MassIVE MSV000085225

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Integrative proteomic and transcriptomic profiling identifies unique and shared functions of oncogenic KRAS and RIT1

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Description

Lo A, Holmes K, Mundt F, Moorthi S, Fung I, Fereshetian S, Watson J, Carr SA, Mertins P, Berger A. Aberrant activation of RAS oncogenes is a prevalent event 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 phosphoproteins including 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 at the post-transcriptional level, including intermediate filament proteins, metallothioneins, and MHC Class I proteins, which are profoundly suppressed by oncogenic KRAS and RIT1 variants. 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. [doi:10.25345/C5SH7G] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: TMT ; phosphorylation

Contact

Principal Investigators:
(in alphabetical order) 		Steven A. Carr, Broad Institute of MIT and Harvard, United States
Submitting User: clauser

Publications

Lo A, Holmes K, Kamlapurkar S, Mundt F, Moorthi S, Fung I, Fereshetian S, Watson J, Carr SA, Mertins P, Berger AH.
Multiomic characterization of oncogenic signaling mediated by wild-type and mutant RIT1.
Sci Signal. 2021 Nov 30;14(711):eabc4520. Epub 2021 Nov 30.

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