id: Q5XX13 gene_symbol: FBXW10 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXW10 (ubiquitin ligase-specificity factor) is a large (1052 aa) member of the F-box/WD40 (FBXW) family, containing an F-box motif and WD40 repeats together with coiled-coil regions. F-box proteins act as the interchangeable substrate-recognition subunits of SCF (SKP1-CUL1-F-box)-type cullin-RING E3 ubiquitin ligase complexes, in which the F-box motif docks onto SKP1/CUL1 and the WD40 propeller recruits substrates for ubiquitination by the RBX1-bound E2, committing them to proteasomal degradation; the F-box protein itself is the substrate adaptor and is not catalytic. Curated interactome resources classify FBXW10 as an E3 cullin-RING-ligase (CRL) adaptor with F-box plus WD40 repeats. FBXW10 is testis-enriched in expression. Functional data are limited: in a study of laminopathy-associated lamin A rod-domain mutants, FBXW10 transcript was induced several-fold in cells expressing these mutants, and ectopic FBXW10 expression depleted heterochromatin protein 1 isoforms HP1-alpha (CBX5) and HP1-beta (CBX1) but not HP1-gamma in a proteasome-dependent manner, implicating FBXW10 in turnover of these chromatin proteins under conditions of nuclear stress. FBXW10 has been reported mutated (missense, nonsense and frameshift) in T-cell prolymphocytic leukemia and was nominated as a candidate susceptibility gene (an in-frame WD-propeller deletion, p.Ile440del) in familial non-medullary thyroid cancer, and it shows tumor-type-specific expression changes in pan-cancer analyses. Its direct, physiological ubiquitination substrates and its assembly into a defined SCF complex have not been biochemically demonstrated; the HP1 isoforms are best regarded as candidate/affected substrates rather than validated direct targets. existing_annotations: - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:20498703 qualifier: part_of review: summary: ComplexPortal/family-based assignment of SCF complex membership (CPX-7786, SCF complex FBXW10 variant), consistent with the F-box motif and with curated interactome classification of FBXW10 as an E3 CRL adaptor; the cited study links FBXW10 to SCF-mediated proteasomal degradation of HP1 isoforms. action: ACCEPT reason: Core assembly annotation for an F-box protein; supported by the F-box domain, the UniProt function statement describing FBXW10 as a probable SCF substrate-recognition component, and interactome-level annotation as an E3 CRL adaptor. Direct biochemical reconstitution of an SCF(FBXW10) complex has not been shown. additional_reference_ids: - file:human/FBXW10/FBXW10-deep-research-falcon.md supported_by: - reference_id: file:human/FBXW10/FBXW10-uniprot.txt supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex - reference_id: file:human/FBXW10/FBXW10-deep-research-falcon.md supporting_text: FBXW10 is explicitly categorized as an **E3 CRL adaptor** with **F-box + WD repeats** - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: NAS original_reference_id: PMID:20498703 qualifier: involved_in review: summary: Assignment of involvement in SCF-dependent proteasomal degradation; ectopic FBXW10 depletes HP1-alpha/beta via the proteasome in cells expressing lamin A mutants, and proteasome inhibitors (MG132/lactacystin) rescue HP1 levels. action: ACCEPT reason: Core biological process for an SCF substrate receptor; supported by the experimental observation that FBXW10 expression drives proteasome-dependent depletion of HP1 isoforms. Direct in vitro ubiquitination of HP1 by reconstituted SCF(FBXW10) was not demonstrated, so HP1-alpha/beta are best treated as candidate/affected substrates. additional_reference_ids: - file:human/FBXW10/FBXW10-deep-research-falcon.md supported_by: - reference_id: PMID:20498703 supporting_text: ectopic expression of FBXW10 in HeLa cells led to depletion of HP1alpha and beta without alteration of HP1gamma levels - reference_id: file:human/FBXW10/FBXW10-deep-research-falcon.md supporting_text: ectopic FBXW10 is sufficient to deplete HP1α and HP1β, but not HP1γ, supporting a role in selective ubiquitin-proteasome-mediated turnover of HP1 isoforms - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952618 qualifier: located_in review: summary: Reactome pathway-level cytosol localization (AcM-UBE2M transfers NEDD8 to CRL1) propagated to FBXW10 as an SCF subunit. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible for an SCF subunit but not FBXW10-specific, and the one functional study implicates a nuclear/heterochromatin context. supported_by: - reference_id: file:human/FBXW10/FBXW10-uniprot.txt supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952620 qualifier: located_in review: summary: Reactome pathway-level cytosol localization (NEDD8:AcM-UBE2M binds CRL1) propagated to FBXW10. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific. supported_by: - reference_id: file:human/FBXW10/FBXW10-uniprot.txt supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955241 qualifier: located_in review: summary: Reactome pathway-level cytosol localization (CAND1 binds cytosolic CRL ligases) propagated to FBXW10. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific. supported_by: - reference_id: file:human/FBXW10/FBXW10-uniprot.txt supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955289 qualifier: located_in review: summary: Reactome pathway-level cytosol localization (COMMDs displace CAND1) propagated to FBXW10. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific. supported_by: - reference_id: file:human/FBXW10/FBXW10-uniprot.txt supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956040 qualifier: located_in review: summary: Reactome pathway-level cytosol localization (COP9 signalosome deneddylates CRLs) propagated to FBXW10. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific. supported_by: - reference_id: file:human/FBXW10/FBXW10-uniprot.txt supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956200 qualifier: located_in review: summary: Reactome pathway-level cytosol localization (MyrG-DCUN1D3 binds CRL1) propagated to FBXW10. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific. supported_by: - reference_id: file:human/FBXW10/FBXW10-uniprot.txt supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983140 qualifier: located_in review: summary: Reactome pathway-level cytosol localization (transfer of Ub from E2 to substrate) propagated to FBXW10. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific. supported_by: - reference_id: file:human/FBXW10/FBXW10-uniprot.txt supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983147 qualifier: located_in review: summary: Reactome pathway-level cytosol localization (release of E3 from polyubiquitinated substrate) propagated to FBXW10. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific. supported_by: - reference_id: file:human/FBXW10/FBXW10-uniprot.txt supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983156 qualifier: located_in review: summary: Reactome pathway-level cytosol localization (polyubiquitination of substrate) propagated to FBXW10. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific. supported_by: - reference_id: file:human/FBXW10/FBXW10-uniprot.txt supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983157 qualifier: located_in review: summary: Reactome pathway-level cytosol localization (interaction of E3 with substrate and E2-Ub complex) propagated to FBXW10. action: KEEP_AS_NON_CORE reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific. supported_by: - reference_id: file:human/FBXW10/FBXW10-uniprot.txt supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex references: - id: PMID:20498703 title: Lamin A rod domain mutants target heterochromatin protein 1alpha and beta for proteasomal degradation by activation of F-box protein, FBXW10. findings: - statement: In HeLa cells, lamin A rod-domain mutants induced FBXW10 transcript several-fold and triggered proteasomal degradation of HP1-alpha (CBX5) and HP1-beta (CBX1) but not HP1-gamma; ectopic FBXW10 expression alone depleted HP1-alpha/beta, implicating FBXW10 (an F-box protein involved in E3 ubiquitin ligase activity) in this turnover. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified; sole functional study of FBXW10. Supports SCF-dependent proteasomal degradation involvement and the CBX5/CBX1 substrate link, though direct in vitro ubiquitination by FBXW10 was not demonstrated. - id: Reactome:R-HSA-8952618 title: AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex findings: [] - id: Reactome:R-HSA-8952620 title: NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex findings: [] - id: Reactome:R-HSA-8955241 title: CAND1 binds cytosolic CRL E3 ubiquitin ligases findings: [] - id: Reactome:R-HSA-8955289 title: COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes findings: [] - id: Reactome:R-HSA-8956040 title: COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes findings: [] - id: Reactome:R-HSA-8956200 title: MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex findings: [] - id: Reactome:R-HSA-983140 title: Transfer of Ub from E2 to substrate and release of E2 findings: [] - id: Reactome:R-HSA-983147 title: Release of E3 from polyubiquitinated substrate findings: [] - id: Reactome:R-HSA-983156 title: Polyubiquitination of substrate findings: [] - id: Reactome:R-HSA-983157 title: Interaction of E3 with substrate and E2-Ub complex findings: [] - id: file:human/FBXW10/FBXW10-deep-research-falcon.md title: Falcon deep research report for human FBXW10 findings: - statement: Curated interactome/UPS resources classify FBXW10 (Q5XX13, 1052 aa) as an E3 cullin-RING-ligase adaptor with F-box plus WD40 repeats, consistent with an SCF-type substrate-receptor architecture rather than an enzyme. supporting_text: FBXW10 is explicitly categorized as an **E3 CRL adaptor** with **F-box + WD repeats** - statement: The strongest functional evidence is that lamin A rod-domain mutants induce FBXW10 and ectopic FBXW10 is sufficient to deplete HP1-alpha/HP1-beta but not HP1-gamma in a proteasome-dependent manner, though direct in vitro ubiquitination of HP1 by purified SCF(FBXW10) was not shown. supporting_text: ectopic FBXW10 is sufficient to deplete HP1α and HP1β, but not HP1γ, supporting a role in selective ubiquitin-proteasome-mediated turnover of HP1 isoforms - statement: FBXW10 has been reported mutated (missense, nonsense, frameshift) in T-cell prolymphocytic leukemia, and the function/substrates remain largely unknown. supporting_text: FBXW10 harbors **missense, nonsense, and frameshift mutations** in **T-cell prolymphocytic leukemia (T-PLL)** - statement: A candidate familial non-medullary thyroid cancer variant (p.Ile440del) maps to a beta-hairpin within a WD-propeller blade, implicating the WD40 substrate-binding region, though FBXW10 was ranked a second-priority candidate. supporting_text: Ile440 is evolutionarily conserved down to placental mammals and lies in a **β-hairpin of a WD-propeller blade** reference_review: relevance: HIGH correctness: VERIFIED review_notes: Falcon synthesis grounded chiefly in Chaturvedi & Parnaik 2010 (PLoS ONE, doi:10.1371/journal.pone.0010620; the sole functional study, already cited here as PMID:20498703) plus Poirson et al. 2017 (FEBS J, doi:10.1111/febs.14193; interactome classification as E3 CRL adaptor), Sahasrabuddhe & Elenitoba-Johnson 2015 (Immunol Rev, doi:10.1111/imr.12236; T-PLL mutations), and Majdalani et al. 2023 (IJMS, doi:10.3390/ijms24098233; FNMTC candidate variant p.Ile440del). Cross-checked against UniProt Q5XX13 FUNCTION/INDUCTION statements and ComplexPortal CPX-7786. The disease/genetics findings are hypothesis-generating and do not alter the existing annotation calls; the HP1 link is supported but not biochemically reconstituted. core_functions: - description: Probable substrate-recognition (substrate-adaptor) subunit of an SCF (SKP1-CUL1-F-box) cullin-RING E3 ubiquitin ligase complex that, when induced, promotes proteasome-dependent depletion of the heterochromatin proteins HP1-alpha (CBX5) and HP1-beta (CBX1) under conditions of nuclear/lamin stress. FBXW10 is non-catalytic (ubiquitin transfer is RBX1's), and direct reconstituted ubiquitination of HP1 has not been shown, so HP1 isoforms remain candidate/affected substrates. supported_by: - reference_id: file:human/FBXW10/FBXW10-uniprot.txt supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins - reference_id: PMID:20498703 supporting_text: ectopic expression of FBXW10 in HeLa cells led to depletion of HP1alpha and beta without alteration of HP1gamma levels locations: - id: GO:0005829 label: cytosol directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process proposed_new_terms: - proposed_name: ubiquitin-like ligase-substrate adaptor activity proposed_definition: Bridging a substrate to a ubiquitin-like protein ligase, as performed by an SCF F-box substrate-recognition subunit that binds both SKP1/the ligase scaffold and the substrate to facilitate the substrate's ubiquitination. This corresponds to the existing GO term GO:1990756, which is not currently in FBXW10's annotation set. justification: FBXW10 is classified as an E3 CRL adaptor with an F-box and WD40 propeller and, when induced, promotes proteasome-dependent depletion of HP1-alpha/beta, consistent with a substrate-adaptor molecular function rather than catalysis (which is RBX1's). Adding GO:1990756 would give FBXW10 an informative molecular-function term, currently absent from its annotation set. proposed_parent: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity supported_by: - reference_id: file:human/FBXW10/FBXW10-uniprot.txt supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins - reference_id: file:human/FBXW10/FBXW10-deep-research-falcon.md supporting_text: FBXW10 is explicitly categorized as an **E3 CRL adaptor** with **F-box + WD repeats** suggested_questions: - question: Does FBXW10 directly ubiquitinate HP1-alpha (CBX5) and HP1-beta (CBX1) within a reconstituted SCF complex, or is the observed depletion indirect? - question: Given testis-enriched expression, what is FBXW10's physiological role and substrate repertoire in spermatogenesis, distinct from the lamin-stress-induced HP1 turnover? - question: Are the T-PLL mutations and the familial thyroid-cancer WD-propeller variant (p.Ile440del) loss-of-function for substrate recognition, and what substrate do they affect? suggested_experiments: - description: Reconstitute SCF(FBXW10) with SKP1, CUL1, RBX1 and an E2 in vitro and test direct ubiquitination of CBX5/CBX1, with F-box-deletion FBXW10 as a negative control. - description: Co-immunoprecipitation of endogenous FBXW10 with SKP1/CUL1 and with CBX5/CBX1 in testis-derived cells, plus FBXW10 knockdown to assess effects on endogenous HP1 isoform stability. - description: Express the WD-propeller variant p.Ile440del and T-PLL truncating alleles and assay SCF assembly (SKP1/CUL1 binding) and HP1-alpha/beta turnover relative to wild-type FBXW10.