RIT1 oncoproteins escape LZTR1-mediated proteolysis

• DOI: 10.1126/science.aav1444
• Publication Date: 2019-03-14T23:44:28Z
• Authors: Pau Castel; Alice Cheng; Antonio Cuevas-Na...; David B. Everman; Alex G. Papageorge; Dhirendra K. Sima...; Alexandra Tankka; Jacqueline Galeas; Anatoly Urisman; Frank McCormick
• Keywords: Oncogene Proteins; 0301 basic medicine; 0303 health sciences; General Science & Technology; Noonan Syndrome; Mass Spectrometry; Mice, Mutant Strains; 3. Good health; Mutant Strains; Mice; 03 medical and health sciences; HEK293 Cells; Hela Cells; Proteolysis; Genetics; ras Proteins; 2.1 Biological and endogenous factors; Animals; Humans; Gene Knock-In Techniques; Aetiology; Germ-Line Mutation; Cancer; HeLa Cells; Transcription Factors

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