Oncogenic Mutations in RIT1 Ablate LZTR1-mediated Proteolysis

Noonan syndrome (NS) is a genetic disorder caused by mutations in members of the RAS GTPase family. Mutations in RIT1 are found in 5% to 9% of patients with NS and also occur in cancers where KRAS or NRAS mutations are frequent, but RIT1 mutations do not render RIT1 resistant to GAP activity like other common oncogenic RAS GTPase mutations. To assess the role of mutant RIT1 in NS, Castel and colleagues generated a knock-in mouse expressing Rit1^M90I. Germline expression of Rit1^M90I resulted in a phenotype resembling NS, displayed an enhanced response to growth factor, and expressed higher levels of RIT1 protein despite similar levels of Rit1 mRNA to wild-type mice. Pulldown of RIT1 followed by mass spectrometry identified leucine zipper–like transcription regulator 1 (LZTR1) as a binding partner that preferentially interacted with GDP-bound RIT1. LZTR1 is also mutated in NS, and LTZR1 and RIT1 mutations are mutually exclusive, suggesting they operate in the same pathway. Overexpression of LZTR1 resulted in polyubiquitylation of RIT1 in a K48-dependent manner and reduced RIT1 protein levels, suggesting that LZTR1 acts as an adaptor for proteasome-mediated degradation. In support of this, RIT1 protein levels were rescued by inhibition of the proteasome or overexpression of a dominant negative mutant of the E3 ligase cullin 3 (CUL3). The majority of oncogenic mutations found in RIT1 ablated LZTR1-mediated degradation, as did several point mutations within the Kelch repeat domain of LZTR1. Knockout of Lztr1 in mouse embryonic fibroblasts resulted in increased RIT1 protein levels and enhanced response to growth factor stimulation, and primary skin fibroblasts derived from patients with NS harboring mutations in LZTR1 displayed increased RIT1 protein levels compared with their heterozygous parents. Taken together, these results establish a direct role for LZTR1 in the regulation of RIT1 proteolysis and provide insight into the consequences of pathogenic mutations in RIT1 and LZTR1.

Castel P, Cheng A, Cuevas-Navarro A, Everman DB, Papageorge AG, Simanshu DK, et al. RIT1 oncoproteins escape LZTR1-mediated proteolysis. Science 2019;363:1226–30.

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