Schematic representation of the main findings reported by Zhou et al. The authors show that NOTCH2 is a target of the cullin-ring ubiquitin type 3 ligase KLHL6. Ubiquitination of the intracellular part of NOTCH2 causes protein degradation and pathway inhibition. Loss-of-function mutations in KLHL6 or NOTCH2 mutations in the C-terminal domains result in both failed ubiquitination and failed pathway inhibition, leading to activation of a RAS/extracellular signal-regulated kinase–dependent signaling and chemoresistance. NLS, nuclear localization signal; PEST, proline/glutamic acid/serine/threonine; TAD, transcriptional activation domain; Ub, ubiquitination.