FBXW10

FBXW10 is an F-box protein that functions as the substrate-recognition subunit of SCF-type E3 ubiquitin ligase complexes, directing both K48-linked degradative and K63-linked activating polyubiquitination of distinct substrates. FBXW10 promotes proteasomal degradation of the heterochromatin proteins HP1α and HP1β and of the Hippo pathway kinase LATS2, the latter requiring an intact F-box domain (PMID:20498703, PMID:36990424). FBXW10 also catalyzes K63-linked polyubiquitination and activation of ANXA2 (dependent on S6K1-mediated phosphorylation) and of GAPDH (dependent on VRK2-mediated Ser151 phosphorylation), thereby engaging MEK/ERK and NF-κB oncogenic signaling, respectively, and driving hepatocellular carcinoma proliferation, metastasis, and immune evasion (PMID:37277019, PMID:37450367). FBXW10 transcription is directly activated by ZNF169 binding its promoter, and FBXW10 is required for ZNF169-driven proliferation in thyroid cancer (PMID:39875985).

1. 2010 Medium

   Establishing FBXW10 as an F-box E3 ligase component capable of targeting specific chromatin-associated substrates for proteasomal degradation answered the initial question of whether FBXW10 has ubiquitin ligase activity and identified HP1α/β as its first substrates.

   Evidence Ectopic overexpression in HeLa cells with proteasomal inhibitor rescue and ubiquitination assays

   PMID:20498703

   Open questions at the time

   • No in vitro reconstitution of FBXW10-dependent ubiquitination of HP1α/β
   • Physiological conditions triggering FBXW10-mediated HP1 degradation beyond lamin A mutant context are unknown
   • Whether SCF complex assembly is required was not directly tested
2. 2023 High

   Demonstrating that FBXW10 can catalyze non-degradative K63-linked polyubiquitination (of ANXA2 and GAPDH) expanded its functional repertoire beyond proteasomal targeting and linked it to activation of MEK/ERK and NF-κB oncogenic pathways in HCC, while revealing that upstream kinases (S6K1 for ANXA2, VRK2 for GAPDH) gate substrate recognition.

   Evidence K63-linkage-specific ubiquitination assays, phosphorylation site mutagenesis (GAPDH S151), Co-IP of substrate–effector interactions (ANXA2–KRAS, GAPDH–TRAF2), subcellular fractionation, and in vivo HCC/metastasis models including transgenic mice

   PMID:37277019 PMID:37450367

   Open questions at the time

   • Direct biochemical reconstitution of FBXW10 SCF complex with purified substrates has not been performed
   • How FBXW10 selects between K48 and K63 ubiquitin chain linkages on different substrates is unknown
   • Male-specific HCC phenotype linked to GAPDH–NF-κB–AR axis has not been validated in independent cohorts
3. 2023 Medium

   Identifying LATS2 as a degradative substrate of FBXW10 and mapping the requirement for the F-box domain established that FBXW10 promotes angiogenesis and colorectal cancer metastasis through Hippo pathway inactivation, broadening its oncogenic substrate repertoire beyond HCC.

   Evidence Co-IP, ubiquitination assays, F-box domain deletion mutants, in vivo knockdown/overexpression with angiogenesis and liver metastasis readouts

   PMID:36990424

   Open questions at the time

   • Degron motif on LATS2 recognized by FBXW10 WD40 repeats has not been mapped
   • Whether LATS2 ubiquitination requires prior phosphorylation (analogous to ANXA2/GAPDH) is untested
   • Single-lab finding without independent replication
4. 2025 Medium

   Showing that ZNF169 directly binds the FBXW10 promoter to drive its transcription answered how FBXW10 expression is regulated and placed it within a defined transcriptional–oncogenic axis in thyroid cancer.

   Evidence ChIP-PCR, luciferase reporter assay, knockdown/overexpression epistasis rescue in cells and xenograft models

   PMID:39875985

   Open questions at the time

   • Other transcription factors regulating FBXW10 in different tumor contexts are unknown
   • Whether ZNF169-driven FBXW10 expression engages the same downstream substrates (ANXA2, GAPDH, LATS2) in thyroid cancer has not been tested
   • Single-lab finding in one cancer type

• The structural basis for FBXW10 substrate recognition by its WD40 repeats, the mechanism determining K48 versus K63 ubiquitin chain specificity, and the full spectrum of physiological substrates remain uncharacterized.
• No crystal or cryo-EM structure of FBXW10 or its SCF complex exists
• No unbiased proteomics screen for FBXW10 substrates has been reported
• Mechanism of ubiquitin chain-type selection is unknown