Science 362, 1171–1177 (2018)

Science 362, 1177–1182 (2018)

LZTR1 is an adaptor for the CUL3 ubiquitin ligase complex, and mutations in LZTR1 have been identified in liver and brain cancers and Noonan syndrome; however, the exact molecular role of LZTR1 in these disorders was not clear. Bigenzahn et al. used haploid genetic screens to connect LZTR1 with regulation of MAPK signaling and resistance to tyrosine kinase inhibitors. To identify substrates of LZTR1-containing complexes, Stekov et al. utilized a mass spectrometry approach that traps protein complexes in viral particles, whereas Bigenzahn et al. used a proximity biotinylation proteomic approach to detect complexes of LZTR1 and the main RAS GTPase family members K-, N- and HRAS. Formation of this complex resulted in the ubiquitination of RAS proteins, decreasing RAS activity and MAPK signaling. LZTR1 pathogenic mutations reduced binding to CUL3 and RAS, interfering with RAS ubiquitination and leading to enhanced RAS protein levels and plasma-membrane localization. Interestingly, Stekov et al. found that HRAS gets ubiquitinated at K170, and molecular simulations with lipidated RAS supported the notion that K170 ubiquitination prevented membrane association. Overall, these findings reveal a new mechanism of RAS regulation providing a potential explanation for LZTR1 mutations in human disease.