is_preprint":false},{"year":2014,"finding":"SCF(FBXW11) binds, polyubiquitylates, and destabilizes RAPGEF2 (a RAP1 guanine nucleotide exchange factor). Substrate trapping proteomics identified 21 known and 23 novel candidate substrates for FBXW11.","method":"PAC (parallel adapter capture) substrate-trapping proteomics with proteasome inhibition, mass spectrometry, immunopurification, ubiquitination assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate-trapping MS plus functional ubiquitination assay for RAPGEF2, single lab","pmids":["25332235"],"is_preprint":false},{"year":2019,"finding":"De novo missense variants in FBXW11 clustering at the surface loops of the substrate-binding WD40 domain cause diverse developmental anomalies in humans. Structural analyses predicted destabilization of the protein and/or its substrate interactions. Knockdown of zebrafish fbxw11a and fbxw11b orthologs produced smaller/misshapen eyes and abnormal jaw and pectoral fin development, consistent with roles in Wnt (β-catenin) and Hh (GLI) signaling during development.","method":"Whole exome/genome sequencing, structural modeling, in situ hybridization, zebrafish morpholino knockdown","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — zebrafish loss-of-function with specific developmental phenotypes plus structural analysis; genetic evidence links substrate-binding domain to function","pmids":["31402090"],"is_preprint":false},{"year":2021,"finding":"FBXW11 physically interacts with ASK1 (apoptosis signal-regulating kinase 1) and promotes its ubiquitination, leading to aberrant activation of NF-κB and MAPK signaling pathways in microglial cells. Hippocampus-specific knockout of FBXW11 reduced Aβ plaque load, neuronal death, and microglial activation in Alzheimer's disease mouse models through restraint of ASK1/MAPKs/NF-κB signaling.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, hippocampus-specific knockout mouse model, immunofluorescence","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo KO model, single lab","pmids":["33640602"],"is_preprint":false},{"year":2021,"finding":"FBXW11 targets HIC1 (hypermethylated in cancer 1) for ubiquitination and proteasomal degradation in colorectal cancer cells. Loss of HIC1 leads to upregulation of SIRT1 transcription, promoting stem-cell-like features and liver metastasis.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA/shRNA knockdown, xenograft mouse models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay plus in vivo xenograft, single lab","pmids":["34642302"],"is_preprint":false},{"year":2025,"finding":"FBXW11 mechanistically promotes HIC1 ubiquitination and proteasomal degradation in pancreatic acinar cells during acute pancreatitis. This releases IRF1 from transcriptional suppression by HIC1, increasing inflammatory cytokine production (IL-6, TNF-α, IL-1β). Silencing FBXW11 reduced inflammation and apoptosis in vitro and in vivo.","method":"Co-immunoprecipitation, ubiquitination assay, chromatin immunoprecipitation (ChIP), murine cerulein AP model, RNA-seq","journal":"Digestive diseases and sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination, ChIP assays plus in vivo model, single lab","pmids":["41288880"],"is_preprint":false},{"year":2024,"finding":"FBXW11 ubiquitinates IL-17RA through K27-linked polyubiquitin chains, targeting it for proteasomal degradation. The domain spanning residues 665–804 of IL-17RA is critical for interaction with FBXW11 and subsequent ubiquitination.","method":"Co-immunoprecipitation, ubiquitination assay, domain mapping, bioinformatics","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping and ubiquitination linkage type identified, single lab","pmids":["38672111"],"is_preprint":false},{"year":2025,"finding":"FBXW11 directly interacts with the cold shock domain (CSD) of YB1 and promotes K48-linked polyubiquitination and proteasomal degradation of YB1 in hepatocellular carcinoma, thereby suppressing the YB1/Akt/mTOR signaling pathway and inhibiting tumor growth.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, xenograft mouse models, rescue experiments with YB1 re-expression","journal":"Journal of cancer research and clinical oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain identification, K48-linkage specificity, in vivo xenograft rescue, single lab","pmids":["40944757"],"is_preprint":false},{"year":2025,"finding":"FBXW11 targets S100A11 for ubiquitination-mediated proteasomal degradation in ovarian cancer cells. Increased S100A11 degradation leads to less efficient DNA damage repair, sensitizing cells to PARP inhibitors.","method":"4D label-free quantitative proteomics, ubiquitination assay, siRNA/overexpression, xenograft mouse models","journal":"Journal of pharmaceutical analysis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic substrate identification plus ubiquitination assay and in vivo validation, single lab","pmids":["40747341"],"is_preprint":false},{"year":2025,"finding":"A recurrent FBXW11 missense mutation (p.F517S) found in salivary basal cell adenomas causes defective binding to β-catenin, resulting in higher nuclear β-catenin levels and activation of the Wnt/β-catenin pathway. This mutation is mutually exclusive with CTNNB1 gain-of-function mutations, establishing FBXW11-mediated β-catenin binding/degradation as the canonical tumor suppressive mechanism.","method":"Next-generation sequencing of tumor cohort, in vitro binding assays for β-catenin interaction, immunofluorescence for nuclear β-catenin, mutual exclusivity analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional binding assay with mutant plus in situ nuclear localization evidence, single cohort","pmids":["40389436"],"is_preprint":false},{"year":2025,"finding":"circMAN1A2 competes with FBXW11 for binding to SFPQ, preventing FBXW11-mediated K48-linked ubiquitination and proteasomal degradation of SFPQ, thereby stabilizing SFPQ expression in gastric cancer cells.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, RNA pull-down","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay with K48-linkage specificity demonstrated, single lab; note this establishes SFPQ as an FBXW11 substrate","pmids":["39856764"],"is_preprint":false},{"year":2018,"finding":"Fbxw11 overexpression in lymphocytic leukemia cells promotes cell proliferation and cell cycle progression through concomitant activation of NF-κB and β-catenin/TCF signaling pathways, as demonstrated by reporter gene assays and blocking experiments.","method":"Cell proliferation assays, reporter gene assays, pathway blocking experiments, xenograft tumor formation in vivo","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — reporter assays and pharmacological blocking establish pathway activation but no direct substrate ubiquitination shown; single lab","pmids":["29555946"],"is_preprint":false}],"current_model":"FBXW11 (βTrCP2) is an F-box substrate-recognition subunit of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex that binds substrates via its WD40 repeat domain and promotes their polyubiquitination and proteasomal degradation; established substrates include β-catenin (regulating Wnt/Hh signaling), PKR (hijacked by RVFV NSs via a DDGFVE degron), RAPGEF2, HIC1 (releasing SIRT1/IRF1 transcription), ASK1 (modulating NF-κB/MAPK), YB1 (K48-linked, suppressing Akt/mTOR), S100A11 (affecting DNA repair), IL-17RA (K27-linked), and SFPQ, with loss-of-function mutations in the substrate-binding domain causing developmental anomalies by impairing substrate interactions."},"narrative":{"mechanistic_narrative":"FBXW11 (βTrCP2) is the substrate-recognition F-box subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase that selects diverse substrates for polyubiquitination and proteasomal degradation, thereby tuning developmental and inflammatory signaling pathways [PMID:26837067, PMID:27122577, PMID:25332235]. It engages substrates through its WD40 domain and assembles them into a CUL1-based ligase whose activity is neddylation-dependent, as PKR degradation during Rift Valley fever virus infection is abolished by the neddylation inhibitor MLN4924; in this case the viral NSs protein hijacks FBXW11 (and its paralog β-TRCP1/FBXW1) via a DDGFVE degron to redirect the ligase against the antiviral kinase PKR [PMID:26837067, PMID:27122577]. The canonical physiological output is restraint of Wnt/β-catenin signaling: a recurrent p.F517S mutation in the substrate-binding domain abolishes β-catenin binding, elevates nuclear β-catenin, and is mutually exclusive with CTNNB1 gain-of-function mutations in salivary basal cell adenoma, defining FBXW11-mediated β-catenin turnover as a tumor-suppressive mechanism [PMID:40389436]. Beyond β-catenin, FBXW11 directs degradation of a broad substrate set with linkage-specific chains — RAPGEF2 [PMID:25332235], the transcriptional repressor HIC1 (de-repressing SIRT1 and IRF1) [PMID:34642302, PMID:41288880], ASK1 (driving NF-κB/MAPK signaling in microglia) [PMID:33640602], YB1 via K48 chains (suppressing Akt/mTOR) [PMID:40944757], IL-17RA via K27 chains [PMID:38672111], S100A11 (impairing DNA repair) [PMID:40747341], and SFPQ [PMID:39856764] — placing the ligase at control points in inflammation, DNA-damage response, and tumor growth. De novo missense variants clustering on the WD40 surface loops cause human developmental anomalies, and knockdown of zebrafish orthologs disrupts eye, jaw, and fin development consistent with impaired β-catenin/GLI signaling [PMID:31402090].","teleology":[{"year":2014,"claim":"Established FBXW11 as a substrate-selecting SCF subunit with a definable substrate repertoire, moving beyond single known targets to a proteome-scale catalog.","evidence":"Parallel adapter capture substrate-trapping proteomics with proteasome inhibition and a ubiquitination assay validating RAPGEF2","pmids":["25332235"],"confidence":"Medium","gaps":["Most of the 23 novel candidate substrates were not individually validated","Physiological contexts for RAPGEF2 degradation not defined"]},{"year":2016,"claim":"Showed the SCF(FBXW11) ligase can be hijacked by a viral protein to eliminate an antiviral kinase, defining a degron-based substrate-redirection mechanism.","evidence":"siRNA knockdown, MLN4924 neddylation inhibition, viral degron mutants, and Co-IP in RVFV infection; F-box siRNA screen showing both FBXW11 and β-TRCP1 are required","pmids":["26837067","27122577"],"confidence":"High","gaps":["Relative contribution of FBXW11 versus β-TRCP1 to PKR turnover not quantified","Whether endogenous (non-viral) degrons engage PKR not addressed"]},{"year":2019,"claim":"Linked FBXW11 substrate-binding domain integrity to human development, establishing that WD40-surface variants cause developmental anomalies through impaired substrate engagement.","evidence":"Whole exome/genome sequencing, structural modeling, and zebrafish ortholog morpholino knockdown with eye/jaw/fin phenotypes","pmids":["31402090"],"confidence":"Medium","gaps":["Direct substrate(s) responsible for developmental phenotypes not pinpointed","Morpholino phenotypes not confirmed with stable genetic mutants"]},{"year":2021,"claim":"Connected FBXW11 to inflammatory and neurodegenerative signaling via degradation of ASK1 and the repressor HIC1, revealing context-specific disease roles.","evidence":"Co-IP, ubiquitination assays, siRNA knockdown, and tissue-specific knockout/xenograft mouse models in Alzheimer's and colorectal cancer settings","pmids":["33640602","34642302"],"confidence":"Medium","gaps":["Ubiquitin chain linkage types for ASK1 and HIC1 not defined","Each mechanism shown in a single lab and single disease context"]},{"year":2024,"claim":"Demonstrated linkage-specific ubiquitination by FBXW11, expanding its output beyond canonical K48 degradation signals.","evidence":"Co-IP, domain mapping (IL-17RA residues 665–804), and ubiquitination assays identifying K27-linked chains on IL-17RA","pmids":["38672111"],"confidence":"Medium","gaps":["Functional consequence of K27 chains on IL-17RA signaling not fully resolved","Single-lab finding without in vivo confirmation"]},{"year":2025,"claim":"Consolidated FBXW11 as a tumor suppressor whose substrate-binding-domain mutation activates Wnt/β-catenin, and broadened its substrate set across multiple cancers (YB1, S100A11, SFPQ, HIC1/IRF1).","evidence":"Tumor cohort sequencing with β-catenin binding assays and mutual-exclusivity analysis; Co-IP/MS, K48-linkage ubiquitination assays, ChIP, RNA pull-down, and xenograft rescue across HCC, ovarian, gastric, and pancreatic models","pmids":["40389436","40944757","40747341","39856764","41288880"],"confidence":"Medium","gaps":["Each substrate validated in a single tumor type and lab","Whether one ligase regulates these substrates simultaneously in the same cell is untested"]},{"year":null,"claim":"It remains unresolved how FBXW11 substrate choice and ubiquitin-chain linkage (K48 vs K27) are governed across tissues, and how its activity is distributed relative to the paralog β-TRCP1.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of FBXW11 bound to most substrates","Determinants of K27 versus K48 chain selection unknown","Functional redundancy versus specialization with FBXW1 not systematically mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,4,5,7,8,9,11]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,2,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,3]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,4,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,7,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,5,8,9,10]}],"complexes":["SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase"],"partners":["CTNNB1","PKR","RAPGEF2","ASK1","HIC1","YB1","IL17RA","SFPQ"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UKB1","full_name":"F-box/WD repeat-containing protein 11","aliases":["F-box and WD repeats protein beta-TrCP2","F-box/WD repeat-containing protein 1B","Homologous to Slimb protein","HOS"],"length_aa":542,"mass_kda":62.1,"function":"Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:10437795, PubMed:10648623, PubMed:11158290, PubMed:19966869, PubMed:20347421, PubMed:22017875, PubMed:22017876, PubMed:36608670). Probably recognizes and binds to phosphorylated target proteins: the interaction with substrates requires the phosphorylation of the two serine residues in the substrates' destruction motif D-S-G-X(2,3,4)-S (PubMed:10437795, PubMed:10648623, PubMed:19966869, PubMed:20347421, PubMed:22017875, PubMed:22017876, PubMed:36608670). SCF(FBXW11) mediates the ubiquitination of phosphorylated CTNNB1 and participates in Wnt signaling regulation (PubMed:10321728). SCF(FBXW11) plays a key role in NF-kappa-B activation by mediating ubiquitination of phosphorylated NFKBIA, leading to its degradation by the proteasome, thereby allowing the associated NF-kappa-B complex to translocate into the nucleus and to activate transcription (PubMed:10321728, PubMed:10437795, PubMed:10644755, PubMed:20347421). The SCF(FBXW11) complex also regulates NF-kappa-B by mediating ubiquitination of phosphorylated NFKB1: specifically ubiquitinates the p105 form of NFKB1, leading to its degradation (PubMed:11158290). SCF(FBXW11) mediates the ubiquitination of IFNAR1 (PubMed:14532120, PubMed:15337770). SCF(FBXW11) mediates the ubiquitination of CEP68; this is required for centriole separation during mitosis (PubMed:25503564). Involved in the oxidative stress-induced a ubiquitin-mediated decrease in RCAN1 (PubMed:18575781). Mediates the degradation of CDC25A induced by ionizing radiation in cells progressing through S phase and thus may function in the intra-S-phase checkpoint (PubMed:14603323). Has an essential role in the control of the clock-dependent transcription via degradation of phosphorylated PER1 and phosphorylated PER2 (PubMed:15917222). SCF(FBXW11) mediates the ubiquitination of CYTH1, and probably CYTH2 (PubMed:29420262). SCF(FBXW11) acts as a regulator of mTORC1 signaling pathway by catalyzing ubiquitination and subsequent proteasomal degradation of phosphorylated DEPTOR, TFE3 and MITF (PubMed:22017875, PubMed:22017876, PubMed:36608670) (Microbial infection) Target of human immunodeficiency virus type 1 (HIV-1) protein VPU to polyubiquitinate and deplete BST2 from cells and antagonize its antiviral action","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UKB1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBXW11","classification":"Not Classified","n_dependent_lines":573,"n_total_lines":1208,"dependency_fraction":0.47433774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FBXW11","total_profiled":1310},"omim":[{"mim_id":"618914","title":"NEURODEVELOPMENTAL, JAW, EYE, AND DIGITAL SYNDROME; NEDJED","url":"https://www.omim.org/entry/618914"},{"mim_id":"614460","title":"UBIQUITIN-SPECIFIC PROTEASE 47; USP47","url":"https://www.omim.org/entry/614460"},{"mim_id":"609577","title":"CULLIN 7; CUL7","url":"https://www.omim.org/entry/609577"},{"mim_id":"605651","title":"F-BOX AND WD40 DOMAIN PROTEIN 11; FBXW11","url":"https://www.omim.org/entry/605651"},{"mim_id":"601434","title":"S-PHASE KINASE-ASSOCIATED PROTEIN 1; SKP1","url":"https://www.omim.org/entry/601434"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FBXW11"},"hgnc":{"alias_symbol":["KIAA0696","Fbw1b","BTRCP2","BTRC2","Hos","Fbw11"],"prev_symbol":["FBXW1B"]},"alphafold":{"accession":"Q9UKB1","domains":[{"cath_id":"1.20.1280.50","chopping":"118-191_199-223","consensus_level":"medium","plddt":94.3333,"start":118,"end":223},{"cath_id":"2.130.10.10","chopping":"228-525","consensus_level":"medium","plddt":97.3742,"start":228,"end":525}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKB1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKB1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKB1-F1-predicted_aligned_error_v6.png","plddt_mean":85.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBXW11","jax_strain_url":"https://www.jax.org/strain/search?query=FBXW11"},"sequence":{"accession":"Q9UKB1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UKB1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UKB1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKB1"}},"corpus_meta":[{"pmid":"26837067","id":"PMC_26837067","title":"Protein Kinase R Degradation Is Essential for Rift Valley Fever Virus Infection and Is Regulated by SKP1-CUL1-F-box (SCF)FBXW11-NSs E3 Ligase.","date":"2016","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/26837067","citation_count":62,"is_preprint":false},{"pmid":"25332235","id":"PMC_25332235","title":"Substrate trapping proteomics reveals targets of the βTrCP2/FBXW11 ubiquitin ligase.","date":"2014","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25332235","citation_count":56,"is_preprint":false},{"pmid":"27122577","id":"PMC_27122577","title":"NSs Virulence Factor of Rift Valley Fever Virus Engages the F-Box Proteins FBXW11 and β-TRCP1 To Degrade the Antiviral Protein Kinase PKR.","date":"2016","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/27122577","citation_count":51,"is_preprint":false},{"pmid":"29736206","id":"PMC_29736206","title":"MiR-182 promotes cell proliferation by suppressing FBXW7 and FBXW11 in non-small 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Degradation.","date":"2024","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/38672111","citation_count":3,"is_preprint":false},{"pmid":"40944757","id":"PMC_40944757","title":"FBXW11 inhibits tumorigenesis by ubiquitinating YB1 in hepatocarcinoma.","date":"2025","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40944757","citation_count":2,"is_preprint":false},{"pmid":"40747341","id":"PMC_40747341","title":"E3 ubiquitin ligase FBXW11-mediated downregulation of S100A11 promotes sensitivity to PARP inhibitor in ovarian cancer.","date":"2025","source":"Journal of pharmaceutical analysis","url":"https://pubmed.ncbi.nlm.nih.gov/40747341","citation_count":0,"is_preprint":false},{"pmid":"41934765","id":"PMC_41934765","title":"FBXW11 regulates macrophage polarization and enhances the anti-tumor activity.","date":"2026","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41934765","citation_count":0,"is_preprint":false},{"pmid":"41288880","id":"PMC_41288880","title":"Mechanistic Investigation of FBXW11-Mediated Ubiquitination and Degradation of HIC1 in Regulating IRF1 Transcription and Accelerating Acute Pancreatitis Progression.","date":"2025","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41288880","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.21.619442","title":"Activation of Wnt/β-catenin signalling by mutually exclusive  <i>FBXW11</i>  and  <i>CTNNB1</i>  hotspot mutations drives salivary gland basal cell adenoma","date":"2024-10-24","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.21.619442","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.31.630861","title":"Single-cell RNA sequencing analysis reveals new insights for intersex gonad initiation and early sex differentiation of goats","date":"2024-12-31","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.31.630861","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15186,"output_tokens":3309,"usd":0.047596,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10867,"output_tokens":3027,"usd":0.065005,"stage2_stop_reason":"end_turn"},"total_usd":0.112601,"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\": 2016,\n      \"finding\": \"FBXW11 serves as the F-box substrate recognition subunit of the SCF(FBXW11) E3 ubiquitin ligase complex that mediates proteasomal degradation of PKR (protein kinase R) during Rift Valley fever virus (RVFV) infection. The viral NSs protein recruits PKR to the SCF(FBXW11) complex by binding FBXW11 via a six-amino-acid degron sequence (DDGFVE) and recruiting PKR through an alternate binding site. siRNA knockdown of FBXW11 or MLN4924 treatment blocked PKR degradation, activating PKR and suppressing RVFV replication.\",\n      \"method\": \"siRNA knockdown, small-molecule inhibitor (MLN4924), degron mutant viruses, co-immunoprecipitation\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional evidence from multiple orthogonal approaches (siRNA, inhibitor, viral degron mutants) replicated across two independent labs (PMID:26837067 and PMID:27122577)\",\n      \"pmids\": [\"26837067\", \"27122577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Both FBXW11 and β-TRCP1 (FBXW1) F-box proteins are required for full NSs-mediated PKR degradation; maximal PKR protection required simultaneous knockdown of both paralogs. NSs was found to interact with both FBXW11 and β-TRCP1.\",\n      \"method\": \"siRNA screen of ~70 human F-box proteins, co-immunoprecipitation, PKR phosphorylation assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide siRNA screen plus Co-IP, single lab, orthogonal validation by eIF2α phosphorylation\",\n      \"pmids\": [\"27122577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SCF(FBXW11) binds, polyubiquitylates, and destabilizes RAPGEF2 (a RAP1 guanine nucleotide exchange factor). Substrate trapping proteomics identified 21 known and 23 novel candidate substrates for FBXW11.\",\n      \"method\": \"PAC (parallel adapter capture) substrate-trapping proteomics with proteasome inhibition, mass spectrometry, immunopurification, ubiquitination assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate-trapping MS plus functional ubiquitination assay for RAPGEF2, single lab\",\n      \"pmids\": [\"25332235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"De novo missense variants in FBXW11 clustering at the surface loops of the substrate-binding WD40 domain cause diverse developmental anomalies in humans. Structural analyses predicted destabilization of the protein and/or its substrate interactions. Knockdown of zebrafish fbxw11a and fbxw11b orthologs produced smaller/misshapen eyes and abnormal jaw and pectoral fin development, consistent with roles in Wnt (β-catenin) and Hh (GLI) signaling during development.\",\n      \"method\": \"Whole exome/genome sequencing, structural modeling, in situ hybridization, zebrafish morpholino knockdown\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — zebrafish loss-of-function with specific developmental phenotypes plus structural analysis; genetic evidence links substrate-binding domain to function\",\n      \"pmids\": [\"31402090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBXW11 physically interacts with ASK1 (apoptosis signal-regulating kinase 1) and promotes its ubiquitination, leading to aberrant activation of NF-κB and MAPK signaling pathways in microglial cells. Hippocampus-specific knockout of FBXW11 reduced Aβ plaque load, neuronal death, and microglial activation in Alzheimer's disease mouse models through restraint of ASK1/MAPKs/NF-κB signaling.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, hippocampus-specific knockout mouse model, immunofluorescence\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo KO model, single lab\",\n      \"pmids\": [\"33640602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBXW11 targets HIC1 (hypermethylated in cancer 1) for ubiquitination and proteasomal degradation in colorectal cancer cells. Loss of HIC1 leads to upregulation of SIRT1 transcription, promoting stem-cell-like features and liver metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA/shRNA knockdown, xenograft mouse models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay plus in vivo xenograft, single lab\",\n      \"pmids\": [\"34642302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXW11 mechanistically promotes HIC1 ubiquitination and proteasomal degradation in pancreatic acinar cells during acute pancreatitis. This releases IRF1 from transcriptional suppression by HIC1, increasing inflammatory cytokine production (IL-6, TNF-α, IL-1β). Silencing FBXW11 reduced inflammation and apoptosis in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, chromatin immunoprecipitation (ChIP), murine cerulein AP model, RNA-seq\",\n      \"journal\": \"Digestive diseases and sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination, ChIP assays plus in vivo model, single lab\",\n      \"pmids\": [\"41288880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBXW11 ubiquitinates IL-17RA through K27-linked polyubiquitin chains, targeting it for proteasomal degradation. The domain spanning residues 665–804 of IL-17RA is critical for interaction with FBXW11 and subsequent ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, domain mapping, bioinformatics\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping and ubiquitination linkage type identified, single lab\",\n      \"pmids\": [\"38672111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXW11 directly interacts with the cold shock domain (CSD) of YB1 and promotes K48-linked polyubiquitination and proteasomal degradation of YB1 in hepatocellular carcinoma, thereby suppressing the YB1/Akt/mTOR signaling pathway and inhibiting tumor growth.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, xenograft mouse models, rescue experiments with YB1 re-expression\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain identification, K48-linkage specificity, in vivo xenograft rescue, single lab\",\n      \"pmids\": [\"40944757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXW11 targets S100A11 for ubiquitination-mediated proteasomal degradation in ovarian cancer cells. Increased S100A11 degradation leads to less efficient DNA damage repair, sensitizing cells to PARP inhibitors.\",\n      \"method\": \"4D label-free quantitative proteomics, ubiquitination assay, siRNA/overexpression, xenograft mouse models\",\n      \"journal\": \"Journal of pharmaceutical analysis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic substrate identification plus ubiquitination assay and in vivo validation, single lab\",\n      \"pmids\": [\"40747341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A recurrent FBXW11 missense mutation (p.F517S) found in salivary basal cell adenomas causes defective binding to β-catenin, resulting in higher nuclear β-catenin levels and activation of the Wnt/β-catenin pathway. This mutation is mutually exclusive with CTNNB1 gain-of-function mutations, establishing FBXW11-mediated β-catenin binding/degradation as the canonical tumor suppressive mechanism.\",\n      \"method\": \"Next-generation sequencing of tumor cohort, in vitro binding assays for β-catenin interaction, immunofluorescence for nuclear β-catenin, mutual exclusivity analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional binding assay with mutant plus in situ nuclear localization evidence, single cohort\",\n      \"pmids\": [\"40389436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"circMAN1A2 competes with FBXW11 for binding to SFPQ, preventing FBXW11-mediated K48-linked ubiquitination and proteasomal degradation of SFPQ, thereby stabilizing SFPQ expression in gastric cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, RNA pull-down\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay with K48-linkage specificity demonstrated, single lab; note this establishes SFPQ as an FBXW11 substrate\",\n      \"pmids\": [\"39856764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Fbxw11 overexpression in lymphocytic leukemia cells promotes cell proliferation and cell cycle progression through concomitant activation of NF-κB and β-catenin/TCF signaling pathways, as demonstrated by reporter gene assays and blocking experiments.\",\n      \"method\": \"Cell proliferation assays, reporter gene assays, pathway blocking experiments, xenograft tumor formation in vivo\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reporter assays and pharmacological blocking establish pathway activation but no direct substrate ubiquitination shown; single lab\",\n      \"pmids\": [\"29555946\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXW11 (βTrCP2) is an F-box substrate-recognition subunit of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex that binds substrates via its WD40 repeat domain and promotes their polyubiquitination and proteasomal degradation; established substrates include β-catenin (regulating Wnt/Hh signaling), PKR (hijacked by RVFV NSs via a DDGFVE degron), RAPGEF2, HIC1 (releasing SIRT1/IRF1 transcription), ASK1 (modulating NF-κB/MAPK), YB1 (K48-linked, suppressing Akt/mTOR), S100A11 (affecting DNA repair), IL-17RA (K27-linked), and SFPQ, with loss-of-function mutations in the substrate-binding domain causing developmental anomalies by impairing substrate interactions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FBXW11 (\\u03b2TrCP2) is the substrate-recognition F-box subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase that selects diverse substrates for polyubiquitination and proteasomal degradation, thereby tuning developmental and inflammatory signaling pathways [#0, #2]. It engages substrates through its WD40 domain and assembles them into a CUL1-based ligase whose activity is neddylation-dependent, as PKR degradation during Rift Valley fever virus infection is abolished by the neddylation inhibitor MLN4924; in this case the viral NSs protein hijacks FBXW11 (and its paralog \\u03b2-TRCP1/FBXW1) via a DDGFVE degron to redirect the ligase against the antiviral kinase PKR [#0, #1]. The canonical physiological output is restraint of Wnt/\\u03b2-catenin signaling: a recurrent p.F517S mutation in the substrate-binding domain abolishes \\u03b2-catenin binding, elevates nuclear \\u03b2-catenin, and is mutually exclusive with CTNNB1 gain-of-function mutations in salivary basal cell adenoma, defining FBXW11-mediated \\u03b2-catenin turnover as a tumor-suppressive mechanism [#10]. Beyond \\u03b2-catenin, FBXW11 directs degradation of a broad substrate set with linkage-specific chains \\u2014 RAPGEF2 [#2], the transcriptional repressor HIC1 (de-repressing SIRT1 and IRF1) [#5, #6], ASK1 (driving NF-\\u03baB/MAPK signaling in microglia) [#4], YB1 via K48 chains (suppressing Akt/mTOR) [#8], IL-17RA via K27 chains [#7], S100A11 (impairing DNA repair) [#9], and SFPQ [#11] \\u2014 placing the ligase at control points in inflammation, DNA-damage response, and tumor growth. De novo missense variants clustering on the WD40 surface loops cause human developmental anomalies, and knockdown of zebrafish orthologs disrupts eye, jaw, and fin development consistent with impaired \\u03b2-catenin/GLI signaling [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established FBXW11 as a substrate-selecting SCF subunit with a definable substrate repertoire, moving beyond single known targets to a proteome-scale catalog.\",\n      \"evidence\": \"Parallel adapter capture substrate-trapping proteomics with proteasome inhibition and a ubiquitination assay validating RAPGEF2\",\n      \"pmids\": [\"25332235\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Most of the 23 novel candidate substrates were not individually validated\", \"Physiological contexts for RAPGEF2 degradation not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed the SCF(FBXW11) ligase can be hijacked by a viral protein to eliminate an antiviral kinase, defining a degron-based substrate-redirection mechanism.\",\n      \"evidence\": \"siRNA knockdown, MLN4924 neddylation inhibition, viral degron mutants, and Co-IP in RVFV infection; F-box siRNA screen showing both FBXW11 and \\u03b2-TRCP1 are required\",\n      \"pmids\": [\"26837067\", \"27122577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of FBXW11 versus \\u03b2-TRCP1 to PKR turnover not quantified\", \"Whether endogenous (non-viral) degrons engage PKR not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked FBXW11 substrate-binding domain integrity to human development, establishing that WD40-surface variants cause developmental anomalies through impaired substrate engagement.\",\n      \"evidence\": \"Whole exome/genome sequencing, structural modeling, and zebrafish ortholog morpholino knockdown with eye/jaw/fin phenotypes\",\n      \"pmids\": [\"31402090\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate(s) responsible for developmental phenotypes not pinpointed\", \"Morpholino phenotypes not confirmed with stable genetic mutants\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected FBXW11 to inflammatory and neurodegenerative signaling via degradation of ASK1 and the repressor HIC1, revealing context-specific disease roles.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, siRNA knockdown, and tissue-specific knockout/xenograft mouse models in Alzheimer's and colorectal cancer settings\",\n      \"pmids\": [\"33640602\", \"34642302\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin chain linkage types for ASK1 and HIC1 not defined\", \"Each mechanism shown in a single lab and single disease context\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated linkage-specific ubiquitination by FBXW11, expanding its output beyond canonical K48 degradation signals.\",\n      \"evidence\": \"Co-IP, domain mapping (IL-17RA residues 665\\u2013804), and ubiquitination assays identifying K27-linked chains on IL-17RA\",\n      \"pmids\": [\"38672111\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of K27 chains on IL-17RA signaling not fully resolved\", \"Single-lab finding without in vivo confirmation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Consolidated FBXW11 as a tumor suppressor whose substrate-binding-domain mutation activates Wnt/\\u03b2-catenin, and broadened its substrate set across multiple cancers (YB1, S100A11, SFPQ, HIC1/IRF1).\",\n      \"evidence\": \"Tumor cohort sequencing with \\u03b2-catenin binding assays and mutual-exclusivity analysis; Co-IP/MS, K48-linkage ubiquitination assays, ChIP, RNA pull-down, and xenograft rescue across HCC, ovarian, gastric, and pancreatic models\",\n      \"pmids\": [\"40389436\", \"40944757\", \"40747341\", \"39856764\", \"41288880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each substrate validated in a single tumor type and lab\", \"Whether one ligase regulates these substrates simultaneously in the same cell is untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how FBXW11 substrate choice and ubiquitin-chain linkage (K48 vs K27) are governed across tissues, and how its activity is distributed relative to the paralog \\u03b2-TRCP1.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of FBXW11 bound to most substrates\", \"Determinants of K27 versus K48 chain selection unknown\", \"Functional redundancy versus specialization with FBXW1 not systematically mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 4, 5, 7, 8, 9, 11]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 3]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 4, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 7, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 5, 8, 9, 10]}\n    ],\n    \"complexes\": [\"SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase\"],\n    \"partners\": [\"CTNNB1\", \"PKR\", \"RAPGEF2\", \"ASK1\", \"HIC1\", \"YB1\", \"IL17RA\", \"SFPQ\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}