title: Multiple site acetylation of Rictor stimulates mammalian target of rapamycin complex 2 (mTORC2)-dependent phosphorylation of Akt protein.
abstract: The serine/threonine protein kinase Akt is a critical regulator of cell growth and survival in response to growth factors. A key step in Akt activation is phosphorylation at Ser-473 by the mammalian target of rapamycin (mTOR) complex 2 (mTORC2). Although Rictor is required for the stability and activity of mTORC2, little is known about functional regions or post-translational modifications within Rictor that are responsible for regulating mTORC2. Here, we demonstrate that Rictor contains two distinct central regions critical for mTORC2 function. One we refer to as the stability region because it is critical for interaction with Sin1.1 and LST8, and a second adjacent region is required for multisite acetylation. p300-mediated acetylation of Rictor increases mTORC2 activity toward Akt, whereas site-directed mutants within the acetylation region of Rictor exhibit reduced insulin-like growth factor 1 (IGF-1)-stimulated mTORC2 kinase activity. Inhibition of deacetylases, including the NAD+-dependent sirtuins, promotes Rictor acetylation and IGF-1-mediated Akt phosphorylation. These results suggest that multiple-site acetylation of Rictor signals for increased activation of mTORC2, providing a critical link between nutrient-sensitive deacetylases and mTORC2 signaling to Akt.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, 22908.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Glidden
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, 22908.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Gray
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, 22908.
authors.forename: Suneil
authors.initials: S
authors.lastname: Vemuru
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, 22908.
authors.forename: Duo
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908.
authors.forename: Thurl E
authors.initials: TE
authors.lastname: Harris
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, 22908. Electronic address: mwm3y@virginia.edu.
authors.forename: Marty W
authors.initials: MW
authors.lastname: Mayo
mesh_terms: D000107:Acetylation; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010766:Phosphorylation; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D012694:Serine / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D002352:Carrier Proteins; C492571:RICTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D012694:Serine; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
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