| Aspect | Key points | Best recent sources (2023-2024 prioritized) with publication date and URL |
|---|---|---|
| Identity/complex | FBXW7 in this report matches human UniProt Q969H0 and the historical aliases hCDC4, SEL-10, and AGO/archipelago homolog. It is the substrate-recognition subunit of the SCF (SKP1-CUL1-RBX1-FBXW7) Cullin-RING E3 ubiquitin ligase complex that promotes ubiquitination and proteasomal degradation of phosphorylated substrates, especially growth- and cell-cycle regulators (pqac-00000000, pqac-00000002, pqac-00000008, pqac-00000015). | de la Cova, *Cells* (2023-08), https://doi.org/10.3390/cells12172141; Di Fiore et al., *Cells* (2023-05), https://doi.org/10.3390/cells12101415; Zhang et al., *Oncology Letters* (2020-06), https://doi.org/10.3892/ol.2020.11728 |
| Domains/isoforms/localization | FBXW7 contains an N-terminal dimerization region, an F-box that binds SKP1, and a C-terminal WD40 β-propeller substrate-binding domain. Human isoforms are N-terminally distinct: FBXW7α is mainly nuclear/nucleoplasmic, FBXW7β is cytoplasmic, and FBXW7γ is nucleolar; this matches the UniProt F-box/WD40 annotation and explains compartment-specific substrate control (pqac-00000000, pqac-00000001, pqac-00000002, pqac-00000005). | de la Cova, *Cells* (2023-08), https://doi.org/10.3390/cells12172141; Zhang et al., *Oncology Letters* (2020-06), https://doi.org/10.3892/ol.2020.11728 |
| Degron recognition/kinases | FBXW7 recognizes phosphorylated Cdc4 phosphodegrons (CPDs) using its WD40 domain; a high-affinity consensus described in recent review is pThr-Pro-Pro-X-pSer, though lower-affinity/noncanonical CPDs also exist. Substrate phosphorylation is often created or reinforced by GSK3, and can involve kinase cascades including CDK1/2 and ERK/MAPK; hotspot arginines such as R465/R479/R505 are critical for phosphodegron recognition and are recurrently mutated in cancer (pqac-00000008, pqac-00000009, pqac-00000010, pqac-00000011, pqac-00000014). | de la Cova, *Cells* (2023-08), https://doi.org/10.3390/cells12172141; Chen et al., *J Exp Clin Cancer Res* (2023-09), https://doi.org/10.1186/s13046-023-02767-1 |
| Key substrates | Canonical and strongly supported substrates include Cyclin E, c-MYC, c-JUN, NOTCH1/NOTCH4, MCL1, KLF5, mTOR, and BRAF. Recent primary studies extend the substrate list to EGFR (direct target in colorectal organoids/patients), LEF1 and TCF7L2 (endometrial cancer models), and PINK1 via SCF-FBW7β in the cytosol; recent systematic/functional work also highlights context-dependent effects on CRY2, ZEB2, and others (pqac-00000010, pqac-00000013, pqac-00000017, pqac-00000027, pqac-00000028, pqac-00000029). | Boretto et al., *PNAS* (2024-03), https://doi.org/10.1073/pnas.2309902121; Brown et al., *EMBO Mol Med* (2023-08), https://doi.org/10.15252/emmm.202217094; Jeon & Chung, *J Biol Chem* (2024-04), https://doi.org/10.1016/j.jbc.2024.107198 |
| 2023-2024 primary study highlights | 2024 PNAS: EGFR was identified as a direct FBXW7 substrate; FBXW7 hotspot-mutant colon organoids showed markedly increased EGFR stability and ~10,000-fold reduced EGF dependence, with poorer response to EGFR-MAPK blockade and faster progression in FBXW7-mutant metastatic CRC on anti-EGFR therapy (pqac-00000017). 2024 Science Advances: FBXW7 mutations in RNF43-mutant/RSPO-fusion cancers caused intrinsic resistance to anti-Wnt therapies, with loss of β-catenin dependence but retained sensitivity to multi-CDK inhibition (pqac-00000023). 2024 JBC: SCF-FBW7β promoted K48-linked polyubiquitination and proteasomal degradation of PINK1, with endogenous interaction primarily in the cytosol (pqac-00000028, pqac-00000029, pqac-00000030). 2023 EMBO Mol Med: LEF1 and TCF7L2 were validated as novel FBXW7-interacting substrates, and WD40 hotspot mutation weakened binding (LEF1 co-IP ratio ~1.0→0.44; TCF7L2 ~1.0→0.17) (pqac-00000027). | Boretto et al., *PNAS* (2024-03), https://doi.org/10.1073/pnas.2309902121; Zhong & Virshup, *Science Advances* (2024-04), https://doi.org/10.1126/sciadv.adk1031; Jeon & Chung, *J Biol Chem* (2024-04), https://doi.org/10.1016/j.jbc.2024.107198; Brown et al., *EMBO Mol Med* (2023-08), https://doi.org/10.15252/emmm.202217094 |
| Clinical/genomic statistics | FBXW7 is among the most recurrently altered F-box genes in cancer. In CRC, recent summaries place mutation prevalence around 6-10% overall, with cohort-specific estimates near 14.8-18.75% in several Asian series and ~18% in one 2023 clinicogenomic analysis (pqac-00000018, pqac-00000024, pqac-00000026). In the 2023 Frontiers in Oncology CRC study, patients with FBXW7 mutations had better overall survival overall (HR 0.67, 95% CI 0.55-0.80, P<0.001), but the specific R465C variant had worse survival than other FBXW7 variants (HR 1.6, 95% CI 1.13-3.1, P=0.015) and versus R465H (HR 3.08, 95% CI 1.28-7.39, P=0.0082) (pqac-00000024). RNF43 mutations occur in ~5-10% of pancreatic cancers and RSPO2/3 fusions in ~2-10% of CRC; within that molecular subgroup, FBXW7 mutation marks likely anti-Wnt resistance (pqac-00000023). | Liu et al., *Frontiers in Oncology* (2023-03), https://doi.org/10.3389/fonc.2023.1154432; Afolabi et al., *Heliyon* (2024-06), https://doi.org/10.1016/j.heliyon.2024.e31471; Zhong & Virshup, *Science Advances* (2024-04), https://doi.org/10.1126/sciadv.adk1031 |
| Therapeutic/application implications | Current translational interest centers on biomarker use and pathway-guided therapy rather than direct FBXW7-targeted drugs. FBXW7 status may help predict resistance to anti-EGFR therapy in metastatic CRC, primary resistance to anti-Wnt/PORCN-pathway inhibition in RNF43/RSPO tumors, and altered sensitivity to apoptosis-targeted approaches when MCL1 accumulates. Mechanistically informed alternatives proposed in recent work include multi-CDK inhibition for FBXW7-mutant Wnt-independent tumors, MCL1-directed strategies, and exploiting synthetic vulnerabilities created by FBXW7 loss; reviews also emphasize potential immunotherapy relevance and the need for hotspot-specific interpretation rather than treating all FBXW7 variants as equivalent (pqac-00000016, pqac-00000017, pqac-00000022, pqac-00000023). | Wang et al., *Frontiers in Pharmacology* (2024-12), https://doi.org/10.3389/fphar.2024.1505027; Wang et al., *Frontiers in Pharmacology* (2023-11), https://doi.org/10.3389/fphar.2023.1278056; Chen et al., *Frontiers in Oncology* (2023-03), https://doi.org/10.3389/fonc.2023.1147239; Boretto et al., *PNAS* (2024-03), https://doi.org/10.1073/pnas.2309902121 |


*Table: This table summarizes verified identity, molecular function, localization, substrates, recent 2023-2024 discoveries, and translational implications for human FBXW7 (UniProt Q969H0). It is useful as a compact evidence map for narrative functional annotation and recent literature synthesis.*