Affinage

FBXL6

F-box/LRR-repeat protein 6 · UniProt Q8N531

Length
539 aa
Mass
58.6 kDa
Annotated
2026-06-09
10 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FBXL6 is the substrate-recognition subunit of an SCF (Skp1-Cul1-F-box) E3 ubiquitin ligase complex that drives cell proliferation, metabolic reprogramming, and oncogenesis by deploying linkage-specific ubiquitination to opposite ends, stabilizing oncoproteins while degrading tumor suppressors (PMID:32576198, PMID:38124228). Through non-degradative K63-linked polyubiquitination it stabilizes or activates a set of pro-tumorigenic clients including HSP90AA1, KRAS/KRAS-G12D (at Lys128, enhancing RAF binding and MEK/ERK/mTOR signaling), transketolase (recruited via VRK2-mediated Thr287 phosphorylation, driving ROS-mTOR/PD-L1 signaling), ATAD3A, and the glycolytic enzyme ENO1 (bound through the FBXL6 LRR domain) (PMID:32576198, PMID:38124228, PMID:37653031, PMID:40975350, PMID:42091879). Several of these activities converge on glycolytic and ROS-mTOR metabolic rewiring across HCC, lung, breast, and bladder cancers (PMID:37653031, PMID:40975350, PMID:42091879). In parallel, FBXL6 directs K48-linked polyubiquitination and proteasomal degradation of tumor suppressors, including Ser315-phosphorylated p53 and CDKN1C (p57Kip2) (PMID:33568778, PMID:41443404). FBXL6 is embedded in transcriptional feedback circuits: stabilized HSP90AA1 prevents c-MYC degradation while c-MYC induces FBXL6, forming a positive loop, whereas p53 represses FBXL6 in a negative loop (PMID:32576198, PMID:33568778). Distinct from its oncogenic substrate set, FBXL6 also performs cotranslational quality control by ubiquitinating newly synthesized, cytosolically translated mitochondrial ribosomal proteins in concert with chaperones and ribosome-associated quality control factors, preventing accumulation of mistranslated protein aggregates (PMID:37267103).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2020 High

    Established that FBXL6 is an SCF substrate-recognition subunit and that, atypically for an F-box ligase, it can stabilize rather than degrade a substrate via K63-linked ubiquitination, embedding it in an oncogenic feedback loop.

    Evidence Reciprocal Co-IP, IP/MS, in vivo ubiquitination, luciferase and ChIP assays, shRNA knockdown in HCC cells and xenografts

    PMID:32576198

    Open questions at the time
    • Linkage-specificity determinants on FBXL6 not mapped
    • Whether c-MYC-FBXL6 loop operates outside HCC unknown
  2. 2021 High

    Showed FBXL6 also acts as a classical degradative ligase, selectively recognizing phospho-Ser315 p53 for K48-linked degradation, defining a phospho-dependent route by which FBXL6 suppresses tumor-suppressor signaling.

    Evidence Co-IP, ubiquitination assay, proteasome inhibitor rescue, luciferase reporter, shRNA knockdown with cell-cycle/apoptosis readouts

    PMID:33568778

    Open questions at the time
    • Kinase generating p53-pSer315 for FBXL6 recognition not identified
    • Reconciliation of degradative vs stabilizing modes by FBXL6 unresolved
  3. 2023 High

    Demonstrated FBXL6 ubiquitinates KRAS at Lys128 to activate it and engage RAF/MEK/ERK/mTOR signaling, extending FBXL6's stabilizing ubiquitination to a canonical oncogene and linking output to PRELID2/ROS.

    Evidence Co-IP, ubiquitination assay, site-specific K128 mutagenesis, RAS activity assay, transgenic mouse models, multiomics

    PMID:38124228

    Open questions at the time
    • Mechanism by which K128 ubiquitination enhances RAF binding not structurally defined
    • Relationship between PRELID2-ROS and FBXL6 recruitment unclear
  4. 2023 High

    Connected FBXL6 to metabolic reprogramming and immune evasion by showing VRK2-phosphorylated TKT recruits FBXL6 for activating ubiquitination, driving ROS-mTOR-PD-L1 signaling and metastasis.

    Evidence Co-IP, ubiquitination and phosphorylation assays, knockdown/overexpression, transgenic mouse and xenograft models

    PMID:37653031

    Open questions at the time
    • Ubiquitin linkage type on TKT not specified
    • Generality of the VRK2-TKT-FBXL6 axis beyond HCC untested
  5. 2023 High

    Revealed a non-oncogenic housekeeping role: FBXL6 ubiquitinates newly synthesized mitochondrial ribosomal proteins as cotranslational quality control, partnering with chaperones and RQC factors to prevent aggregate accumulation.

    Evidence Co-IP, ubiquitination assays, FBXL6-knockout cells, mitochondrial functional assays, proteomics, cell-cycle analysis

    PMID:37267103

    Open questions at the time
    • Identity of specific chaperone/RQC partners not fully enumerated
    • Relationship between QC function and oncogenic substrate roles unknown
  6. 2022 Medium

    Placed c-MYC genetically downstream of FBXL6 in a non-cancer proliferative context (keloid fibroblasts), broadening FBXL6's proliferation-promoting role beyond tumors.

    Evidence shRNA knockdown, overexpression, c-MYC rescue, CCK-8 viability, Western blot, RT-PCR

    PMID:35606330

    Open questions at the time
    • No direct biochemical interaction or ubiquitination assay in this system
    • Single lab, mechanism of c-MYC induction by FBXL6 not biochemically defined
  7. 2025 Medium

    Identified CDKN1C (p57Kip2) as a second degradative tumor-suppressor substrate of FBXL6, mediating its pro-tumorigenic effects in lung adenocarcinoma.

    Evidence Co-IP, ubiquitination assay, shRNA knockdown, overexpression, rescue, in vivo xenograft

    PMID:41443404

    Open questions at the time
    • Single study without independent replication
    • Ubiquitin linkage and degron not defined
  8. 2025 Medium

    Extended FBXL6's stabilizing K63-ubiquitination to ATAD3A, linking FBXL6 to aerobic glycolysis in triple-negative breast cancer.

    Evidence Co-IP, ubiquitination assay, genetic depletion, cell and animal models, Western blot, IHC

    PMID:40975350

    Open questions at the time
    • Single study, no independent replication
    • Mechanism linking ATAD3A stabilization to glycolysis not detailed
  9. 2026 Medium

    Mapped a direct LRR-domain interaction between FBXL6 and ENO1 driving K63-stabilizing ubiquitination and enhanced glycolysis in bladder cancer, providing domain-level evidence for substrate engagement.

    Evidence Co-IP, GST pull-down, domain mapping, ubiquitination assay, shRNA knockdown, ENO1 rescue, transcriptomic/metabolic analyses

    PMID:42091879

    Open questions at the time
    • Single study without independent replication
    • Whether LRR-mediated binding generalizes to other FBXL6 substrates untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FBXL6 selects between K63-linked stabilizing ubiquitination of oncoproteins and K48-linked degradative ubiquitination of tumor suppressors, and what dictates linkage choice per substrate, remains unresolved.
  • No structural model of FBXL6 substrate/E2 engagement
  • Linkage-determining cofactors or E2 enzymes not identified
  • Integration of QC and oncogenic functions unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016874 ligase activity 4
Pathway
R-HSA-1643685 Disease 6 R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-162582 Signal Transduction 2
Partners
ATAD3ACDKN1CCUL1ENO1HSP90AA1KRASSKP1TKT
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
2020 FBXL6 acts as a substrate recognition subunit of the SCF (Skp1-Cul1-F-box protein) E3 ubiquitin ligase complex and directly interacts with HSP90AA1, promoting its K63-linked polyubiquitination, which stabilizes (rather than degrades) HSP90AA1. Stabilized HSP90AA1 in turn prevents c-MYC degradation, and c-MYC transcriptionally induces FBXL6 expression by binding its promoter, forming a positive feedback loop. Co-immunoprecipitation, IP/Mass Spectrometry, in vivo ubiquitination assay, luciferase reporter assay, ChIP assay, shRNA knockdown in HCC cells and xenograft mouse model Cell communication and signaling : CCS High 32576198
2021 FBXL6 directly targets phosphorylated p53 (phospho-Ser315) to mediate its K48-linked polyubiquitination and proteasomal degradation, thereby suppressing p53 signaling. Conversely, p53 transcriptionally represses FBXL6 expression by binding its core promoter, forming a negative feedback loop. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor rescue experiments, luciferase reporter assay, shRNA knockdown with cell cycle and apoptosis readouts Cell death and differentiation High 33568778
2023 FBXL6 promotes polyubiquitination of both wild-type KRAS and mutant KRASG12D specifically at lysine 128, leading to their activation and enhanced binding to RAF kinase, thereby activating MEK/ERK/mTOR signaling. The oncogenic output of this axis depends on PRELID2-induced ROS generation. Co-immunoprecipitation, ubiquitination assay, RAS activity detection assay, transgenic mouse models (LC, KC, KLC), multiomics, pharmacological inhibitors Military Medical Research High 38124228
2023 VRK2 kinase phosphorylates TKT (transketolase) at Thr287, which recruits FBXL6 to promote TKT ubiquitination and activation. Activated TKT drives ROS-mTOR signaling to upregulate PD-L1 and VRK2, leading to immune evasion and HCC metastasis. Co-immunoprecipitation, ubiquitination assay, phosphorylation assays, knockdown/overexpression in vitro, transgenic mouse models, in vivo xenograft Experimental & molecular medicine High 37653031
2023 FBXL6 functions as an E3 ubiquitin ligase that specifically ubiquitinates newly synthesized (cytosolically translated) mitochondrial ribosomal proteins to control their quality. FBXL6 physically associates with chaperones involved in folding/trafficking of newly synthesized peptides and with ribosomal-associated quality control proteins; deletion of these interacting partners abolishes FBXL6-substrate interactions. FBXL6-knockout cells fail to degrade mistranslated mitochondrial ribosomal proteins, accumulate mitochondrial ribosomal protein aggregates, display altered mitochondrial metabolism, and exhibit inhibited cell cycle in oxidative conditions. Co-immunoprecipitation, ubiquitination assays, FBXL6 knockout cells, mitochondrial functional assays, proteomics, cell cycle analysis Cell reports High 37267103
2022 FBXL6 promotes keloid fibroblast proliferation by inducing c-MYC expression; FBXL6 knockdown reduces c-MYC levels along with cyclins A1, D2, E1, and Collagen I, and c-MYC overexpression rescues the proliferative defect caused by FBXL6 depletion, placing c-MYC downstream of FBXL6 in this pathway. shRNA knockdown, overexpression plasmid transfection, rescue experiment with c-MYC overexpression, cell viability assay (CCK-8), Western blot, RT-PCR International wound journal Medium 35606330
2025 FBXL6 directly binds CDKN1C (p57Kip2) and promotes its polyubiquitination and proteasomal degradation, destabilizing this tumor suppressor. Rescue experiments confirmed that CDKN1C mediates the pro-tumorigenic effects of FBXL6 on lung adenocarcinoma cell proliferation and metastasis. Co-immunoprecipitation, ubiquitination assay, shRNA knockdown, overexpression, rescue assay, in vivo mouse xenograft Experimental cell research Medium 41443404
2025 FBXL6 promotes K63-linked polyubiquitination of ATAD3A (ATPase family AAA domain-containing protein 3A), stabilizing it and activating aerobic glycolysis to promote triple-negative breast cancer progression. Co-immunoprecipitation, ubiquitination assay, genetic depletion of ATAD3A and FBXL6, cell and animal models, Western blot, IHC International journal of biological macromolecules Medium 40975350
2026 FBXL6 directly interacts with ENO1 via its LRR domain (binding the C-terminal region of ENO1), promotes K63-linked polyubiquitination of ENO1, thereby stabilizing ENO1 and enhancing glycolytic activity to drive bladder cancer progression. ENO1 re-expression partially rescues the anti-proliferative and anti-migratory effects of FBXL6 knockdown. Co-immunoprecipitation, GST pull-down assay, ubiquitination assay, domain mapping, shRNA knockdown, ENO1 rescue experiments, transcriptomic and metabolic analyses Cell death discovery Medium 42091879

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 FBXL6 governs c-MYC to promote hepatocellular carcinoma through ubiquitination and stabilization of HSP90AA1. Cell communication and signaling : CCS 72 32576198
2023 Elevated FBXL6 activates both wild-type KRAS and mutant KRASG12D and drives HCC tumorigenesis via the ERK/mTOR/PRELID2/ROS axis in mice. Military Medical Research 44 38124228
2021 FBXL6 degrades phosphorylated p53 to promote tumor growth. Cell death and differentiation 30 33568778
2023 Elevated FBXL6 expression in hepatocytes activates VRK2-transketolase-ROS-mTOR-mediated immune evasion and liver cancer metastasis in mice. Experimental & molecular medicine 28 37653031
2022 FBXL6 depletion restrains clear cell renal cell carcinoma progression. Translational oncology 9 36183674
2022 FBXL6 is dysregulated in keloids and promotes keloid fibroblast growth by inducing c-Myc expression. International wound journal 8 35606330
2023 The E3 ubiquitin ligase FBXL6 controls the quality of newly synthesized mitochondrial ribosomal proteins. Cell reports 5 37267103
2025 Elevated FBXL6 activates ATAD3A through K63-linked polyubiquitination and promotes the malignant progression of TNBC via metabolic reprogramming. International journal of biological macromolecules 1 40975350
2026 FBXL6 promotes bladder cancer progression by stabilizing ENO1 through K63-linked ubiquitination. Cell death discovery 0 42091879
2025 FBXL6 drives tumorigenesis in lung adenocarcinoma through ubiquitination and proteasomal degradation of CDKN1C. Experimental cell research 0 41443404

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