| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 2039251 | Cell Reports | 2016 | 14 Pages |
•RAS interacts with AGO2 in the membrane component of the endoplasmic reticulum•The N terminus of AGO2 directly binds the Switch II domain of RAS•Oncogenic KRAS association inhibits AGO2-mediated microRNA duplex unwinding•AGO2 interaction elevates oncogenic KRAS levels to enhance cellular transformation
SummaryOncogenic mutations in RAS provide a compelling yet intractable therapeutic target. Using co-immunoprecipitation mass spectrometry, we uncovered an interaction between RAS and Argonaute 2 (AGO2). Endogenously, RAS and AGO2 co-sediment and co-localize in the endoplasmic reticulum. The AGO2 N-terminal domain directly binds the Switch II region of KRAS, agnostic of nucleotide (GDP/GTP) binding. Functionally, AGO2 knockdown attenuates cell proliferation in mutant KRAS-dependent cells and AGO2 overexpression enhances KRASG12V-mediated transformation. Using AGO2−/− cells, we demonstrate that the RAS-AGO2 interaction is required for maximal mutant KRAS expression and cellular transformation. Mechanistically, oncogenic KRAS attenuates AGO2-mediated gene silencing. Overall, the functional interaction with AGO2 extends KRAS function beyond its canonical role in signaling.
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