Multiomic characterization of oncogenic signaling mediated by wild-type and mutant RIT1
| Autor: | Filip Mundt, Jacqueline Watson, Steven A. Carr, Sitapriya Moorthi, April Lo, Iris Fung, Shriya Kamlapurkar, Kristin D. Holmes, Alice H. Berger, Shaunt Fereshetian, Philipp Mertins |
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| Rok vydání: | 2021 |
| Předmět: |
Mutant
Guanosine GTPase Biology medicine.disease_cause Biochemistry Article chemistry.chemical_compound Germline mutation Oncogenic signaling medicine Humans Molecular Biology Wild type Oncogenes Cell Biology medicine.disease digestive system diseases respiratory tract diseases HEK293 Cells chemistry ras Proteins Cancer research Adenocarcinoma KRAS Signal Transduction |
| Zdroj: | Sci Signal |
| ISSN: | 1937-9145 1945-0877 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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