| Literature DB >> 26854235 |
Sunita Shankar1, Sethuramasundaram Pitchiaya2, Rohit Malik1, Vishal Kothari1, Yasuyuki Hosono1, Anastasia K Yocum1, Harika Gundlapalli1, Yasmine White3, Ari Firestone3, Xuhong Cao4, Saravana M Dhanasekaran1, Jeanne A Stuckey5, Gideon Bollag6, Kevin Shannon3, Nils G Walter7, Chandan Kumar-Sinha1, Arul M Chinnaiyan8.
Abstract
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 KRAS-dependent 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.Entities:
Keywords: Argonaute 2; EIF2C2; KRAS; RNA silencing; cancer
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Year: 2016 PMID： 26854235 PMCID： PMC4758864 DOI： 10.1016/j.celrep.2016.01.034
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423