Protein phosphatase 2A as a therapeutic target in inflammation and neurodegeneration

Abstract

Protein phosphatase 2A (PP2A) is a highly complex heterotrimeric enzyme that catalyzes the selective removal of phosphate groups from protein serine and threonine residues. Emerging evidence suggests that it functions as a tumor suppressor by constraining phosphorylation-dependent signalling pathways that regulate cellular transformation and metastasis. Therefore, PP2A-activating drugs (PADs) are being actively sought and investigated as potential novel anti-cancer treatments. Here we explore the concept that PP2A also constrains inflammatory responses through its inhibitory effects on various signalling pathways, suggesting that PADs may be effective in the treatment of inflammation-mediated pathologies.

Keywords: Alzheimer’s disease; Cancer; Inflammation; Multiple sclerosis; Neurodegeneration; Protein phosphatase 2A.

Fig. 1

Composition of the PP2A holoenzyme. Systematic names are indicated for scaffolding (A), regulatory (B) and catalytic (C) protein subunits. Alternative names are indicated in Table 1.

Fig. 2

Sphingolipid metabolism. Representative structures of lipid compounds are illustrated. For comparison, structures of FTY-720 and phospho-FTY-720 are also shown.

Fig. 3

Therapeutic targeting of PP2A. Various compounds reported to activate PP2A are shown, with licensed drugs boxed. A) FTY720 and derived compounds; B) Metformin; C) the anti-psychotic phenothiazine chlorpromazine and daughter compound DBK-1154; D) compounds reported to promote alkylation of PPP2CA; E) β-adrenergic receptor agonists; F) caffeine-related compounds theophylline and EHT, and the PME-1 inhibitor compound 28.

Fig. 4

Sites of action of PP2A in Toll-like receptor 4- (TLR4-) mediated signaling. TLR4 regulates gene expression via the assembly of large signaling complexes and the activation of various phosphorylation-mediated signaling cascades, which are shown here in cartoon form. Signals via TRAM and TRIF to IRF3 originate from an endosomal compartment, which for reasons of simplicity is not indicated here. Black symbols represent protein dephosphorylation by PP2A. Grey circles represent linear or K63-linked poly-ubiquitin chains. AP-1, activator protein 1; IκBα, α inhibitor of NF-κB; IKK, IκBα kinase; IRF, interferon-regulatory factor; JNK, cJun N-terminal kinase; LUBAC, linear ubiquitin chain assembly complex; MAPK, mitogen-activated protein kinase; MK2, MAPK-activated kinase 2; MKK, MAPK kinase; MyD88, myeloid differentiation factor 88; NF-κB, nuclear factor κ enhancer of activated B cells; TAB, TAK1 binding protein; TAK1, transforming growth factor β-activated kinase; TIRAP, Toll/interleukin 1 receptor domain-containing adaptor protein; TLR, Toll-like receptor; TRAF, TNF receptor interacting factor; TRAM, Toll/interleukin 1 receptor domain-containing adaptor molecule; TRIF, Toll/interleukin 1 receptor domain-containing adaptor inducing interferon β; TTP, tristetraprolin.