id: Q8N531
gene_symbol: FBXL6
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXL6 (F-box/LRR-repeat protein 6, FBL6) is a member of the FBXL subfamily of
  F-box proteins, characterized by an N-terminal F-box domain (residues ~10-162)
  followed by a C-terminal region of ~11 leucine-rich repeats (LRRs). It functions
  as the substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin
  ligase complex: the F-box domain docks the protein onto SKP1 (and through it
  CUL1 and the catalytic RING subunit RBX1), while the LRR region binds substrate
  proteins, frequently in a phosphodegron-dependent manner. FBXL6 catalyzes both
  degradative and non-degradative ubiquitination depending on the substrate. In
  hepatocellular carcinoma it promotes K48-linked degradation of phosphorylated
  p53 (recognizing p53 phosphorylated on Ser315 and ubiquitinating Lys291/Lys292),
  thereby relieving tumor-suppressive signaling, and degrades the ETS transcription
  factor ETV6/TEL and cyclin A2 (CCNA2). Conversely it mediates K63-linked,
  non-degradative ubiquitination that stabilizes or activates clients including the
  chaperone HSP90AA1 (sustaining c-MYC), the GTPase KRAS (ubiquitinating Lys128 to
  enhance RAF binding and MEK/ERK/mTOR signaling), and transketolase (TKT, recruited
  after VRK2 phosphorylation of Thr287, driving ROS-mTOR signaling, PD-L1 induction,
  and immune evasion). FBXL6 is broadly but weakly expressed across tissues
  (low tissue specificity) and is frequently overexpressed in hepatocellular
  carcinoma and acute myeloid leukemia, where it represents a tumor dependency,
  particularly in FLT3-ITD-mutated AML. The SCF mechanistic framework implies
  cytosolic and nuclear sites of action depending on substrate; explicit
  subcellular localization has not been firmly mapped experimentally.
alternative_products:
- name: '1'
  id: Q8N531-1
- name: '2'
  id: Q8N531-2
  sequence_note: VSP_008498
existing_annotations:
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: InterPro/domain-based electronic assignment that FBXL6 is part of an SCF ubiquitin ligase complex, consistent with its F-box domain and documented SKP1/CUL1 interaction.
    action: ACCEPT
    reason: FBXL6 has a canonical F-box domain and directly interacts with SKP1 and CUL1, making SCF complex membership the correct core cellular component for an F-box substrate receptor.
    supported_by:
    - reference_id: file:human/FBXL6/FBXL6-uniprot.txt
      supporting_text: 'Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19159283
  qualifier: enables
  review:
    summary: IntAct interaction with SKP1 (WITH/FROM UniProtKB:P63208) captured by the Array MAPPIT high-throughput screen. The SKP1 interaction is the defining F-box-domain partnership, but the bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally meaningful FBXL6-SKP1 interaction (the basis of SCF assembly), but bare protein binding is uninformative per curation guidelines; the SCF-complex annotation captures this relationship.
    supported_by:
    - reference_id: file:human/FBXL6/FBXL6-uniprot.txt
      supporting_text: 'Q8N531; P63208: SKP1; NbExp=4; IntAct=EBI-2322696, EBI-307486;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27705803
  qualifier: enables
  review:
    summary: IntAct interaction with SKP1 (WITH/FROM UniProtKB:P63208) captured by the Polycomb complexome AP-MS study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the FBXL6-SKP1 interaction underlying SCF assembly, but bare protein binding is uninformative; captured by the SCF-complex annotation.
    supported_by:
    - reference_id: file:human/FBXL6/FBXL6-uniprot.txt
      supporting_text: 'Q8N531; P63208: SKP1; NbExp=4; IntAct=EBI-2322696, EBI-307486;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: IntAct interaction with SKP1 (WITH/FROM UniProtKB:P63208) captured by the BioPlex dual proteome-scale interactome. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the FBXL6-SKP1 interaction, but bare protein binding is uninformative; captured by the SCF-complex annotation.
    supported_by:
    - reference_id: file:human/FBXL6/FBXL6-uniprot.txt
      supporting_text: 'Q8N531; P63208: SKP1; NbExp=4; IntAct=EBI-2322696, EBI-307486;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: IntAct interaction with SKP1 (WITH/FROM UniProtKB:P63208) captured by a multimodal cell-map interactome study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the FBXL6-SKP1 interaction, but bare protein binding is uninformative; captured by the SCF-complex annotation.
    supported_by:
    - reference_id: file:human/FBXL6/FBXL6-uniprot.txt
      supporting_text: 'Q8N531; P63208: SKP1; NbExp=4; IntAct=EBI-2322696, EBI-307486;'
- 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: ComplexPortal/NAS assignment that FBXL6, as an SCF substrate receptor, participates in SCF-dependent proteasomal degradation. This is the core biological process for an F-box protein, and FBXL6-specific degradative substrates are now reported in the literature (e.g. phospho-p53, ETV6/TEL, cyclin A2).
    action: ACCEPT
    reason: Consistent with FBXL6 being a substrate-recognition subunit of an SCF E3 ligase; SCF-dependent proteasomal degradation is the canonical core process for F-box/LRR proteins. Beyond the documented SKP1/CUL1 association, FBXL6 has reported degradative substrates including phosphorylated p53 (K291/K292), ETV6, and CCNA2, supporting this process term. Note that FBXL6 also mediates non-degradative (K63-linked) ubiquitination of other clients (HSP90AA1, KRAS, TKT), which is not captured by this proteasomal-catabolism term.
    additional_reference_ids:
    - file:human/FBXL6/FBXL6-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/FBXL6/FBXL6-uniprot.txt
      supporting_text: 'Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.'
    - reference_id: file:human/FBXL6/FBXL6-deep-research-falcon.md
      supporting_text: "FBXL6 binds phosphorylated p53 (S315) and promotes p53 polyubiquitination at K291/K292 leading to proteasomal degradation, consistent with a role in dampening p53 signaling."
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: TAS
  original_reference_id: PMID:10531035
  qualifier: enables
  review:
    summary: Author statement from the original F-box family paper attributing ubiquitin-protein transferase activity to FBXL6. However, F-box proteins are substrate-recognition subunits and are not themselves the catalytic transferase; the transferase activity resides in the RING subunit (RBX1)/E2. This term over-attributes the catalytic activity to the receptor.
    action: MODIFY
    reason: FBXL6 is the substrate-recognition adaptor of the SCF complex, not the catalytic ubiquitin transferase. The more accurate molecular function is ubiquitin-like ligase-substrate adaptor activity; catalysis is contributed by RBX1/E2.
    proposed_replacement_terms:
    - id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    additional_reference_ids:
    - file:human/FBXL6/FBXL6-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/FBXL6/FBXL6-uniprot.txt
      supporting_text: 'Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.'
    - reference_id: file:human/FBXL6/FBXL6-deep-research-falcon.md
      supporting_text: "This implies that FBXL6 is expected to act primarily as an adaptor/substrate receptor—rather than a catalytic enzyme—governing which client proteins are ubiquitinated and what downstream signaling consequences follow."
- term:
    id: GO:0006508
    label: proteolysis
  evidence_type: TAS
  original_reference_id: PMID:10531035
  qualifier: involved_in
  review:
    summary: Author statement linking FBXL6 to proteolysis, reflecting its presumed role in SCF-mediated protein degradation. This is correct but very generic.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic proteolysis is far less informative than the specific SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146) already annotated; FBXL6 does not itself perform peptide-bond hydrolysis.
    supported_by:
    - reference_id: file:human/FBXL6/FBXL6-uniprot.txt
      supporting_text: 'Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.'
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: PMID:10531035
  title: Identification of a family of human F-box proteins.
  findings:
  - statement: FBXL6 (FBL6) was identified as one of a family of human F-box proteins; F-box proteins act as substrate-recognition components of SCF ubiquitin ligase complexes.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Original identification of FBXL6 as a human F-box protein; full text not in cache (abstract-only). Source of the TAS transferase/proteolysis annotations, which over-attribute catalysis to the receptor.
- id: PMID:19159283
  title: 'Array MAPPIT: high-throughput interactome analysis in mammalian cells.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput MAPPIT interactome; FBXL6 GOA IPI WITH/FROM is SKP1 (P63208). Abstract-only in cache.
- id: PMID:27705803
  title: A High-Density Map for Navigating the Human Polycomb Complexome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: AP-MS complexome map; the FBXL6 IPI here is to SKP1 (WITH/FROM P63208), consistent with SCF assembly rather than a Polycomb-specific function. Abstract-only in cache.
- id: PMID:33234069
  title: 'The FBXL family of F-box proteins: variations on a theme.'
  findings:
  - statement: FBXL-family F-box proteins serve as substrate-recognition subunits of SCF E3 ubiquitin ligases, using their LRR domains for substrate binding and the F-box for SKP1/CUL1 recruitment.
    reference_section_type: LITERATURE_REVIEW
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Family-level review (full text available) supporting the general FBXL SCF substrate-receptor model; no FBXL6-specific functional data found in the text.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex interactome; FBXL6 IPI WITH/FROM is SKP1 (P63208).
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Multimodal cell-map interactome; FBXL6 IPI WITH/FROM is SKP1 (P63208).
- id: file:human/FBXL6/FBXL6-deep-research-falcon.md
  title: Falcon deep research report for human FBXL6
  findings:
  - statement: FBXL6 acts as an SCF substrate receptor that both promotes proteasomal degradation of targets and adds non-degradative ubiquitin chains that stabilize/activate clients in oncogenic contexts.
    supporting_text: "FBXL6’s most defensible “primary function” from the available literature is as an SCF-type ubiquitin ligase substrate receptor/adaptor that (i) promotes proteasomal degradation of certain targets and (ii) can also add non-degradative ubiquitin chains that stabilize/activate specific client proteins in oncogenic contexts."
  - statement: FBXL6 binds phosphorylated p53 (Ser315) and promotes its polyubiquitination at K291/K292, leading to proteasomal degradation and dampened p53 signaling.
    supporting_text: "FBXL6 binds phosphorylated p53 (S315) and promotes p53 polyubiquitination at K291/K292 leading to proteasomal degradation, consistent with a role in dampening p53 signaling."
  - statement: FBXL6 promotes K63-linked ubiquitination of HSP90AA1, stabilizing it and sustaining c-MYC activation in hepatocellular carcinoma, illustrating a non-degradative outcome.
    supporting_text: "FBXL6 promotes **K63-dependent ubiquitination** of HSP90AA1, stabilizing HSP90AA1 and indirectly sustaining c-MYC activation in hepatocellular carcinoma models; this illustrates a non-degradative ubiquitin outcome mediated by FBXL6."
  - statement: VRK2-mediated phosphorylation of transketolase at Thr287 recruits FBXL6, whose F-box is required to promote TKT ubiquitination and activation.
    supporting_text: "VRK2-mediated phosphorylation of TKT at **Thr287** recruits FBXL6 to promote TKT ubiquitination and activation; the FBXL6 F-box is required (FBXL6ΔF fails to increase ubiquitination)."
  - statement: FBXL6 is a dependency in AML, especially FLT3-ITD-mutated lines, identified by CRISPR drop-out screening of the human F-box gene family.
    supporting_text: "A 2024 Leukemia paper identified FBXL6 as a prominent dependency in AML cell lines using pooled CRISPR drop-out screening across the full set of 72 human F-box genes. FBXL6 knockout decreased proliferation/viability in multiple assays, with stronger effects in FLT3-ITD–mutated AML lines (e.g., MOLM-13/MV4-11) than OCI-AML3, suggesting genotype-dependent sensitivity."
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: Falcon (Edison Scientific) deep research synthesis. Reports multiple experimentally-supported FBXL6 substrates (p53, HSP90AA1, KRAS, TKT, CCNA2, ETV6) from primary literature citing DOIs rather than PMIDs; these primary papers are not in the local cache so the citations are not independently PubMed-verified here. Treated as leads that substantially enrich the previously "poorly characterized" framing.
core_functions:
- description: Substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex; uses its F-box domain to assemble with SKP1/CUL1/RBX1 and its leucine-rich repeats to recruit substrates for ubiquitination and proteasomal degradation. Specific substrates remain to be established experimentally.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations: []
  supported_by:
  - reference_id: file:human/FBXL6/FBXL6-uniprot.txt
    supporting_text: 'Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.'
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
proposed_new_terms: []
suggested_questions:
- question: What are the physiological substrates recognized by the FBXL6 leucine-rich repeat domain, and in which tissues or conditions are they degraded?
- question: Does FBXL6 form a catalytically active SCF complex in vivo, and what determines its expression and assembly relative to other FBXL paralogs?
- question: Does FBXL6 have a non-oncogenic homeostatic role (e.g. in mitochondrial ribosomal protein quality control), distinct from the oncogenic substrate axes (p53, KRAS, TKT, HSP90AA1) described in hepatocellular carcinoma and AML?
suggested_experiments:
- description: Perform affinity purification-mass spectrometry of tagged FBXL6 (stabilized with proteasome and neddylation inhibitors) to identify candidate substrates enriched over a substrate-binding-deficient LRR mutant.
- description: Reconstitute SCF-FBXL6 (SKP1-CUL1-RBX1-FBXL6) in vitro and test ubiquitination of candidate substrates, and use CRISPR knockout followed by quantitative proteomics to identify proteins stabilized upon FBXL6 loss.