Abstract
Protein Phosphatase 2A (PP2A) is a major serine/threonine phosphatase in cells. It consists of a catalytic subunit (C), a structural subunit (A), and a regulatory/variable B-type subunit. PP2A has a critical role to play in homeostasis where its predominant function is as a phosphatase that regulates the major cell signaling pathways in cells. Changes in the assembly, activity and substrate specificity of the PP2A holoenzyme have a direct role in disease and are a major contributor to the maintenance of the transformed phenotype in cancer. We have learned a lot about how PP2A functions from specific mutations that disrupt the core assembly of PP2A and from viral proteins that target PP2A and inhibit its effect as a phosphatase. This prompted various studies revealing that restoration of PP2A activity benefits some cancer patients. However, our understanding of the mechanism of action of this is limited because of the complex nature of PP2A holoenzyme assembly and because it acts through a wide variety of signaling pathways. Information on PP2A is also conflicting as there are situations whereby inactivation of PP2A induces apoptosis in many cancer cells. In this review we discuss this relationship and we also address many of the pertinent and topical questions that relate to novel therapeutic strategies aimed at altering PP2A activity.
Highlights
Reversible phosphorylation is a very important mechanism of signal transduction in eukaryotic cells and is mediated by a series of kinases and phosphatases [1,2]
One pre-clinical study showed that oestrogen receptor negative (ER−) breast cancer cell lines were more sensitive to FTY720 than cells that express the oestrogen receptor (ER+) [101]
This is attributed to ER− breast cancer cell lines having suppressed levels of Phosphatase 2A (PP2A) activity in comparison to ER+ breast cancer cell lines having a higher sensitivity to a PP2A activator such as FTY720
Summary
Reversible phosphorylation is a very important mechanism of signal transduction in eukaryotic cells and is mediated by a series of kinases and phosphatases [1,2]. These kinases and phosphatases allow proteins to react rapidly to the external environment by tightly regulating the activity, location and substrate specificity of proteins. Protein Phosphatase 2A (PP2A) is a major serine/threonine phosphatase and is ubiquitously expressed in eukaryotic cells It is one of the most conserved proteins and together with PP1, is responsible for up to 90% of all serine/threonine activity in a cell [3,8,9]. PP2A functions in many of the major cell signaling pathways including those that regulate the cell cycle, cell metabolism, cell migration and cell survival [10,11,12,13]
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