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Multiple Site Acetylation of Rictor Stimulates Mammalian Target of Rapamycin Complex 2 (mTORC2)-dependent Phosphorylation of Akt Protein

J. Biol. Chem., 2 January 2012
Vol. 287, Issue 1, p. 581-588
DOI: 10.1074/jbc.M111.304337

Multiple Site Acetylation of Rictor Stimulates Mammalian Target of Rapamycin Complex 2 (mTORC2)-dependent Phosphorylation of Akt Protein

  1. Emily J. Glidden,
  2. Lisa G. Gray,
  3. Suneil Vemuru,
  4. Duo Li,
  5. Thurl E. Harris§ and
  6. Marty W. Mayo,1
  1. From the Departments of Biochemistry and Molecular Genetics and
  2. §Pharmacology, University of Virginia, Charlottesville, Virginia 22908
  1. 1 Supported by the University of Virginia Tobacco Research Program, a gift of Philip Morris USA. To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Genetics, Box 800733, Jordan Hall, Rm. 6233, University of Virginia, Charlottesville, VA 22908. Tel.: 1-434-924-2509; Fax: 1-434-924-5069; E-mail: mwm3y{at}virginia.edu.

Background: Rictor is an essential component of the mammalian target of rapamycin complex 2 (mTORC2).

Results: Rictor contains two central regions that (i) bind mSin1 and LST8 and (ii) function in multisite acetylation.

Conclusion: Rictor acetylation is a post-translational modification that potentiates mTORC2 activity.

Significance: Understanding the molecular mechanisms by which acetylation potentiates mTORC2 activity links nutrient signaling with critical metabolic kinases.

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.

  • Metabolism
  • mTOR Complex (mTORC)
  • Protein Acylation
  • Signal Transduction
  • Akt
  • Mammalian Target of Rapamycin Complex 2
  • Protein Acetylation
  • Rictor
  • Sirtuin

Footnotes

  • * This work was supported, in whole or in part, by National Institutes of Health Grants CA132580 and CA104397 through the NCI (to M. W. M.) and Grant DK052753 through the NIDDK (to T. E. H.).

  • Embedded Image This article contains supplemental Figs. 1 and 2.

  • Received September 14, 2011.
  • Revision received October 31, 2011.

Citation:

E. J. Glidden, L. G. Gray, S. Vemuru, D. Li, T. E. Harris, and M. W. Mayo, Multiple Site Acetylation of Rictor Stimulates Mammalian Target of Rapamycin Complex 2 (mTORC2)-dependent Phosphorylation of Akt Protein. J. Biol. Chem. 287, 581-588 (2012).

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