Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
Alice Cheng
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States
Katherine A Rauen
UC Davis MIND Institute, University of California Davis, Sacramento, United States; Department of Pediatrics, University of California Davis, Sacramento, United States
Department of Anatomic Pathology, University of California San Francisco, San Francisco, United States
Frank McCormick
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States
Gerardo Jimenez
Institute for Molecular Biology of Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
RAS GTPases are highly conserved proteins involved in the regulation of mitogenic signaling. We have previously described a novel Cullin 3 RING E3 ubiquitin ligase complex formed by the substrate adaptor protein LZTR1 that binds, ubiquitinates, and promotes proteasomal degradation of the RAS GTPase RIT1. In addition, others have described that this complex is also responsible for the ubiquitination of classical RAS GTPases. Here, we have analyzed the phenotypes of Lztr1 loss-of-function mutants in both fruit flies and mice and have demonstrated a biochemical preference for their RIT1 orthologs. Moreover, we show that Lztr1 is haplosufficient in mice and that embryonic lethality of the homozygous null allele can be rescued by deletion of Rit1. Overall, our results indicate that, in model organisms, RIT1 orthologs are the preferred substrates of LZTR1.
