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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0019005 SCF ubiquitin ligase complex | IEA GO_REF:0000002 | ACCEPT | 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. 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. Supporting Evidence: file:human/FBXL6/FBXL6-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. |
| GO:0005515 protein binding | IPI PMID:19159283 Array MAPPIT: high-throughput interactome analysis in mammal... | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/FBXL6/FBXL6-uniprot.txt Q8N531; P63208: SKP1; NbExp=4; IntAct=EBI-2322696, EBI-307486; |
| GO:0005515 protein binding | IPI PMID:27705803 A High-Density Map for Navigating the Human Polycomb Complex... | KEEP AS NON CORE | Summary: IntAct interaction with SKP1 (WITH/FROM UniProtKB:P63208) captured by the Polycomb complexome AP-MS study. Bare protein binding is uninformative. Reason: Records the FBXL6-SKP1 interaction underlying SCF assembly, but bare protein binding is uninformative; captured by the SCF-complex annotation. Supporting Evidence: file:human/FBXL6/FBXL6-uniprot.txt Q8N531; P63208: SKP1; NbExp=4; IntAct=EBI-2322696, EBI-307486; |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: IntAct interaction with SKP1 (WITH/FROM UniProtKB:P63208) captured by the BioPlex dual proteome-scale interactome. Bare protein binding is uninformative. Reason: Records the FBXL6-SKP1 interaction, but bare protein binding is uninformative; captured by the SCF-complex annotation. Supporting Evidence: file:human/FBXL6/FBXL6-uniprot.txt Q8N531; P63208: SKP1; NbExp=4; IntAct=EBI-2322696, EBI-307486; |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: IntAct interaction with SKP1 (WITH/FROM UniProtKB:P63208) captured by a multimodal cell-map interactome study. Bare protein binding is uninformative. Reason: Records the FBXL6-SKP1 interaction, but bare protein binding is uninformative; captured by the SCF-complex annotation. Supporting Evidence: file:human/FBXL6/FBXL6-uniprot.txt Q8N531; P63208: SKP1; NbExp=4; IntAct=EBI-2322696, EBI-307486; |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | NAS PMID:33234069 The FBXL family of F-box proteins: variations on a theme. | ACCEPT | 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). 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. Supporting Evidence: file:human/FBXL6/FBXL6-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. file:human/FBXL6/FBXL6-deep-research-falcon.md FBXL6 binds phosphorylated p53 (S315) and promotes p53 polyubiquitination at K291/K292 leading to proteasomal degradation, consistent with a role in dampening p53 signaling. |
| GO:0004842 ubiquitin-protein transferase activity | TAS PMID:10531035 Identification of a family of human F-box proteins. | MODIFY | 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. 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 replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: file:human/FBXL6/FBXL6-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. file:human/FBXL6/FBXL6-deep-research-falcon.md 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. |
| GO:0006508 proteolysis | TAS PMID:10531035 Identification of a family of human F-box proteins. | MARK AS OVER ANNOTATED | Summary: Author statement linking FBXL6 to proteolysis, reflecting its presumed role in SCF-mediated protein degradation. This is correct but very generic. 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. Supporting Evidence: file:human/FBXL6/FBXL6-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. |
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Download this section (compressed HTML)Q: What are the physiological substrates recognized by the FBXL6 leucine-rich repeat domain, and in which tissues or conditions are they degraded?
Q: Does FBXL6 form a catalytically active SCF complex in vivo, and what determines its expression and assembly relative to other FBXL paralogs?
Q: 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?
Experiment: 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.
Experiment: 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.
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