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Mapping the unique and shared functions of oncogenic KRAS and RIT1 with proteome and transcriptome profiling

By April Lo, Kristin Holmes, Filip Mundt, Sitapriya Moorthi, Iris Fung, Shaunt Fereshetian, Jackie Watson, Steven A Carr, Philipp Mertins, Alice H. Berger

Posted 11 Apr 2020
bioRxiv DOI: 10.1101/2020.04.10.030460

Aberrant activation of RAS oncogenes is prevalent in lung adenocarcinoma, with somatic mutation of KRAS occurring in ~30% of tumors. Recently, we identified somatic mutation of the RAS-family GTPase RIT1 in lung adenocarcinoma, but relatively little is known about the biological pathways regulated by RIT1 and how these relate to the oncogenic KRAS network. Here we present quantitative proteomic and transcriptomic profiles from KRAS-mutant and RIT1-mutant isogenic lung epithelial cells and globally characterize the signaling networks regulated by each oncogene. We find that both mutant KRAS and mutant RIT1 promote S6 kinase, AKT, and RAF/MEK signaling, and promote epithelial-to-mesenchymal transition and immune evasion via HLA protein loss. However, KRAS and RIT1 diverge in regulation of phosphorylation sites on EGFR, USO1, and AHNAK proteins. The majority of the proteome changes are related to altered transcriptional regulation, but a small subset of proteins are differentially regulated by both oncoproteins at the post-transcriptional level, including intermediate filament proteins, metallothioneins, and MHC Class I proteins. These data provide the first global, unbiased characterization of oncogenic RIT1 network and identify the shared and divergent functions of oncogenic RIT1 and KRAS GTPases in lung cancer. ### Competing Interest Statement The authors have declared no competing interest.

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