RIT1 oncoproteins escape LZTR1-mediated proteolysis

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Science  15 Mar 2019:
Vol. 363, Issue 6432, pp. 1226-1230
DOI: 10.1126/science.aav1444

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Defective degradation as disease mechanism

Ubiquitination often targets proteins for destruction. Castel et al. describe a mechanism by which mutations in the small guanine triphosphatase RIT1 may act to cause certain developmental disorders and cancers. They detected a protein, LZTR1, that interacted with wild-type RIT1 but not with oncogenic mutant forms of RIT1. LZTR1 acts as a substrate-specific adaptor for a ubiquitin ligase. Altered forms of RIT1 that are not subject to ubiquitin-mediated degradation thus accumulate. Because RIT1 functions in growth factor signaling and excessive signaling, these findings may explain the malignancies associated with RIT1 mutations.

Science, this issue p. 1226


RIT1 oncoproteins have emerged as an etiologic factor in Noonan syndrome and cancer. Despite the resemblance of RIT1 to other members of the Ras small guanosine triphosphatases (GTPases), mutations affecting RIT1 are not found in the classic hotspots but rather in a region near the switch II domain of the protein. We used an isogenic germline knock-in mouse model to study the effects of RIT1 mutation at the organismal level, which resulted in a phenotype resembling Noonan syndrome. By mass spectrometry, we detected a RIT1 interactor, leucine zipper–like transcription regulator 1 (LZTR1), that acts as an adaptor for protein degradation. Pathogenic mutations affecting either RIT1 or LZTR1 resulted in incomplete degradation of RIT1. This led to RIT1 accumulation and dysregulated growth factor signaling responses. Our results highlight a mechanism of pathogenesis that relies on impaired protein degradation of the Ras GTPase RIT1.

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