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Showing FBXW5 — FBW5 is a alias.

FBXW5

F-box/WD repeat-containing protein 5 · UniProt Q969U6

Length
566 aa
Mass
63.9 kDa
Annotated
2026-06-09
18 papers in source corpus 14 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FBXW5 is an F-box/WD40 substrate receptor that operates within multiple cullin-RING E3 ubiquitin ligase complexes to select substrates for ubiquitin-dependent degradation, placing it at the control point of centrosome duplication, autophagy, growth signaling, and ciliogenesis (PMID:21725316, PMID:30596474). It functions both as the substrate-targeting subunit of an SCF complex (SKP1-CUL1-FBXW5) and within the DDB1-CUL4-ROC1 (CRL4) complex, depending on the substrate engaged (PMID:18381890, PMID:21725316). Through the CRL4 pathway it binds and degrades the mTOR-pathway tumor suppressor TSC2, an interaction that is blocked when TSC1 is co-expressed or when Tnfaip8l1/Oxi-β competes for FBXW5 binding to stabilize TSC2 (PMID:18381890, PMID:24444419, PMID:24372178). As an SCF substrate receptor it limits centrosome duplication by degrading the centriolar protein HsSAS-6; this activity is switched off by PLK4-mediated phosphorylation of FBXW5 at Ser151, while FBXW5 itself is degraded by APC/C during mitosis and G1 so that its levels peak at G1/S (PMID:21725316). The same SCF-FBXW5 ligase degrades kinesin-13 family members (MCAK/Kif2a/Kif2b) to permit ciliogenesis in quiescent cells, a reaction reconstituted in vitro with neddylated SCF-FBXW5 and Cdc34 (PMID:34368969). FBXW5 additionally restrains autophagy under nutrient-replete conditions by degrading the COPII component SEC23B, an interaction relieved by ULK1 phosphorylation of SEC23B during starvation (PMID:30596474). Across cancer contexts FBXW5 degrades the Hippo kinases LATS1/2 to activate YAP1, and degrades DLC1, AQP3, and the transcriptional repressor KLF13 (PMID:24082123, PMID:35210431, PMID:38726865, PMID:40696794). FBXW5 also acts as a negative regulator of TAK1-driven MAPK and NF-κB signaling in inflammatory and cardiac-hypertrophy settings, and can enhance sumoylation rather than ubiquitination of c-Myb (PMID:19232515, PMID:22910413, PMID:32971071).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2008 High

    Established FBXW5 as a substrate receptor that links a specific substrate to a cullin-RING ligase, identifying TSC2 as its first target and connecting it to mTOR-pathway growth control.

    Evidence Reciprocal Co-IP, in vivo ubiquitination, and Drosophila genetic epistasis (Ddb1/Cul4 vs Gigas/Tsc2)

    PMID:18381890

    Open questions at the time
    • Did not resolve whether FBXW5 also functions in SCF (CUL1) complexes
    • Direct ubiquitination of TSC2 by reconstituted ligase not shown
  2. 2009 Medium

    Extended FBXW5 beyond degradation by showing it associates with TAK1 in an IL-1β-dependent manner and negatively regulates inflammatory MAPK/NF-κB signaling.

    Evidence TAP-MS in HeLa, Co-IP, and gain/loss-of-function with kinase and pathway readouts

    PMID:19232515

    Open questions at the time
    • Whether regulation is ubiquitin-dependent was not established
    • Single lab; no in vitro reconstitution
  3. 2011 High

    Defined FBXW5 as the SCF substrate receptor for HsSAS-6 controlling centrosome copy number, and revealed two layers of regulation: PLK4 phosphorylation inhibiting its activity and APC/C degradation restricting its abundance to G1/S.

    Evidence Co-IP, in vivo ubiquitination, centrosome counting, phospho-site mutagenesis, cell-cycle staging

    PMID:21725316

    Open questions at the time
    • Structural basis of HsSAS-6 recognition not resolved
    • Interplay between SCF and CRL4 usage not addressed
  4. 2012 Medium

    Showed FBXW5 can promote sumoylation rather than ubiquitination of a substrate (c-Myb), broadening its biochemical repertoire and adding a transcriptional output.

    Evidence Co-IP, sumoylation assays, reporter assays, immunofluorescence

    PMID:22910413

    Open questions at the time
    • Mechanism by which FBXW5 enhances SUMO conjugation unclear
    • Single lab
  5. 2013 Medium

    Identified DLC1 as a CRL4A-FBXW5 substrate, linking FBXW5 to RhoA-GTP signaling and tumor suppressor turnover in lung cancer.

    Evidence siRNA knockdown, Co-IP, in vivo ubiquitination, RhoA-GTP pulldown in NSCLC cells

    PMID:24082123

    Open questions at the time
    • No in vitro reconstitution of DLC1 ubiquitination
    • Single lab
  6. 2014 Medium

    Revealed competitive regulation of FBXW5 substrate selection, with Tnfaip8l1/Oxi-β displacing TSC2 to stabilize it and tune mTOR/autophagy under oxidative stress.

    Evidence Co-IP, competition binding, ubiquitination assay, siRNA, autophagy markers in dopaminergic neurons

    PMID:24372178 PMID:24444419

    Open questions at the time
    • Binding site on FBXW5 not mapped
    • Same-lab replication only
  7. 2018 High

    Connected FBXW5 to autophagy regulation by identifying SEC23B as a degradation target whose stabilization upon ULK1 phosphorylation reroutes COPII to drive autophagosome biogenesis.

    Evidence Co-IP, in vivo ubiquitination, phospho-mapping, ULK1 kinase assay, flux assays, imaging

    PMID:30596474

    Open questions at the time
    • Which cullin scaffold mediates SEC23B degradation not specified
    • Single rigorous study
  8. 2021 High

    Provided the most direct biochemical proof of FBXW5 ligase activity by reconstituting SCF-FBXW5-mediated polyubiquitylation of kinesin-13 proteins in vitro, and tied this to ciliogenesis control in G0/G1.

    Evidence Protein microarray, in vitro ubiquitination reconstitution with neddylated SCF and Cdc34, siRNA, ciliogenesis rescue

    PMID:34368969

    Open questions at the time
    • Recognition determinants on MCAK/Kif2a/Kif2b not defined
    • Single lab
  9. 2020 Medium

    Demonstrated in vivo physiological relevance of FBXW5-TAK1 antagonism by showing FBXW5 knockout aggravates and overexpression protects against pressure-overload cardiac hypertrophy.

    Evidence Co-IP, FBXW5 knockout mice, AAV9 overexpression, pressure-overload model, TAK1 inhibitor epistasis

    PMID:32971071

    Open questions at the time
    • Whether FBXW5 ubiquitinates TAK1 not shown
    • Single lab
  10. 2022 Medium

    Linked FBXW5 to Hippo pathway control by showing it binds the LATS1/2 PPxY motif and degrades these kinases to activate YAP1, driving gastric cancer invasion and chemoresistance.

    Evidence Co-IP, in vivo ubiquitination, siRNA/overexpression, mouse xenograft, LATS1-YAP1 rescue

    PMID:35210431

    Open questions at the time
    • Which ligase scaffold is used not defined
    • Single lab
  11. 2024 Medium

    Added AQP3 as an SCF-FBXW5 substrate and traced a degradation cascade through PDPK1 to AKT-mTOR inactivation and autophagic cell death in hepatocellular carcinoma.

    Evidence Co-IP, in vivo ubiquitination, siRNA, lysosomal inhibition, autophagy assays

    PMID:38726865

    Open questions at the time
    • Direct ubiquitination not reconstituted in vitro
    • Single lab
  12. 2025 Medium

    Implicated FBXW5 in EMT by showing it degrades the transcriptional repressor KLF13, relieving repression of TROAP in lung adenocarcinoma.

    Evidence Co-IP, ubiquitination assay, ChIP, dual luciferase, siRNA, xenograft

    PMID:40696794

    Open questions at the time
    • Ligase scaffold not defined
    • Single recent study

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how FBXW5 selects between SCF (CUL1) and CRL4 (CUL4) scaffolds for different substrates, and whether its non-degradative outputs (sumoylation enhancement, TAK1 inhibition) share a common biochemical basis.
  • No structural model of FBXW5-substrate or FBXW5-cullin assembly
  • Scaffold choice rules across the substrate set undefined
  • Mechanism of sumoylation enhancement and TAK1 antagonism not biochemically dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005815 microtubule organizing center 2 GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-9612973 Autophagy 2 R-HSA-1640170 Cell Cycle 1 R-HSA-168256 Immune System 1 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
DDB1DLC1HSSAS-6LATS1/2MCAKSEC23BTAK1TSC2
Complex memberships
CRL4 (DDB1-CUL4-ROC1)SCF (SKP1-CUL1-FBXW5)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 FBXW5 (FBW5) binds TSC2 and recruits it to the DDB1-CUL4-ROC1 E3 ubiquitin ligase complex, promoting TSC2 ubiquitination and proteasomal degradation. TSC1 co-expression abrogates this degradation. Drosophila Ddb1 or Cul4 mutations cause Gigas/TSC2 accumulation and growth defects rescuable by Gigas/Tsc2 reduction, confirming epistatic relationship. Co-IP, overexpression/depletion assays, in vivo ubiquitination, Drosophila genetic epistasis Genes & development High 18381890
2011 FBXW5 acts as the substrate-targeting subunit of the SCF-FBXW5 E3 ubiquitin ligase that ubiquitylates and degrades the centriolar protein HsSAS-6, thereby limiting centrosome duplication. PLK4 phosphorylates FBXW5 at Ser151 to suppress its ubiquitylation activity toward HsSAS-6. APC/C targets FBXW5 for degradation during mitosis and G1, restricting centrosome re-duplication. FBXW5 levels peak at the G1/S transition. Co-IP, in vivo ubiquitination assay, depletion/overexpression with centrosome counting, phosphorylation site mutagenesis, cell-cycle staging Nature cell biology High 21725316
2018 FBXW5 targets SEC23B (a COPII component) for proteasomal degradation, limiting autophagic flux under nutrient-replete conditions. ULK1 phosphorylates SEC23B on Ser186 during starvation, blocking the FBXW5–SEC23B interaction and stabilizing SEC23B, which then associates with SEC24A/B (not SEC24C/D) and re-localizes to the ERGIC to promote autophagosome biogenesis. Co-IP, in vivo ubiquitination, phosphorylation site mapping, ULK1 kinase assay, co-localization imaging, autophagy flux assays eLife High 30596474
2013 FBXW5 is the substrate receptor of the CRL4A (CUL4A-DDB1-ROC1) complex that ubiquitinates and degrades the RhoA-GAP tumor suppressor DLC1. siRNA knockdown of CUL4A, DDB1, or FBXW5 restores DLC1 protein and reduces active RhoA-GTP levels and RhoA effector signaling in NSCLC cells. siRNA knockdown, Co-IP, in vivo ubiquitination assay, RhoA-GTP pulldown, proliferation assays Proceedings of the National Academy of Sciences of the United States of America Medium 24082123
2009 FBXW5 associates with endogenous TAK1 in an IL-1β-dependent manner (identified by TAP-MS in HeLa cells). Overexpression of FBXW5 inhibits IL-1β-induced JNK/p38 MAPK and NF-κB activation and blocks TAK1 phosphorylation at Thr187; knockdown prolongs TAK1 activation, establishing FBXW5 as a negative regulator of TAK1 in the IL-1β signaling pathway. Tandem affinity purification / mass spectrometry, Co-IP, overexpression and siRNA knockdown with kinase activity and pathway readouts Biochemical and biophysical research communications Medium 19232515
2012 FBXW5, via the DDB1-CUL4A-RBX1 complex, enhances sumoylation (rather than ubiquitination) of nuclear c-Myb, causing c-Myb re-localization to nuclear dot-like domains and suppression of c-Myc promoter transactivation. FBXW5 localizes to both nucleus and cytosol. Co-IP, sumoylation assays, reporter gene assays, immunofluorescence localization Biochemical and biophysical research communications Medium 22910413
2014 Tnfaip8l1/Oxi-β binds FBXW5 and competes with TSC2 for FBXW5 binding, thereby preventing TSC2 ubiquitination and degradation by the CUL4 E3 ligase complex. This stabilizes TSC2, reduces mTOR phosphorylation, and increases autophagy in dopaminergic neurons under oxidative stress. Co-IP, competition binding assay, ubiquitination assay, siRNA knockdown, autophagy markers Journal of neurochemistry Medium 24372178 24444419
2021 SCF-FBXW5 targets kinesin-13 family members MCAK (Kif2c), Kif2a, and Kif2b for proteasomal degradation. In vitro reconstitution with neddylated SCF-FBXW5 and Cdc34 demonstrates efficient polyubiquitylation of MCAK without requiring prior modifications. Loss of Fbxw5 elevates MCAK levels at basal bodies and impairs ciliogenesis in G1/G0; concomitant knockdown of MCAK, Kif2a, or Kif2b rescues ciliogenesis. Protein microarray screening, in vitro ubiquitination reconstitution, siRNA knockdown, ciliogenesis assay, rescue experiments The EMBO journal High 34368969
2022 FBXW5 binds the PPxY sequence in the LATS1/2 kinase domain and promotes LATS1/2 ubiquitination and degradation, thereby inactivating the Hippo pathway and increasing YAP1 activity in gastric cancer cells. Blocking LATS1-YAP1 signaling abolishes FBXW5-mediated effects on invasion and chemoresistance. Co-IP, in vivo ubiquitination assay, siRNA/overexpression, mouse xenograft Cell death discovery Medium 35210431
2024 FBXW5 (as part of the SCF complex) directly ubiquitinates AQP3 (aquaporin 3), targeting it for proteasomal degradation. FBXW5 knockdown stabilizes AQP3, which then promotes lysosomal degradation of PDPK1, inactivating the AKT-mTOR pathway and inducing autophagic cell death in hepatocellular carcinoma cells. Co-IP, in vivo ubiquitination assay, siRNA knockdown, lysosomal inhibitor experiments, autophagy assays Autophagy Medium 38726865
2020 FBXW5 directly interacts with TAK1 and blocks MAPK signaling in cardiomyocytes. FBXW5 knockout mice develop aggravated pressure overload-induced cardiac hypertrophy, while AAV9-mediated FBXW5 overexpression is protective. TAK1 inhibition prevents the hypertrophic effects of FBXW5 loss, placing FBXW5 upstream of TAK1-MAPK in pathological cardiac hypertrophy. Co-IP, FBXW5 knockout mice, AAV9-mediated overexpression, pressure overload model, TAK1 inhibitor epistasis Journal of molecular and cellular cardiology Medium 32971071
2025 FBXW5 promotes ubiquitinated degradation of KLF13, a transcriptional repressor. Loss of KLF13 protein relieves transcriptional repression of TROAP, facilitating EMT in lung adenocarcinoma cells. Co-IP, ubiquitination assay, ChIP, dual luciferase reporter, siRNA knockdown, xenograft model Molecular carcinogenesis Medium 40696794
2021 FBXW5 promotes phosphorylation of ASK1 in a TRAF6-dependent manner in hepatic ischemia/reperfusion injury, activating MAPK and IKK pathways. Blockade of TRAF6 abolished FBXW5-driven ASK1 phosphorylation. FBXW5 overexpression/inhibition in vivo and in vitro, TRAF6 blockade epistasis, pathway phosphorylation assays International immunopharmacology Low 34217994

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 WD40 protein FBW5 promotes ubiquitination of tumor suppressor TSC2 by DDB1-CUL4-ROC1 ligase. Genes & development 142 18381890
2011 The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and targets HsSAS-6 to control centrosome duplication. Nature cell biology 128 21725316
2018 The ULK1-FBXW5-SEC23B nexus controls autophagy. eLife 71 30596474
2013 CRL4A-FBXW5-mediated degradation of DLC1 Rho GTPase-activating protein tumor suppressor promotes non-small cell lung cancer cell growth. Proceedings of the National Academy of Sciences of the United States of America 58 24082123
2014 Tnfaip8 l1/Oxi-β binds to FBXW5, increasing autophagy through activation of TSC2 in a Parkinson's disease model. Journal of neurochemistry 51 24444419
2021 FBXW5 aggravates hepatic ischemia/reperfusion injury via promoting phosphorylation of ASK1 in a TRAF6-dependent manner. International immunopharmacology 44 34217994
2022 The E3 ubiquitin ligase, FBXW5, promotes the migration and invasion of gastric cancer through the dysregulation of the Hippo pathway. Cell death discovery 34 35210431
2019 FBXW5 Promotes Tumorigenesis and Metastasis in Gastric Cancer via Activation of the FAK-Src Signaling Pathway. Cancers 20 31213005
2009 An F-box protein, FBXW5, negatively regulates TAK1 MAP3K in the IL-1beta signaling pathway. Biochemical and biophysical research communications 16 19232515
2024 SCFFBXW5-mediated degradation of AQP3 suppresses autophagic cell death through the PDPK1-AKT-MTOR axis in hepatocellular carcinoma cells. Autophagy 15 38726865
2020 FBXW5 acts as a negative regulator of pathological cardiac hypertrophy by decreasing the TAK1 signaling to pro-hypertrophic members of the MAPK signaling pathway. Journal of molecular and cellular cardiology 15 32971071
2021 SCFFbxw5 targets kinesin-13 proteins to facilitate ciliogenesis. The EMBO journal 13 34368969
2019 FBXW5 reduction alleviates spinal cord injury (SCI) by blocking microglia activity: A mechanism involving p38 and JNK. Biochemical and biophysical research communications 12 31060780
2012 Fbxw5 suppresses nuclear c-Myb activity via DDB1-Cul4-Rbx1 ligase-mediated sumoylation. Biochemical and biophysical research communications 10 22910413
2011 FBXW5 controls centrosome number. Nature cell biology 9 21808243
2013 Tnfaip8l1/Oxi-β binds to FBXW5, increasing autophagy through activation of TSC2 in a Parkinson's disease model. Journal of neurochemistry 5 24372178
2025 FBXW5 Promotes Epithelial-Mesenchymal Transition in Lung Adenocarcinoma Through the KLF13/TROAP Signaling Pathway. Molecular carcinogenesis 1 40696794
2025 The structure and function of FBXW5 in human diseases. Biochemistry and biophysics reports 0 40989716

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