EGFR and neoplasm: In this study, we identify PTPN23 as a novel substrate of WDR4-based Cul4 ligase and WDR4-mediated PTPN23 proteolysis prevents the lysosomal degradation of not only wild type EGFR but also TKI-resistant EGFR mutant and c-MET, thereby sustaining the downstream signaling of these RTKs to support various tumor-promoting functions.