Affinage

FBXW11

F-box/WD repeat-containing protein 11 · UniProt Q9UKB1

Length
542 aa
Mass
62.1 kDa
Annotated
2026-06-09
20 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2014 Medium

    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

    PMID:25332235

    Open questions at the time
    • Most of the 23 novel candidate substrates were not individually validated
    • Physiological contexts for RAPGEF2 degradation not defined
  2. 2016 High

    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

    PMID:26837067 PMID:27122577

    Open questions at the time
    • Relative contribution of FBXW11 versus β-TRCP1 to PKR turnover not quantified
    • Whether endogenous (non-viral) degrons engage PKR not addressed
  3. 2019 Medium

    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

    PMID:31402090

    Open questions at the time
    • Direct substrate(s) responsible for developmental phenotypes not pinpointed
    • Morpholino phenotypes not confirmed with stable genetic mutants
  4. 2021 Medium

    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

    PMID:33640602 PMID:34642302

    Open questions at the time
    • Ubiquitin chain linkage types for ASK1 and HIC1 not defined
    • Each mechanism shown in a single lab and single disease context
  5. 2024 Medium

    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

    PMID:38672111

    Open questions at the time
    • Functional consequence of K27 chains on IL-17RA signaling not fully resolved
    • Single-lab finding without in vivo confirmation
  6. 2025 Medium

    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

    PMID:39856764 PMID:40389436 PMID:40747341 PMID:40944757 PMID:41288880

    Open questions at the time
    • Each substrate validated in a single tumor type and lab
    • Whether one ligase regulates these substrates simultaneously in the same cell is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016874 ligase activity 3 GO:0098772 molecular function regulator activity 2
Pathway
R-HSA-1643685 Disease 5 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1266738 Developmental Biology 1
Partners
ASK1CTNNB1HIC1IL17RAPKRRAPGEF2SFPQYB1
Complex memberships
SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 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. siRNA knockdown, small-molecule inhibitor (MLN4924), degron mutant viruses, co-immunoprecipitation PLoS pathogens High 26837067 27122577
2016 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. siRNA screen of ~70 human F-box proteins, co-immunoprecipitation, PKR phosphorylation assays Journal of virology Medium 27122577
2014 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. PAC (parallel adapter capture) substrate-trapping proteomics with proteasome inhibition, mass spectrometry, immunopurification, ubiquitination assay Molecular and cellular biology Medium 25332235
2019 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. Whole exome/genome sequencing, structural modeling, in situ hybridization, zebrafish morpholino knockdown American journal of human genetics Medium 31402090
2021 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. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, hippocampus-specific knockout mouse model, immunofluorescence Biochemical and biophysical research communications Medium 33640602
2021 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. Co-immunoprecipitation, ubiquitination assay, siRNA/shRNA knockdown, xenograft mouse models Cell death & disease Medium 34642302
2025 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. Co-immunoprecipitation, ubiquitination assay, chromatin immunoprecipitation (ChIP), murine cerulein AP model, RNA-seq Digestive diseases and sciences Medium 41288880
2024 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. Co-immunoprecipitation, ubiquitination assay, domain mapping, bioinformatics Biomedicines Medium 38672111
2025 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. Co-immunoprecipitation, mass spectrometry, ubiquitination assay, xenograft mouse models, rescue experiments with YB1 re-expression Journal of cancer research and clinical oncology Medium 40944757
2025 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. 4D label-free quantitative proteomics, ubiquitination assay, siRNA/overexpression, xenograft mouse models Journal of pharmaceutical analysis Medium 40747341
2025 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. Next-generation sequencing of tumor cohort, in vitro binding assays for β-catenin interaction, immunofluorescence for nuclear β-catenin, mutual exclusivity analysis Nature communications Medium 40389436
2025 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. Co-immunoprecipitation, mass spectrometry, ubiquitination assay, RNA pull-down Journal of experimental & clinical cancer research Medium 39856764
2018 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. Cell proliferation assays, reporter gene assays, pathway blocking experiments, xenograft tumor formation in vivo Cell death & disease Low 29555946

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 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. PLoS pathogens 62 26837067
2014 Substrate trapping proteomics reveals targets of the βTrCP2/FBXW11 ubiquitin ligase. Molecular and cellular biology 56 25332235
2016 NSs Virulence Factor of Rift Valley Fever Virus Engages the F-Box Proteins FBXW11 and β-TRCP1 To Degrade the Antiviral Protein Kinase PKR. Journal of virology 51 27122577
2018 MiR-182 promotes cell proliferation by suppressing FBXW7 and FBXW11 in non-small cell lung cancer. American journal of translational research 49 29736206
2018 Fbxw11 promotes the proliferation of lymphocytic leukemia cells through the concomitant activation of NF-κB and β-catenin/TCF signaling pathways. Cell death & disease 45 29555946
2019 The long noncoding RNA PCGEM1 promotes cell proliferation, migration and invasion via targeting the miR-182/FBXW11 axis in cervical cancer. Cancer cell international 43 31832017
2019 De Novo Missense Variants in FBXW11 Cause Diverse Developmental Phenotypes Including Brain, Eye, and Digit Anomalies. American journal of human genetics 41 31402090
2021 FBXW11 contributes to stem-cell-like features and liver metastasis through regulating HIC1-mediated SIRT1 transcription in colorectal cancer. Cell death & disease 35 34642302
2020 MicroRNA-221 Promotes Cell Proliferation and Inhibits Apoptosis in Osteosarcoma Cells by Directly Targeting FBXW11 and Regulating Wnt Signaling. Archives of medical research 21 33131925
2006 Holoprosencephaly and preaxial polydactyly associated with a 1.24 Mb duplication encompassing FBXW11 at 5q35.1. Journal of human genetics 17 16865294
2021 FBXW11 deletion alleviates Alzheimer's disease by reducing neuroinflammation and amyloid-β plaque formation via repression of ASK1 signaling. Biochemical and biophysical research communications 15 33640602
2025 GC-derived exosomal circMAN1A2 promotes cancer progression and suppresses T-cell antitumour immunity by inhibiting FBXW11-mediated SFPQ degradation. Journal of experimental & clinical cancer research : CR 13 39856764
2025 Wnt/β-catenin activation by mutually exclusive FBXW11 and CTNNB1 hotspot mutations drives salivary basal cell adenoma. Nature communications 7 40389436
2023 Expression of FBXW11 in normal and disease-associated osteogenic cells. Journal of cellular and molecular medicine 7 37199076
2022 Fbxw11 impairs the repopulation capacity of hematopoietic stem/progenitor cells. Stem cell research & therapy 4 35690796
2024 SCFFBXW11 Complex Targets Interleukin-17 Receptor A for Ubiquitin-Proteasome-Mediated Degradation. Biomedicines 3 38672111
2025 FBXW11 inhibits tumorigenesis by ubiquitinating YB1 in hepatocarcinoma. Journal of cancer research and clinical oncology 2 40944757
2026 FBXW11 regulates macrophage polarization and enhances the anti-tumor activity. Molecular immunology 0 41934765
2025 E3 ubiquitin ligase FBXW11-mediated downregulation of S100A11 promotes sensitivity to PARP inhibitor in ovarian cancer. Journal of pharmaceutical analysis 0 40747341
2025 Mechanistic Investigation of FBXW11-Mediated Ubiquitination and Degradation of HIC1 in Regulating IRF1 Transcription and Accelerating Acute Pancreatitis Progression. Digestive diseases and sciences 0 41288880

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