Multiomic characterization of oncogenic signaling mediated by wild-type and mutant RIT1.

Szczegóły
Abstrakt

Tytuł:: Multiomic characterization of oncogenic signaling mediated by wild-type and mutant RIT1.
Autorzy:: Lo A; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Holmes K; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Kamlapurkar S; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Mundt F; Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Department of Oncology-Pathology, Karolinska Institute, 171 77 Stockholm, Sweden.
Moorthi S; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Fung I; Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Fereshetian S; Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Watson J; Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Carr SA; Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Mertins P; Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Berger AH; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Źródło:: Science signaling [Sci Signal] 2021 Nov 30; Vol. 14 (711), pp. eabc4520. Date of Electronic Publication: 2021 Nov 30.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.
Język:: English
Imprint Name(s):: Original Publication: Washington, D.C. : American Association for the Advancement of Science
MeSH Terms:: Oncogenes*
Signal Transduction*
ras Proteins*/genetics
HEK293 Cells ; Humans
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Grant Information:: R37 CA252050 United States CA NCI NIH HHS; K99 CA197762 United States CA NCI NIH HHS; P30 CA015704 United States CA NCI NIH HHS; U24 CA210986 United States CA NCI NIH HHS; R00 CA197762 United States CA NCI NIH HHS; T32 GM007270 United States GM NIGMS NIH HHS; U01 CA214125 United States CA NCI NIH HHS; P50 CA228944 United States CA NCI NIH HHS
Substance Nomenclature:: EC 3.6.1.- (RIT1 protein, human)
EC 3.6.5.2 (ras Proteins)
Entry Date(s):: Date Created: 20211130 Date Completed: 20220117 Latest Revision: 20230922
Update Code:: 20240105
PubMed Central ID:: PMC8848860
DOI:: 10.1126/scisignal.abc4520
PMID:: 34846918
: Czasopismo naukowe

Aberrant activation of the RAS family of guanosine triphosphatases (GTPases) is prevalent in lung adenocarcinoma, with somatic mutation of KRAS 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 RIT1 in lung and other cancers may be tumorigenic.

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