Affinage

FBXL7

F-box/LRR-repeat protein 7 · UniProt Q9UJT9

Length
491 aa
Mass
54.6 kDa
Annotated
2026-04-28
16 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FBXL7 is the substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase that targets multiple proteins for polyubiquitylation and proteasomal degradation, linking ubiquitin-dependent proteolysis to mitotic control, apoptosis, epithelial integrity, and glucose metabolism. FBXL7 ubiquitylates Aurora A kinase at centrosomes during mitosis and survivin at specific lysine residues (Lys-90/91), impairing mitochondrial function; it also degrades phospho-Ser104 c-SRC to suppress epithelial-to-mesenchymal transition and metastasis, and degrades the glycolytic regulator PFKFB4 (PMID:22306998, PMID:25778398, PMID:32839549, PMID:37179372). In Drosophila, the ortholog acts downstream of the protocadherin Fat to control planar-polarized localization of the atypical myosin Dachs at the apical membrane, thereby regulating Hippo pathway output and tissue size; biallelic loss-of-function of FBXL7 in humans is associated with Hennekam syndrome, consistent with its placement in the FAT4 signaling pathway (PMID:25107277, PMID:25256343, PMID:31633297). FBXL7 abundance is itself regulated by Fbxl18-mediated ubiquitylation at Lys-109 and by transcriptional repression through promoter hypermethylation or EZH2-dependent epigenetic silencing under hypoxia (PMID:25654763, PMID:32839549, PMID:37179372).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2012 Medium

    Establishing that FBXL7 functions as an SCF-type E3 ligase subunit resolved its molecular activity: it polyubiquitylates Aurora A at centrosomes during mitosis, causing G2/M arrest and spindle defects, thereby linking FBXL7 to cell division control.

    Evidence Co-immunoprecipitation, cell-based ubiquitination assay, flow cytometry, and immunofluorescence in human cell lines

    PMID:22306998

    Open questions at the time
    • No in vitro reconstituted ubiquitylation assay for Aurora A
    • Physiological relevance of FBXL7-Aurora A axis not tested in vivo
    • Degron or phosphodegron on Aurora A recognized by FBXL7 not mapped
  2. 2014 High

    Two independent Drosophila studies established that Fbxl7 acts downstream of the protocadherin Fat, localizing to the apical membrane in a Fat-dependent and planar-polarized manner to restrict Dachs levels and asymmetric localization, thus controlling Hippo pathway signaling and tissue growth.

    Evidence Genetic loss-of-function, GFP live imaging, protein interaction assays, immunofluorescence, and tissue overgrowth phenotype analysis in Drosophila wing discs

    PMID:25107277 PMID:25256343

    Open questions at the time
    • Whether Fbxl7 directly ubiquitylates Dachs or acts through an intermediate mechanism is unresolved
    • Conservation of Fat-Fbxl7-Dachs axis in mammalian Hippo signaling not demonstrated biochemically
  3. 2015 High

    Identification of survivin as an FBXL7 substrate, with specific interaction (Glu-126) and ubiquitin-acceptor (Lys-90/91) residues mapped, established that FBXL7-mediated degradation impairs mitochondrial function and linked FBXL7 to apoptosis regulation beyond its mitotic role.

    Evidence Co-IP, ubiquitylation assay, site-directed mutagenesis with functional rescue using ubiquitylation-resistant survivin mutants

    PMID:25778398

    Open questions at the time
    • In vivo significance of survivin degradation by FBXL7 not tested in animal models
    • Whether survivin degradation is cell-cycle dependent is not established
  4. 2015 High

    Discovery that Fbxl18 ubiquitylates FBXL7 at Lys-109 via recognition of an FQ motif revealed a hierarchical regulatory mechanism controlling FBXL7 protein abundance and its pro-apoptotic output.

    Evidence Co-IP, ubiquitylation assay, mutagenesis of degron and acceptor lysine, apoptosis rescue upon depletion of Fbxl18

    PMID:25654763

    Open questions at the time
    • Signals that regulate the Fbxl18-FBXL7 axis (e.g., upstream kinases) are unknown
    • Whether other E3 ligases also target FBXL7 is unexplored
  5. 2019 Low

    A human genetic finding linked biallelic FBXL7 loss-of-function (exon 3 deletion removing the F-box and LRR domains) to Hennekam syndrome, placing FBXL7 in the FAT4 pathway in humans and providing clinical relevance for the Drosophila Fat-Fbxl7 connection.

    Evidence Genomic sequencing and copy-number analysis in a patient with Hennekam syndrome phenotype, pathway inference from Drosophila ortholog data

    PMID:31633297

    Open questions at the time
    • Single family report without functional rescue or biochemical validation in human cells
    • Mechanism linking FBXL7 loss to lymphatic/developmental features of Hennekam syndrome not elucidated
    • Not independently replicated in additional kindreds
  6. 2020 High

    Identification of phospho-Ser104 c-SRC as an FBXL7 substrate demonstrated that FBXL7 acts as a tumor suppressor by degrading active c-SRC, and that epigenetic silencing of FBXL7 by promoter hypermethylation drives EMT and metastasis — a mechanism reversible by decitabine in vivo.

    Evidence Co-IP, ubiquitylation assay, promoter methylation analysis, in vivo xenograft metastasis models with pharmacological rescue (decitabine, dasatinib)

    PMID:32839549

    Open questions at the time
    • Structural basis for phospho-Ser104-dependent recognition by FBXL7 is unknown
    • Whether FBXL7 silencing is a general feature across cancer types beyond those tested is unclear
  7. 2023 Medium

    Discovery that FBXL7 ubiquitylates the glycolytic regulator PFKFB4, and that hypoxia-driven EZH2 epigenetically represses FBXL7 to stabilize PFKFB4 and enhance glycolysis, extended FBXL7's tumor-suppressive role to metabolic reprogramming in lung cancer.

    Evidence TAP/mass spectrometry substrate identification, ubiquitination assay, EZH2 knockdown, in vivo tumor models in NSCLC

    PMID:37179372

    Open questions at the time
    • Degron on PFKFB4 recognized by FBXL7 not mapped
    • Single-lab finding; independent confirmation pending
    • Whether FBXL7-PFKFB4 axis operates in normal metabolism or only in cancer is unknown
  8. 2025 Medium

    Identification of PTEN as an FBXL7 substrate whose degradation is enhanced by the proteasome activator PSME3 revealed a mechanism by which FBXL7 promotes glycolysis and Treg infiltration in hepatocellular carcinoma, adding an immunometabolic dimension to FBXL7 function.

    Evidence Co-IP, ubiquitination assay, functional in vivo and in vitro experiments in HCC models

    PMID:41094239

    Open questions at the time
    • Single-lab finding without independent replication
    • How PSME3 mechanistically facilitates the FBXL7-PTEN interaction is unexplained
    • Apparent contradiction with tumor-suppressive roles of FBXL7 (c-SRC, PFKFB4 degradation) is not reconciled

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how FBXL7 discriminates among its diverse substrates in different cellular contexts, whether there is a unifying degron logic, and how its apparently contradictory pro-tumorigenic (PTEN degradation) and anti-tumorigenic (c-SRC, PFKFB4 degradation) activities are regulated in a tissue- or context-specific manner.
  • No structural data for FBXL7 or any FBXL7-substrate complex
  • No consensus degron motif across substrates
  • Context-dependent regulation of substrate selectivity is unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6
Localization
GO:0005886 plasma membrane 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-162582 Signal Transduction 2 R-HSA-1640170 Cell Cycle 2 R-HSA-5357801 Programmed Cell Death 2
Partners
AURKABIRC5CUL1FBXL18PFKFB4PTENSKP1SRC
Complex memberships
SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 FBXL7 (as SCFFBXL7 E3 ligase complex) mediates polyubiquitination and proteasomal degradation of Aurora A kinase, causing G2/M arrest, tetraploidy, and monopolar/multipolar spindle formation. FBXL7 co-localizes with Aurora A at the centrosome during mitosis and interacts with Aurora A specifically during mitosis but not interphase. Co-immunoprecipitation, ectopic overexpression, cell cycle analysis (flow cytometry), immunofluorescence co-localization, ubiquitination assay Cell cycle (Georgetown, Tex.) Medium 22306998
2015 FBXL7 mediates polyubiquitylation and proteasomal degradation of survivin by interacting with Glu-126 within survivin's C-terminal α-helix, with Lys-90 and Lys-91 serving as ubiquitin acceptor sites. This degradation impairs mitochondrial function, and survivin mutants (E126A or KK90RR/KK91RR) that resist FBXL7-mediated ubiquitylation protect mitochondria from FBXL7-induced damage. Co-immunoprecipitation, ubiquitylation assay, site-directed mutagenesis, mitochondrial function assay (CCCP treatment), ectopic overexpression and depletion The Journal of biological chemistry High 25778398
2015 Fbxl18 (another F-box protein) targets FBXL7 for polyubiquitylation and proteasomal degradation, with Lys-109 of FBXL7 as the ubiquitin acceptor site and an FQ motif within FBXL7 as the molecular recognition site for Fbxl18 binding. Fbxl18 thereby limits Fbxl7-induced apoptosis. Co-immunoprecipitation, ubiquitylation assay, site-directed mutagenesis, apoptosis assay, ectopic overexpression and depletion Cell death & disease High 25654763
2014 Drosophila Fbxl7 binds to a specific region of the intracellular domain (ICD) of the protocadherin Fat, co-localizes with Fat at the proximal edge of cells, and regulates the levels and asymmetric localization of the atypical myosin Dachs at the apical membrane, thereby controlling Hippo signaling and tissue growth. Fbxl7 also regulates trafficking of proteins between the apical membrane and intracellular vesicles. Genetic loss-of-function (mutations), protein interaction assays, immunofluorescence co-localization, tissue overgrowth phenotype analysis eLife High 25107277
2014 Drosophila FbxL7 localizes to the plasma membrane in a Fat-dependent manner and is planar polarized; it controls the level and localization of Dachs (restricting it to the distal side) and also influences Dachsous levels, acting downstream of Fat to regulate tissue size via the Hippo pathway and tissue shape. GFP-tagging and live imaging, genetic loss-of-function and overexpression, immunofluorescence Development (Cambridge, England) High 25256343
2020 FBXL7 mediates ubiquitylation and proteasomal degradation of active c-SRC after c-SRC is phosphorylated at Ser-104. Epigenetic silencing of FBXL7 by promoter hypermethylation leads to c-SRC accumulation, promoting epithelial-to-mesenchymal transition and metastasis. Restoration of FBXL7 expression (by decitabine) or c-SRC inhibition (dasatinib) prevents metastasis in vivo. Co-immunoprecipitation, ubiquitylation assay, promoter methylation analysis, in vivo xenograft metastasis models, pharmacological rescue (decitabine, dasatinib), siRNA knockdown Nature cell biology High 32839549
2023 FBXL7 ubiquitinates and promotes proteasomal degradation of PFKFB4, suppressing glucose metabolism in non-small cell lung cancer. Under hypoxia, HIF-1α upregulates EZH2, which epigenetically represses FBXL7 transcription, leading to PFKFB4 stabilization and enhanced glycolysis. EZH2 knockdown impedes tumor growth through the FBXL7/PFKFB4 axis. Tandem affinity purification/mass spectrometry (substrate identification), ubiquitination assay, siRNA knockdown, EZH2 inhibition, in vivo tumor models Cell death & disease Medium 37179372
2025 PSME3 enhances binding between PTEN and FBXL7, promoting FBXL7-mediated ubiquitination and degradation of PTEN, thereby enhancing glycolysis and supporting Treg infiltration in hepatocellular carcinoma. Co-immunoprecipitation, ubiquitination assay, functional in vivo and in vitro experiments Oncogene Medium 41094239
2019 Biallelic loss-of-function of FBXL7 (homozygous deletion of exon 3, encoding the F-box domain and leucine-rich repeats) is associated with a Hennekam syndrome phenotype, placing FBXL7 in the same pathway as FAT4 (human ortholog of Drosophila Fat) consistent with the Drosophila Fbxl7-Fat interaction. Genomic sequencing, copy-number analysis, database analysis of control individuals, genetic pathway inference from Drosophila orthologs American journal of medical genetics. Part A Low 31633297

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 The Proapoptotic F-box Protein Fbxl7 Regulates Mitochondrial Function by Mediating the Ubiquitylation and Proteasomal Degradation of Survivin. The Journal of biological chemistry 61 25778398
2012 Novel E3 ligase component FBXL7 ubiquitinates and degrades Aurora A, causing mitotic arrest. Cell cycle (Georgetown, Tex.) 47 22306998
2020 Epigenetic silencing of the ubiquitin ligase subunit FBXL7 impairs c-SRC degradation and promotes epithelial-to-mesenchymal transition and metastasis. Nature cell biology 39 32839549
2015 F-box protein Fbxl18 mediates polyubiquitylation and proteasomal degradation of the pro-apoptotic SCF subunit Fbxl7. Cell death & disease 39 25654763
2014 The Drosophila F-box protein Fbxl7 binds to the protocadherin fat and regulates Dachs localization and Hippo signaling. eLife 38 25107277
2014 The ubiquitin ligase FbxL7 regulates the Dachsous-Fat-Dachs system in Drosophila. Development (Cambridge, England) 35 25256343
2022 Complete Genome Sequencing and Comparative Genomics of Three Potential Probiotic Strains, Lacticaseibacillus casei FBL6, Lacticaseibacillus chiayiensis FBL7, and Lacticaseibacillus zeae FBL8. Frontiers in microbiology 26 35069490
2020 miR-152-5p suppresses glioma progression and tumorigenesis and potentiates temozolomide sensitivity by targeting FBXL7. Journal of cellular and molecular medicine 19 32150671
2023 Hypoxia-mediated promotion of glucose metabolism in non-small cell lung cancer correlates with activation of the EZH2/FBXL7/PFKFB4 axis. Cell death & disease 17 37179372
2019 Biallelic mutation of FBXL7 suggests a novel form of Hennekam syndrome. American journal of medical genetics. Part A 14 31633297
2022 Functional characterization of FBXL7 as a novel player in human cancers. Cell death discovery 7 35906197
2023 Dexmedetomidine mitigates neuroinflammation in an Alzheimer's disease mouse model via the miR-204-3p/FBXL7 signaling axis. Brain research 4 37778649
2021 7-Ethoxyrosmanol alleviates hyperglycemia-induced vascular endothelial dysfunction by regulating FBXL7 expression. Journal of bioenergetics and biomembranes 4 34427826
2020 Epigenetic suppression of FBXL7 promotes metastasis. Molecular & cellular oncology 4 33235922
2022 FBXL7 Body Hypomethylation Is Frequent in Tumors from the Digestive and Respiratory Tracts and Is Associated with Risk-Factor Exposure. International journal of molecular sciences 2 35887149
2025 PSME3 drives Tregs infiltration and anti-PD1 resistance in hepatocellular carcinoma by regulating FBXL7/PTEN-mediated metabolic reprogramming. Oncogene 0 41094239