Science 363, 1226–1230 (2019)

RIT1 is a Ras-related small GTPase, and mutations in RIT1 at the switch II region have been identified in lung adenocarcinoma and Noonan syndrome resulting in increased growth factor signaling and RIT1 protein levels. Given that RIT1 oncogenic mutations were not found in the traditional GTPase hotspots that alter GDP/GTP exchange, it was speculated that RIT1 might undergo a distinct form of regulation. Castel et al. utilized a mass spectrometry approach and identified the leucine-zipper-like transcription regulator 1 (LZTR1), an adaptor for the CUL3 ubiquitin ligase complex, as a binding partner specifically for the GDP-bound form of RIT1. LZTR1–RIT1 interactions resulted in CUL3-mediated ubiquitination and degradation of RIT1. LZTR1 knockdown or RIT1 oncogenic mutations block degradation, resulting in increased RIT1 protein levels and growth factor signaling. Overall, these findings reveal a new form of GTPase regulation by proteasome degradation.