Affinage

FBXW10

F-box/WD repeat-containing protein 10 · UniProt Q5XX13

Length
1052 aa
Mass
119.8 kDa
Annotated
2026-06-09
16 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FBXW10 is an F-box protein that functions as the substrate-recognition subunit of SCF-type E3 ubiquitin ligase complexes, directing the polyubiquitination of diverse substrates to either destabilize or activate them and thereby controlling chromatin regulators, DNA-damage signaling, and pro-oncogenic pathways (PMID:20498703, PMID:37277019, PMID:36990424). In its degradative mode it targets the heterochromatin proteins HP1alpha and HP1beta but not HP1gamma for proteasomal turnover (PMID:20498703), drives intranuclear proteasomal degradation of the ATR kinase (PMID:22382637), and eliminates the MAPK regulator SOS and the tumor suppressor kinase LATS2, the latter requiring its intact F-box region (PMID:28397399, PMID:36990424). A distinct, non-degradative branch of FBXW10 activity operates in hepatocellular carcinoma, where it catalyzes K63-linked polyubiquitination that activates rather than destroys its substrates: S6K1-phosphorylated ANXA2 is K63-ubiquitinated, driving its membrane translocation, KRAS binding, and MEK/ERK activation (PMID:37277019), while VRK2-phosphorylated GAPDH (Ser151) is ubiquitinated to engage TRAF2 and amplify NF-kappaB signaling that elevates PD-L1 and androgen-receptor output, producing a male-biased, immune-evasive tumorigenic program (PMID:31400758, PMID:37450367). FBXW10 expression is itself controlled at the promoter level, being induced by mislocalized lamin A mutants, by HDAC inhibition, and by the transcription factor ZNF169 (PMID:20498703, PMID:28397399, PMID:39875985), and its ANXA2 axis is antagonized by VSIG2, which competes for ANXA2 binding to block its K63-ubiquitination (PMID:41185558).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2010 Medium

    Established that FBXW10 acts as an E3 ligase substrate-recognition factor by linking its transcriptional induction to selective proteasomal turnover of heterochromatin proteins.

    Evidence Ectopic FBXW10 overexpression in HeLa cells with MG132 rescue and transcript analysis

    PMID:20498703

    Open questions at the time
    • No direct ubiquitination assay or FBXW10–HP1 binding demonstrated
    • Basis for HP1alpha/beta vs HP1gamma selectivity unknown
    • SCF complex composition not defined
  2. 2012 Medium

    Extended FBXW10 substrate repertoire to DNA-damage signaling by showing it triggers intranuclear proteasomal degradation of ATR kinase.

    Evidence Ectopic FBXW10 overexpression with MG132 and leptomycin B rescue, transcript analysis

    PMID:22382637

    Open questions at the time
    • No direct ubiquitination or binding assay for FBXW10–ATR
    • Phenotypic consequence for DNA-damage response untested
    • Physiological context of induction unclear
  3. 2017 Medium

    Connected FBXW10 to MAPK pathway control by identifying SOS as a degradation target downstream of HDAC inhibition.

    Evidence siRNA knockdown plus belinostat treatment and bortezomib inhibition with phosphoproteomics in lung squamous carcinoma cells

    PMID:28397399

    Open questions at the time
    • Direct FBXW10–SOS ubiquitination not shown
    • Whether FBXW10 binds SOS directly unresolved
  4. 2020 Medium

    Demonstrated an in vivo oncogenic role with male bias, framing FBXW10 as a driver of hepatocarcinogenesis rather than a passive ubiquitin component.

    Evidence FBXW10 transgenic mouse model and HCC cell line proliferation/migration assays

    PMID:31400758

    Open questions at the time
    • No substrate identified in this study
    • Mechanism of male-biased effect undefined
  5. 2023 High

    Revealed a non-degradative, activating mode of FBXW10 ubiquitination, mechanistically explaining the HCC phenotype via two parallel substrate axes.

    Evidence Reciprocal Co-IP, ubiquitination assays, phosphosite mapping, subcellular fractionation, and transgenic mouse models for ANXA2 (S6K1/K63/KRAS-MEK-ERK) and GAPDH (VRK2/Ser151/TRAF2-NF-kappaB/PD-L1/AR)

    PMID:37277019 PMID:37450367

    Open questions at the time
    • How FBXW10 discriminates activating K63 vs degradative K48 linkage is unresolved
    • Direct contribution of SCF core subunits to these reactions not dissected
    • Generality of activating ubiquitination beyond HCC unknown
  6. 2023 Medium

    Showed FBXW10 also degrades a bona fide tumor suppressor in a different cancer, supporting a broad pro-oncogenic function dependent on its F-box.

    Evidence Ubiquitination assays, in vivo xenograft/knockout models, and F-box domain mutagenesis for LATS2 in colorectal cancer

    PMID:36990424

    Open questions at the time
    • Phosphodegron or recognition motif on LATS2 not mapped
    • Single lab
  7. 2025 Medium

    Placed FBXW10 within transcriptional and competitive regulatory circuits, defining how its levels and substrate access are controlled.

    Evidence ZNF169 promoter binding by luciferase/ChIP-PCR in thyroid cancer; VSIG2 competition for ANXA2 binding by Co-IP, immunofluorescence, and in vivo gastric cancer models

    PMID:39875985 PMID:41185558

    Open questions at the time
    • Whether ZNF169 control of FBXW10 operates outside thyroid cancer untested
    • Structural basis of VSIG2/FBXW10 competition for ANXA2 undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular determinants by which FBXW10 chooses degradative versus activating ubiquitin linkage and recognizes its varied substrates remain unresolved.
  • No structure of FBXW10 substrate-binding interface
  • No defined degron/recognition motif shared across substrates
  • Determinant of K48 vs K63 linkage choice unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0016740 transferase activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 2 GO:0005634 nucleus 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3
Partners
ANXA2ATRGAPDHLATS2SOSVSIG2
Complex memberships
SCF E3 ubiquitin ligase

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 FBXW10, an F-box protein involved in E3 ubiquitin ligase activity, is transcriptionally induced by mislocalized lamin A rod domain mutants (G232E, Q294P, R386K) and mediates proteasomal degradation of HP1alpha and HP1beta (but not HP1gamma) via ubiquitin-mediated pathway; ectopic expression of FBXW10 in HeLa cells depleted HP1alpha and HP1beta without altering HP1gamma levels. Ectopic overexpression of FBXW10 in HeLa cells, transcript analysis, proteasomal inhibitor (MG132) rescue experiments PloS one Medium 20498703
2012 FBXW10 (along with RNF123 and HECW2) is transcriptionally upregulated by lamin A mutant expression or lamin A shRNA knockdown, and ectopic expression of FBXW10 directly causes proteasomal degradation of ATR kinase within the nucleus; this degradation was reversed by MG132 but not by the nuclear export inhibitor leptomycin B, indicating nuclear degradation of ATR. Ectopic FBXW10 overexpression, proteasomal inhibitor (MG132) rescue, nuclear export inhibitor (leptomycin B) experiments, transcript analysis Molecular and cellular biochemistry Medium 22382637
2017 Belinostat transcriptionally upregulates FBXW10 (and FBXO3), which directly targets SOS (son of sevenless), an upstream regulator of the MAPK pathway, for proteasome-mediated degradation; siRNA knockdown of FBXW10 abrogated the suppression of the SOS/ERK pathway by belinostat in lung squamous cell carcinoma cells. siRNA knockdown of FBXW10, belinostat drug treatment, phosphoproteomic analysis, bortezomib proteasomal inhibition Molecular oncology Medium 28397399
2020 FBXW10, as a component of SCF E3 ubiquitin ligases, promotes hepatocellular carcinoma cell proliferation and migration in HCC cell lines, and male FBXW10-transgenic mice showed increased susceptibility to tumorigenesis, liver injury, and inflammation, establishing a functional role for FBXW10 in hepatocarcinogenesis with a male-biased effect. FBXW10 transgenic (Tg) mouse model, HCC cell line overexpression/knockdown, proliferation and migration assays Carcinogenesis Medium 31400758
2023 FBXW10, as part of the SCF E3 ubiquitin ligase complex, promotes K63-linked polyubiquitination and activation of ANXA2 (Annexin A2) in male HCC tissues; this process requires S6K1-mediated phosphorylation of ANXA2, and the activated ANXA2 translocates from cytoplasm to cell membrane to bind KRAS, activating the MEK/ERK pathway to drive HCC proliferation and lung metastasis. Co-immunoprecipitation, ubiquitination assays, in vitro and in vivo knockdown/overexpression experiments, phosphorylation site mapping, subcellular fractionation/localization Cancer letters High 37277019
2023 FBXW10 promotes K48- or K63-linked polyubiquitination and activation of GAPDH; VRK2-dependent phosphorylation of GAPDH at Ser151 is required for FBXW10-mediated GAPDH ubiquitination and activation; activated GAPDH interacts with TRAF2 to upregulate canonical and noncanonical NF-κB pathways, increasing PD-L1 and AR-VRK2 expression, leading to immune evasion and HCC tumorigenesis in males; and this axis is driven by androgen receptor (AR)-mediated VRK2 upregulation. In vitro ubiquitination assays, phosphorylation site mutagenesis (Ser151), Co-IP, transgenic mouse models, GAPDH inhibitor (koningic acid) treatment in vivo Cell reports High 37450367
2023 FBXW10 (as SCF E3 ubiquitin ligase) ubiquitinates LATS2 (large tumor suppressor kinase 2) and promotes its proteasomal degradation, requiring the F-box region of FBXW10; this leads to upregulation of angiogenesis and liver metastasis in colorectal cancer. Ubiquitination assays, FBXW10 overexpression/knockdown in vitro and in vivo (xenograft/knockout models), F-box domain mutant analysis The international journal of biochemistry & cell biology Medium 36990424
2025 ZNF169 transcription factor promotes FBXW10 expression by binding to the FBXW10 promoter (demonstrated by luciferase reporter assay and ChIP-PCR), placing FBXW10 downstream of ZNF169 in a regulatory axis driving thyroid cancer proliferation and tumor growth. Luciferase reporter assay, ChIP-PCR, FBXW10 knockdown rescue experiments in vitro and in vivo Cell division Medium 39875985
2025 VSIG2 competes with FBXW10 for binding to ANXA2 at the cell membrane; when VSIG2 levels are high, it blocks FBXW10-mediated K63-linked polyubiquitination of ANXA2, preventing ANXA2 membrane localization and NF-κB activation, thereby suppressing gastric cancer progression. Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assays, in vitro and in vivo (nude mouse) models Acta biochimica et biophysica Sinica Medium 41185558

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia. Blood 218 24825865
2010 Lamin A rod domain mutants target heterochromatin protein 1alpha and beta for proteasomal degradation by activation of F-box protein, FBXW10. PloS one 42 20498703
2012 Lamin misexpression upregulates three distinct ubiquitin ligase systems that degrade ATR kinase in HeLa cells. Molecular and cellular biochemistry 26 22382637
2017 Belinostat exerts antitumor cytotoxicity through the ubiquitin-proteasome pathway in lung squamous cell carcinoma. Molecular oncology 25 28397399
2015 Abnormal methylation status of FBXW10 and SMPD3, and associations with clinical characteristics in clear cell renal cell carcinoma. Oncology letters 25 26722292
2023 FBXW10-S6K1 promotes ANXA2 polyubiquitination and KRAS activation to drive hepatocellular carcinoma development in males. Cancer letters 21 37277019
2019 KMT2C, a histone methyltransferase, is mutated in a family segregating non-syndromic primary failure of tooth eruption. Scientific reports 21 31712638
2023 Elevated FBXW10 drives hepatocellular carcinoma tumorigenesis via AR-VRK2 phosphorylation-dependent GAPDH ubiquitination in male transgenic mice. Cell reports 19 37450367
2020 FBXW10 promotes hepatocarcinogenesis in male patients and mice. Carcinogenesis 14 31400758
2022 Identification of immune-related and autophagy-related genes for the prediction of survival in bladder cancer. BMC genomic data 8 35909123
2023 The E3 ubiquitin ligase SCF (FBXW10)-mediated LATS2 degradation regulates angiogenesis and liver metastasis in colorectal cancer. The international journal of biochemistry & cell biology 4 36990424
2023 Novel Susceptibility Genes Drive Familial Non-Medullary Thyroid Cancer in a Large Consanguineous Kindred. International journal of molecular sciences 3 37175943
2023 FBXW10: a male-biased E3 ligase in liver cancer. Trends in cancer 2 37775405
2025 ZNF169 promotes thyroid cancer progression via upregulating FBXW10. Cell division 1 39875985
2026 Pimozide Reprograms the Ran GTPase-SCF Axis and Matrix Remodeling Pathways in Breast, Colorectal, and Pancreatic Cancer Models. Cancers 0 41749864
2025 VSIG2 hinders gastric cancer progression by suppressing ANXA2-mediated NF-κB pathway activation. Acta biochimica et biophysica Sinica 0 41185558

Missed literature

Know a paper Affinage missed for FBXW10? Flag it for the maintainers and the community.

No submissions yet.