Cross-species analysis of LZTR1 loss-of-function mutants demonstrates dependency to RIT1 orthologs

Elife. 2022 Apr 25:11:e76495. doi: 10.7554/eLife.76495.

Abstract

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.

Keywords: CG3711; D. melanogaster; LZTR1; RASopathy; RIC; RIT1; cancer biology; genetics; genomics; human; mouse; noonan syndrome.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing* / genetics
  • Animals
  • Cell Proliferation
  • Drosophila Proteins* / genetics
  • Mice
  • Signal Transduction
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism
  • Ubiquitination
  • ras Proteins* / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Drosophila Proteins
  • LZTR1 protein, mouse
  • Lztr1 protein, Drosophila
  • Transcription Factors
  • ras Proteins