A tumor suppressor role for PP2A-B56alpha through negative regulation of c-Myc and other key oncoproteins

Abstract

Loss or inhibition of the serine/threonine protein phosphatase 2A (PP2A) has revealed a critical tumor suppressor function for PP2A. However, PP2A has also been shown to have important roles in cell cycle progression and survival. Therefore, PP2A is not a typical tumor suppressor. This is most likely due to the fact that PP2A represents a large number of different holoenzymes. Further understanding of PP2A function(s), and especially its tumor suppressor activity, will depend largely on our ability to determine specific targets for these different PP2A holoenzymes and to gain an understanding of how these targets confer tumor suppressor activity or contribute to cell cycle progression and cell survival. Recent work has identified c-Myc as a target of the PP2A holoenzyme, PP2A-B56alpha. This holoenzyme also negatively regulates beta-catenin expression and modulates the anti-apoptotic activity of Bcl2, thus characterizing PP2A-B56alpha as a tumor suppressor PP2A holoenzyme. This review will focus on the role of PP2A-B56alpha in regulating c-Myc and will place this tumor suppressor activity of PP2A within the context of its other tumor suppressor functions. Finally, the mechanism(s) through which PP2A-B56alpha tumor suppressor activity may be lost in cancer will be discussed.

Fig. 1

Schematic of heterotrimeric PP2A holoenzyme, which is comprised of a structural A subunit, catalytic C subunit and a variable regulatory B subunit from one of four families of regulatory B subunits. The B56/PPP2R5 family of regulatory B subunits are encoded by five genes and the γ and δ genes encode several splice variants. A Subunit Binding Domain 1 and 2 (ASBD1 and 2) are regions of higher amino acid sequence homology that facilitate the association of the B subunits with the A subunit. Known targets of specific B56 family members are shown with indication of suppression or activation by a particular PP2A-B56 holoenzyme

Fig. 2

(a) Schematic showing the sequential reversible phosphorylation pathway that regulates c-Myc protein stability and turnover via the 26S proteosome. Several of the proteins involved in this pathway are coordinated into a degradation complex for c-Myc by the scaffold protein Axin1. (b) Schematic of complexes that PP2A-B56α has been shown to be a part of

Fig. 3

Schematic of known B56α targets and target sequences if available. Also shown is the transcriptional cross-talk connection between known B56α targets and the biological function of these targets

Fig. 4

Schematic representations of mechanism through which B56α function could be lost