Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
Mol Cell. 2013 May 9;50(3):356-67. doi: 10.1016/j.molcel.2013.03.015. Epub 2013 Apr 18.
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.
高通量 RNA 干扰 (RNAi) 筛选针对人类激酶组中的 542 个基因,以发现 RNAi 的调节因子。在这里,我们报告原癌基因 Akt-3/PKBγ (Akt3) 在 S387 处磷酸化 Argonaute 2 (Ago2),这下调了内源性 microRNA (miRNA)-靶向信使 RNA (mRNA) 的切割,并上调了翻译抑制。我们进一步证明 Akt3 与 Ago2 共免疫沉淀,并且 Ago2 在 S387 处的磷酸化促进了其与 GW182 的相互作用,并定位到细胞质处理体 (P 体),miRNA 靶向的 mRNAs 被认为储存在那里并降解。因此,Akt3 介导的 Ago2 磷酸化是 Ago2 靶 mRNA 切割和翻译抑制活性之间的分子开关。