Regulation of the phosphoprotein phosphatase 2A system and its modulation during oxidative stress: A potential therapeutic target?

Abstract

Phosphoprotein phosphatases are of growing interest in the pathophysiology of many diseases and are often the neglected partner of protein kinases. One family member, PP2A, accounts for dephosphorylation of ~55-70% of all serine/threonine phosphosites. Interestingly, dysregulation of kinase signalling is a hallmark of many diseases in which an increase in oxidative stress is also noted. With this in mind, we assess the evidence to support oxidative stress-mediated regulation of the PP2A system In this article, we first present an overview of the PP2A system before providing an analysis of the regulation of PP2A by endogenous inhibitors, post translational modification, and miRNA. Next, a detailed critique of data implicating reactive oxygen species, ischaemia, ischaemia-reperfusion, and hypoxia in regulating the PP2A holoenzyme and associated regulators is presented. Finally, the pharmacological targeting of PP2A, its endogenous inhibitors, and enzymes responsible for its post-translational modification are covered. There is extensive evidence that oxidative stress modulates multiple components of the PP2A system, however, most of the data pertains to the catalytic subunit of PP2A. Irrespective of the underlying aetiology, free radical-mediated attenuation of PP2A activity is an emerging theme. However, in many instances, a dichotomy exists, which requires clarification and mechanistic insight. Nevertheless, this raises the possibility that pharmacological activation of PP2A, either through small molecule activators of PP2A or CIP2A/SET antagonists may be beneficial in modulating the cellular response to oxidative stress. A better understanding of which, will have wide ranging implications for cancer, heart disease and inflammatory conditions.