Affinage

FBXW7

F-box/WD repeat-containing protein 7 · UniProt Q969H0

Length
707 aa
Mass
79.7 kDa
Annotated
2026-04-28
100 papers in source corpus 42 papers cited in narrative 42 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FBXW7 is the substrate-recognition subunit of an SCF-type E3 ubiquitin ligase (SCF^FBXW7) that controls the abundance of a broad network of phosphorylated substrates—including Notch intracellular domains, c-MYC, cyclin E, c-JUN, SOX9, REV-ERBα, rictor, EZH2, TPP1, YTHDF2, and others—by targeting them for K48-linked polyubiquitination and proteasomal degradation, thereby governing cell cycle progression, differentiation, metabolic homeostasis, circadian clock amplitude, telomere integrity, and innate immune sensing (PMID:11461910, PMID:18559665, PMID:27238018, PMID:33086033, PMID:32371478). Substrate recognition requires prior phosphorylation of conserved CDC4 phosphodegron (CPD) motifs by kinases such as GSK3β, CDK1, CDK2, CDK5, ERK, or CHEK1, and high-affinity binding is further modulated by multisite phosphorylation and Pin1-mediated prolyl isomerization (PMID:25897075, PMID:26206584, PMID:29225075, PMID:36991467). FBXW7 stability is itself tightly regulated: autocatalytic self-ubiquitylation—promoted by LSD1 pseudosubstrate binding that blocks FBXW7 dimerization—requires additional K11-branched ubiquitylation by TRIP12 for proteasomal delivery, while deubiquitinases USP28 and USP9X antagonize self-ubiquitylation to stabilize FBXW7, and kinases ERK and DYRK2 phosphorylate FBXW7 to promote its degradation (PMID:31152129, PMID:33824312, PMID:25437563, PMID:29346117, PMID:25753158, PMID:36934104). Germline missense variants clustering at the WD40 substrate-binding surface impair cyclin E turnover and cause a neurodevelopmental syndrome (PMID:35395208).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2001 High

    The initial mechanistic question—what does FBXW7 do biochemically—was resolved by demonstrating it is a ubiquitin ligase adaptor that directly ubiquitinates Notch intracellular domains in a phosphorylation- and PEST-domain-dependent manner, reducing Notch transcriptional activity.

    Evidence In vitro ubiquitination assay, co-IP, luciferase reporter in two independent labs

    PMID:11461910 PMID:11585921

    Open questions at the time
    • Full phosphodegron motif not yet defined
    • Other substrates unknown
    • In vivo relevance not yet established
  2. 2003 High

    Whether FBXW7 has physiological relevance in vivo was established by Fbxw7-null mouse embryos dying at E10.5–11.5 with vascular defects caused specifically by Notch4 accumulation, demonstrating substrate-selective in vivo function.

    Evidence Fbxw7 knockout mice with substrate-level Western blot and vascular explant cultures

    PMID:14672936

    Open questions at the time
    • Mechanism of substrate selectivity (Notch4 but not Notch1/2/3) unclear
    • Adult tissue functions unknown
  3. 2004 High

    FBXW7's role as a tumor suppressor was established by showing it is haploinsufficient and p53-dependent for tumor suppression, with substrate accumulation (Aurora-A, c-Jun, Notch4) driving oncogenesis.

    Evidence Genetic screen in p53+/− mice, siRNA in MEFs

    PMID:15592418

    Open questions at the time
    • Complete substrate repertoire in tumorigenesis unresolved
    • Molecular basis of haploinsufficiency unclear
  4. 2007 High

    Cancer-associated FBW7 mutations were mapped to the phosphodegron-binding surface, explaining how they abolish NICD ubiquitination and cause therapy (GSI) resistance in T-ALL, while viral LANA was shown to competitively inhibit the same surface.

    Evidence Mutational analysis with binding assays in T-ALL samples; competition binding in KSHV-infected cells

    PMID:17646409 PMID:17909182

    Open questions at the time
    • Structural basis of mutation effects not resolved at atomic level
    • Full spectrum of cancer-relevant substrates affected by each mutation unknown
  5. 2008 High

    Isoform-specific functions were delineated: the nucleoplasmic Fbxw7α isoform accounts for nearly all activity toward cyclin E, c-Myc, and SREBP1, and cyclin E sensitivity varies with cell cycle phase through CDK2-dependent autophosphorylation.

    Evidence AAV-mediated isoform-specific gene targeting in human cells with cell cycle synchronization

    PMID:18559665

    Open questions at the time
    • Functions of β and γ isoforms largely uncharacterized
    • Regulation of isoform expression not defined
  6. 2011 High

    Tissue-specific conditional knockouts revealed that FBXW7 controls organ-level cell fate decisions: liver-specific deletion caused steatohepatitis and biliary hamartomas (rescued by RBP-J deletion, proving Notch-dependence), gut-specific deletion accumulated DEK affecting RNA splicing, and cerebellar deletion caused Purkinje cell defects rescued by c-Jun pathway suppression.

    Evidence Liver, gut, and cerebellar conditional KOs with genetic epistasis (RBP-J, c-Jun/junAA double mutants)

    PMID:21123947 PMID:21282377 PMID:21827743

    Open questions at the time
    • Substrate hierarchy in each tissue not fully resolved
    • How FBXW7 substrate selection differs across tissues is mechanistically unclear
  7. 2014 High

    The first regulatory axis controlling FBXW7 stability was defined: USP28 preferentially antagonizes FBXW7 autocatalytic self-ubiquitylation in a dose-dependent manner to stabilize FBXW7 and maintain substrate degradation.

    Evidence Usp28 KO mice (dose-dependent), substrate stability assays in MEFs

    PMID:25437563

    Open questions at the time
    • Molecular basis of USP28 selectivity for auto- vs. substrate-ubiquitylation unknown
    • Whether USP28 acts redundantly with other DUBs not resolved
  8. 2015 High

    Multiple new substrates and the first kinase-driven FBXW7 destabilization mechanism were identified: ERK phosphorylates FBXW7 at Thr205 to trigger its degradation; GSK3β-phosphorylated rictor and CDK5-phosphorylated NDE1 were validated as CPD-dependent substrates connecting FBXW7 to mTORC2 signaling and ciliogenesis, respectively.

    Evidence In vitro kinase assays, phosphosite mutagenesis (T205A, T1695, NDE1 degron), co-IP, epistasis for ciliary length

    PMID:25753158 PMID:25897075 PMID:26206584

    Open questions at the time
    • Whether ERK phosphorylation of FBXW7 occurs on all isoforms not tested
    • Structural basis of CDK5-primed NDE1 degron recognition unresolved
  9. 2016 High

    FBXW7's role was extended beyond cell cycle to circadian and developmental programs: CDK1-phosphorylated REV-ERBα is an FBXW7 substrate controlling circadian amplitude and hepatic metabolism, and GSK3-phosphorylated SOX9 is targeted to suppress medulloblastoma metastasis.

    Evidence Co-IP, ubiquitination assay, liver-specific disruption with metabolic phenotyping; SOX9 degron mutagenesis with in vivo metastasis assay

    PMID:27238018 PMID:27625374

    Open questions at the time
    • Whether all circadian substrates are FBXW7-dependent remains unknown
    • SOX9 degron phosphorylation kinetics not measured
  10. 2017 High

    The biophysical mechanism of CPD recognition was refined: NMR revealed that multisite phosphorylation of c-Jun is required for high-affinity Fbw7 binding, and Pin1-mediated prolyl isomerization modulates this interaction.

    Evidence NMR spectroscopy, fluorescence binding assays, mutagenesis, ubiquitination assays

    PMID:29225075

    Open questions at the time
    • Whether Pin1 regulation applies to other FBXW7 substrates not tested
    • Full structural model of FBXW7–c-Jun complex not determined
  11. 2018 High

    A second deubiquitinase, USP9X, was identified as a direct FBXW7 stabilizer; gut-specific Usp9x KO phenocopies Fbxw7 loss through c-Myc accumulation, and c-Myc heterozygosity rescues tumor burden, establishing the USP9X–FBXW7–c-MYC regulatory axis.

    Evidence MS interactome, co-IP, conditional KO, c-Myc heterozygosity epistasis in intestinal tumors

    PMID:29346117

    Open questions at the time
    • USP9X vs. USP28 specificity and redundancy not compared directly
    • Whether USP9X regulation is tissue-specific not fully defined
  12. 2019 High

    The mechanism of FBXW7 self-destruction was elucidated in molecular detail: LSD1 binds FBXW7 as a pseudosubstrate preventing dimerization and promoting self-ubiquitylation; separately, TRIP12 was shown to add K11-branched ubiquitin chains on auto-ubiquitylated FBXW7 (at K404/K412), which is required for proteasomal delivery, and FBXO45-MYCBP2 targets FBXW7 for degradation specifically during prolonged mitotic arrest.

    Evidence Co-IP, dimerization assays, ubiquitin chain mapping, TRIP12 KO, p62 KO, FBXO45 KO with mitotic fate analysis

    PMID:31152129 PMID:31285543 PMID:33824312

    Open questions at the time
    • Whether LSD1 pseudosubstrate mechanism operates in all tissues unclear
    • Relative contribution of TRIP12 vs. FBXO45 to FBXW7 turnover not compared
  13. 2019 High

    FBXW7's substrate network was expanded to immune and metabolic regulation: EZH2 degradation in macrophages de-represses CCL2/CCL7 to control inflammatory cell recruitment, and PKM2 degradation modulates NADPH/ROS balance to regulate macrophage inflammatory polarization.

    Evidence Myeloid-specific conditional KO, ChIP for H3K27me3, metabolic flux analysis, pharmacological rescue

    PMID:31246581 PMID:32853822

    Open questions at the time
    • Whether FBXW7 regulates additional epigenetic modifiers in macrophages untested
    • Direct ubiquitination of PKM2 not validated by in vitro reconstitution
  14. 2020 High

    FBXW7 was shown to ubiquitinate TPP1 (shelterin component), triggering telomere uncapping and DNA damage response; FBXW7 inhibition by a peptidomimetic (TELODIN) protected telomeres and alleviated lung fibrosis, revealing a telomere maintenance function.

    Evidence Ubiquitination assay with multisite mapping, FBW7 conditional KO, peptidomimetic inhibitor, lung fibrosis mouse model

    PMID:33086033

    Open questions at the time
    • Phosphodegron on TPP1 not mapped
    • Whether FBXW7-TPP1 axis operates in stem cells or cancer not examined
  15. 2020 Medium

    FBXW7 inactivation was linked to immune evasion: loss reduces MDA5/RIG-I dsRNA sensor expression, diminishing type I IFN and MHC-I, and sensitization to anti-PD-1 can be restored by reconstituting dsRNA sensing, establishing FBXW7 as a determinant of tumor immunogenicity.

    Evidence CRISPR KO in murine tumors, in vivo anti-PD-1 experiments, gene expression analysis

    PMID:32371478

    Open questions at the time
    • Direct substrate mediating dsRNA sensor downregulation not identified
    • Whether this mechanism operates across cancer types unknown
  16. 2022 High

    Germline FBXW7 missense variants at the WD40 substrate-binding surface were shown to impair cyclin E turnover and cause a neurodevelopmental syndrome, establishing the first Mendelian disease caused by FBXW7 mutations.

    Evidence Crystal-structure modeling, cyclin E turnover assays, Drosophila neuronal knockdown with learning assay

    PMID:35395208

    Open questions at the time
    • Which substrate(s) drive the neurodevelopmental phenotype in patients not established
    • Whether Notch or c-MYC turnover is also affected in patient cells untested
  17. 2022 High

    The GSK3β/FBXW7 axis was shown to control ERRα stability for hepatic energy homeostasis, with phosphosite knock-in mice demonstrating that FBXW7-resistant ERRα causes insulin resistance and transcriptional reprogramming.

    Evidence Liver-specific conditional KO, ERRα 3SA phosphosite knock-in mice, metabolic phenotyping

    PMID:35440636

    Open questions at the time
    • Whether ERRα degradation is isoform-specific (α vs. β vs. γ) not tested
    • Relationship to REV-ERBα circadian axis not integrated
  18. 2023 Medium

    DYRK2 was identified as another kinase that phosphorylates and destabilizes FBXW7 independent of FBXW7 autoubiquitylation, and CHEK1-phosphorylated MAP4 was validated as a new FBXW7 substrate linking cytoskeletal regulation to MAPK/ERK signaling.

    Evidence Co-IP, kinase assays, phosphosite mutagenesis, LC-MS/MS, xenograft models

    PMID:36934104 PMID:36991467

    Open questions at the time
    • DYRK2 phosphorylation site on FBXW7 not mapped
    • Whether MAP4 degradation is tissue-specific not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for how FBXW7 dimerization versus monomerization switches between substrate ubiquitination and self-ubiquitination; substrate hierarchy and competition in different cell types; the direct substrate(s) mediating FBXW7's effects on innate immune sensing and tumor dormancy; and whether therapeutic modulation of FBXW7 stability (e.g., DUB inhibitors, kinase inhibitors) can be exploited for cancer treatment.
  • No full-length FBXW7–substrate co-crystal structure exists
  • Substrate competition model not quantitatively tested
  • In vivo therapeutic targeting of FBXW7 stability axis not validated in clinical trials

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 12 GO:0098772 molecular function regulator activity 5
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 1
Pathway
R-HSA-392499 Metabolism of proteins 12 R-HSA-162582 Signal Transduction 7 R-HSA-1430728 Metabolism 4 R-HSA-1643685 Disease 4 R-HSA-1640170 Cell Cycle 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1266738 Developmental Biology 2 R-HSA-9909396 Circadian clock 1
Partners
CUL1LSD1PIN1PLK1SKP1TRIP12USP28USP9X
Complex memberships
SCF^FBXW7 (SKP1-CUL1-FBXW7-RBX1)

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 mSel-10 (FBXW7) physically interacts with the Notch1 intracellular domain (IC), ubiquitinates it in a PEST-domain-dependent manner, and reduces Notch1 IC-mediated transcriptional activation; ubiquitination requires the proteasome pathway and ubiquitinated Notch1 IC is a less potent transactivator. Co-immunoprecipitation, in vitro ubiquitination assay, luciferase reporter assay, proteasome inhibitor (MG132) treatment The Journal of biological chemistry High 11461910
2001 SEL-10 (FBXW7) negatively regulates Notch1 and Notch4 signaling by targeting their intracellular domains for ubiquitin-mediated proteasomal degradation; SEL-10 binds Notch4 via its WD40 repeats and preferentially recognizes a phosphorylated form; dominant-negative SEL-10 (WD40-only) stabilizes Notch ICs and increases Notch1 signaling. Dominant-negative expression, co-immunoprecipitation, in vitro ubiquitination assay, domain mapping Molecular and cellular biology High 11585921
2002 Human SEL-10 (FBXW7) interacts with presenilin 1 (PS1), enhances PS1 ubiquitination, alters cellular levels of unprocessed PS1 and its fragments, and co-transfection with APP increases amyloid beta-peptide production. Co-immunoprecipitation, ubiquitination assay, co-transfection in HEK293 cells Journal of neurochemistry Medium 12354302
2003 Mouse Fbxw7 is required for vascular development; Fbxw7-null embryos die at E10.5–11.5 with vascular remodeling defects due to accumulation of Notch4 (but not Notch1/2/3 or cyclin E), leading to increased Hey1 expression and impaired vascular network formation. Fbxw7 knockout mice, Western blot for substrate accumulation, in vitro explant cultures The Journal of biological chemistry High 14672936
2004 Fbxw7 is a p53-dependent haploinsufficient tumor suppressor; Fbxw7-deficient mouse embryo fibroblasts have higher levels of Aurora-A kinase, c-Jun, and Notch4 (but not cyclin E), demonstrating substrate-specific regulation. Genetic screen in p53+/- mice, siRNA knockdown in MEFs, Western blot for substrates Nature High 15592418
2007 FBW7 mutations in T-ALL abolish binding to the Notch intracellular domain (NICD) phosphodegron, preventing NICD ubiquitination and degradation; these same mutants retain MYC binding but fail to target MYC for degradation, leading to resistance to gamma-secretase inhibitors. Mutational analysis, binding assays, GSI resistance assays in cell lines and primary T-ALL samples The Journal of experimental medicine High 17646409
2007 KSHV LANA directly interacts with Sel10/FBXW7 via LANA's C-terminus binding to the F-box and WD40 domains, competing with Notch ICN for Sel10 binding, thereby suppressing ICN ubiquitination and degradation and maintaining enhanced proliferation of KSHV-infected cells. Co-immunoprecipitation in KSHV-infected cells, competition binding assay, ubiquitination assay Proceedings of the National Academy of Sciences of the United States of America Medium 17909182
2008 The nucleoplasmic Fbxw7α isoform accounts for nearly all Fbw7 activity toward cyclin E, c-Myc, and SREBP1; cyclin E sensitivity to Fbw7 varies during the cell cycle, correlating with cyclin E-CDK2-specific activity, cyclin E autophosphorylation, and CDK2 inhibitory phosphorylation. Isoform-specific gene targeting in human cells (AAV-mediated), Western blot, cell cycle synchronization, kinase assays The Journal of cell biology High 18559665
2008 Fbxw7-deficient cells exposed to spindle toxins undergo polyploidy via elevated cyclin E and Aurora-A; combined deregulation of cyclin E and Aurora-A (both Fbxw7 substrates) is required for drug-induced endoreduplication, and Fbxw7 deficiency impairs p53-dependent induction of Lats2 and p21 in response to spindle toxins. Fbxw7 siRNA knockdown, overexpression of substrates, flow cytometry, Western blot Oncogene Medium 18391985
2009 Adenovirus E1A inhibits SCF(Fbw7) ubiquitin ligase by directly binding to Roc1/Rbx1 and CUL1, inhibiting the ubiquitin ligase activity of the Roc1/Rbx1-CUL1 complex in vitro and decelerating degradation of Fbw7 substrates in cells. In vitro reconstitution with purified SCF components, co-immunoprecipitation, substrate stability assays The Journal of biological chemistry High 19679664
2011 FBXW7 deletion in murine gut leads to elevated Notch, c-Jun, and DEK proto-oncogene accumulation; DEK accumulation promotes cell division and alters tropomyosin RNA splicing; FBXW7 targets DEK for ubiquitin-mediated degradation. Conditional Fbxw7 knockout (Villin-Cre), Western blot for substrates, RNA splicing analysis The Journal of experimental medicine Medium 21282377
2011 Fbxw7 deletion in the liver results in hepatomegaly, steatohepatitis, and biliary hamartomas; Notch accumulation drives abnormal biliary differentiation, as corrected by additional loss of Notch cofactor RBP-J; Fbxw7 targets substrates including Notch to regulate lipogenesis and cell fate in the liver. Liver-specific Cre-loxP knockout (Mx1-Cre and Alb-Cre), RBP-J epistasis, liver stem cell differentiation assay in vitro The Journal of clinical investigation High 21123947
2011 FBXW7 degradation of c-Jun (N-terminally phosphorylated) is a critical substrate interaction during cerebellar development; deletion of c-Jun or the junAA knock-in (abolishing N-terminal phosphorylation) rescues Purkinje cell numbers and arborisation defects in Fbxw7-deficient cerebellum. Conditional cerebellar KO, c-Jun KO and junAA knock-in epistasis, Western blot for substrates Developmental biology High 21827743
2014 Usp28 deubiquitinase preferentially antagonizes autocatalytic (self-)ubiquitination of Fbxw7, thereby stabilizing Fbxw7; monoallelic Usp28 deletion maintains stable Fbw7 and drives substrate degradation, while complete Usp28 KO causes Fbw7 degradation and substrate accumulation. Usp28 knockout mice (dose-dependent), Western blot, substrate stability assays in MEFs Cell reports High 25437563
2015 ERK directly interacts with FBW7 and phosphorylates FBW7 at Thr205 (triggered by oncogenic KRAS), which promotes FBW7 ubiquitination and proteasomal degradation; the phospho-deficient T205A FBW7 mutant is resistant to ERK-driven degradation. In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis (T205A), proteasome inhibitor assay, xenograft models Cell research High 25753158
2015 FBW7 recognizes and ubiquitinates NDE1 in a CDK5-dependent manner during G1; CDK5 phosphorylates NDE1 to prime it for FBW7 recognition, and loss of FBW7 or CDK5 elevates NDE1 and reduces ciliary length, which is rescued by co-depletion of NDE1. Co-immunoprecipitation, kinase assay, siRNA depletion, epistasis (double depletion), ciliary length measurement The EMBO journal High 26206584
2015 Rictor undergoes GSK3β-dependent, FBXW7-mediated ubiquitination and proteasomal degradation; GSK3β phosphorylates rictor at Thr-1695 within a CDC4 phospho-degron motif, enabling FBXW7 binding; mutation of Thr-1695 impairs FBXW7 interaction and increases rictor stability and mTORC2 activity. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (Thr1695), dominant-negative and KO approaches, kinase assay The Journal of biological chemistry High 25897075
2015 FBXW7 deletion in murine bone marrow-derived stromal cells causes NOTCH accumulation, transcriptional activation of Ccl2, elevated serum CCL2, and consequent recruitment of myeloid-derived suppressor cells and macrophages that promote metastatic tumor growth; CCL2 receptor antagonism blocks this. BM-specific Fbxw7 conditional KO, serum CCL2 ELISA, pharmacological blockade of CCL2 receptor, flow cytometry The Journal of clinical investigation High 25555218
2016 REV-ERBα is a substrate of FBXW7; CDK1 phosphorylates REV-ERBα, enabling FBXW7 recognition and ubiquitination-dependent degradation; hepatic disruption of FBXW7 alters circadian amplitude of clock genes and perturbs lipid and glucose metabolism. Co-immunoprecipitation, ubiquitination assay, liver-specific FBXW7 disruption, CDK1 kinase assay, metabolic phenotyping Cell High 27238018
2016 FBW7 recognizes SOX9 via a conserved degron at Thr236, phosphorylated by GSK3 kinase, and targets SOX9 for SCFFBxW7α-mediated degradation; degradation-resistant SOX9 promotes medulloblastoma migration, metastasis, and cisplatin resistance. Co-immunoprecipitation, mutagenesis (T236 degron), ubiquitination assay, transcriptional profiling, in vivo metastasis assay The EMBO journal High 27625374
2017 Multisite phosphorylation of c-Jun is required for high-affinity interaction with Fbw7; Pin1 isomerizes a pSer-Pro peptide bond at the c-Jun N-terminus, modulating Fbw7 binding and thus regulating ubiquitin-mediated c-Jun degradation. NMR spectroscopy, fluorescence binding assays, mutagenesis, ubiquitination assays Structure High 29225075
2018 USP9X deubiquitinase directly interacts with FBW7, antagonizes FBW7 auto-ubiquitylation, and stabilizes FBW7 protein; Usp9x deletion destabilizes Fbw7, causing c-Myc accumulation; gut-specific Usp9x KO phenocopies Fbw7 loss, and c-Myc heterozygosity rescues the increased tumor burden. Proteomics (mass spectrometry interactome), co-immunoprecipitation, Usp9x conditional KO, c-Myc heterozygosity epistasis The Journal of clinical investigation High 29346117
2019 LSD1 directly binds FBXW7 as a pseudosubstrate and promotes FBXW7 self-ubiquitylation (by preventing FBXW7 dimerization) without itself being ubiquitylated; the self-ubiquitylated FBXW7 is degraded by proteasome and lysosome in a p62/SQSTM1-dependent manner, independent of LSD1 demethylase activity. Co-immunoprecipitation, ubiquitination assay, FBXW7 dimerization assay, proteasome/lysosome inhibitors, p62 KO Proceedings of the National Academy of Sciences of the United States of America High 31152129
2019 FBXW7 targets EZH2 for degradation in macrophages, suppressing H3K27me3 modification on Ccl2 and Ccl7 promoters and promoting their expression; myeloid-Fbxw7 deficiency reduces CCL2/CCL7 production and accumulation of pro-inflammatory macrophages in colitis. Myeloid-specific conditional KO, co-immunoprecipitation, ubiquitination assay, ChIP for H3K27me3 The Journal of clinical investigation High 31246581
2019 FBXO45-MYCBP2 E3 ubiquitin ligase binds to a conserved acidic N-terminal motif of FBXW7 specifically during prolonged mitotic arrest, ubiquitylates FBXW7, and promotes its proteasomal degradation, thereby promoting mitotic slippage over mitotic cell death. Co-immunoprecipitation, ubiquitination assay, FBXO45 KO/overexpression, flow cytometry for mitotic fate Cell death and differentiation High 31285543
2019 MAP2K1 (MEK1) phosphorylates SHOC2 at T507 to enable binding with FBXWβ (FBXW7β) for ubiquitination and degradation; SHOC2 competes with MTOR for RPTOR binding to inactivate mTORC1 and induce autophagy, establishing a negative feedback loop controlled by FBXW7. Co-immunoprecipitation, kinase assay, competition binding assay, autophagy flux assays Autophagy Medium 31010381
2020 FBW7 binds to telomere protection protein TPP1 and facilitates multisite polyubiquitination and degradation of TPP1, triggering telomere uncapping and DNA damage response; overexpression of TPP1 or genetic/pharmacological inhibition of FBW7 (via TELODIN peptidomimetic) reduces telomere uncapping and senescence. Co-immunoprecipitation, ubiquitination assay, telomere FISH, FBW7 conditional KO, peptidomimetic inhibitor, lung fibrosis mouse model Cell metabolism High 33086033
2020 FBXW7 inactivation decreases tumor-intrinsic expression of dsRNA sensors MDA5 and RIG-I, diminishing type I IFN and MHC-I induction; restoration of dsRNA sensing in Fbxw7-deficient cells sensitizes them to anti-PD-1 therapy, establishing a role for FBXW7 in innate immune sensing. Fbxw7 CRISPR KO in murine tumor lines, immunocompetent animal anti-PD-1 experiments, gene expression analysis Cancer discovery Medium 32371478
2021 TRIP12 (HECT-domain E3 ligase) mediates branched K11-linked ubiquitylation of FBXW7 (after SCFFBW7 auto-ubiquitylation on K404/K412), which is required for FBXW7 proteasomal degradation; SCFFBW7 auto-ubiquitylation alone is insufficient for degradation. shRNA library screen, co-immunoprecipitation, ubiquitination assay with Lys-specific mutants, TRIP12 KO, substrate (MCL1) stability assays Nature communications High 33824312
2021 FBW7 targets YTHDF2 (m6A reader protein) for proteasomal degradation; FBW7 loss stabilizes YTHDF2, which promotes mRNA decay of the pro-apoptotic gene BMF, thereby advancing ovarian cancer progression. IP-mass spectrometry, co-immunoprecipitation, ubiquitination assay, MeRIP-Seq, RNA-Seq, in vivo xenograft Molecular cancer High 33658012
2022 GSK3β/FBXW7 signaling axis controls ERRα stability via phosphorylation-dependent ubiquitination; liver-specific deletion of GSK3β or FBXW7, or ERRα phosphosite mutations (ERRα3SA), accumulate ERRα that no longer responds to insulin, causing transcriptional reprogramming, impaired energy homeostasis, and insulin resistance. Liver-specific conditional KO, ERRα phospho-site knock-in mice, transcriptome analysis, metabolic phenotyping Nature communications High 35440636
2022 Germline monoallelic FBXW7 missense variants cluster at the substrate-binding surface of the WD40 domain and impair CYCLIN E1 and CYCLIN E2 turnover; pan-neuronal knockdown of the Drosophila ortholog archipelago impairs learning; these variants cause a neurodevelopmental syndrome. Crystal-structure modeling, expression of recombinant variants in cultured cells, CYCLIN E turnover assay, Drosophila neuronal knockdown with learning assay American journal of human genetics High 35395208
2022 Mechanical overloading decreases FBXW7 mRNA transcription and FBXW7-mediated MKK7 degradation in chondrocytes, stimulating JNK signaling and inducing chondrocyte senescence; intra-articular AAV-Fbxw7 delivery alleviates OA in mice. Primary chondrocyte culture, Fbxw7 chondrocyte-specific KO, AAV-Fbxw7 intra-articular injection, Western blot for MKK7/JNK, OA scoring Annals of the rheumatic diseases Medium 35058228
2023 DYRK2 kinase interacts with and phosphorylates FBXW7, promoting its proteasomal degradation independent of FBXW7's own ubiquitin ligase activity; DYRK2-dependent FBXW7 destabilization regulates downstream substrates (c-Jun, c-Myc, Cyclin E1, mTOR, Notch1-IC). Co-immunoprecipitation, kinase assay, substrate stability assays, functional cancer cell response assays Cell death & disease Medium 36934104
2019 PKM2 is a ubiquitin substrate of SCFFBW7; FBW7 deficiency in macrophages stabilizes PKM2, decreasing NADPH/GSH production via the pentose phosphate pathway and increasing ROS, which drives pro-inflammatory activation and insulin resistance. Co-immunoprecipitation, ubiquitination assay, metabolic flux analysis, PKM2 pharmacological inhibition, myeloid-specific FBW7 KO Redox biology Medium 32853822
2015 FBW7 directly interacts with and ubiquitinates ENO1, targeting it for proteasomal degradation; FBXW7-depletion elevates ENO1 levels, increasing lactate production, cell proliferation, and migration in colorectal cancer cells. 2D proteomics/mass spectrometry, co-immunoprecipitation, ubiquitination assay, Western blot, functional proliferation/migration assays Laboratory investigation Medium 26097998
2019 PLK1 physically interacts with FBXW7, and PLK1 inhibition suppresses FBXW7 auto poly-ubiquitination, thereby stabilizing FBXW7 and facilitating degradation of c-MYC in medulloblastoma; FBXW7 auto-ubiquitination is modulated by constitutive phosphorylation. Co-immunoprecipitation, ubiquitination assay, PLK1 inhibitor treatment, FBXW7 overexpression and phospho-mutant analysis, in vivo xenograft Cancers Medium 33494392
2020 FBXW7 inhibits SCD1 expression via degradation of NR4A1 (nuclear receptor subfamily 4 group A member 1), suppressing lipid desaturation and promoting ferroptosis and apoptosis in pancreatic cancer cells. Gene expression profiling, metabolic analysis, Western blot for substrates, cell death assays Redox biology Medium 33271455
2024 FBW7 acts with GSK3β kinase to recognize and degrade the m6A reader IGF2BP2 via phosphorylation-dependent ubiquitination, suppressing an IGF2BP2-SLC7A5 positive feedback loop and reducing radioresistance in lung cancer. Co-immunoprecipitation, ubiquitination assay, ChIP-qPCR, RIP-qPCR, MeRIP-qPCR, clonogenic survival assays, xenograft mouse models Journal of experimental & clinical cancer research Medium 38281999
2023 FBXW7 loss of function in esophageal squamous cell carcinoma leads to MAP4 accumulation via impaired ubiquitination-dependent degradation; CHEK1 phosphorylates MAP4 at T521, which is required for FBXW7-mediated degradation; MAP4 accumulation activates MAPK/ERK signaling and upregulates MMP3 and VEGFA. GST-pulldown, LC-MS/MS, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (T521), xenograft models Journal of experimental & clinical cancer research Medium 36991467
2020 Fbxw7 is essential for the maintenance of breast cancer dormancy in disseminated tumor cells (DTCs); genetic ablation of Fbxw7 disrupts quiescence and renders dormant DTCs proliferative and sensitive to paclitaxel chemotherapy in mouse xenograft/allograft models. Fbxw7 genetic ablation in cancer cells, xenograft and allograft mouse models, paclitaxel treatment, DTC quantification JCI insight Medium 30830867
2020 Sox12 promotes Fbw7-mediated ubiquitination and proteasomal degradation of GATA3 in Th2 cells; Fbw7 knockdown partly abrogates Sox12-mediated GATA3 suppression, establishing Sox12 as an adaptor that enhances FBXW7 substrate targeting of GATA3. Co-immunoprecipitation, ubiquitination assay, Sox12 KO mice, Fbw7 siRNA knockdown epistasis Cellular & molecular immunology Medium 32152552

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nature reviews. Cancer 927 18094723
2018 Novel Role of FBXW7 Circular RNA in Repressing Glioma Tumorigenesis. Journal of the National Cancer Institute 891 28903484
2007 FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. The Journal of experimental medicine 561 17646409
2004 Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene. Nature 345 15592418
2001 The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog. The Journal of biological chemistry 340 11461910
2014 Tumor suppression by the Fbw7 ubiquitin ligase: mechanisms and opportunities. Cancer cell 303 25314076
2001 SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation. Molecular and cellular biology 290 11585921
2003 Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development. The Journal of biological chemistry 218 14672936
2020 FBW7-NRA41-SCD1 axis synchronously regulates apoptosis and ferroptosis in pancreatic cancer cells. Redox biology 216 33271455
2011 FBXW7 influences murine intestinal homeostasis and cancer, targeting Notch, Jun, and DEK for degradation. The Journal of experimental medicine 156 21282377
2022 Mechanical overloading promotes chondrocyte senescence and osteoarthritis development through downregulating FBXW7. Annals of the rheumatic diseases 138 35058228
2010 Loss of FBXW7, a cell cycle regulating gene, in colorectal cancer: clinical significance. International journal of cancer 136 19739118
2012 Tumor suppressor functions of FBW7 in cancer development and progression. FEBS letters 135 22673505
2016 Circadian Amplitude Regulation via FBXW7-Targeted REV-ERBα Degradation. Cell 129 27238018
2015 ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer. Cell research 127 25753158
2019 Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammation. The Journal of clinical investigation 118 31246581
2022 Clinical significance of FBXW7 loss of function in human cancers. Molecular cancer 112 35346215
2010 Fbxw7 regulates lipid metabolism and cell fate decisions in the mouse liver. The Journal of clinical investigation 108 21123947
2021 FBW7 suppresses ovarian cancer development by targeting the N6-methyladenosine binding protein YTHDF2. Molecular cancer 106 33658012
2017 Biogenesis and Function of Ago-Associated RNAs. Trends in genetics : TIG 105 28174021
2010 The ubiquitous nature of cancer: the role of the SCF(Fbw7) complex in development and transformation. Oncogene 105 20543859
2015 F-box protein FBXW7 inhibits cancer metastasis in a non-cell-autonomous manner. The Journal of clinical investigation 104 25555218
2010 The tumour suppressor C/EBPδ inhibits FBXW7 expression and promotes mammary tumour metastasis. The EMBO journal 104 21076392
2008 Isoform- and cell cycle-dependent substrate degradation by the Fbw7 ubiquitin ligase. The Journal of cell biology 104 18559665
2012 The Fbw7 and betaTRCP E3 ubiquitin ligases and their roles in tumorigenesis. Frontiers in bioscience (Landmark edition) 100 22652772
2011 MiRNA-27a controls FBW7/hCDC4-dependent cyclin E degradation and cell cycle progression. Cell cycle (Georgetown, Tex.) 100 21597324
2012 Role of the ubiquitin ligase Fbw7 in cancer progression. Cancer metastasis reviews 98 22124735
2018 The deubiquitinase USP9X regulates FBW7 stability and suppresses colorectal cancer. The Journal of clinical investigation 96 29346117
2019 PRMT5 enhances tumorigenicity and glycolysis in pancreatic cancer via the FBW7/cMyc axis. Cell communication and signaling : CCS 93 30922330
2020 Recent insight into the role of FBXW7 as a tumor suppressor. Seminars in cancer biology 91 32113998
2020 FBW7 Mediates Senescence and Pulmonary Fibrosis through Telomere Uncapping. Cell metabolism 90 33086033
2014 FBXW7 mutations in melanoma and a new therapeutic paradigm. Journal of the National Cancer Institute 79 24838835
2014 Dual regulation of Fbw7 function and oncogenic transformation by Usp28. Cell reports 78 25437563
2015 FBXW7 suppresses epithelial-mesenchymal transition, stemness and metastatic potential of cholangiocarcinoma cells. Oncotarget 74 25749036
2012 Fbw7 and p53 cooperatively suppress advanced and chromosomally unstable intestinal cancer. Molecular and cellular biology 73 22473991
2020 Circular RNA circFBXW4 suppresses hepatic fibrosis via targeting the miR-18b-3p/FBXW7 axis. Theranostics 72 32308754
2016 FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma. The EMBO journal 70 27625374
2011 Ancestral roles of small RNAs: an Ago-centric perspective. Cold Spring Harbor perspectives in biology 70 20810548
2015 Cell cycle-dependent ubiquitylation and destruction of NDE1 by CDK5-FBW7 regulates ciliary length. The EMBO journal 69 26206584
2023 Enhancement of TKI sensitivity in lung adenocarcinoma through m6A-dependent translational repression of Wnt signaling by circ-FBXW7. Molecular cancer 68 37393311
2010 Subtype-specific FBXW7 mutation and MYCN copy number gain in Wilms' tumor. Clinical cancer research : an official journal of the American Association for Cancer Research 67 20332316
2019 LSD1 destabilizes FBXW7 and abrogates FBXW7 functions independent of its demethylase activity. Proceedings of the National Academy of Sciences of the United States of America 64 31152129
2015 FBXW7 negatively regulates ENO1 expression and function in colorectal cancer. Laboratory investigation; a journal of technical methods and pathology 64 26097998
2015 Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent, FBXW7-mediated Ubiquitination and Proteasomal Degradation. The Journal of biological chemistry 63 25897075
2022 FBXW7 alleviates hyperglycemia-induced endothelial oxidative stress injury via ROS and PARP inhibition. Redox biology 62 36427396
2020 Inactivation of Fbxw7 Impairs dsRNA Sensing and Confers Resistance to PD-1 Blockade. Cancer discovery 61 32371478
2002 SEL-10 interacts with presenilin 1, facilitates its ubiquitination, and alters A-beta peptide production. Journal of neurochemistry 60 12354302
2019 Loss of Fbxw7 synergizes with activated Akt signaling to promote c-Myc dependent cholangiocarcinogenesis. Journal of hepatology 59 31195063
2015 Usp28 counteracts Fbw7 in intestinal homeostasis and cancer. Cancer research 58 25716680
2011 Emerging roles of the FBW7 tumour suppressor in stem cell differentiation. EMBO reports 57 22157894
2007 Kaposi's sarcoma herpesvirus-encoded latency-associated nuclear antigen stabilizes intracellular activated Notch by targeting the Sel10 protein. Proceedings of the National Academy of Sciences of the United States of America 53 17909182
2021 METTL3-mediated m6A mRNA modification of FBXW7 suppresses lung adenocarcinoma. Journal of experimental & clinical cancer research : CR 48 33676554
2008 Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy. Oncogene 46 18391985
2018 Physiological functions of FBW7 in cancer and metabolism. Cellular signalling 45 29474981
2014 NF-κB1 inhibits c-Myc protein degradation through suppression of FBW7 expression. Oncotarget 45 24457827
2015 MYC is a critical target of FBXW7. Oncotarget 42 25669969
2019 FBXO45-MYCBP2 regulates mitotic cell fate by targeting FBXW7 for degradation. Cell death and differentiation 41 31285543
2019 A novel transthyretin/STAT4/miR-223-3p/FBXW7 signaling pathway affects neovascularization in diabetic retinopathy. Molecular and cellular endocrinology 41 31415795
2011 The two faces of FBW7 in cancer drug resistance. BioEssays : news and reviews in molecular, cellular and developmental biology 41 22006825
2019 Prevention of cancer dormancy by Fbxw7 ablation eradicates disseminated tumor cells. JCI insight 40 30830867
2020 Astragalus polysaccharides inhibit ovarian cancer cell growth via microRNA-27a/FBXW7 signaling pathway. Bioscience reports 38 32159214
2005 Control of genomic instability and epithelial tumor development by the p53-Fbxw7/Cdc4 pathway. Cancer research 35 16061623
2022 Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome. American journal of human genetics 33 35395208
2015 Fbxw7 regulates hepatocellular carcinoma migration and invasion via Notch1 signaling pathway. International journal of oncology 33 25955618
2011 The F-box protein Fbw7 is required for cerebellar development. Developmental biology 33 21827743
2015 Fbw7 and its counteracting forces in stem cells and cancer: Oncoproteins in the balance. Seminars in cancer biology 31 26410034
2023 FBXW7 in breast cancer: mechanism of action and therapeutic potential. Journal of experimental & clinical cancer research : CR 30 37658431
2019 MiR-223 promotes oral squamous cell carcinoma proliferation and migration by regulating FBXW7. Cancer biomarkers : section A of Disease markers 30 30883339
2019 The MTORC1-mediated autophagy is regulated by the FBXW7-SHOC2-RPTOR axis. Autophagy 30 31010381
2018 FBXW7 deletion contributes to lung tumor development and confers resistance to gefitinib therapy. Molecular oncology 30 29633504
2016 Loss of FBXW7 and accumulation of MCL1 and PLK1 promote paclitaxel resistance in breast cancer. Oncotarget 30 27409838
2012 The C. elegans F-box proteins LIN-23 and SEL-10 antagonize centrosome duplication by regulating ZYG-1 levels. Journal of cell science 30 22623721
2009 Adenovirus E1A inhibits SCF(Fbw7) ubiquitin ligase. The Journal of biological chemistry 30 19679664
2022 FBXW7 and the Hallmarks of Cancer: Underlying Mechanisms and Prospective Strategies. Frontiers in oncology 29 35515121
2019 MiR322 mediates cardioprotection against ischemia/reperfusion injury via FBXW7/notch pathway. Journal of molecular and cellular cardiology 29 31150734
2023 G9a promotes immune suppression by targeting the Fbxw7/Notch pathway in glioma stem cells. CNS neuroscience & therapeutics 28 36971192
2017 Regulatory crosstalk between KLF5, miR-29a and Fbw7/CDC4 cooperatively promotes atherosclerotic development. Biochimica et biophysica acta. Molecular basis of disease 28 29074464
2024 FBW7/GSK3β mediated degradation of IGF2BP2 inhibits IGF2BP2-SLC7A5 positive feedback loop and radioresistance in lung cancer. Journal of experimental & clinical cancer research : CR 27 38281999
2014 Role of Fbxw7 expression in hepatocellular carcinoma and adjacent non-tumor liver tissue. Journal of gastroenterology and hepatology 27 24731221
2022 KDM5B promotes tumorigenesis of Ewing sarcoma via FBXW7/CCNE1 axis. Cell death & disease 26 35428764
2021 Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12. Nature communications 26 33824312
2020 KDM5c Promotes Colon Cancer Cell Proliferation Through the FBXW7-c-Jun Regulatory Axis. Frontiers in oncology 26 33042830
2017 Multivalent Interactions with Fbw7 and Pin1 Facilitate Recognition of c-Jun by the SCFFbw7 Ubiquitin Ligase. Structure (London, England : 1993) 26 29225075
2022 FBXW7 and Its Downstream NOTCH Pathway Could be Potential Indicators of Organ-Free Metastasis in Colorectal Cancer. Frontiers in oncology 25 35712679
2020 Sox12 enhances Fbw7-mediated ubiquitination and degradation of GATA3 in Th2 cells. Cellular & molecular immunology 25 32152552
2022 Insulin action and resistance are dependent on a GSK3β-FBXW7-ERRα transcriptional axis. Nature communications 24 35440636
2019 MicroRNA 27b promotes cardiac fibrosis by targeting the FBW7/Snail pathway. Aging 24 31881012
2023 FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2. Cell death & disease 23 36934104
2020 FBW7 regulates HIF-1α/VEGF pathway in the IL-1β induced chondrocytes degeneration. European review for medical and pharmacological sciences 23 32572904
2015 Emerging roles for the FBXW7 ubiquitin ligase in leukemia and beyond. Current opinion in cell biology 23 26426760
2023 Comprehensive characterization of FBXW7 mutational and clinicopathological profiles in human colorectal cancers. Frontiers in oncology 22 37064111
2021 Implications of FBXW7 in Neurodevelopment and Neurodegeneration: Molecular Mechanisms and Therapeutic Potential. Frontiers in cellular neuroscience 22 34512273
2020 Myeloid FBW7 deficiency disrupts redox homeostasis and aggravates dietary-induced insulin resistance. Redox biology 22 32853822
2015 Regulation mechanism of Fbxw7-related signaling pathways (Review). Oncology reports 22 26324296
2021 A Regulatory Loop of FBXW7-MYC-PLK1 Controls Tumorigenesis of MYC-Driven Medulloblastoma. Cancers 21 33494392
2020 Epigenetic modulation of FBW7/Mcl-1 pathway for lung cancer therapy. Cancer biology & therapy 20 33336620
2018 FBXW7 modulates malignant potential and cisplatin-induced apoptosis in cholangiocarcinoma through NOTCH1 and MCL1. Cancer science 20 30302867
2012 CDC4/FBXW7 and the 'just enough' model of tumourigenesis. The Journal of pathology 20 22323043
2017 Fbxw7 haploinsufficiency loses its protection against DNA damage and accelerates MNU-induced gastric carcinogenesis. Oncotarget 19 28422719
2023 FBXW7 loss of function promotes esophageal squamous cell carcinoma progression via elevating MAP4 and ERK phosphorylation. Journal of experimental & clinical cancer research : CR 18 36991467