TY - JOUR TI - Cross-species analysis of LZTR1 loss-of-function mutants demonstrates dependency to RIT1 orthologs AU - Cuevas-Navarro, Antonio AU - Rodriguez-Muñoz, Laura AU - Grego-Bessa, Joaquim AU - Cheng, Alice AU - Rauen, Katherine A AU - Urisman, Anatoly AU - McCormick, Frank AU - Jimenez, Gerardo AU - Castel, Pau A2 - Berger, Alice A2 - Cooper, Jonathan A A2 - Berger, Alice A2 - Abankwa, Daniel VL - 11 PY - 2022 DA - 2022/04/25 SP - e76495 C1 - eLife 2022;11:e76495 DO - 10.7554/eLife.76495 UR - https://doi.org/10.7554/eLife.76495 AB - 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. KW - LZTR1 KW - RIT1 KW - noonan syndrome KW - RASopathy KW - CG3711 KW - RIC JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -