Sirt2 Deacetylase Is A Novel AKT Binding Partner Critical For AKT Activation By Insulin [Metabolism]

January 20th, 2014 by Ramakrishnan, G., Davaakhuu, G., Kaplun, L., Chung, W.-C., Rana, A., Atfi, A., Miele, L., Tzivion, G.

AKT/PKB kinases transmit insulin and growth factor signals downstream of phosphatidyl inositol-3 kinase (PI3K). AKT activation involves phosphorylation at two residues, T308 and S473, mediated by PDK1 and the mammalian target of rapamycin complex 2 (mTORC2), respectively. Impaired AKT activation is a key factor in metabolic disorders involving insulin resistance, while hyper-activation of AKT is linked to cancer pathogenesis. Here, we identify the cytoplasmic NAD+-dependent deacetylase, Sirt2, as a novel AKT interactor, required for optimal AKT activation. Pharmacological inhibition or genetic downregulation of Sirt2 diminished AKT activation in insulin and growth factor-responsive cells, while Sirt2 overexpression enhanced the activation of AKT and its downstream targets. AKT was pre-bound with Sirt2 in serum or glucose-deprived cells and the complex dissociated following insulin treatment. The binding was mediated by the pleckstrin-homology (PH) and the kinase domains of AKT and was dependent on AMP-activated kinase (AMPK). This regulation involved a novel AMPK-dependent Sirt2 phosphorylation at T101. In cells with constitutive PI3K activation, we found that AKT also associated with a nuclear sirtuin, Sirt1, however, inhibition of PI3K resulted in dissociation from Sirt1 and increased association with Sirt2. Sirt1 and Sirt2 inhibitors additively inhibited the constitutive AKT activity in these cells. Our results suggest potential usefulness of Sirt1 and Sirt2 inhibitors in the treatment of cancer cells with upregulated PI3K activity and of Sirt2 activators in the treatment of insulin-resistant metabolic disorders.