Journal
CELL REPORTS
Volume 14, Issue 6, Pages 1448-1461Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.01.034
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Funding
- IFOM Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy (sponsor: Fabrizio D'Adda di Fagagna)
- Prostate Cancer Foundation Young Investigator Award
- Howard Hughes Medical Institute (HHMI) Medical Student Research Fellowship
- Damon Runyon Foundation Fellowship
- Alfred A. Taubman Institute
- HHMI
- NIH grants [NIH 1R21 AI109791, RO1 CA154365, R37 CA40046]
- Prostate Cancer Foundation
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Oncogenic 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 KRASdependent cells and AGO2 overexpression enhances KRAS G12V -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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