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.
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.
Parent term: ubiquitin-like ligase-substrate adaptor activity
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0019005 SCF ubiquitin ligase complex | NAS PMID:20498703 Lamin A rod domain mutants target heterochromatin protein 1a... | ACCEPT | 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. 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. Supporting Evidence: file:human/FBXW10/FBXW10-uniprot.txt Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex file:human/FBXW10/FBXW10-deep-research-falcon.md FBXW10 is explicitly categorized as an **E3 CRL adaptor** with **F-box + WD repeats** |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | NAS PMID:20498703 Lamin A rod domain mutants target heterochromatin protein 1a... | ACCEPT | 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. 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. Supporting Evidence: PMID:20498703 ectopic expression of FBXW10 in HeLa cells led to depletion of HP1alpha and beta without alteration of HP1gamma levels file:human/FBXW10/FBXW10-deep-research-falcon.md ectopic FBXW10 is sufficient to deplete HP1Ξ± and HP1Ξ², but not HP1Ξ³, supporting a role in selective ubiquitin-proteasome-mediated turnover of HP1 isoforms |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952618 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol localization (AcM-UBE2M transfers NEDD8 to CRL1) propagated to FBXW10 as an SCF subunit. 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. Supporting Evidence: file:human/FBXW10/FBXW10-uniprot.txt Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952620 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol localization (NEDD8:AcM-UBE2M binds CRL1) propagated to FBXW10. Reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific. Supporting Evidence: file:human/FBXW10/FBXW10-uniprot.txt Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955241 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol localization (CAND1 binds cytosolic CRL ligases) propagated to FBXW10. Reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific. Supporting Evidence: file:human/FBXW10/FBXW10-uniprot.txt Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955289 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol localization (COMMDs displace CAND1) propagated to FBXW10. Reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific. Supporting Evidence: file:human/FBXW10/FBXW10-uniprot.txt Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956040 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol localization (COP9 signalosome deneddylates CRLs) propagated to FBXW10. Reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific. Supporting Evidence: file:human/FBXW10/FBXW10-uniprot.txt Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956200 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol localization (MyrG-DCUN1D3 binds CRL1) propagated to FBXW10. Reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific. Supporting Evidence: file:human/FBXW10/FBXW10-uniprot.txt Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983140 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol localization (transfer of Ub from E2 to substrate) propagated to FBXW10. Reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific. Supporting Evidence: file:human/FBXW10/FBXW10-uniprot.txt Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983147 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol localization (release of E3 from polyubiquitinated substrate) propagated to FBXW10. Reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific. Supporting Evidence: file:human/FBXW10/FBXW10-uniprot.txt Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983156 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol localization (polyubiquitination of substrate) propagated to FBXW10. Reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific. Supporting Evidence: file:human/FBXW10/FBXW10-uniprot.txt Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983157 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol localization (interaction of E3 with substrate and E2-Ub complex) propagated to FBXW10. Reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific. Supporting Evidence: file:human/FBXW10/FBXW10-uniprot.txt Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex |
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Download this section (compressed HTML)Q: Does FBXW10 directly ubiquitinate HP1-alpha (CBX5) and HP1-beta (CBX1) within a reconstituted SCF complex, or is the observed depletion indirect?
Q: Given testis-enriched expression, what is FBXW10's physiological role and substrate repertoire in spermatogenesis, distinct from the lamin-stress-induced HP1 turnover?
Q: 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?
Experiment: 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.
Experiment: 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.
Experiment: 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.
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