RIT1 oncoproteins escape LZTR1-mediated proteolysis

• Published in: Science (American Association for the Advancement of Science) Vol. 363; no. 6432; pp. 1226 - 1230
• Main Authors: Castel, Pau, Cheng, Alice, Cuevas-Navarro, Antonio, Everman, David B., Papageorge, Alex G., Simanshu, Dhirendra K., Tankka, Alexandra, Galeas, Jacqueline, Urisman, Anatoly, McCormick, Frank
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 15.03.2019; The American Association for the Advancement of Science
• Subjects: Animals; Biodegradation; Cancer; Degradation; Developmental disabilities; Etiology; Gene Knock-In Techniques; Germ-Line Mutation; Growth factors; Guanine; Guanosine triphosphatases; HEK293 Cells; HeLa Cells; Humans; Leucine; Leucine zipper proteins; Mass Spectrometry; Mass spectroscopy; Mice; Mice, Mutant Strains; Mutation; Noonan Syndrome - genetics; Noonan's syndrome; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Oncoproteins; Pathogenesis; Phenotypes; Proteins; Proteolysis; Ras protein; ras Proteins - genetics; ras Proteins - metabolism; Signaling; Substrates; Transcription Factors - genetics; Transcription Factors - metabolism; Triphosphatase; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aav1444

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.