کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2039251 | 1073039 | 2016 | 14 صفحه PDF | دانلود رایگان |
• 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.
Graphical AbstractFigure optionsDownload as PowerPoint slide
Journal: - Volume 14, Issue 6, 16 February 2016, Pages 1448–1461