| Study (first author, year) | Publication date/month | URL/DOI | Model/system | FBXW2 role (SCF substrate receptor vs substrate) | Direct substrate(s) validated | Recognition requirement (degron/phosphorylation/acetylation) | Ubiquitin linkage/site (if given) | Key phenotypes and quantitative associations | Notes/limitations |
|---|---|---|---|---|---|---|---|---|---|
| Xu, 2017 | Jan 2017 | https://doi.org/10.1038/ncomms14002 | Human lung cancer cells; xenograft/tumor assays; patient survival analyses | Dual role: FBXW2 is a **substrate** of SCF^β-TrCP1 and also an SCF **substrate receptor/E3** for SKP2 | SKP2; FBXW2 itself is targeted by β-TrCP1 | FBXW2 contains conserved β-TrCP-binding motif **SSGART**; β-TrCP binding is phospho-dependent; **CK1** and **VRK2** implicated in phosphorylating FBXW2; SKP2 binding depends on putative **TSELLS** motif; FBXW2ΔF mutant loses activity | Ubiquitylation/degradation shown, but linkage chemistry/site not specified in gathered evidence | FBXW2 overexpression shortens SKP2 half-life; depletion extends it; FBXW2 tumor-suppressive in lung cancer; **E269K** mutant increased tumor size/weight at Day 28 (**P < 0.01**), increased Ki-67, reduced p21 and cleaved caspase-3; higher FBXW2 associated with **better survival** | Strong mechanistic paper defining β-TrCP–FBXW2–SKP2 axis; localization data not captured in gathered evidence; quantitative half-life values not available here (pqac-00000001, pqac-00000003) |
| Yang, 2019 | Mar 2019 | https://doi.org/10.1038/s41467-019-09289-5 | Human lung cancer cells; in vitro invasion/migration assays; in vivo metastasis models; human lung cancer specimens | SCF **substrate receptor/E3** for β-catenin | β-catenin | FBXW2 recognizes β-catenin after **EGF–AKT1** phosphorylation at **Ser552**; conserved FBXW2 degron motif **TSXXXS** mapped on β-catenin | Ubiquitylation and proteasomal degradation shown; linkage/site not specified in gathered evidence | FBXW2 overexpression reduced β-catenin level and half-life; knockdown increased β-catenin level, half-life, and transcriptional activity; inhibited β-catenin-driven MMP transactivation, migration, invasion, metastasis; FBXW2 inversely correlated with β-catenin and lymph-node metastasis; **low FBXW2 + high β-catenin predicted worse survival** | High-quality mechanistic study; figure model explicitly links EGF/AKT1→pSer552 β-catenin→FBXW2-mediated degradation; exact ubiquitin linkage and detailed localization not provided in gathered excerpts (pqac-00000002, pqac-00000011, pqac-00000012) |
| Yang, 2019 | May 2019 | https://doi.org/10.1080/23723556.2019.1607458 | Commentary/research summary focused on NSCLC findings | Summary of dual roles above: FBXW2 as SCF **substrate receptor/E3** for SKP2 and β-catenin; FBXW2 itself regulated as a **substrate** by β-TrCP | SKP2, β-catenin | States **VRK2** phosphorylation enables β-TrCP-dependent FBXW2 degradation; β-catenin binding depends on **AKT1-mediated phosphorylation** | Not specified | FBXW2 described as downregulated in NSCLC and associated with **better patient survival** when higher; frames tumor suppressor function in proliferation and invasion control | Secondary source/commentary rather than primary mechanistic dataset; useful for integrating the SKP2 and β-catenin studies but not for new quantitative measurements (pqac-00000005) |
| Ren, 2022 | Aug 2022 | https://doi.org/10.1038/s41418-021-00862-4 | Breast cancer cell lines; in vitro ubiquitination; confocal IF; FBXW2-knockout mice; xenograft and paclitaxel-resistance models; clinical breast cancer specimens | SCF **substrate receptor/E3** for NF-κB p65 | NF-κB p65 (RELA) | Direct binding mapped to **FBXW2 aa 1–100** and **p65 aa 1–291**; p65 contains conserved **SDRELS** motif resembling FBXW2 degron; binding requires phosphorylation, with **PKA** activity and **S276**-region integrity important; **p300-mediated acetylation** of p65 blocks FBXW2-induced ubiquitination | **p65 K122** identified as FBXW2 ubiquitination site; polyubiquitination shown; linkage type not specified in gathered evidence; ubiquitination occurs in **cytoplasm and nucleus** | FBXW2 lowered p65 stability/half-life and SOX2 expression, suppressing breast cancer stemness, tumorigenesis, and paclitaxel resistance; FBXW2 mRNA/protein lower in breast cancer and **negatively correlated with p65** | Strong evidence for direct ubiquitination and regulatory PTM crosstalk (phosphorylation/acetylation); gathered excerpts do not specify chain type (e.g., K48) or full clinical statistics (pqac-00000006, pqac-00000007, pqac-00000008) |
| Barik, 2023 | Sep 2023 | https://doi.org/10.1038/s41419-023-06127-x | Breast cancer cell lines, patient datasets/samples, in vivo tumor studies | SCF **substrate receptor/E3** for Moesin; indirectly restrains SKP2 via Moesin | Moesin; functional linkage to SKP2 | FBXW2 directly interacts with Moesin; **AKT** phosphorylation of Moesin at **Thr558** weakens FBXW2–Moesin association and protects Moesin from degradation | **Lys-48-linked polyubiquitination** of Moesin reported | FBXW2 underexpressed while Moesin upregulated in breast cancer; inverse FBXW2–Moesin correlation; higher FBXW2 associated with **better recurrence-free survival**, higher Moesin with poorer RFS; FBXW2 suppresses breast tumor progression by restricting **AKT–Moesin–SKP2** axis | Important 2023 mechanistic expansion of FBXW2 substrate space; exact effect sizes not in gathered excerpt (pqac-00000004) |
| Wang, 2020 | Aug 2020 | https://doi.org/10.1002/advs.202001800 | Macrophages; myeloid-specific knockout mice; obesity/atherosclerosis murine models | SCF **substrate receptor/E3** in inflammatory/metabolic disease context | **KSRP** | WD40/C-terminal region implicated in substrate recognition; gathered evidence does not specify precise degron or phosphorylation trigger | Ubiquitination/degradation of KSRP shown; linkage/site not specified in gathered evidence | Myeloid FBXW2 deficiency improved obesity-associated insulin resistance and atherosclerosis, with reduced inflammatory responses and macrophage infiltration; **P3** region of FBXW2 competitively inhibited KSRP degradation and ameliorated disease progression | Demonstrates non-cancer role and translational inhibitor concept; mechanistic details in current evidence are less granular than for cancer substrates (pqac-00000000) |
| Zhou, 2022 | May 2022 | https://doi.org/10.1007/s00018-022-04320-3 | Prostate cancer cells; in vitro and in vivo proliferation/metastasis models | SCF **substrate receptor/E3** for EGFR | EGFR | FBXW2 binds EGFR via consensus degron motif **TSNNST** (reported around residues 1041/1042 and 1045/1046) | Ubiquitylation/degradation shown; specific linkage/site not captured in gathered evidence | FBXW2 overexpression attenuated proliferation and metastasis; depletion extended EGFR half-life and promoted malignant behavior; supports tumor suppressor role in prostate cancer | Important additional validated substrate outside lung/breast systems; not part of initial gather_evidence output but available from retrieved paper abstract, so quantitative clinical details remain limited here (pqac-00000000) |
| Lin, 2025 | Jul 2025 | https://doi.org/10.1038/s41420-025-02643-1 | Gastric cancer cell lines; label-free proteomics; Co-IP; IF; doxycycline-inducible xenografts and lung metastasis models; clinical/database analyses | SCF **substrate receptor/E3** for WASL; FBXW2 transcriptionally repressed upstream by **FOXP2** | **WASL** | WASL identified by proteomics and predicted interaction; endogenous and exogenous Co-IP validated binding; double IF showed **cytoplasmic co-localization**; specific degron/phosphorylation requirement not reported in gathered evidence | Ubiquitination of WASL increased by FBXW2; MG132 blocked degradation; linkage/site not specified | FBXW2 downregulated in gastric adenocarcinoma and low FBXW2 associated with **worse prognosis**; inducible FBXW2 reduced tumor growth and lung metastasis; WASL overexpression partially rescued FBXW2 tumor-suppressive effects | Useful as emerging evidence for a new substrate and upstream transcriptional regulation, but 2025 paper is very recent and not yet broadly validated/cited (pqac-00000009, pqac-00000010) |
| Huang, 2022 | Dec 2022 | https://doi.org/10.3389/fimmu.2022.1084339 | TCGA pan-cancer bioinformatic analysis of FBXW family | Not a mechanistic substrate study; family-level expression/prognostic context for FBXW2 | None experimentally validated | Not applicable | Not applicable | Reported FBXW family heterogeneity across tumors; FBXW2 noted among family members with altered stage/prognostic associations in some cancers | Useful for recent statistics/context, but evidence is bioinformatic rather than direct functional validation (pqac-00000000) |
| NCT06758700 | 2025 | https://clinicaltrials.gov/study/NCT06758700 | Phase II, single-arm trial in extensive-stage small cell lung cancer | Clinical biomarker mention rather than mechanistic role | None | Trial text refers to patients with **“high expression of the c-Myc-driven FBXW2/MYC gene”**; no mechanistic FBXW2 assay details provided | Not applicable | Teniposide 60 mg/m2 IV for 3–5 consecutive days every 21 days; estimated enrollment **15**; ORR primary endpoint; shows emerging clinical use of FBXW2-related expression language in patient selection/rationale | Relevance to FBXW2 is indirect/ambiguous and likely part of a broader MYC-driven signature rather than validated FBXW2-targeted intervention (pqac-00000013) |


*Table: This table summarizes the main experimentally supported functions and substrates reported for human FBXW2, including its roles as an SCF substrate receptor and as a substrate of β-TrCP. It also highlights recognition requirements, ubiquitination details, disease phenotypes, and limitations of the current evidence base.*