Affinage

FBXL14

F-box/LRR-repeat protein 14 · UniProt Q8N1E6

Length
418 aa
Mass
45.9 kDa
Annotated
2026-04-28
24 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FBXL14 is the substrate-recognition subunit of an SCF-type E3 ubiquitin ligase that polyubiquitinates and targets for proteasomal degradation a diverse set of short-lived regulatory proteins, thereby broadly controlling epithelial-mesenchymal transition, stem cell self-renewal, ribosome biogenesis, and cellular senescence. Its validated substrates include the EMT transcription factors SNAIL1 and Twist1, the oncoprotein c-Myc, the Notch effector HES1 (recognized via a conserved WRPW motif), the transmembrane adaptor CDCP1, the RNA Polymerase I catalytic subunit RPA194, vimentin, and the phosphatase DUSP6 (PMID:19955572, PMID:26257063, PMID:27923907, PMID:29070679, PMID:29973690, PMID:36372232, PMID:33801272, PMID:40051291). FBXL14-mediated ubiquitination is antagonized by the deubiquitinase USP13—whose activity toward c-Myc and Twist1 is enhanced by CLK3-dependent phosphorylation—and by substrate modifications such as SNAIL1 acetylation (read by BRD4) and β-hydroxybutyrylation at K152, which sterically block FBXL14 recognition (PMID:27923907, PMID:36732432, PMID:32453420, PMID:31311807, PMID:40675949). FBXL14 expression itself is suppressed during hypoxia (partly via TWIST1) and by oncogenic miR-17/20a, and its access to substrates is modulated by the upstream kinase LKB1 and the sequestering protein NIPSNAP1 (PMID:19955572, PMID:29973690, PMID:29601127, PMID:37340421).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2009 High

    Identifying FBXL14 as a GSK-3β-independent E3 ligase for SNAIL1 established it as a new node controlling EMT independently of the canonical β-TrCP pathway and revealed that hypoxia stabilizes SNAIL1 by repressing FBXL14 expression.

    Evidence Co-IP, in vivo ubiquitination assays, shRNA knockdown stabilizing endogenous SNAIL1, hypoxia and TWIST1-siRNA experiments in human cancer cells

    PMID:19955572

    Open questions at the time
    • No structural basis for SNAIL1 recognition by FBXL14
    • Whether FBXL14 targets additional EMT factors was unknown
    • Mechanism of TWIST1-mediated FBXL14 transcriptional repression not defined
  2. 2015 Medium

    Demonstrating that FBXL14 also ubiquitinates and degrades Twist1 expanded its role from a single-substrate EMT regulator to a broad EMT-suppressive E3 ligase and showed that small molecules (imipramine blue) could pharmacologically enhance this activity.

    Evidence Polyubiquitination assays, FBXL14 overexpression/knockdown, imipramine blue treatment in head and neck squamous cell carcinoma cells

    PMID:26257063

    Open questions at the time
    • Direct binding site on Twist1 not mapped
    • Mechanism by which imipramine blue enhances FBXL14 activity unresolved
    • No in vivo validation of Twist1 degradation by FBXL14
  3. 2016 High

    Showing that FBXL14 ubiquitinates c-Myc and that USP13 antagonizes this activity established a ubiquitin-deubiquitinase axis governing glioblastoma stem cell self-renewal, with genetic epistasis (T58A-c-Myc rescue) confirming substrate specificity.

    Evidence FBXL14 overexpression causing c-Myc degradation and GSC differentiation, T58A-c-Myc mutant rescue, USP13 depletion promoting c-Myc ubiquitination, in vivo tumor growth assays

    PMID:27923907

    Open questions at the time
    • Whether T58 phosphorylation is required for FBXL14 recognition or is coincidental
    • Structural basis for FBXL14-c-Myc interaction unknown
    • Generalizability of FBXL14-c-Myc axis beyond GSCs not tested
  4. 2017 High

    Identification of a conserved WRPW motif on HES1 as the FBXL14 recognition element provided the first degron-level characterization of an FBXL14 substrate and linked FBXL14 to Notch pathway regulation and neuronal differentiation.

    Evidence siRNA screen, Co-IP, in vivo ubiquitination, WRPW motif mutagenesis, RBX1/CUL1 knockdown, neuronal differentiation assays in mES and F9 cells

    PMID:29070679

    Open questions at the time
    • Whether the WRPW-type motif is shared by other FBXL14 substrates not tested
    • No crystal structure of FBXL14-HES1 interaction
    • Role of FBXL14 in Notch signaling in vivo not established
  5. 2018 Medium

    Two studies extended the FBXL14 substrate repertoire and its regulatory logic: LKB1 was shown to facilitate the SNAIL1–FBXL14 interaction, and miR-17/20a were identified as transcriptional repressors of FBXL14 that stabilize the transmembrane adaptor CDCP1 in breast cancer.

    Evidence Co-IP of LKB1-SNAIL1-FBXL14 ternary complex with metformin modulation; Co-IP and ubiquitination assays for CDCP1, miR-17/20a regulation of FBXL14 mRNA

    PMID:29601127 PMID:29973690

    Open questions at the time
    • Whether LKB1 phosphorylates SNAIL1 directly to promote FBXL14 binding is unclear
    • Direct binding of FBXL14 to CDCP1 cytoplasmic domain not mapped
    • Whether miR-17/20a regulation of FBXL14 extends to non-breast tissues unknown
  6. 2019 Medium

    Showing that BRD4 reads acetylated K146/K187 on SNAIL1 to shield it from FBXL14 and β-TrCP1 recognition established substrate post-translational modification as a competitive mechanism blocking FBXL14 access.

    Evidence Co-IP, ubiquitination assays, acetylation site mutagenesis (K146/K187), BRD4 overexpression/knockdown effects on SNAIL1 stability and FBXL14 interaction

    PMID:31311807

    Open questions at the time
    • Identity of the acetyltransferase modifying K146/K187 not determined in this study
    • Whether BRD4-mediated shielding applies to other FBXL14 substrates unknown
    • Quantitative competition between BRD4 binding and FBXL14 recognition not measured
  7. 2020 Medium

    Placing FBXL14 downstream of the CLK3–USP13 kinase–deubiquitinase axis for c-Myc stabilization in cholangiocarcinoma revealed a phosphorylation-dependent switch (USP13-Y708) that controls FBXL14-mediated c-Myc turnover and downstream purine metabolism.

    Evidence In vitro kinase assay (CLK3 phosphorylating USP13-Y708), Co-IP, ubiquitination assay, metabolic profiling in cholangiocarcinoma cells

    PMID:32453420

    Open questions at the time
    • Whether CLK3-USP13 axis also regulates FBXL14-mediated degradation of substrates other than c-Myc unknown
    • No direct structural evidence for how Y708 phosphorylation enhances USP13–c-Myc binding
  8. 2021 Medium

    Demonstrating that IGFBP-3 acts as a co-adaptor to promote vimentin association with FBXL14 and subsequent degradation extended the model that FBXL14 substrate recruitment can be facilitated by accessory proteins.

    Evidence Co-IP with domain mapping (IGFBP-3 C-terminus and vimentin head domain), ubiquitination assay, migration/invasion assays, Igfbp3 KO mice

    PMID:33801272

    Open questions at the time
    • Whether FBXL14 can ubiquitinate vimentin without IGFBP-3 not tested
    • Specific ubiquitinated lysines on vimentin not identified
    • In vivo validation of FBXL14 role in vimentin turnover lacking
  9. 2022 High

    An RNAi screen identified FBXL14 as the E3 ligase responsible for stress-induced degradation of RPA194 (RNA Pol I catalytic subunit), linking FBXL14 for the first time to ribosome biogenesis and transcriptional stress responses, with degradation-site lysines mapped in the yeast ortholog.

    Evidence RNAi screen, Co-IP, ubiquitination assays in BMH-21-treated cancer cells, yeast lysine mutagenesis (K1150/K1153/K1156 on Rpa190)

    PMID:36372232

    Open questions at the time
    • Human RPA194 ubiquitination sites not directly confirmed
    • How transcriptional stress triggers FBXL14 recruitment to RPA194 unknown
    • Whether this pathway operates under physiological (non-drug) stress unclear
  10. 2023 Medium

    Two studies refined the antagonistic regulation of FBXL14: USP13 was shown to specifically cleave K48-linked polyubiquitin chains on Twist1 placed by FBXL14 (with Twist1 in turn repressing USP13 transcription), while NIPSNAP1 was found to sequester FBXL14 itself to prevent c-Myc degradation and suppress senescence.

    Evidence GST-pulldown and K48-specific ubiquitination assay for USP13-Twist1; proteomic screening, Co-IP (NIPSNAP1-FBXL14), senescence and xenograft assays for NIPSNAP1

    PMID:36732432 PMID:37340421

    Open questions at the time
    • Whether NIPSNAP1 sequesters FBXL14 from all substrates or selectively from c-Myc unknown
    • Structural basis of NIPSNAP1-FBXL14 interaction not determined
    • Physiological contexts regulating USP13-Twist1 feedback loop not defined
  11. 2025 Medium

    β-Hydroxybutyrylation of SNAIL1 at K152 was identified as a second metabolite-driven modification that blocks FBXL14 recognition, and DUSP6 was added as a new FBXL14 substrate linking the ligase to NRF2 signaling and atherosclerosis.

    Evidence Mass spectrometry, K152 mutagenesis, Co-IP showing reduced FBXL14-SNAIL1 interaction; IP-based ubiquitination of DUSP6, siRNA/OE rescue, ApoE−/− mouse model

    PMID:40051291 PMID:40675949

    Open questions at the time
    • Whether β-hydroxybutyrylation affects FBXL14 recognition of substrates beyond SNAIL1 unknown
    • Direct in vitro reconstitution of FBXL14-mediated DUSP6 ubiquitination not shown
    • Physiological regulation of FBXL14 in vascular cells not characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • No structural model of FBXL14 exists, the degron rules governing its broad substrate selectivity remain undefined beyond the WRPW motif of HES1, and whether FBXL14 activity is itself regulated by post-translational modification or auto-ubiquitination has not been addressed.
  • No crystal or cryo-EM structure of FBXL14 or any FBXL14–substrate complex
  • Consensus degron motif across diverse substrates not established
  • Post-translational regulation of FBXL14 protein itself unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10
Localization
GO:0005829 cytosol 3
Pathway
R-HSA-392499 Metabolism of proteins 10 R-HSA-162582 Signal Transduction 2 R-HSA-1266738 Developmental Biology 1
Partners
CDCP1HES1MYCNIPSNAP1POLR1ASNAI1TWIST1USP13
Complex memberships
SCF-FBXL14 (SKP1-CUL1-FBXL14-RBX1)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 FBXL14 (FBXl14) functions as an F-box E3 ubiquitin ligase that directly interacts with SNAIL1, promotes its polyubiquitination, and targets it for proteasome degradation independently of GSK-3β phosphorylation. FBXL14 expression is downregulated during hypoxia (partly via TWIST1), providing a mechanism for hypoxia-induced SNAIL1 stabilization. Co-immunoprecipitation, ubiquitination assays, shRNA knockdown of FBXL14 (stabilized endogenous and ectopic SNAIL1), siRNA for Twist1 preventing Fbxl14 downregulation The Journal of biological chemistry High 19955572
2016 FBXL14 mediates ubiquitination and proteasomal degradation of c-Myc in glioblastoma stem cells (GSCs). The deubiquitinase USP13 antagonizes FBXL14-mediated c-Myc ubiquitination to stabilize c-Myc; the ubiquitin-insensitive T58A-c-Myc mutant rescues FBXL14 overexpression effects, placing FBXL14 upstream of c-Myc in GSC self-renewal. Overexpression of FBXL14 (c-Myc degradation, GSC differentiation, tumor growth inhibition), epistasis with T58A-c-Myc mutant rescue, USP13 depletion promoting c-Myc ubiquitination The Journal of experimental medicine High 27923907
2015 FBXL14 promotes polyubiquitination of the EMT transcription factor Twist1 and targets it for proteasome degradation. The compound imipramine blue enhances FBXL14-mediated Twist1 ubiquitination, suppressing EMT in head and neck squamous cell carcinoma cells. Polyubiquitination assays, FBXL14 overexpression/knockdown, imipramine blue treatment with FBXL14-dependent Twist1 degradation measured by Western blot and functional invasion assays Oncogene Medium 26257063
2017 The SCF-FBXL14 complex ubiquitinates HES1 and promotes its proteasomal degradation. A conserved WRPW motif in the C-terminus of HES1 is required for binding to FBXL14 and for ubiquitin-dependent HES1 degradation. FBXL14 knockdown stabilizes HES1 and inhibits neuronal differentiation. siRNA screen, co-immunoprecipitation, in vivo ubiquitination assay, FBXL14 overexpression/silencing (HES1 levels and half-life), WRPW motif mutagenesis, RBX1/CUL1 knockdown, neuronal differentiation assays in mES and F9 cells The Journal of biological chemistry High 29070679
2018 FBXL14 interacts with CDCP1 (CUB-domain-containing protein 1), a transmembrane adaptor protein, and facilitates its ubiquitination and proteasomal degradation, thereby suppressing breast cancer metastasis. miR-17/20a repress FBXL14 expression, establishing FBXL14 as an upstream regulator of the CDCP1 pathway. Co-immunoprecipitation, ubiquitination assays, FBXL14 overexpression suppressing CDCP1 protein stability, miR-17/20a regulation of FBXL14 Oncogene Medium 29973690
2018 LKB1 promotes SNAIL1 interaction with FBXL14, leading to increased ubiquitin-mediated SNAIL1 degradation. Metformin augments cytoplasmic localization of LKB1 and its expression, increasing Snail ubiquitination via the LKB1/FBXL14/Snail axis. Co-immunoprecipitation (LKB1 boosting SNAIL1-FBXL14 interaction), ubiquitination assays, LKB1 knockdown/overexpression, metformin treatment altering LKB1 localization and Snail ubiquitination Cancer science Medium 29601127
2019 BRD4, an acetylation reader, binds acetylated lysines K146 and K187 on SNAIL1 in an acetylation-dependent manner to prevent SNAIL1 recognition by FBXL14 and β-TrCP1, thereby blocking SNAIL1 polyubiquitination and proteasomal degradation. Co-immunoprecipitation, ubiquitination assays, acetylation site mutagenesis (K146/K187), BRD4 overexpression/knockdown effects on Snail stability and FBXL14 interaction Cancer research Medium 31311807
2022 FBXL14 (as part of an SCF complex) is the E3 ubiquitin ligase that ubiquitinates and promotes proteasomal degradation of RPA194, the catalytic subunit of RNA Polymerase I, in response to transcriptional stress (induced by BMH-21). Mutation analysis in yeast identified lysines K1150, K1153, and K1156 on Rpa190 (yeast ortholog) as relevant degradation sites. RNAi screen, Co-IP (FBXL14 binding RPA194), ubiquitination assays in cancer cells treated with BMH-21, yeast lysine mutagenesis identifying degradation sites The Journal of biological chemistry High 36372232
2021 IGFBP-3 binds vimentin directly (via C-terminal domain of IGFBP-3 and the head domain of vimentin) and promotes vimentin association with FBXL14, leading to vimentin proteasomal degradation and suppression of cancer cell migration and invasion. Co-immunoprecipitation, domain mapping (C-terminal IGFBP-3 and vimentin head domain interaction), FBXL14-mediated vimentin ubiquitination assay, in vitro and in vivo migration/invasion assays, Igfbp3 KO mice Cancers Medium 33801272
2023 USP13 stabilizes Twist1 by cleaving K48-linked polyubiquitin chains induced by FBXL14. FBXL14 directly ubiquitinates Twist1, and USP13 directly interacts with Twist1 to antagonize FBXL14-mediated ubiquitination, promoting breast cancer metastasis. Twist1 in turn transcriptionally represses USP13, forming a negative feedback loop. Co-immunoprecipitation, GST-pulldown, ubiquitination assay (K48-linkage specificity), USP13 overexpression/knockdown on Twist1 protein levels, ChIP and luciferase reporter (Twist1 repressing USP13 transcription), in vivo lung metastasis assay Cellular oncology Medium 36732432
2023 FBXL14 mediates ubiquitination and proteasomal degradation of c-Myc. NIPSNAP1 sequesters FBXL14 to prevent c-Myc turnover, maintaining c-Myc levels and cancer cell proliferation while suppressing P27-dependent senescence. Proteomic screening, RNAi knockdown, co-immunoprecipitation (NIPSNAP1-FBXL14 interaction), proteasome degradation assays, colony formation, cell cycle, senescence assays (SA-β-gal, SAHF), xenograft model Journal of translational medicine Medium 37340421
2025 FBXL14 ubiquitinates DUSP6 and promotes its proteasomal degradation, leading to activation of the NRF2 signaling pathway and suppression of foam cell formation and inflammation in atherosclerosis. Immunoprecipitation (DUSP6 ubiquitination), bioinformatics identification of FBXL14 as E3 ligase for DUSP6, siRNA/overexpression experiments, Western blot for NRF2 pathway activation, Oil Red O staining and cholesterol assays, ApoE-/- mouse model with sh-DUSP6 adenovirus Journal of receptor and signal transduction research Medium 40051291
2025 β-Hydroxybutyrylation (Kbhb) of SNAIL1 at lysine K152 prevents recognition of SNAIL1 by FBXL14 (and other E3 ligases), blocking ubiquitin-mediated degradation and enhancing SNAIL1 stability to promote pancreatic cancer metastasis. Mass spectrometry identification of Kbhb site, site-specific mutagenesis (K152), co-immunoprecipitation showing reduced FBXL14-SNAIL1 interaction upon K152 modification, ubiquitination assays, in vivo metastasis models Nature communications Medium 40675949
2020 CLK3 phosphorylates USP13 at Y708, which promotes USP13 binding to c-Myc and prevents FBXL14-mediated c-Myc ubiquitination, thereby activating c-Myc transcriptional targets including purine metabolic genes in cholangiocarcinoma. In vitro kinase assay (CLK3 phosphorylating USP13-Y708), Co-immunoprecipitation (USP13 binding c-Myc), ubiquitination assay (FBXL14-mediated c-Myc ubiquitination rescued by CLK3/USP13 axis), metabolic profiling The Journal of experimental medicine Medium 32453420

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 The hypoxia-controlled FBXL14 ubiquitin ligase targets SNAIL1 for proteasome degradation. The Journal of biological chemistry 156 19955572
2016 Deubiquitinase USP13 maintains glioblastoma stem cells by antagonizing FBXL14-mediated Myc ubiquitination. The Journal of experimental medicine 129 27923907
2015 F-box proteins: Keeping the epithelial-to-mesenchymal transition (EMT) in check. Seminars in cancer biology 109 26506454
2019 BRD4 Promotes Gastric Cancer Progression and Metastasis through Acetylation-Dependent Stabilization of Snail. Cancer research 104 31311807
2013 Nuclear ubiquitination by FBXL5 modulates Snail1 DNA binding and stability. Nucleic acids research 84 24157836
2013 Degradation of the transcription factor Twist, an oncoprotein that promotes cancer metastasis. Discovery medicine 67 23375009
2020 Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism. The Journal of experimental medicine 54 32453420
2015 Imipramine blue halts head and neck cancer invasion through promoting F-box and leucine-rich repeat protein 14-mediated Twist1 degradation. Oncogene 45 26257063
2018 LKB1 obliterates Snail stability and inhibits pancreatic cancer metastasis in response to metformin treatment. Cancer science 32 29601127
2010 1.39 Mb inherited interstitial deletion in 12p13.33 associated with developmental delay. European journal of medical genetics 26 21144913
2014 A 1.5Mb terminal deletion of 12p associated with autism spectrum disorder. Gene 20 24613754
2023 USP13 promotes breast cancer metastasis through FBXL14-induced Twist1 ubiquitination. Cellular oncology (Dordrecht, Netherlands) 19 36732432
2018 FBXL14 abolishes breast cancer progression by targeting CDCP1 for proteasomal degradation. Oncogene 18 29973690
2017 The E3 ubiquitin ligase SCFFBXL14 complex stimulates neuronal differentiation by targeting the Notch signaling factor HES1 for proteolysis. The Journal of biological chemistry 16 29070679
2021 Insulin-Like Growth Factor Binding Protein-3 Exerts Its Anti-Metastatic Effect in Aerodigestive Tract Cancers by Disrupting the Protein Stability of Vimentin. Cancers 14 33801272
2023 NIPSNAP1 directs dual mechanisms to restrain senescence in cancer cells. Journal of translational medicine 12 37340421
2022 Establishment and characterization of the third non-functional human pancreatic neuroendocrine tumor cell line. Human cell 12 35394261
2022 Identification of an E3 ligase that targets the catalytic subunit of RNA Polymerase I upon transcription stress. The Journal of biological chemistry 9 36372232
2025 β-Hydroxybutyrate promotes cancer metastasis through β-hydroxybutyrylation-dependent stabilization of Snail. Nature communications 5 40675949
2018 Characterization of the F-box Proteins FBXW2 and FBXL14 in the Initiation of Bone Regeneration in Transplants given to Nude Mice. The open biomedical engineering journal 5 30450135
2022 Identification of the key exosomal lncRNAs/mRNAs in the serum during distraction osteogenesis. Journal of orthopaedic surgery and research 2 35643547
2025 FBXL14 inhibits foam cell formation and atherosclerosis plaque progression by activating the NRF2 signal axis through ubiquitination of DUSP6. Journal of receptor and signal transduction research 1 40051291
2023 Identification of hypertrophy-modulating Cullin-RING ubiquitin ligases in primary cardiomyocytes. Frontiers in physiology 1 36969608
2025 Scaffold-Free Bone Regeneration Through Collaboration Between Type IV Collagen and FBXL14. Journal of clinical medicine 0 41156030