Affinage

FBXW5

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

Length
566 aa
Mass
63.9 kDa
Annotated
2026-04-28
18 papers in source corpus 13 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FBXW5 is an F-box and WD40-repeat substrate receptor that assembles into two distinct cullin-RING E3 ubiquitin ligase complexes—SCF-FBXW5 (SKP1-CUL1-RBX1) and CRL4-FBXW5 (DDB1-CUL4-ROC1)—to ubiquitinate and target diverse substrates for proteasomal degradation, thereby regulating centrosome duplication, ciliogenesis, mTOR/autophagy signaling, Rho GTPase activity, Hippo pathway output, and COPII-dependent membrane trafficking (PMID:18381890, PMID:21725316, PMID:24082123, PMID:30596474, PMID:34368969, PMID:35210431). Through the CRL4 complex, FBXW5 degrades TSC2 to activate mTOR and degrades the RhoGAP DLC1 to sustain RhoA signaling, while through SCF it targets HsSAS-6 to restrict centrosome number, SEC23B to limit autophagosome biogenesis under nutrient-replete conditions, and kinesin-13 depolymerases (MCAK/Kif2a/Kif2b) to permit ciliogenesis (PMID:18381890, PMID:24082123, PMID:21725316, PMID:30596474, PMID:34368969). FBXW5 activity is itself cell-cycle regulated: PLK4 phosphorylation at Ser151 inhibits its ubiquitin ligase function toward HsSAS-6 during S phase, and APC/C-mediated degradation eliminates FBXW5 during mitosis and G1 (PMID:21725316). Independent of its ligase function, FBXW5 binds TAK1 and negatively regulates IL-1β-induced MAPK/NF-κB signaling and pathological cardiac hypertrophy (PMID:19232515, PMID:32971071).

Mechanistic history

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

    Establishing that FBXW5 is not solely an SCF component but also a DDB1-binding WD40 receptor for the CRL4 E3 ligase, with TSC2 identified as its first substrate—linking FBXW5 to growth control via the TSC/mTOR axis.

    Evidence Co-IP, in vivo ubiquitination, and Drosophila genetic epistasis showing Gigas/TSC2 accumulation upon Ddb1/Cul4 loss

    PMID:18381890

    Open questions at the time
    • Whether SCF-FBXW5 also targets TSC2 was not tested
    • Structural basis for FBXW5-TSC2 recognition unknown
    • Physiological contexts beyond Drosophila growth not explored
  2. 2009 Medium

    Revealing a ligase-independent function: FBXW5 associates with TAK1 and acts as a negative regulator of IL-1β-induced MAPK and NF-κB signaling, expanding its role beyond substrate-targeted ubiquitination.

    Evidence Tandem affinity purification identifying endogenous TAK1 association; overexpression/knockdown modulating JNK/p38/NF-κB activation

    PMID:19232515

    Open questions at the time
    • Whether FBXW5 ubiquitinates TAK1 or acts through a non-catalytic mechanism was not resolved
    • Single-lab study without independent confirmation
    • Downstream effector specificity unclear
  3. 2011 High

    Demonstrating that FBXW5 functions in the SCF complex to ubiquitinate HsSAS-6 and limit centrosome duplication, while itself being regulated by PLK4 phosphorylation and APC/C-mediated degradation—establishing a cell-cycle-integrated control circuit for centriole copy number.

    Evidence Co-IP, in vivo ubiquitination, Ser151 phosphosite mutagenesis, APC/C substrate validation, cell cycle analysis

    PMID:21725316

    Open questions at the time
    • Crystal structure of FBXW5-HsSAS-6 interface not determined
    • Whether PLK4 phosphorylation affects other FBXW5 substrates untested
  4. 2012 Medium

    Unexpectedly showing that the CRL4-FBXW5 complex can promote sumoylation rather than ubiquitination of c-Myb, suppressing its transactivation—raising the possibility that FBXW5-containing ligases have dual SUMO/ubiquitin activity.

    Evidence Co-IP, sumoylation assay, transcriptional reporter, subcellular localization imaging

    PMID:22910413

    Open questions at the time
    • Mechanism by which a CRL promotes sumoylation instead of ubiquitination not explained
    • Not independently replicated
    • Endogenous c-Myb sumoylation dependence on FBXW5 not shown
  5. 2013 High

    Identifying DLC1, a RhoGAP tumor suppressor, as a CRL4A-FBXW5 substrate, thereby linking FBXW5 to Rho GTPase signaling and cancer cell proliferation.

    Evidence siRNA of CUL4A/DDB1/FBXW5 restoring DLC1 and reducing RhoA-GTP; Co-IP and ubiquitination assay in NSCLC cells

    PMID:24082123

    Open questions at the time
    • DLC1 degron recognized by FBXW5 not mapped
    • Whether FBXW5-DLC1 axis operates in non-cancer contexts not addressed
  6. 2014 Medium

    Demonstrating that Tnfaip8l1/Oxi-β competes with TSC2 for FBXW5 binding, providing the first example of a competitive inhibitor of FBXW5 substrate recognition and linking the FBXW5-TSC2 axis to autophagy and dopaminergic neuron survival under oxidative stress.

    Evidence Co-IP competition assay, protein stability, mTOR phosphorylation, and autophagy marker readouts

    PMID:24372178 PMID:24444419

    Open questions at the time
    • Direct binding competition not shown with purified proteins
    • In vivo neuronal relevance not confirmed in animal models
  7. 2018 High

    Showing that SCF-FBXW5 ubiquitinates SEC23B to limit autophagosome biogenesis in fed conditions, and that ULK1 phosphorylation of SEC23B at Ser186 blocks FBXW5 recognition upon starvation—revealing FBXW5 as a nutrient-sensitive gatekeeper of COPII-dependent autophagy.

    Evidence Co-IP, ubiquitination assay, phosphosite mutagenesis, mass spectrometry, autophagic flux assays, ERGIC localization

    PMID:30596474

    Open questions at the time
    • Whether other COPII components are also FBXW5 substrates unknown
    • Structural basis for phospho-switch disrupting FBXW5-SEC23B interaction unresolved
  8. 2020 Medium

    Extending the FBXW5-TAK1 axis in vivo: FBXW5 knockout mice develop aggravated cardiac hypertrophy via enhanced TAK1-MAPK signaling, and AAV9-mediated overexpression is protective—validating a physiological role for FBXW5 in cardiac stress responses.

    Evidence FBXW5 knockout mice, AAV9 overexpression, pressure-overload model, TAK1 inhibitor rescue

    PMID:32971071

    Open questions at the time
    • Whether FBXW5 ubiquitinates TAK1 or acts non-catalytically still unresolved
    • Cardiac-specific versus systemic effects not dissected
  9. 2021 High

    Identifying kinesin-13 microtubule depolymerases (MCAK, Kif2a, Kif2b) as direct modification-independent substrates of SCF-FBXW5, and establishing that their degradation during G2 is required for subsequent ciliogenesis in G0/G1.

    Evidence Protein microarray, reconstituted in vitro ubiquitylation with neddylated SCF-FBXW5 and Cdc34, co-knockdown rescue of ciliogenesis defect

    PMID:34368969

    Open questions at the time
    • How FBXW5 recognizes these substrates without prior modification is structurally unexplained
    • Whether this pathway operates in multiciliated cells unknown
  10. 2022 Medium

    Showing FBXW5 binds the PPxY motif of LATS1/2 kinases and promotes their ubiquitination and degradation, inactivating the Hippo pathway and enhancing YAP1-driven transcription in gastric cancer.

    Evidence Co-IP, ubiquitination assay, siRNA, xenograft model

    PMID:35210431

    Open questions at the time
    • Which E3 complex (SCF or CRL4) mediates LATS1/2 degradation not specified
    • PPxY motif recognition by WD40 repeats not structurally characterized
    • Single-lab finding
  11. 2024 Medium

    Identifying AQP3 as an SCF-FBXW5 substrate whose stabilization upon FBXW5 loss triggers lysosomal PDPK1 degradation, AKT-mTOR pathway inactivation, and autophagic cell death in hepatocellular carcinoma—revealing a non-canonical route by which FBXW5 controls mTOR signaling.

    Evidence Co-IP, ubiquitination assay, siRNA, lysosomal inhibitor experiments, AKT-mTOR readouts

    PMID:38726865

    Open questions at the time
    • Mechanism by which AQP3 stabilization causes PDPK1 lysosomal targeting is indirect
    • Single-lab study
  12. 2025 Medium

    Extending FBXW5 substrates to transcription factor KLF13, whose degradation de-represses TROAP transcription and promotes EMT in lung adenocarcinoma.

    Evidence Co-IP, ubiquitination assay, ChIP, luciferase reporter, xenograft model

    PMID:40696794

    Open questions at the time
    • KLF13 degron not mapped
    • Which CRL complex is involved not specified
    • Single-lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • No high-resolution structural information exists for FBXW5 in complex with any substrate, leaving the molecular determinants of its unusually broad substrate recognition—spanning modification-dependent and modification-independent modes—unresolved.
  • No crystal or cryo-EM structure of FBXW5 alone or in complex
  • Rules governing SCF versus CRL4 complex assembly choice unclear
  • Comprehensive substrate landscape under physiological conditions not systematically defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8
Localization
GO:0005815 microtubule organizing center 2 GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-392499 Metabolism of proteins 8 R-HSA-162582 Signal Transduction 4 R-HSA-9612973 Autophagy 3 R-HSA-1640170 Cell Cycle 2 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
CUL1CUL4ADDB1HSSAS-6PLK4SKP1TAK1TSC2
Complex memberships
CRL4-FBXW5 (DDB1-CUL4-ROC1-FBXW5)SCF-FBXW5 (SKP1-CUL1-RBX1-FBXW5)

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 FBXW5 (FBW5) acts as a DDB1-binding WD40 substrate receptor that recruits TSC2 to the DDB1-CUL4-ROC1 E3 ubiquitin ligase complex, promoting TSC2 ubiquitination and proteasomal degradation. TSC1 co-expression abrogates this degradation. In Drosophila, Ddb1 or Cul4 mutations cause Gigas/TSC2 accumulation and growth defects partially rescued by Gigas/Tsc2 reduction. Co-immunoprecipitation, overexpression/depletion assays, in vivo ubiquitination, Drosophila genetic epistasis Genes & development High 18381890
2011 FBXW5 functions as the F-box/substrate-targeting subunit of SCF-FBXW5 E3 ubiquitin ligase that binds and ubiquitylates the centriolar protein HsSAS-6, targeting it for proteasomal degradation to limit centrosome duplication. PLK4 phosphorylates FBXW5 at Ser151 to suppress its ability to ubiquitylate HsSAS-6. FBXW5 itself is a substrate of APC/C, which degrades it during mitosis and G1 to reset the centrosome duplication machinery. Co-immunoprecipitation, in vivo ubiquitination assay, siRNA depletion/overexpression, phosphorylation mapping, cell cycle analysis Nature cell biology High 21725316
2009 FBXW5 associates with endogenous TAK1 in an IL-1β-dependent manner, identified by tandem affinity purification. Overexpression of FBXW5 inhibits IL-1β-induced JNK/p38 MAPK and NF-κB activation and TAK1 phosphorylation at Thr187, while FBXW5 knockdown prolongs TAK1 activation, indicating FBXW5 negatively regulates TAK1 signaling. Tandem affinity purification (TAP), Co-immunoprecipitation, overexpression/knockdown with signaling readouts Biochemical and biophysical research communications Medium 19232515
2012 FBXW5, acting via the DDB1-CUL4A-RBX1 complex, enhances sumoylation of nuclear c-Myb rather than ubiquitination, localizing c-Myb to nuclear dot-like domains and suppressing its transactivation of the c-myc promoter. This demonstrates the DDB1-CUL4A-RBX1 complex can function as a dual SUMO/ubiquitin ligase depending on substrate. Co-immunoprecipitation, sumoylation assay, transcriptional reporter assay, subcellular localization imaging Biochemical and biophysical research communications Medium 22910413
2013 FBXW5 acts as the substrate receptor of the CRL4A (CUL4A-DDB1-RBX1) ubiquitin ligase to ubiquitinate and degrade the RhoGAP tumor suppressor DLC1, suppressing RhoA-GTP levels and RhoA effector signaling. siRNA knockdown of CUL4A, DDB1, or FBXW5 restores DLC1 protein and reduces RhoA activity in NSCLC cells. siRNA knockdown, Co-immunoprecipitation, ubiquitination assay, RhoA-GTP pulldown, proliferation assays Proceedings of the National Academy of Sciences of the United States of America High 24082123
2014 Tnfaip8l1/Oxi-β competes with TSC2 for binding to FBXW5, preventing FBXW5-mediated ubiquitination of TSC2 and thereby stabilizing TSC2 to decrease mTOR phosphorylation and enhance autophagy in dopaminergic neurons under oxidative stress. Co-immunoprecipitation, protein stability assay, mTOR phosphorylation readout, autophagy markers Journal of neurochemistry Medium 24372178 24444419
2018 FBXW5 targets SEC23B, a component of the COPII coat complex, for proteasomal degradation via the SCF-FBXW5 complex, limiting autophagic flux in nutrient-replete conditions. ULK1 phosphorylates SEC23B on Serine 186 in response to starvation, preventing SEC23B-FBXW5 interaction and stabilizing SEC23B. Stabilized, phosphorylated SEC23B associates selectively with SEC24A and SEC24B and relocalizes to the ER-Golgi intermediate compartment to promote autophagosome biogenesis. Co-immunoprecipitation, in vivo ubiquitination assay, phosphorylation site mutagenesis, mass spectrometry, subcellular fractionation/localization, autophagic flux assays eLife High 30596474
2020 FBXW5 directly interacts with TAK1 and negatively regulates pathological cardiac hypertrophy by blocking MAPK signaling downstream of TAK1. FBXW5 knockout mice show aggravated pressure-overload-induced hypertrophy, while AAV9-mediated overexpression is protective. TAK1 inhibition prevents the pro-hypertrophic effects of FBXW5 loss. Co-immunoprecipitation, FBXW5 knockout mice, AAV9 overexpression, pressure-overload model, MAPK phosphorylation readouts Journal of molecular and cellular cardiology Medium 32971071
2021 SCFFbxw5 ubiquitylates kinesin-13 microtubule depolymerases MCAK (Kif2c), Kif2a, and Kif2b in vitro without requiring preceding substrate modifications, using neddylated SCFFbxw5 and Cdc34. In cells, SCFFbxw5 targets MCAK for proteasomal degradation predominantly during G2. Loss of Fbxw5 increases MCAK levels at basal bodies and impairs ciliogenesis in G1/G0, which is rescued by co-knockdown of MCAK, Kif2a, or Kif2b. Protein microarray screening, in vitro reconstituted ubiquitylation assay, siRNA knockdown, co-knockdown rescue, ciliogenesis assay, cell cycle staging The EMBO journal High 34368969
2022 FBXW5 binds to the PPxY motif in the LATS1/2 kinase domain and promotes their ubiquitination and proteasomal degradation, thereby inactivating the Hippo pathway and increasing YAP1 activity in gastric cancer cells. Co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown, xenograft mouse model Cell death discovery Medium 35210431
2024 FBXW5 targets AQP3 (aquaporin 3) for ubiquitination and proteasomal degradation via the SCF-FBXW5 complex. FBXW5 knockdown stabilizes AQP3, which leads to lysosomal-dependent degradation of PDPK1, inactivating the AKT-mTOR pathway and inducing autophagic cell death in hepatocellular carcinoma cells. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, lysosomal inhibitor experiments, AKT-mTOR pathway readouts Autophagy Medium 38726865
2025 FBXW5 promotes ubiquitination and degradation of KLF13, which in turn relieves KLF13-mediated transcriptional suppression of TROAP, facilitating EMT in lung adenocarcinoma cells. Co-immunoprecipitation, ubiquitination assay, ChIP, luciferase reporter assay, siRNA knockdown, xenograft model Molecular carcinogenesis Medium 40696794

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 141 18381890
2011 The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and targets HsSAS-6 to control centrosome duplication. Nature cell biology 125 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
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
2024 SCFFBXW5-mediated degradation of AQP3 suppresses autophagic cell death through the PDPK1-AKT-MTOR axis in hepatocellular carcinoma cells. Autophagy 9 38726865
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