Multiomic characterization of oncogenic signaling mediated by wild-type and mutant RIT1.
Aberrant activation of the RAS family of guanosine triphosphatases (GTPases) is prevalent in lung adenocarcinoma, with somatic mutation of occurring in ~30% of tumors. We previously identified somatic mutations and amplifications of the gene encoding RAS family GTPase RIT1 in lung adenocarcinomas. To explore the biological pathways regulated by RIT1 and how they relate to the oncogenic KRAS network, we performed quantitative proteomic, phosphoproteomic, and transcriptomic profiling of isogenic lung epithelial cells in which we ectopically expressed wild-type or cancer-associated variants of RIT1 and KRAS. We found that both mutant KRAS and mutant RIT1 promoted canonical RAS signaling and that overexpression of wild-type RIT1 partially phenocopied oncogenic RIT1 and KRAS, including induction of epithelial-to-mesenchymal transition. Our findings suggest that RIT1 protein abundance is a factor in its pathogenic function. Therefore, chromosomal amplification of wild-type in lung and other cancers may be tumorigenic.
|Year of Publication
2021 Nov 30
|PubMed Central ID
R37 CA252050 / CA / NCI NIH HHS / United States
K99 CA197762 / CA / NCI NIH HHS / United States
P30 CA015704 / CA / NCI NIH HHS / United States
U24 CA210986 / CA / NCI NIH HHS / United States
R00 CA197762 / CA / NCI NIH HHS / United States
T32 GM007270 / GM / NIGMS NIH HHS / United States
U01 CA214125 / CA / NCI NIH HHS / United States