The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
The literature evidence retrieved matches the specified target: human FBXW10 encoding F-box/WD repeat-containing protein 10, UniProt Q5XX13. A curated interactome/UPS resource explicitly lists FBXW10 as UniProt Q5XX13, 1052 aa, annotated as an E3 CRL adaptor with F-box domain + WD repeats, consistent with an SCF-type substrate receptor architecture (Poirson et al., 2017-10, FEBS J; https://doi.org/10.1111/febs.14193) (poirson2017mappingtheinteractome pages 23-23). Review literature also classifies FBXW10 as a WD40-repeat F-box (FBXW-class) protein (Sahasrabuddhe & Elenitoba-Johnson, 2015-01, Immunol Rev; https://doi.org/10.1111/imr.12236) (sahasrabuddhe2015roleofthe pages 4-5).
F-box proteins are best understood as substrate-recognition subunits of SCF (SKP1–CUL1–F-box) cullin-RING E3 ubiquitin ligase complexes, where the F-box motif supports binding to Skp1 and additional domains (e.g., WD40 repeats) support substrate recruitment. In the UPS interactome mapping paper, FBXW10 is explicitly categorized as an E3 CRL adaptor with F-box + WD repeats (poirson2017mappingtheinteractome pages 23-23). In a hematologic malignancy review, FBXW10 is described as a WD40-repeat F-box protein (FBXW class) and discussed in the context of substrate specificity in SCF E3 ligases (sahasrabuddhe2015roleofthe pages 4-5).
FBXW10’s F-box plus WD40/β-propeller domain architecture is typical of F-box substrate receptors, in which WD40 repeats form a propeller-like scaffold enabling selective protein–protein interactions. Consistent with this, a 2023 hereditary thyroid cancer genetics study interpreted a disease-candidate variant (p.Ile440del) within the WD-repeat propeller, using an AlphaFold model for human FBXW10 (Q5XX13) and noting high model confidence (pLDDT > 90) near the affected region (Majdalani et al., 2023-05, IJMS; https://doi.org/10.3390/ijms24098233) (majdalani2023novelsusceptibilitygenes pages 5-7).
A central mechanistic study (Chaturvedi & Parnaik, 2010-05, PLoS ONE; https://doi.org/10.1371/journal.pone.0010620) reports that lamin A rod-domain disease mutants in HeLa cells are associated with proteasomal depletion of heterochromatin protein 1 (HP1) isoforms and that FBXW10 is induced and sufficient to drive depletion of specific HP1 isoforms (chaturvedi2010laminarod pages 1-2).
Key findings:
- FBXW10 induction: qRT-PCR (Table 3) shows FBXW10 transcript levels increased in lamin-mutant contexts (e.g., G232E: 5.64 ± 0.49 vs GFP control 1.71 ± 0.43; R386K: 2.35 ± 0.44), consistent with several-fold induction (chaturvedi2010laminarod pages 5-7).
- Isoform specificity: Ectopic expression of FBXW10 caused depletion of HP1α and HP1β but not HP1γ (HP1c) (chaturvedi2010laminarod pages 1-2, chaturvedi2010laminarod pages 5-7).
- Cell-level penetrance: FBXW10 overexpression depleted HP1α/β in ~80–90% of cells (chaturvedi2010laminarod pages 5-7).
- Proteasome dependence / pharmacologic rescue: Proteasome inhibitors restored HP1 and partially corrected lamin mutant phenotypes. For example, MG132 increased nuclear rim localization of lamin mutants from 19.6% ± 6.09 → 83.2% ± 6.11 (G232E) and 15.4% ± 5.11 → 61.0% ± 6.40 (R386K); lactacystin also improved rim localization (G232E 73.2% ± 9.07; R386K 39.8% ± 8.57) (chaturvedi2010laminarod pages 5-7). In the same work, HP1-positive-cell frequencies (immunofluorescence) were markedly restored by MG132/lactacystin for multiple lamin mutants (chaturvedi2010laminarod pages 2-4).
Interpretation for functional annotation:
- These results support FBXW10 as an E3-ligase adaptor/substrate receptor that can promote (directly or indirectly via SCF) the ubiquitin–proteasome-dependent turnover of HP1α/HP1β under specific cellular conditions (chaturvedi2010laminarod pages 1-2, chaturvedi2010laminarod pages 5-7, chaturvedi2010laminarod pages 2-4).
- However, the study does not establish purified-complex biochemistry (e.g., reconstituted SCF-FBXW10 ubiquitination of HP1 in vitro) and is largely based on induction/overexpression and proteasome-inhibitor phenotypic rescue; thus, HP1 isoforms are best treated as supported candidate substrates/affected proteins rather than definitively validated direct substrates of SCF-FBXW10 (chaturvedi2010laminarod pages 1-2, chaturvedi2010laminarod pages 5-7).
Visual evidence (figures/tables): The paper contains Western blot and tabular qRT-PCR evidence of HP1 depletion/FBXW10 induction and the ability of FBXW10 overexpression to deplete HP1α/β (chaturvedi2010laminarod media 9af6f79a, chaturvedi2010laminarod media 7bc1e356, chaturvedi2010laminarod media 2d73f981).
The functional evidence above places the FBXW10-associated phenotype in nuclear organization/heterochromatin maintenance pathways, via effects on HP1α/β and lamin mutant nuclear morphology in cultured cells (chaturvedi2010laminarod pages 1-2, chaturvedi2010laminarod pages 2-4). While the provided excerpts do not directly map FBXW10 itself to a specific subcellular compartment by microscopy under endogenous expression, the implicated pathway is nuclear: HP1 proteins are heterochromatin-associated and lamin A mutants perturb nuclear architecture (chaturvedi2010laminarod pages 1-2, chaturvedi2010laminarod pages 2-4).
A 2023 whole-exome sequencing study of a large consanguineous kindred with FNMTC nominated FBXW10 among candidate susceptibility genes (Majdalani et al., 2023-05; https://doi.org/10.3390/ijms24098233) (majdalani2023novelsusceptibilitygenes pages 4-5).
This constitutes recent genetics evidence suggesting potential involvement in thyroid cancer predisposition, but not causal proof (majdalani2023novelsusceptibilitygenes pages 5-7, majdalani2023novelsusceptibilitygenes pages 9-10).
A 2015 review of the ubiquitin-proteasome system in hematologic malignancies reports that FBXW10 harbors missense, nonsense, and frameshift mutations in T-cell prolymphocytic leukemia (T-PLL) (e.g., R318N, R416*, K966fs) (Sahasrabuddhe & Elenitoba-Johnson, 2015-01; https://doi.org/10.1111/imr.12236) (sahasrabuddhe2015roleofthe pages 4-5). The review emphasizes that very little is known about FBXW10’s function and that identifying substrates would be critical to understand consequences of inactivation in T-PLL (sahasrabuddhe2015roleofthe pages 4-5).
A 2024 pan-cancer analysis of the FBXW family reports that FBXW10 shows tumor-type-specific expression differences (Huang et al., 2024-12, Front Immunol; https://doi.org/10.3389/fimmu.2022.1084339) (huang2024pancanceranalysisof pages 5-7).
Limitations: The accessible text excerpt does not provide hazard ratios, coefficients, or p-values; those may be contained in the figures or supplementary material (huang2024pancanceranalysisof pages 7-10, huang2024pancanceranalysisof pages 5-7).
Majdalani et al. (2023) exemplifies a current trend in functional annotation that combines human genetics with AlphaFold-based structural reasoning to prioritize candidate variants in less-characterized proteins, here mapping p.Ile440del to a WD-propeller structural element with high confidence (majdalani2023novelsusceptibilitygenes pages 5-7).
Based on the evidence available in this run, current “applications” of FBXW10 are primarily:
- Candidate-gene prioritization in hereditary cancer studies using WES plus segregation and structural prediction (e.g., FNMTC candidate p.Ile440del) (majdalani2023novelsusceptibilitygenes pages 5-7, majdalani2023novelsusceptibilitygenes pages 4-5).
- Pan-cancer transcriptomic association analyses to identify cancer types where FBXW10 expression correlates with stage/prognosis features, potentially motivating future validation as a biomarker or mechanistic node (huang2024pancanceranalysisof pages 7-10, huang2024pancanceranalysisof pages 5-7).
Chaturvedi & Parnaik (2010) provide a conceptual application in cell biology: using lamin mutant phenotypes and proteasome modulation to infer that FBXW10 is part of a pathway connecting nuclear lamina disruption to proteasome-dependent loss of heterochromatin regulators (HP1α/β) (chaturvedi2010laminarod pages 1-2, chaturvedi2010laminarod pages 5-7, chaturvedi2010laminarod pages 2-4). While not a “clinical implementation,” it is a real-world experimental implementation informing laminopathy-related hypotheses.
A key expert/authoritative assessment comes from the Immunological Reviews article, which notes reported FBXW10 mutations in T-PLL but explicitly states that “very little is known” about FBXW10 function and that substrate identification would be important for understanding disease consequences (sahasrabuddhe2015roleofthe pages 4-5). This aligns with the evidence landscape in this run: strong domain-based inference and one direct cellular study, but limited substrate-validated biochemistry.
The following table consolidates the evidence types, assays, key quantitative results, and limitations.
| Evidence type | Key finding | System/assay | Quantitative/statistical detail | Source (authors, year, journal) | URL/DOI | Notes/limitations |
|---|---|---|---|---|---|---|
| Domain/complex | Human FBXW10 is identified as UniProt Q5XX13, a 1052-aa F-box/WD-repeat protein annotated as an “E3 CRL adaptor,” consistent with an SCF-type substrate receptor architecture. (poirson2017mappingtheinteractome pages 23-23) | Proteome/interactome annotation table | Length reported as 1052 aa; row annotated with F-box domain and WD repeats. (poirson2017mappingtheinteractome pages 23-23) | Poirson et al., 2017, The FEBS Journal | https://doi.org/10.1111/febs.14193 | Classification/annotation evidence rather than direct biochemical demonstration of SCF assembly or substrate binding. |
| Substrate/function | Lamin A rod-domain mutants induce FBXW10, and ectopic FBXW10 is sufficient to deplete HP1α and HP1β, but not HP1γ, supporting a role in selective ubiquitin-proteasome-mediated turnover of HP1 isoforms. (chaturvedi2010laminarod pages 1-2, chaturvedi2010laminarod pages 5-7) | HeLa cell expression studies; immunofluorescence; western blot; qRT-PCR | FBXW10 qRT-PCR: GFP 1.71 ± 0.43, WT lamin A 1.66 ± 0.70, G232E 5.64 ± 0.49, R386K 2.35 ± 0.44; ectopic FBXW10 depleted HP1α/β in 80–90% of cells. (chaturvedi2010laminarod pages 5-7) | Chaturvedi & Parnaik, 2010, PLoS ONE | https://doi.org/10.1371/journal.pone.0010620 | Evidence is from overexpression/mutant-lamin context; direct ubiquitination of HP1 by purified SCF-FBXW10 was not shown. |
| Substrate/rescue | HP1α/β loss in lamin-mutant cells is proteasome-dependent, and proteasome inhibition restores HP1 and partially rescues lamin/emerin nuclear-rim localization, linking FBXW10-associated phenotype to proteasomal degradation. (chaturvedi2010laminarod pages 1-2, chaturvedi2010laminarod pages 5-7, chaturvedi2010laminarod pages 2-4) | HeLa cells treated with MG132 or lactacystin; immunofluorescence; western blot | MG132 restored G232E rim localization from 19.6% ± 6.09 to 83.2% ± 6.11 and R386K from 15.4% ± 5.11 to 61.0% ± 6.40; lactacystin restored G232E to 73.2% ± 9.07 and R386K to 39.8% ± 8.57; HP1-positive cells also increased markedly with inhibitors. (chaturvedi2010laminarod pages 5-7, chaturvedi2010laminarod pages 2-4) | Chaturvedi & Parnaik, 2010, PLoS ONE | https://doi.org/10.1371/journal.pone.0010620 | Rescue implicates the proteasome but does not by itself prove FBXW10 is the only E3 responsible. |
| Disease/genetics | FBXW10 has been reported mutated in T-cell prolymphocytic leukemia (T-PLL), supporting possible disease relevance of loss/alteration of function. (sahasrabuddhe2015roleofthe pages 4-5) | Literature review of hematologic malignancy genetics | Reported variants include missense, nonsense, and frameshift changes such as R318N, R416*, and K966fs. (sahasrabuddhe2015roleofthe pages 4-5) | Sahasrabuddhe & Elenitoba-Johnson, 2015, Immunological Reviews | https://doi.org/10.1111/imr.12236 | Review explicitly states that very little is known about FBXW10 biology and substrates; mutation significance remains uncertain. |
| Disease/variant interpretation | In familial non-medullary thyroid cancer (FNMTC), FBXW10 was nominated as a candidate susceptibility gene carrying a heterozygous in-frame deletion p.Ile440del. (majdalani2023novelsusceptibilitygenes pages 5-7, majdalani2023novelsusceptibilitygenes pages 4-5) | Whole-exome sequencing and pedigree segregation analysis | Variant: c.1317_1319delCAT; p.Ile440del; chr17:18661699; segregated in heterozygous state in multiple family members with incomplete penetrance. (majdalani2023novelsusceptibilitygenes pages 5-7, majdalani2023novelsusceptibilitygenes pages 4-5) | Majdalani et al., 2023, International Journal of Molecular Sciences | https://doi.org/10.3390/ijms24098233 | Candidate-gene evidence only; authors prioritized ARHGEF28 over FBXW10 as the strongest causal candidate. |
| Domain/structure | The p.Ile440del candidate variant lies in the WD-repeat propeller region, where structural modeling predicts disruption of a beta-hairpin within a propeller blade. (majdalani2023novelsusceptibilitygenes pages 5-7) | Conservation analysis and AlphaFold-based structural interpretation | Ile440 conserved down to placental mammals; AlphaFold model around site reported with pLDDT > 90; ACMG evidence listed as PM2, PM4. (majdalani2023novelsusceptibilitygenes pages 5-7) | Majdalani et al., 2023, International Journal of Molecular Sciences | https://doi.org/10.3390/ijms24098233 | Inference is structural/computational, not functional validation in cells or animals. |
| Expression/cancer association | FBXW10 shows differential expression across cancers in pan-cancer analysis, with higher expression in several tumor types and lower expression in some kidney cancers and thyroid cancer. (huang2024pancanceranalysisof pages 5-7) | TCGA-based pan-cancer expression analysis | Higher in LUAD, LUSC, LIHC, PRAD, STAD; reduced in KICH, KIRC, THCA versus normal tissues. (huang2024pancanceranalysisof pages 5-7) | Huang et al., 2024, Frontiers in Immunology | https://doi.org/10.3389/fimmu.2022.1084339 | Expression correlations do not establish mechanism, substrate specificity, or causal function in these cancers. |
Table: This table summarizes the main published evidence supporting functional annotation of human FBXW10/Q5XX13, including domain architecture, experimentally supported substrate-linked effects, disease-associated variants, and cancer-expression findings. It is useful for distinguishing direct evidence from inference and highlighting the major limitations of the current literature.
Most defensible annotation (supported by evidence): FBXW10 is an F-box/WD-repeat cullin-RING E3 ligase adaptor/substrate receptor (consistent with SCF-type E3 complexes) and can promote proteasome-dependent depletion of HP1α/HP1β in a lamin-mutant nuclear stress context (poirson2017mappingtheinteractome pages 23-23, chaturvedi2010laminarod pages 1-2, chaturvedi2010laminarod pages 5-7).
Likely cellular role (inference plus context): Through protein–protein interactions mediated by its WD-repeat propeller, FBXW10 likely contributes to selective ubiquitination pathways affecting nuclear/heterochromatin proteins, but direct substrate validation beyond the HP1-linked cellular evidence remains limited in the retrieved corpus (chaturvedi2010laminarod pages 1-2, sahasrabuddhe2015roleofthe pages 4-5).
Disease relevance (current status): FBXW10 has (i) reported mutations in T-PLL (reviewed) (sahasrabuddhe2015roleofthe pages 4-5), (ii) a 2023 candidate hereditary thyroid cancer variant with structural rationale but not definitive causality (majdalani2023novelsusceptibilitygenes pages 5-7, majdalani2023novelsusceptibilitygenes pages 9-10), and (iii) pan-cancer expression/prognostic associations without mechanistic resolution in the accessible excerpt (huang2024pancanceranalysisof pages 7-10, huang2024pancanceranalysisof pages 5-7).
These database pages can be consulted for curated annotations, isoforms, and cross-references:
- UniProt Q5XX13 (FBXW10): https://www.uniprot.org/uniprotkb/Q5XX13
- InterPro (domain signatures; e.g., F-box-like, WD40 repeats): https://www.ebi.ac.uk/interpro/
References
(poirson2017mappingtheinteractome pages 23-23): Juline Poirson, Elise Biquand, Marie‐Laure Straub, Patricia Cassonnet, Yves Nominé, Louis Jones, Sylvie van der Werf, Gilles Travé, Katia Zanier, Yves Jacob, Caroline Demeret, and Murielle Masson. Mapping the interactome of hpv e6 and e7 oncoproteins with the ubiquitin‐proteasome system. The FEBS Journal, 284:3171-3201, Oct 2017. URL: https://doi.org/10.1111/febs.14193, doi:10.1111/febs.14193. This article has 74 citations.
(sahasrabuddhe2015roleofthe pages 4-5): Anagh A. Sahasrabuddhe and Kojo S. J. Elenitoba‐Johnson. Role of the ubiquitin proteasome system in hematologic malignancies. Immunological Reviews, 263:224-239, Jan 2015. URL: https://doi.org/10.1111/imr.12236, doi:10.1111/imr.12236. This article has 45 citations and is from a domain leading peer-reviewed journal.
(majdalani2023novelsusceptibilitygenes pages 5-7): Pierre Majdalani, Uri Yoel, Tayseer Nasasra, Merav Fraenkel, Alon Haim, Neta Loewenthal, Raz Zarivach, Eli Hershkovitz, and Ruti Parvari. Novel susceptibility genes drive familial non-medullary thyroid cancer in a large consanguineous kindred. International Journal of Molecular Sciences, 24:8233, May 2023. URL: https://doi.org/10.3390/ijms24098233, doi:10.3390/ijms24098233. This article has 4 citations.
(chaturvedi2010laminarod pages 1-2): Pankaj Chaturvedi and Veena K. Parnaik. Lamin a rod domain mutants target heterochromatin protein 1α and β for proteasomal degradation by activation of f-box protein, fbxw10. PLoS ONE, 5:e10620, May 2010. URL: https://doi.org/10.1371/journal.pone.0010620, doi:10.1371/journal.pone.0010620. This article has 59 citations and is from a peer-reviewed journal.
(chaturvedi2010laminarod pages 5-7): Pankaj Chaturvedi and Veena K. Parnaik. Lamin a rod domain mutants target heterochromatin protein 1α and β for proteasomal degradation by activation of f-box protein, fbxw10. PLoS ONE, 5:e10620, May 2010. URL: https://doi.org/10.1371/journal.pone.0010620, doi:10.1371/journal.pone.0010620. This article has 59 citations and is from a peer-reviewed journal.
(chaturvedi2010laminarod pages 2-4): Pankaj Chaturvedi and Veena K. Parnaik. Lamin a rod domain mutants target heterochromatin protein 1α and β for proteasomal degradation by activation of f-box protein, fbxw10. PLoS ONE, 5:e10620, May 2010. URL: https://doi.org/10.1371/journal.pone.0010620, doi:10.1371/journal.pone.0010620. This article has 59 citations and is from a peer-reviewed journal.
(chaturvedi2010laminarod media 9af6f79a): Pankaj Chaturvedi and Veena K. Parnaik. Lamin a rod domain mutants target heterochromatin protein 1α and β for proteasomal degradation by activation of f-box protein, fbxw10. PLoS ONE, 5:e10620, May 2010. URL: https://doi.org/10.1371/journal.pone.0010620, doi:10.1371/journal.pone.0010620. This article has 59 citations and is from a peer-reviewed journal.
(chaturvedi2010laminarod media 7bc1e356): Pankaj Chaturvedi and Veena K. Parnaik. Lamin a rod domain mutants target heterochromatin protein 1α and β for proteasomal degradation by activation of f-box protein, fbxw10. PLoS ONE, 5:e10620, May 2010. URL: https://doi.org/10.1371/journal.pone.0010620, doi:10.1371/journal.pone.0010620. This article has 59 citations and is from a peer-reviewed journal.
(chaturvedi2010laminarod media 2d73f981): Pankaj Chaturvedi and Veena K. Parnaik. Lamin a rod domain mutants target heterochromatin protein 1α and β for proteasomal degradation by activation of f-box protein, fbxw10. PLoS ONE, 5:e10620, May 2010. URL: https://doi.org/10.1371/journal.pone.0010620, doi:10.1371/journal.pone.0010620. This article has 59 citations and is from a peer-reviewed journal.
(majdalani2023novelsusceptibilitygenes pages 4-5): Pierre Majdalani, Uri Yoel, Tayseer Nasasra, Merav Fraenkel, Alon Haim, Neta Loewenthal, Raz Zarivach, Eli Hershkovitz, and Ruti Parvari. Novel susceptibility genes drive familial non-medullary thyroid cancer in a large consanguineous kindred. International Journal of Molecular Sciences, 24:8233, May 2023. URL: https://doi.org/10.3390/ijms24098233, doi:10.3390/ijms24098233. This article has 4 citations.
(majdalani2023novelsusceptibilitygenes pages 9-10): Pierre Majdalani, Uri Yoel, Tayseer Nasasra, Merav Fraenkel, Alon Haim, Neta Loewenthal, Raz Zarivach, Eli Hershkovitz, and Ruti Parvari. Novel susceptibility genes drive familial non-medullary thyroid cancer in a large consanguineous kindred. International Journal of Molecular Sciences, 24:8233, May 2023. URL: https://doi.org/10.3390/ijms24098233, doi:10.3390/ijms24098233. This article has 4 citations.
(huang2024pancanceranalysisof pages 5-7): Tingting Huang, XIaoxiao OuYang, Jiwei Li, Bingbing Shi, Zhengda Shan, Zhiyuan Shi, and Zhangru Yang. Pan-cancer analysis of fbxw family with potential implications in prognosis and immune infiltration. Frontiers in Immunology, Dec 2024. URL: https://doi.org/10.3389/fimmu.2022.1084339, doi:10.3389/fimmu.2022.1084339. This article has 6 citations and is from a peer-reviewed journal.
(huang2024pancanceranalysisof pages 7-10): Tingting Huang, XIaoxiao OuYang, Jiwei Li, Bingbing Shi, Zhengda Shan, Zhiyuan Shi, and Zhangru Yang. Pan-cancer analysis of fbxw family with potential implications in prognosis and immune infiltration. Frontiers in Immunology, Dec 2024. URL: https://doi.org/10.3389/fimmu.2022.1084339, doi:10.3389/fimmu.2022.1084339. This article has 6 citations and is from a peer-reviewed journal.