Akt-Mediated Phosphorylation of Argonaute 2 Downregulates Cleavage and Upregulates Translational Repression of MicroRNA Targets

• DOI: 10.1016/j.molcel.2013.03.015
• Publication Date: 2013-04-18T16:38:59Z
• Authors: Shane R. Horman; Maja M. Janas; Claudia Litterst; Bingbing Wang; Ian J. MacRae; Mary J. Sever; David V. Morrissey; Paul Graves; Biao Luo; Shaikamjad Umesalma; Hank H. Qi; Loren J. Miraglia; Carl D. Novina; Anthony P. Orth
• Keywords: 0301 basic medicine; 0303 health sciences; Down-Regulation; Cell Biology; Proto-Oncogene Mas; Cell Line; Up-Regulation; MicroRNAs; 03 medical and health sciences; HEK293 Cells; Cell Line, Tumor; Argonaute Proteins; Humans; Phosphorylation; Molecular Biology; Proto-Oncogene Proteins c-akt; HeLa Cells

A high-throughput RNA interference (RNAi) screen targeting 542 genes of the human kinome was used to discover regulators of RNAi. Here we report that the proto-oncogene Akt-3/PKBγ (Akt3) phosphorylates Argonaute 2 (Ago2) at S387, which downregulates cleavage and upregulates translational repression of endogenous microRNA (miRNA)-targeted messenger RNAs (mRNAs). We further demonstrate that Akt3 coimmunoprecipitates with Ago2 and phosphorylation of Ago2 at S387 facilitates its interaction with GW182 and localization to cytoplasmic processing bodies (P bodies), where miRNA-targeted mRNAs are thought to be stored and degraded. Therefore, Akt3-mediated phosphorylation of Ago2 is a molecular switch between target mRNA cleavage and translational repression activities of Ago2.