FBXO42

FBXO42 is an F-box protein that serves as the substrate-recognition subunit of an SCF/CRL1 (SKP1–CUL1–F-box) E3 ubiquitin ligase, using its F-box and Kelch domains to assemble the complex and capture substrates for ubiquitination (PMID:38774470, PMID:41986709). Through this activity it controls the abundance and assembly state of multiple regulatory targets, most prominently protein phosphatases: it degrades holoenzyme-free PP2A catalytic subunit (PP2Ac) using CCDC6 as a dimeric co-adaptor that templates recruitment of multiple PP2Ac copies along a coiled coil, recognizing both the CCDC6–PP2Ac quaternary structure and the methylated PP2Ac C-terminal tail (PMID:41986709), and it ubiquitinates the PP4 complex to restrain PP4 phosphatase activity, in part by acting on the catalytic subunit PPP4C (PMID:41484364). A central cellular role of FBXO42 is the maintenance of mitotic fidelity: its activity prevents chromosome alignment defects and spindle assembly checkpoint activation, and FBXO42 inactivation triggers an Mps1-dependent mitotic arrest and cell death in sensitive cancer cells (PMID:38774470). FBXO42 also shapes signaling outputs by K63-linked polyubiquitination of RBPJ at lysine-175, which enhances RBPJ–chromatin association and Notch pathway activation to drive leukemia (PMID:36129980), and by directing degradation of additional substrates including ROCK2, ACAA2, p57Kip2, and (in Drosophila) the RNA-binding protein Ataxin-2, the last linking FBXO42 to release of Xbp1 mRNA and terminal UPR-driven cell death (PMID:33692332, PMID:37528093, PMID:40842039, PMID:40804044). Across these contexts FBXO42 frequently behaves as a tumor-promoting and cancer-essential ligase (PMID:36129980, PMID:40842039).

1. 2019 Low

   First implicated FBXO42 as an E3 ubiquitin ligase with a signaling role, connecting its loss to altered P38/TAK1 signaling and drug resistance.

   Evidence Genome-wide CRISPR-Cas9 knockout screen with P38 activation readout and trametinib combination experiments in NRAS-mutant melanoma

   PMID:31549767

   Open questions at the time

   • Pathway placement inferred from P38 activation, no direct substrate identified
   • No biochemical demonstration of ubiquitination
   • Single lab, screen-level evidence
2. 2021 High

   Established FBXO42 as the substrate receptor of a CUL1 ligase that can be redirected by small molecules and adaptor bridging, demonstrating ligand-induced neosubstrate ubiquitination.

   Evidence CRISPR knockout screen, pull-down proteomics, biolayer interferometry, and Co-IP showing HB007/CAPRIN1-induced FBXO42 recruitment of SUMO1

   PMID:34644148

   Open questions at the time

   • SUMO1 is a drug-induced neosubstrate, not necessarily a physiological target
   • Endogenous adaptor logic beyond CAPRIN1 not defined
3. 2021 Medium

   Placed FBXO42 in a transcriptional-to-degradation circuit by showing it mediates K63-linked ubiquitination/degradation of ROCK2 downstream of GASC1.

   Evidence ChIP/transcriptional repression assay, K63-linkage ubiquitination assay, knockdown/overexpression, and xenograft model in hepatocellular carcinoma

   PMID:33692332

   Open questions at the time

   • Direct vs indirect ubiquitination of ROCK2 not fully resolved
   • Single lab
   • Mechanism of K63 chains driving degradation unclear
4. 2021 Low

   Linked FBXO42 loss to mitotic vulnerability, foreshadowing a cell-cycle role through chemical-genetic sensitivity to mitotic inhibitors.

   Evidence Chemical-genetic CRISPR screen with 41 compounds and mitotic phenotype scoring

   PMID:33539788

   Open questions at the time

   • No direct biochemical mechanism established for FBXO42
   • Substrate driving aberrant mitoses not identified
5. 2022 High

   Defined a non-degradative ubiquitination function: K63-linked polyubiquitination of RBPJ at K175 that activates Notch signaling and promotes leukemia.

   Evidence Co-IP/MS, K175 site-directed mutagenesis, chromatin fractionation, and in vivo leukemia model with FBXO42 depletion/inhibition

   PMID:36129980

   Open questions at the time

   • Mechanism by which K63 chains enhance chromatin remodeler recruitment not structurally defined
   • Relationship to FBXO42 degradative substrates unclear
6. 2023 High

   Demonstrated CAND1-regulated assembly of a CUL1-FBXO42-ACAA2 complex driving ACAA2 degradation, tying FBXO42 to CRL assembly control and metabolism.

   Evidence Co-IP, hepatocyte-specific CAND1 KO/KI mouse models, and ACAA2 overexpression rescue

   PMID:37528093

   Open questions at the time

   • Physiological signals controlling ACAA2 targeting unclear
   • How CAND1 status tunes substrate choice not defined
7. 2024 Medium

   Identified the cancer-essential function of FBXO42 as prevention of SAC-driven mitotic arrest, requiring both F-box and Kelch domains and independent of previously proposed substrates.

   Evidence Functional genomic lethality screens, FBXO42 inactivation with mitotic readouts, Mps1 chemical inhibition, and domain mutants

   PMID:38774470

   Open questions at the time

   • The mitotically relevant substrate was not identified in this study
   • Mechanism connecting FBXO42 loss to SAC activation undefined
   • Single lab
8. 2024 Low

   Connected FBXO42 to mutant-p53 stabilization, working with CCDC6 to control USP28-mediated stabilization and promote TP53-dependent proliferation.

   Evidence Genome-wide CRISPR screens for p53 stability regulators and proliferation assays in neuroblastoma

   PMID:38580884 PMID:39134694

   Open questions at the time

   • Limited mechanistic follow-up beyond screen identification
   • Direct vs indirect effect on p53 not established
   • How CCDC6/USP28 cooperation is wired unclear
9. 2025 Medium

   Extended FBXO42 substrate range to p57Kip2 and demonstrated transcriptional upregulation by YY1, linking FBXO42 to CDK-inhibitor turnover in HCC.

   Evidence Co-IP (UbiBrowser-predicted, validated), ubiquitination assay, and proliferation/migration assays

   PMID:40842039

   Open questions at the time

   • Direct ubiquitination linkage type not defined
   • Single lab
   • Relationship to other HCC substrates (ROCK2) unclear
10. 2025 Medium

    Identified PPP4C as a CCDC6-independent FBXO42 substrate whose deregulation drives death of FBXO42-essential neuroblastoma cells, with synthetic lethality to γ-TuRC components.

    Evidence MS proteomics, CRISPR synthetic lethality screen, ubiquitination assays, and knockdown rescue (preprint)

    PMID:bio_10.1101_2025.04.22.649889

    Open questions at the time

    • Preprint, not yet peer-reviewed
    • Relationship between PPP4C control and mitotic SAC phenotype not fully resolved
11. 2025 High

    Defined a conserved FBXO42-Ataxin-2 axis in the terminal UPR, where FBXO42 degrades Ataxin-2 in stress granules to release Xbp1 mRNA and trigger cell death.

    Evidence Drosophila genetic screen, ubiquitylation assay, granule imaging, and epistasis (Fbxo42 KO suppresses Xbp1s-induced death)

    PMID:40804044

    Open questions at the time

    • Conservation of the Ataxin-2 axis in mammalian cells not shown in timeline
    • Mechanism of FBXO42 recruitment to granules undefined
12. 2026 High

    Provided the structural and mechanistic basis for FBXO42-mediated phosphatase control: a CCDC6-templated multivalent scaffold degrading PP2Ac, and ubiquitination of PP4 to restrain its activity.

    Evidence Cryo-EM of FBXO42-CCDC6-PP2Ac with reconstitution and ubiquitination/viability assays; Co-IP, ubiquitination and PP4 activity assays for PP4

    PMID:41484364 PMID:41986709

    Open questions at the time

    • How phosphatase control intersects with the mitotic SAC phenotype not integrated
    • Regulation of CCDC6-dependent vs -independent substrate choice unresolved

• The substrate(s) responsible for FBXO42's core cancer-essential mitotic function and how its many degradative and non-degradative targets are coordinated remain unresolved.
• Mitotic substrate not definitively assigned
• Rules governing CCDC6-dependent vs -independent and K48 vs K63 outcomes undefined
• Tissue-specific substrate selection mechanism unknown