Therapeutic targeting of PP2A

Abstract

Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase that regulates many cellular processes. Given the central role of PP2A in regulating diverse biological functions and its dysregulation in many diseases, including cancer, PP2A directed therapeutics have become of great interest. The main approaches leveraged thus far can be categorized as follows: 1) inhibiting endogenous inhibitors of PP2A, 2) targeted disruption of post translational modifications on PP2A subunits, or 3) direct targeting of PP2A. Additional insight into the structural, molecular, and biological framework driving the efficacy of these therapeutic strategies will provide a foundation for the refinement and development of novel and clinically tractable PP2A targeted therapies.

Keywords: ABL-127; Bortezomib; CIP2A; Cancer; Celastrol; Cell signaling; Drug development; Erlotinib; FTY720; LB-100; LCMT-1; OP449; PME-1; PP2A; Phenothiazines; Protein phosphatase 2A; Protein phosphatases; SET; SMAPs; Tumor suppressors.

Figure 1. Structure of protein phosphatase 2A (PP2A)

The Protein Phosphatase 2A (PP2A) holoenzyme is composed of three subunits. A) The scaffolding subunit A (left) exists in two isoforms, Aα and Aβ, and are encoded by separate genes. The A subunit binds both the B and C subunits through its flexible 15 consecutive HEAT-repeat helical structure (PDB code: 2IAE). The catalytic subunit C (right) also exists in two isoforms, Cα and Cβ, and are encoded by separate genes. Both of the isoforms of the C subunit contain conserved C - terminal domain that undergoes post-translational modification as a regulatory mechanism (PDB code: 2IAE). B) The regulatory subunits consist of 4 unique classes of proteins: B (PDB code: 3DW8), B’ (PDB code: 2IAE), B”(PDB code: 4I5L), and B”’, which have not been crystallized. Within each class, multiple isoforms exist and each isoform is encoded by a separate gene. C) The core enzyme structure (left) consists of Aα subunit (blue) and Cα subunit (pink) (PDB code: 2IE3). One of the solved PP2A holoenzyme structures (right) with Aα (in blue) subunit, B’ subunit (in yellow), and Cα (in pink) subunit (PDB code: 2IAE).

Figure 2. Endogenous Regulation of PP2A

A) Endogenous inhibitors of PP2A (Red) have evolved to target the PP2A holoenzyme (PDB code: 2IAE). Endogenous activators, such as ceramide (green), counteract some of the endogenous inhibitors. B) LCMT1 (in green) utilizes S-adenosylmethionine (SAM) as a substrate to transfer a methyl group onto the terminal carboxyl group of the L309 residue of C subunit (in pink). PDB code: 3P71. PME-1 (in red) regulates PP2A activity by demethylating the PP2A-C subunit (PP2A A subunit shown in blue). PDB code: 3C5W.

Figure 3. Exogenous PP2A modulators

A) Several groups have developed ways to target PP2A indirectly by binding and inhibiting SET and CIP2A (blue). An additional group of drugs function through the transcriptional down-regulation of CIP2A (left). B) Compounds, such as ABL-127, have been developed to inhibit PME-1 methylesterase activity. Inhibition of PME-1 using this strategy results in an increase or stabilization of L309 methylation levels on the PP2AC subunit. C) Two classes of molecules have been shown to directly bind to PP2A. The first class, SMAPs and perphenazine, bind the A subunit and activate the phosphatase. The second class, LB-100 binds to the C subunit and inhibits PP2A catalytic activity. Additional molecules are thought to modulate PP2A activity through unknown or indirect mechanisms.