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Review
. 2016 Mar;283(6):1004-24.
doi: 10.1111/febs.13573. Epub 2015 Nov 14.

All Roads Lead to PP2A: Exploiting the Therapeutic Potential of This Phosphatase

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Free PMC article
Review

All Roads Lead to PP2A: Exploiting the Therapeutic Potential of This Phosphatase

Jaya Sangodkar et al. FEBS J. .
Free PMC article

Abstract

Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase involved in the regulation of many cellular processes. A confirmed tumor suppressor protein, PP2A is genetically altered or functionally inactivated in many cancers highlighting a need for its therapeutic reactivation. In this review we discuss recent literature on PP2A: the elucidation of its structure and the functions of its subunits, and the identification of molecular lesions and post-translational modifications leading to its dysregulation in cancer. A final section will discuss the proteins and small molecules that modulate PP2A and how these might be used to target dysregulated forms of PP2A to treat cancers and other diseases.

Keywords: CIP2A; PP2A; SET; cancer; cancer biology; cell signaling; drug development; protein phosphatases; structural biology; tumor suppressors.

Figures

Figure 1
Figure 1
PP2A is a heterotrimeric complex consisting of a scaffolding subunit (A), a regulatory subunit (B), and a catalytic subunit (C). PP2A A subunit is composed of 15 tandem HEAT repeats in two isoforms α and β. PP2A C subunit also exists in two possible isoforms α and β. PP2A B subunit consists of four classes: B (B55/PR55), B′ (B56/PR61), B″(PR48/PR72/PR130) and B‴(PR93/PR110).
Figure 2
Figure 2
Structures of PP2A core enzyme and holoenzyme. (A) (PDB code: 2IE3) Core Enzyme consisting of Aα (in magenta) subunit and Cα (in yellow) subunit. The C subunit binds A at Heat Repeats 11–15. The active site of the C subunit consists of 2 manganese atoms and is positioned away from the ridge of the A subunit HEAT Repeats. Binding with the catalytic subunit shifts HEAT repeats 13–15 by 20–30 Å (B) (PDB code: 3DW8) Core Enzyme binding to B family subunit (in cyan), Bα/PR55α. Members of this subunit family bind the A subunit at two interfaces. The first is via a seven bladed propeller, composed of WD40 repeats. The bottom face of the propeller binds to A subunit HEAT domains 3–7. The second is through a β-hairpin handle that interacts with A subunit HEAT repeats 1 and 2. Upon binding to the holoenzyme, the B subunit substrate binding site lies on the top face proximal to the active site of the catalytic subunit. (C) (PDB code: 2IAE) Core enzyme binding to B′ family subunit (in cyan), Bγ1/PR61γ1. The B′ structures are similar to the A subunit, composed of 8 HEAT-like repeats. These interact with HEAT repeats 2–8 of the A subunit, and with the C subunit. Much like binding to B family subunits, the substrate binding site of B′ is proximal to the active site of the catalytic subunit upon holoenzyme formation. Binding to the B′ subunits forces the N-terminal repeat of the A subunit to twist 50–60 Å, rearranging the hydrophobic core of the scaffolding subunit. (D) (PDB code: 4I5L) Core Enzyme binding to B″ family subunit PR72 (in cyan). B″ subunits consist of a linear arrangement of different functional motifs that include an N-terminal hydrophobic motif and 2 EF hand calcium binding motifs. The N-terminal hydrophobic motif and one EF hand bind to the A subunit at HEAT repeats 1–7 and binds to the catalytic subunit via a helix on the subunit at residues 439–446 near the active site, positioning the substrate binding site near the active site. The resulting conformation of this holoenzyme is wider and taller than that which forms with B or B′ subunits.
Figure 3
Figure 3
(A) Pie chart of the frequency of PP2A mutations across 9,759 tumor samples. Mutational information was analyzed from Cbioportal.org, which includes 85 different sequencing studies, including TCGA data. Studies with targeted sequencing or expression only data were excluded from the total number. (B) Pie chart of the frequency of PP2A mutations divided by PP2A subunit families: A, B, B′, B″, and C. Bold black lines divide each subunit. Mutational information was analyzed from Cbioportal.org, which includes 85 different sequencing studies, including TCGA data. Studies with targeted sequencing or expression only data were excluded from the total number. The results shown here are in part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/.
Figure 4
Figure 4
(A) The C-terminus of the catalytic C subunit undergoes methylation at L309 via LCMT, a SAM-dependent methyltransferase. PME-1 mediates demethylation. (B) Decreased methylation at L309 and increased phosphorylation of Y307 and T304 of the catalytic C subunit are posttranslational modifications that inhibit PP2A.
Figure 5
Figure 5
(A) (PDB code: 3C5W) Structure of PP2A and PME-1 complex with scaffold subunit in magenta, catalytic subunit in yellow, and PME-1 in red. (B) (PDB code: 3P71) Structure of PP2A and LCMT complex with catalytic subunit in yellow and LCMT in green (C) (PDB code: 4LAC) Structure of PP2A and PTPA complex with scaffold subunit in magenta, catalytic subunit in yellow, and PTPA in orange.
Figure 6
Figure 6
Activators of PP2A. Several strategies to activate PP2A include: decreasing PP2A Y307 phosphorylation, inhibiting endogenous inhibitors (SET and CIP2A), inhibiting PME-1, and using promethylating agents.

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