PP2A: The Wolf in Sheep’s Clothing?

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.

Regulation of β-Catenin Phosphorylation by PR55β in Adenoid Cystic Carcinoma

“…Cancer cells are generally characterized by constitutive phosphorylation, and many phosphatases, including PP2A, have been found to act as tumor suppressors (12,13). However, in this report, we have presented data indicating a tumor-promoting role of PR55β, one of the regulatory subunits of PP2A.…”

RACK1 stabilises the activity of PP2A to regulate the transformed phenotype in mammary epithelial cells

“…Inhibition of PP2A has already been the subject of many investigations as a therapeutic strategy in cancer in recent years (reviewed in [23]. Indeed, two PP2A-inhibitory compounds, LB-100 and LB-102 (from Lixte Biotechnology, Inc.), are now showing promise as chemotherapy drug sensitizers.…”

“…It is largely recognised as a tumour suppressor and has been found to be mutated in many cancer types [27,[32][33][34]. However, inhibition of PP2A has shown potential as an anti-cancer strategy in some cell models [23,[35][36][37][38]. This apparent contradiction may arise, in part, because PP2A inhibition increases tumour chemo-sensitivity to many chemotherapeutic drugs (reviewed in [39]) but also because PP2A has been shown to play an anti-apoptotic role within signalling pathways (reviewed in [23]).…”

“…Once assembled, the structural subunit (A) and catalytic subunit (C) form the core dimer while the regulatory subunit (B) confers substrate specificity, full activity and subcellular location of the PP2A holoenyme when bound to the core dimer. There are two A isoforms (α and β) which share 87% sequence homology and two C subunits (α and β) which share 97% homology [21][22][23].…”

The protein phosphatase 4 - PEA15 axis regulates the survival of breast cancer cells

“…This is despite the tumour suppressor function of protein phosphatase 2A (PP2A), a major serine/threonine phosphatase, having been clearly demonstrated in breast, gastric and ovarian cancer cells [6].…”