title: Akt-mediated phosphorylation of argonaute 2 downregulates cleavage and upregulates translational repression of MicroRNA targets.
abstract: 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.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Shane R
authors.initials: SR
authors.lastname: Horman
authors.forename: Maja M
authors.initials: MM
authors.lastname: Janas
authors.forename: Claudia
authors.initials: C
authors.lastname: Litterst
authors.forename: Bingbing
authors.initials: B
authors.lastname: Wang
authors.forename: Ian J
authors.initials: IJ
authors.lastname: MacRae
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Sever
authors.forename: David V
authors.initials: DV
authors.lastname: Morrissey
authors.forename: Paul
authors.initials: P
authors.lastname: Graves
authors.forename: Biao
authors.initials: B
authors.lastname: Luo
authors.forename: Shaikamjad
authors.initials: S
authors.lastname: Umesalma
authors.forename: Hank H
authors.initials: HH
authors.lastname: Qi
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Miraglia
authors.forename: Carl D
authors.initials: CD
authors.lastname: Novina
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Orth
mesh_terms: D060565:Argonaute Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D015536:Down-Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; C000715470:MAS1 protein, human; D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt