FBXL7

FBXL7 is the substrate-recognition subunit of an SCF (SKP1–CUL1–F-box) E3 ubiquitin ligase that selects diverse cell-cycle, apoptotic, and metabolic regulators for polyubiquitylation and proteasomal degradation (PMID:25778398, PMID:32839549). In mitosis it associates with Aurora A kinase at the centrosome during spindle formation and drives its degradation, and ectopic FBXL7 produces G2/M arrest, tetraploidy, and aberrant spindle poles (PMID:22306998). It also degrades survivin by binding Glu-126 in the survivin C-terminal α-helix and ubiquitylating Lys-90/Lys-91, an activity that impairs mitochondrial function (PMID:25778398). Substrate recognition is frequently licensed by a modification on the target: FBXL7 captures active c-SRC only after phosphorylation at Ser-104, and loss of FBXL7 by promoter hypermethylation in prostate and pancreatic cancers stabilizes c-SRC to promote EMT and metastasis (PMID:32839549). Its metabolic substrates include PFKFB4, whose degradation suppresses glycolysis and is relieved when HIF-1α/EZH2 represses FBXL7 transcription in NSCLC, and PTEN, whose FBXL7-mediated degradation is enhanced by PSME3 to drive glycolysis in hepatocellular carcinoma (PMID:37179372, PMID:41094239). FBXL7 is itself a substrate, being targeted by SCF^FBXL18 through an FQ recognition motif and ubiquitylation at Lys-109, linking its turnover to apoptotic output (PMID:25654763). In Drosophila, the FBXL7 ortholog binds the Fat protocadherin intracellular domain, localizes to the proximal cell edge in a Fat-dependent manner, and controls the level and planar-polarized localization of the atypical myosin Dachs, thereby tuning Hippo signaling and tissue growth (PMID:25107277, PMID:25256343).

1. 2012 Medium

   Established FBXL7 as a mitotic SCF ligase by identifying Aurora A as a degradation target, answering whether FBXL7 controls cell-cycle progression.

   Evidence Reciprocal co-IP, centrosomal co-localization, and ectopic expression with flow-cytometry cell-cycle analysis in mammalian cells

   PMID:22306998

   Open questions at the time

   • Ubiquitin acceptor sites on Aurora A not mapped
   • Cell-cycle-restricted interaction mechanism not defined
   • In vitro reconstitution of the ligase complex not shown
2. 2014 High

   Defined the Drosophila ortholog as a Fat-pathway effector, showing how FBXL7 couples a protocadherin to Hippo-dependent growth control.

   Evidence Genetic loss-of-function, direct binding to the Fat ICD, GFP localization/planar polarity, and epistasis with Fat and Dachs in two independent studies

   PMID:25107277 PMID:25256343

   Open questions at the time

   • Whether Dachs is a direct ubiquitylation substrate not established
   • Conservation of this Fat/Hippo role in mammals untested
   • Mechanism of Fat-dependent membrane recruitment not resolved
3. 2015 High

   Mapped the survivin recognition and ubiquitylation determinants and linked FBXL7 activity to mitochondrial integrity, resolving how it triggers apoptotic/mitochondrial phenotypes.

   Evidence Co-IP, site-directed mutagenesis (E126A binding site; KK90/91RR acceptor sites), in-cell ubiquitylation, and mitochondrial function assays with functional rescue

   PMID:25778398

   Open questions at the time

   • Connection between survivin degradation and specific mitochondrial pathways incomplete
   • In vitro reconstitution not performed
4. 2015 High

   Showed FBXL7 is itself controlled by ubiquitin-mediated turnover, identifying SCF^FBXL18 as its upstream regulator and connecting FBXL7 levels to apoptosis.

   Evidence Co-IP, mutagenesis of the Lys-109 acceptor site and FQ recognition motif, in-cell ubiquitylation, and apoptosis assays after siRNA/overexpression

   PMID:25654763

   Open questions at the time

   • Physiological signals controlling FBXL18-mediated FBXL7 turnover unknown
   • Crosstalk with FBXL7's own substrate degradation not defined
5. 2020 High

   Demonstrated phosphodegron-based recognition of active c-SRC and connected FBXL7 epigenetic silencing to EMT/metastasis, establishing a tumor-suppressive axis.

   Evidence Co-IP, ubiquitylation assays, Ser-104 phospho-mapping, siRNA, promoter methylation analysis, and in vivo metastasis/rescue models with decitabine

   PMID:32839549

   Open questions at the time

   • Kinase generating the Ser-104 phosphodegron not identified
   • Generality of phospho-dependent recognition across substrates unclear
6. 2023 Medium

   Extended FBXL7 function to glucose metabolism by identifying PFKFB4 as a substrate within a HIF-1α/EZH2 transcriptional repression circuit.

   Evidence TAP/MS substrate identification, ubiquitylation assays, EZH2 knockdown, HIF-1α pathway and glucose-metabolism assays in NSCLC

   PMID:37179372

   Open questions at the time

   • PFKFB4 ubiquitin acceptor sites not mapped
   • Single-lab substrate validation
   • Direct ligase reconstitution not shown
7. 2025 Medium

   Added PTEN as an FBXL7 substrate and PSME3 as a binding enhancer, linking FBXL7 activity to glycolysis and OPN secretion in hepatocellular carcinoma.

   Evidence Co-IP, ubiquitylation assays, glycolysis assays, and in vivo experiments in HCC cells

   PMID:41094239

   Open questions at the time

   • Mechanism by which PSME3 enhances PTEN–FBXL7 binding undefined
   • Single co-IP/ubiquitylation study without reciprocal validation
   • PTEN acceptor sites not mapped

• How FBXL7 substrate selection is coordinated across its many targets and whether its mammalian role in Fat/Hippo-type growth control parallels the Drosophila ortholog remain unresolved.
• No unifying model for substrate prioritization among mitotic, apoptotic, and metabolic targets
• Mammalian Fat/Hippo connection untested
• Structural basis of LRR-substrate recognition not determined