Cell Biology

Rictor Acetylation and Akt

Science Signaling  10 Jan 2012:
Vol. 5, Issue 206, pp. ec15
DOI: 10.1126/scisignal.2002832

Stimulation of cells by growth factors, such as insulin-like growth factor 1 (IGF-1), results in the phosphorylation and activation of the serine and threonine kinase Akt, which is required for cell survival and proliferation. The activation of Akt occurs through phosphorylation of two residues: Thr308, which is phosphorylated by the kinase PDK1, and Ser473, which is targeted by the mammalian target of rapamycin (mTOR) complex 2 (mTORC2). Glidden et al. investigated how the posttranslational modification of mTORC2 by acetylation affected its activity. They found that the mTORC2 adaptor protein rictor, but not other mTORC2 components, was acetylated by p300 in HeLa cells stimulated with IGF-1. Inhibitor studies showed that rictor was targeted by multiple histone deacetylases (HDACs), including those activated during nutrient depletion, such as SIRT1. Increasing the abundance of mTORC2 components in transfected cells enhanced the extent of rictor acetylation compared with that in control cells, and rictor acetylation correlated with increased mTORC2 activity in IGF-1–stimulated cells, as demonstrated by the increased abundance of Akt phosphorylated at Ser473. Experiments with various deletion mutants of rictor showed that it contained two functional regions that were required for mTORC2 activity. The first was required for the interaction between rictor and the mTORC2 components LST8 and mSin1.1, whereas the second region contained multiple lysine residues that were targeted for acetylation. In vitro kinase assays showed that deletion of the lysine-rich region of rictor resulted in decreased mTORC2 activity without compromising the ability of rictor to interact with mSin1.1 and LST8. Together, these data suggest that the activity of mTORC2 is increased by the acetylation of rictor, which can be reversed, in part, by nutrient-responsive HDACs.

E. J. Glidden, L. G. Gray, S. Vemuru, D. Li, T. E. Harris, 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). [Abstract] [Full Text]