Journal
ELIFE
Volume 11, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.76495
Keywords
LZTR1; RIT1; noonan syndrome; RASopathy; CG3711; RIC; D; melanogaster; Human; Mouse
Categories
Funding
- National Cancer Institute [F31CA265066, R35CA197709, R00CA245122]
- DOD CDMRP Neurofibromatosis Research Program [W81XWH-20-1-0391]
- Communidad de Madrid
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The research findings suggest that RIT1 orthologs are preferred substrates of LZTR1, with specific phenotypes observed in fruit flies and mice. In mice, Lztr1 is haplosufficient, and deletion of Rit1 can rescue embryonic lethality caused by homozygous null allele.
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.
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