id: Q9UJT9
gene_symbol: FBXL7
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXL7 (F-box/LRR-repeat protein 7) is the substrate-recognition (F-box)
  subunit of an SCF (SKP1-CUL1-RBX1-F-box) cullin-RING E3 ubiquitin ligase that
  controls mitotic progression and apoptosis by directing the ubiquitination and
  proteasomal degradation of mitotic regulators. Within the SCF(FBXL7) complex,
  FBXL7 binds SKP1 via its F-box domain and uses its leucine-rich repeats to
  recruit substrates, so that CUL1-RBX1 drives their polyubiquitination. Its
  best-characterized substrates are the mitotic kinase Aurora A (AURKA), which
  FBXL7 colocalizes with and targets for centrosomal degradation during mitosis
  to promote mitotic arrest, and the inhibitor-of-apoptosis protein
  survivin/BIRC5 (recognized via survivin Glu126; ubiquitinated at Lys90/Lys91),
  whose FBXL7-mediated degradation regulates mitochondrial function and promotes
  apoptosis. FBXL7 (a 491-residue protein with an N-terminal F-box motif and
  roughly eleven C-terminal leucine-rich repeats) additionally targets active
  c-SRC (after Ser104 phosphorylation) and the EMT transcription factor
  SNAI1/Snail1 for degradation, acting as a metastasis suppressor that restrains
  SRC- and Snail1-driven epithelial-mesenchymal transition and invasion, and it
  ubiquitinates the glycolytic enzyme PFKFB4, coupling FBXL7 to metabolic
  reprogramming. FBXL7 localizes to the centrosome during spindle formation.
  FBXL7 is itself a proapoptotic factor whose cellular abundance is controlled by
  the related F-box protein FBXL18, which ubiquitinates FBXL7 (at Lys109) for
  proteasomal degradation, and its expression is repressed transcriptionally
  (e.g. by hypoxia-induced EZH2 and by promoter hypermethylation in cancer).
  Through these activities FBXL7 contributes to the G2/M transition, spindle
  dynamics, apoptotic signaling, EMT/metastasis suppression, and metabolic
  control, and is implicated in cancer progression and drug resistance.
alternative_products:
- name: '1'
  id: Q9UJT9-1
- name: '2'
  id: Q9UJT9-2
  sequence_note: VSP_054751
existing_annotations:
- term:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:25778398
  qualifier: enables
  review:
    summary: Proposed core molecular function. As the F-box/LRR substrate-recognition subunit of SCF(FBXL7), FBXL7 selects substrates (AURKA, survivin/BIRC5) for SCF-dependent polyubiquitination. This more informative MF term is not in the GOA, which lacks any explicit MF annotation for FBXL7.
    action: NEW
    reason: Captures the precise molecular function of FBXL7 as an SCF substrate-recognition adaptor, more informative than the bare protein binding annotations and absent from the existing GOA.
    supported_by:
    - reference_id: PMID:25778398
      supporting_text: Fbxl7 mediates polyubiquitylation and proteasomal degradation of survivin by interacting with Glu-126 within its carboxyl-terminal α helix
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Combined automated electronic assignment of centrosome localization, where FBXL7 acts during spindle formation. Core localization for its mitotic role.
    action: ACCEPT
    reason: Core localization; FBXL7 localizes to the centrosome during spindle formation, consistent with its mitotic substrate-targeting role.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary interactome reference map interactions. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: 'Q9UJT9; Q92609: TBC1D5; NbExp=3; IntAct=EBI-914660, EBI-742381'
- term:
    id: GO:0000086
    label: G2/M transition of mitotic cell cycle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based electronic assignment of involvement in the G2/M transition, consistent with FBXL7-driven AURKA degradation and mitotic arrest.
    action: ACCEPT
    reason: Core biological process; FBXL7 regulates mitotic progression (mitotic arrest via AURKA degradation).
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: During mitosis, it mediates the ubiquitination and subsequent proteasomal degradation of AURKA, causing mitotic arrest
- term:
    id: GO:0000209
    label: protein polyubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Combined automated electronic assignment of protein polyubiquitination, the specific modification FBXL7 directs onto its substrates.
    action: ACCEPT
    reason: Correct; FBXL7 mediates substrate polyubiquitination, supported by IDA/IMP evidence (survivin).
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: regulates mitochondrial function by mediating the ubiquitination and proteasomal degradation of the apoptosis inhibitor BIRC5
- term:
    id: GO:0000278
    label: mitotic cell cycle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based electronic assignment of involvement in the mitotic cell cycle, consistent with FBXL7's role in mitotic regulation.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic relative to the specific G2/M transition and SCF-dependent degradation annotations.
    supported_by:
    - reference_id: PMID:25778398
      supporting_text: Fbxl7, a component of the Skp1·Cul1·F-box protein type ubiquitin E3 ligase, regulates mitotic cell cycle progression
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Combined automated electronic assignment of protein ubiquitination, a parent of the specific SCF-dependent polyubiquitination FBXL7 mediates.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific SCF-dependent catabolic / polyubiquitination annotations better capture the role.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: Combined automated electronic assignment of SCF complex membership, the core assembly context for FBXL7.
    action: ACCEPT
    reason: Core cellular component; redundant with IDA/ISS evidence.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXL7) composed of CUL1, SKP1, RBX1 and FBXL7
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Combined automated electronic assignment of SCF-dependent proteasomal degradation, the core biological process of SCF(FBXL7).
    action: ACCEPT
    reason: Core biological process; redundant with the experimental IDA/IMP evidence (survivin/AURKA degradation).
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: regulates mitochondrial function by mediating the ubiquitination and proteasomal degradation of the apoptosis inhibitor BIRC5
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:33234069
  qualifier: involved_in
  review:
    summary: Author-statement (FBXL family review) assignment of the core SCF-dependent proteasomal degradation process.
    action: ACCEPT
    reason: Core biological process; consistent with the experimental substrate-degradation evidence.
    supported_by:
    - reference_id: PMID:25778398
      supporting_text: Fbxl7 mediates polyubiquitylation and proteasomal degradation of survivin
- term:
    id: GO:0042981
    label: regulation of apoptotic process
  evidence_type: NAS
  original_reference_id: PMID:25654763
  qualifier: involved_in
  review:
    summary: Author-statement (ComplexPortal) assignment of regulation of apoptosis; FBXL7 is a proapoptotic factor and its degradation of survivin/BIRC5 promotes apoptosis.
    action: ACCEPT
    reason: Supported biological process; FBXL7 is proapoptotic and regulates apoptosis via degradation of the IAP survivin/BIRC5.
    supported_by:
    - reference_id: PMID:25654763
      supporting_text: Fbxl18 regulates apoptosis by mediating ubiquitin-dependent proteasomal degradation of the pro-apoptotic protein Fbxl7
- term:
    id: GO:0000209
    label: protein polyubiquitination
  evidence_type: IMP
  original_reference_id: PMID:28218735
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that FBXL7 mediates polyubiquitination of BIRC5/survivin. Core activity.
    action: ACCEPT
    reason: Directly supported substrate polyubiquitination (survivin/BIRC5); consistent with FBXL7's SCF substrate-receptor function.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: this interaction allows BIRC5 to be polyubiquitinated by the SCF(FBXL7) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28218735
  qualifier: enables
  review:
    summary: Interaction with BIRC5/survivin (a FBXL7 substrate). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally important FBXL7-BIRC5 substrate interaction but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: Interacts with BIRC5; this interaction allows BIRC5 to be polyubiquitinated by the SCF(FBXL7)
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:25778398
  qualifier: part_of
  review:
    summary: Direct evidence that FBXL7 is a component of the SCF (SKP1-CUL1-F-box) E3 ligase complex. Core cellular component.
    action: ACCEPT
    reason: Core cellular component; FBXL7 is the F-box substrate receptor of the SCF(FBXL7) complex.
    supported_by:
    - reference_id: PMID:25778398
      supporting_text: Fbxl7, a component of the Skp1·Cul1·F-box protein type ubiquitin E3 ligase, regulates mitotic cell cycle progression
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:25778398
  qualifier: involved_in
  review:
    summary: Direct evidence that SCF(FBXL7) drives proteasomal degradation of survivin/BIRC5. Core biological process.
    action: ACCEPT
    reason: Core biological process directly demonstrated; FBXL7 targets survivin for SCF-dependent proteasomal degradation.
    supported_by:
    - reference_id: PMID:25778398
      supporting_text: Fbxl7 mediates polyubiquitylation and proteasomal degradation of survivin
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:28218735
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence linking FBXL7 to SCF-dependent degradation of survivin in the AURKA/gastric-cancer study. Core biological process.
    action: ACCEPT
    reason: Core biological process; FBXL7 mediates proteasomal degradation of survivin/BIRC5.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: regulates mitochondrial function by mediating the ubiquitination and proteasomal degradation of the apoptosis inhibitor BIRC5
- term:
    id: GO:0000209
    label: protein polyubiquitination
  evidence_type: IDA
  original_reference_id: PMID:25778398
  qualifier: involved_in
  review:
    summary: Direct evidence that FBXL7 polyubiquitinates survivin (at Lys90/Lys91). Core activity.
    action: ACCEPT
    reason: Directly demonstrated substrate polyubiquitination of survivin/BIRC5.
    supported_by:
    - reference_id: PMID:25778398
      supporting_text: Fbxl7 mediates polyubiquitylation and proteasomal degradation of survivin
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25778398
  qualifier: enables
  review:
    summary: Interaction with survivin (via Glu-126 in its C-terminal helix). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally important FBXL7-survivin substrate interaction but bare protein binding is uninformative.
    supported_by:
    - reference_id: PMID:25778398
      supporting_text: Fbxl7 mediates polyubiquitylation and proteasomal degradation of survivin by interacting with Glu-126 within its carboxyl-terminal α helix
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8854051
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (SCF-FBXL18 ubiquitinates FBXL7). Consistent with the cytoplasmic site of action.
    action: KEEP_AS_NON_CORE
    reason: Correct cytoplasmic compartment; the functionally salient localization is the centrosome during spindle formation.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8854071
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (proteasome-mediated degradation of PolyUb-FBXL7). Consistent with the cytoplasmic site of action.
    action: KEEP_AS_NON_CORE
    reason: Correct cytoplasmic compartment; the functionally salient localization is the centrosome.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8853496
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (SCF:FBXL7 binds AURKA). Consistent with the cytoplasmic site of action.
    action: KEEP_AS_NON_CORE
    reason: Correct cytoplasmic compartment; the functionally salient localization is the centrosome.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: During mitosis, it mediates the ubiquitination and subsequent proteasomal degradation of AURKA
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8854041
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (SCF-FBXL7 ubiquitinates AURKA). Consistent with the cytoplasmic site of action.
    action: KEEP_AS_NON_CORE
    reason: Correct cytoplasmic compartment; the functionally salient localization is the centrosome.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: During mitosis, it mediates the ubiquitination and subsequent proteasomal degradation of AURKA
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8854044
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (proteasome degrades AURKA ubiquitinated by SCF-FBXL7). Consistent with the cytoplasmic site of action.
    action: KEEP_AS_NON_CORE
    reason: Correct cytoplasmic compartment; the functionally salient localization is the centrosome.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: During mitosis, it mediates the ubiquitination and subsequent proteasomal degradation of AURKA
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8854052
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (formation of the SCF-FBXL7 complex). Consistent with the cytoplasmic site of action.
    action: KEEP_AS_NON_CORE
    reason: Correct cytoplasmic compartment; the functionally salient localization is the centrosome.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXL7) composed of CUL1, SKP1, RBX1 and FBXL7
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952618
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (neddylation of CRL1). Generic CRL-pathway localization.
    action: KEEP_AS_NON_CORE
    reason: Correct cytoplasmic compartment but from generic CRL neddylation-pathway context; the functionally salient localization is the centrosome.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952620
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (NEDD8:UBE2M binds CRL1). Generic CRL-pathway localization.
    action: KEEP_AS_NON_CORE
    reason: Correct cytoplasmic compartment but from generic CRL-pathway context; redundant.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955241
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (CAND1 binds cytosolic CRL). Generic CRL-pathway localization.
    action: KEEP_AS_NON_CORE
    reason: Correct cytoplasmic compartment but from generic CRL-regulation pathway context; redundant.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955289
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (COMMDs displace CAND1). Generic CRL-pathway localization.
    action: KEEP_AS_NON_CORE
    reason: Correct cytoplasmic compartment but from generic CRL-regulation pathway context; redundant.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956040
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (COP9 signalosome deneddylates CRL). Generic CRL-pathway localization.
    action: KEEP_AS_NON_CORE
    reason: Correct cytoplasmic compartment but from generic CRL-regulation pathway context; redundant.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956200
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (DCUN1D3 binds CRL1). Generic CRL-pathway localization.
    action: KEEP_AS_NON_CORE
    reason: Correct cytoplasmic compartment but from generic CRL-regulation pathway context; redundant.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983140
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (transfer of Ub from E2 to substrate). Generic ubiquitination-pathway localization.
    action: KEEP_AS_NON_CORE
    reason: Correct cytoplasmic compartment but from generic ubiquitination-pathway context; redundant.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983147
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (release of E3 from polyubiquitinated substrate). Generic ubiquitination-pathway localization.
    action: KEEP_AS_NON_CORE
    reason: Correct cytoplasmic compartment but from generic ubiquitination-pathway context; redundant.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983156
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (polyubiquitination of substrate). Generic ubiquitination-pathway localization.
    action: KEEP_AS_NON_CORE
    reason: Correct cytoplasmic compartment but from generic ubiquitination-pathway context; redundant.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983157
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (interaction of E3 with substrate and E2-Ub). Generic ubiquitination-pathway localization.
    action: KEEP_AS_NON_CORE
    reason: Correct cytoplasmic compartment but from generic ubiquitination-pathway context; redundant.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome
- term:
    id: GO:0000086
    label: G2/M transition of mitotic cell cycle
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity assignment of involvement in the G2/M transition, consistent with FBXL7-driven AURKA degradation.
    action: ACCEPT
    reason: Core biological process; FBXL7 regulates the mitotic G2/M transition.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: During mitosis, it mediates the ubiquitination and subsequent proteasomal degradation of AURKA, causing mitotic arrest
- term:
    id: GO:0000278
    label: mitotic cell cycle
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity assignment of involvement in the mitotic cell cycle.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic relative to the specific G2/M transition annotation.
    supported_by:
    - reference_id: PMID:25778398
      supporting_text: Fbxl7, a component of the Skp1·Cul1·F-box protein type ubiquitin E3 ligase, regulates mitotic cell cycle progression
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity assignment of centrosome localization, where FBXL7 acts during spindle formation. Core localization.
    action: ACCEPT
    reason: Core localization; FBXL7 localizes to the centrosome during spindle formation.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: Localizes to the centrosome during spindle formation.
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity assignment of protein ubiquitination, a parent of the specific SCF-dependent polyubiquitination FBXL7 mediates.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific polyubiquitination/SCF-dependent catabolic annotations better capture the role.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: part_of
  review:
    summary: Sequence-similarity assignment of SCF complex membership, the core assembly context for FBXL7.
    action: ACCEPT
    reason: Core cellular component; redundant with IDA/IEA evidence.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXL7) composed of CUL1, SKP1, RBX1 and FBXL7
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity assignment of SCF-dependent proteasomal degradation, the core biological process of SCF(FBXL7).
    action: ACCEPT
    reason: Core biological process; redundant with the experimental IDA/IMP evidence.
    supported_by:
    - reference_id: PMID:25778398
      supporting_text: Fbxl7 mediates polyubiquitylation and proteasomal degradation of survivin
- term:
    id: GO:0000151
    label: ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:10531035
  qualifier: part_of
  review:
    summary: Author-statement assignment (original F-box family paper) of being part of a ubiquitin ligase complex. A generic parent of the specific SCF complex.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; subsumed by the specific SCF ubiquitin ligase complex annotation.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXL7)
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:10531035
  qualifier: involved_in
  review:
    summary: Author-statement assignment of ubiquitin-dependent protein catabolism, a parent of the specific SCF-dependent proteasomal degradation FBXL7 mediates.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific GO:0031146 (SCF-dependent proteasomal catabolic process) better captures the role.
    supported_by:
    - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
      supporting_text: regulates mitochondrial function by mediating the ubiquitination and proteasomal degradation of the apoptosis inhibitor BIRC5
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10531035
  title: Identification of a family of human F-box proteins.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Original identification of FBXL7 as an F-box protein; source of the generic ubiquitin ligase complex and ubiquitin-dependent catabolic NAS annotations. Full text not in cache.
- id: PMID:25654763
  title: F-box protein Fbxl18 mediates polyubiquitylation and proteasomal degradation of the pro-apoptotic SCF subunit Fbxl7.
  findings:
  - statement: FBXL7 is a proapoptotic SCF subunit that induces mitotic arrest; its abundance is controlled by FBXL18, which ubiquitinates FBXL7 (at Lys109, via an FQ recognition motif) for proteasomal degradation, thereby limiting FBXL7-driven apoptosis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; establishes FBXL7 as proapoptotic and mitotic-arrest-inducing, and that FBXL18 controls FBXL7 stability. Supports the regulation-of-apoptosis annotation.
- id: PMID:25778398
  title: The Proapoptotic F-box Protein Fbxl7 Regulates Mitochondrial Function by Mediating the Ubiquitylation and Proteasomal Degradation of Survivin.
  findings:
  - statement: FBXL7, a component of the SCF (SKP1-CUL1-F-box) E3 ligase that regulates mitotic progression, mediates polyubiquitylation (at survivin Lys90/Lys91, via FBXL7 contact with survivin Glu126) and proteasomal degradation of survivin/BIRC5, regulating mitochondrial function.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes survivin/BIRC5 as a direct FBXL7 substrate and FBXL7 as an SCF component regulating mitosis and mitochondrial function. Abstract-only in cache; supports IDA SCF/polyubiquitination/catabolic annotations.
- id: PMID:28218735
  title: Aurora kinase A regulates Survivin stability through targeting FBXL7 in gastric cancer drug resistance and prognosis.
  findings:
  - statement: In gastric cancer, AURKA upregulates the anti-apoptotic protein survivin; FBXL7 interacts with and polyubiquitinates survivin/BIRC5 for proteasomal degradation, linking the AURKA-FBXL7-survivin axis to drug resistance and prognosis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes FBXL7-BIRC5 interaction and FBXL7-mediated survivin polyubiquitination in a cancer context. Abstract-only in cache; supporting text for substrate annotations drawn from UniProt summary of this paper.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Binary interactome reference map; source of a bare protein binding annotation.
- id: PMID:33234069
  title: 'The FBXL family of F-box proteins: variations on a theme.'
  findings:
  - statement: Review of the FBXL family describing FBXL7 as an SCF substrate receptor mediating SCF-dependent proteasomal degradation of its targets.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text available; family review supporting the SCF-dependent catabolic process annotation.
- id: Reactome:R-HSA-8853496
  title: SCF:FBXL7 binds AURKA
  findings: []
- id: Reactome:R-HSA-8854041
  title: SCF-FBXL7 ubiquitinates AURKA
  findings: []
- id: Reactome:R-HSA-8854044
  title: Proteasome degrades AURKA ubiquitinated by SCF-FBXL7
  findings: []
- id: Reactome:R-HSA-8854051
  title: SCF-FBXL18 ubiquitinates FBXL7
  findings: []
- id: Reactome:R-HSA-8854052
  title: Formation of the SCF-FBXL7 complex
  findings: []
- id: Reactome:R-HSA-8854071
  title: Proteasome-mediated degradation of PolyUb-FBXL7
  findings: []
- id: Reactome:R-HSA-8952618
  title: AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8952620
  title: NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8955241
  title: CAND1 binds cytosolic CRL E3 ubiquitin ligases
  findings: []
- id: Reactome:R-HSA-8955289
  title: COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes
  findings: []
- id: Reactome:R-HSA-8956040
  title: COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes
  findings: []
- id: Reactome:R-HSA-8956200
  title: MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-983140
  title: Transfer of Ub from E2 to substrate and release of E2
  findings: []
- id: Reactome:R-HSA-983147
  title: Release of E3 from polyubiquitinated substrate
  findings: []
- id: Reactome:R-HSA-983156
  title: Polyubiquitination of substrate
  findings: []
- id: Reactome:R-HSA-983157
  title: Interaction of E3 with substrate and E2-Ub complex
  findings: []
- id: file:human/FBXL7/FBXL7-deep-research-falcon.md
  title: Falcon deep research report for human FBXL7
  findings:
  - statement: FBXL7 is a 491-residue FBXL-family protein with an N-terminal F-box motif (for SKP1/SCF assembly) and roughly eleven C-terminal leucine-rich repeats (the substrate-binding interface); it is the substrate-recognition subunit of an SCF (SKP1-CUL1-RBX1-F-box) E3 ligase.
    supporting_text: A 2022 expert review explicitly describes **human FBXL7** as a **491-aa** protein on chromosome **5p15.1** containing an **N-terminal F-box motif** (for SCF complex binding) and **~11 C-terminal leucine-rich repeats (LRRs)** (substrate binding), matching the UniProt domain expectations (F-box + LRRs) and the FBXL family classification.
  - statement: FBXL7 colocalizes with Aurora A and targets it for centrosomal polyubiquitylation and degradation during mitosis, linking FBXL7 to spindle defects, polyploidy, and G2/M / mitotic arrest.
    supporting_text: Multiple authoritative sources cite **Aurora A kinase (AURKA)** as an early/central FBXL7 substrate, with FBXL7 promoting AURKA polyubiquitylation and degradation during mitosis and associating this with mitotic spindle/cell-cycle phenotypes.
  - statement: SCF-FBXL7 targets the anti-apoptotic protein survivin/BIRC5 for proteasomal degradation (recognition via survivin E126, ubiquitin acceptor sites K90/K91), making FBXL7 proapoptotic and regulating mitochondrial function.
    supporting_text: 'Mapping of FBXL7–survivin interaction determinants and ubiquitylation acceptor sites: **E126** is important for recognition, and **K90/K91** serve as ubiquitin acceptors (mutants resist FBXL7-mediated effects).'
  - statement: FBXL7 acts as a metastasis suppressor by ubiquitinating and degrading additional substrates - active c-SRC (after Ser104 phosphorylation) and the EMT transcription factor SNAI1/Snail1 - and is itself silenced in cancer by promoter hypermethylation and by hypoxia-induced EZH2 (which stabilizes the FBXL7 substrate PFKFB4 to drive glycolysis).
    supporting_text: 'A high-impact cancer epigenetics study established FBXL7 as a **metastasis-suppressor axis component** through control of **active c-SRC**: FBXL7 mediates **ubiquitylation and proteasomal degradation of active c-SRC after phosphorylation at Ser104**, and loss of FBXL7 promotes EMT and metastasis.'
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: Falcon (Edison Scientific) deep-research synthesis. The AURKA and survivin/BIRC5 substrate axes are corroborated by the experimental cache (PMID:25778398, PMID:28218735). The additional substrates (c-SRC Ser104, SNAI1/Snail1, PFKFB4) and the EZH2/hypoxia and promoter-methylation regulation are drawn from primary cancer studies cited by author-year/DOI (liu2015, moro2020, tang2021, zhou2023, wang2022) rather than PMIDs and are not independently PubMed-verified here, so marked UNVERIFIED; treated as leads used to enrich the gene narrative, not to add unsupported GO terms.
core_functions:
- description: Functions as the substrate-recognition (F-box) subunit of an SCF (SKP1-CUL1-RBX1-FBXL7) cullin-RING E3 ubiquitin ligase that recruits the mitotic kinase Aurora A (AURKA) during mitosis for polyubiquitination and proteasomal degradation, contributing to control of the G2/M transition and mitotic progression.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005813
    label: centrosome
  supported_by:
  - reference_id: file:human/FBXL7/FBXL7-uniprot.txt
    supporting_text: During mitosis, it mediates the ubiquitination and subsequent proteasomal degradation of AURKA, causing mitotic arrest
  directly_involved_in:
  - id: GO:0000086
    label: G2/M transition of mitotic cell cycle
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
- description: As the SCF(FBXL7) substrate receptor, binds the inhibitor-of-apoptosis protein survivin/BIRC5 and directs its polyubiquitination and proteasomal degradation, thereby regulating mitochondrial function and promoting apoptosis.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:25778398
    supporting_text: Fbxl7 mediates polyubiquitylation and proteasomal degradation of survivin
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  - id: GO:0042981
    label: regulation of apoptotic process
- description: As the SCF(FBXL7) substrate receptor, recognizes and directs the polyubiquitination and proteasomal degradation of additional substrates that drive epithelial-mesenchymal transition and metabolic reprogramming - active c-SRC (after Ser104 phosphorylation), the EMT transcription factor SNAI1/Snail1, and the glycolytic enzyme PFKFB4 - acting in cancer as a metastasis suppressor whose loss (via promoter hypermethylation or hypoxia/EZH2-driven transcriptional repression) promotes invasion and glycolysis. (Substrates beyond AURKA/survivin are reported in primary cancer literature summarized by the Falcon deep-research report and are not yet in the curated GOA.)
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/FBXL7/FBXL7-deep-research-falcon.md
    supporting_text: 'A high-impact cancer epigenetics study established FBXL7 as a **metastasis-suppressor axis component** through control of **active c-SRC**: FBXL7 mediates **ubiquitylation and proteasomal degradation of active c-SRC after phosphorylation at Ser104**, and loss of FBXL7 promotes EMT and metastasis.'
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
proposed_new_terms: []
suggested_questions:
- question: Are the two best-described FBXL7 substrates (AURKA and survivin/BIRC5) targeted by the same FBXL7 pool and cell-cycle window, or do distinct localizations (centrosomal versus cytosolic) and timing govern each substrate?
- question: How does the FBXL18-FBXL7 regulatory axis controlling FBXL7 abundance influence the balance between mitotic progression and apoptosis, and is it dysregulated in cancers with AURKA/survivin overexpression?
- question: FBXL7 is reported to degrade a broad substrate set (AURKA, survivin/BIRC5, active c-SRC, SNAI1/Snail1, PFKFB4) and behaves as a tumor suppressor or context-dependent oncogenic factor across tissues; which of these substrate axes is dominant in a given cell type, and what determines whether FBXL7 loss is pro- or anti-tumorigenic?
suggested_experiments:
- description: Reconstitute SCF(FBXL7)-mediated ubiquitination of AURKA and of survivin/BIRC5 in vitro with purified SKP1, CUL1, RBX1, an E2, and wild-type versus substrate-binding-mutant FBXL7 to map substrate lysine sites and confirm direct, SCF-dependent polyubiquitination.
- description: Perform synchronized cell-cycle proteomics and live-cell imaging in FBXL7-knockout versus wild-type cells to quantify AURKA and survivin turnover across mitosis, define FBXL7's centrosomal localization dynamics, and test the apoptotic consequences of substrate stabilization.