ArticleCell death & disease2023
PTPN23 ubiquitination by WDR4 suppresses EGFR and c-MET degradation to define a lung cancer therapeutic target.
Article in Cell death & disease, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 24 citations in OpenAlex.
- Article
- Review
- From EGFR PTM network to TKI resistance: spatial subtypes and targeting in lung cancer.Cancer drug resistance (Alhambra, Calif.) · 2026Review
- Article
- From intracellular drivers to immune modulators: emerging paradigms in oncogenic pathway-directed immunotherapy optimization.Cell communication and signaling : CCS · 2025Review
- Extracellular vesicles: biogenesis mechanism and impacts on tumor immune microenvironment.Journal of biomedical science · 2025Review
- Generation of a Biliary Tract Cancer Cell Line Atlas Identifies Molecular Subtypes and Therapeutic Targets.Cancer discovery · 2025Article
- Mechanistic Insights and Therapeutic Potentials of Ubiquitin-Proteasome System in Non-Small Cell Lung Cancer.Cell proliferation · 2025Review
- Upregulation of WDR4 mediated by RBFOX2 promotes laryngeal cancer progression through the WDR4/m7G/lncRNA ZFAS1/RBFOX2 axis.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- PTPN23-dependent activation of PI3KC2α is a therapeutic vulnerability of BRAF-mutant cancers.The Journal of experimental medicine · 2025Article
- N7-methylguanosine modification in cancers: from mechanisms to therapeutic potential.Journal of hematology & oncology · 2025Review
- Comprehensive multi-omics analysis reveals the prognostic and immune regulatory characteristics of the PTPN family in osteosarcoma.PloS one · 2025Article
- Role of Epiregulin on Lipopolysaccharide-Induced Hepatocarcinogenesis as a Mediator via EGFR Signaling in the Cancer Microenvironment.International journal of molecular sciences · 2024Article
- Erianin promotes apoptosis and inhibits Akt-mediated aerobic glycolysis of cancer cells.Journal of Cancer · 2024Article
Corrections and comments
- Erratum issued
Authors and funding
11 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aberrant overexpression or activation of EGFR drives the development of non-small cell lung cancer (NSCLC) and acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) by secondary EGFR mutations or c-MET amplification/activation remains as a major hurdle for NSCLC treatment. We previously identified WDR4 as a substrate adaptor of Cullin 4 ubiquitin ligase and an association of WDR4 high expression with poor prognosis of lung cancer. Here, using an unbiased ubiquitylome analysis, we uncover PTPN23, a component of the ESCRT complex, as a substrate of WDR4-based ubiquitin ligase. WDR4-mediated PTPN23 ubiquitination leads to its proteasomal degradation, thereby suppressing lysosome trafficking and degradation of wild type EGFR, EGFR mutant, and c-MET. Through this mechanism, WDR4 sustains EGFR and c-MET signaling to promote NSCLC proliferation, migration, invasion, stemness, and metastasis. Clinically, PTPN23 is downregulated in lung cancer and its low expression correlates with WDR4 high expression and poor prognosis. Targeting WDR4-mediated PTPN23 ubiquitination by a peptide that competes with PTPN23 for binding WDR4 promotes EGFR and c-MET degradation to block the growth and progression of EGFR TKI-resistant NSCLC. These findings identify a central role of WDR4/PTPN23 axis in EGFR and c-MET trafficking and a potential therapeutic target for treating EGFR TKI-resistant NSCLC.
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