Redox control of cytosolic Akt phosphorylation in PTEN null cells

Abstract

This article demonstrates a role for intracellular reactive oxygen species in the hyperphosphorylation of Akt in cells that have lost the expression of the tumor suppressor PTEN. Using mouse embryonic fibroblasts in which the expression of PTEN was knocked out, we show that a decrease in intracellular superoxide anion resulted in a rapid dephosphorylation of Akt at Thr308 followed by Ser473. Whereas dephosphorylation was detected in the cytosolic pool of Akt, phosphorylation of the membrane pool of the kinase remained unaffected. Dephosphorylation of cytosolic Akt was attributed to an increase in the interaction between Akt and the catalytic subunit of the protein phosphatase PP2A, which correlated with an increase in the amount of the oxidized versus the reduced form of the kinase. These results were corroborated in the PTEN knockout prostate cancer cell line LNCaP and in the melanoma cell line M14 stably transfected with a constitutively active form of Rac1. © 2012 Elsevier Inc. All rights reserved.