University of Birmingham Protein phosphatase 2A as a therapeutic target in inflammation and neurodegeneration Clark, Andrew R.; Ohlmeyer, Michael DOI: 10.1016/j.pharmthera.2019.05.016 License: Creative Commons: Attribution (CC BY) Document Version Publisher's PDF, also known as Version of record Citation for published version (Harvard): Clark, AR & Ohlmeyer, M 2019, 'Protein phosphatase 2A as a therapeutic target in inflammation and neurodegeneration', Pharmacology & Therapeutics, vol. 201, pp. 181-201. https://doi.org/10.1016/j.pharmthera.2019.05.016 Link to publication on Research at Birmingham portal General rights Unless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or the copyright holders. 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Clark a,⁎, Michael Ohlmeyer b a Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom b Atux Iskay LLC, Plainsboro, NJ, USA article info abstract Available online 1 June 2019 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 Keywords: tumor suppressor by constraining phosphorylation-dependent signalling pathways that regulate cellular trans- Protein phosphatase 2A formation and metastasis. Therefore, PP2A-activating drugs (PADs) are being actively sought and investigated fl In ammation as potential novel anti-cancer treatments. Here we explore the concept that PP2A also constrains inflammatory Cancer responses through its inhibitory effects on various signalling pathways, suggesting that PADs may be effective in Neurodegeneration the treatment of inflammation-mediated pathologies. Alzheimer’sdisease Multiple sclerosis © 2019 Published by Elsevier Inc. Contents 1. Introduction............................................... 181 2. TheregulationofPP2Afunction...................................... 182 3. PP2Aandcancer............................................. 184 4. Involvement of PP2A in the control of inflammation............................. 186 5. Neuro-inflammationandneuro-degeneration............................... 190 6. Remainingquestions........................................... 192 7. Conclusion............................................... 193 Conflictofintereststatement......................................... 193 Acknowledgements.............................................. 193 References.................................................. 193 1. Introduction translational odification alters the charge, local shape and global confor- mation of substrate proteins, influencing their interactions with other Protein phosphorylation, the reversible, covalent addition of phos- molecules, and modulating their subcellular localization, stability or phate groups to serine, threonine or tyrosine residues, is a rapid and function. The human genome encodes more than 500 kinases that cata- efficient mechanism for modulating protein function. This post- lyze protein phosphorylation, and fewer than 200 protein phosphatases Abbreviations: AD, Alzheimer’s disease; AP-1, activator protein 1; BBB, blood-brain barrier; CCR4/NOT, carbon catabolite repressor 4/never on TATA-less; CIP2A, cancerous inhibitor of PP2A; CNS, central nervous system; DC, dendritic cell; EAE, experimental autoimmune encephalopathy; HEAT, Huntingtin - Elongation factor - A subunit of PP2A - Target of rapamycin domain; IκBα, α inhibitor of NF-κB; IKK, IκBα kinase; IL, interleukin; IRF, interferon-regulatory factor; JNK, cJun N-terminal kinase; LCMT-1, leucine carboxymethyl transferase 1; LUBAC, linear ubiquitin chain assembly complex; MAPK, mitogen-activated protein kinase; MK2, MAPK-activated kinase 2; MKK, MAPK kinase; MS, multiple sclerosis; MyD88, myeloid differentiation factor 88; NF-κB, nuclear factor κ enhancer of activated B cells; NFT, neurofibrillary tangles; PAD, PP2A-activating drug; PAMP, pathogen-associated molecular pattern; PME- 1, protein phosphatase methylesterase 1; PP2A, protein phosphatase 2A; PRR, pattern recognition receptor; ROS, reactive oxygen species; S1P, sphingosine-1-phosphate; S1PR, S1P recep- tor; SphK, sphingosine kinase; STRN, striatin; TAB, TAK1 binding protein; TAK1, transforming growth factor β-activated kinase; TGFβ, transforming growth factor β; TIRAP, Toll/interleukin 1 receptor domain-containing adaptor protein; TLR, Toll-like receptor; TNF, tumor necrosis factor; 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; UVB, ultraviolet B. ⁎ Corresponding author. E-mail address: [email protected] (A.R. Clark). https://doi.org/10.1016/j.pharmthera.2019.05.016 0163-7258/© 2019 Published by Elsevier Inc. 182 A.R. Clark, M. Ohlmeyer / Pharmacology & Therapeutics 201 (2019) 181–201 that catalyze the reverse reaction. However, these numbers may be mis- leading. In some cases substrate specificity can be conferred by regula- tory subunits distinct from the proteins that possess catalytic activity. Duplication and evolutionary diversification of regulatory subunits can therefore greatly expand the functional roles of kinases or phosphatases without a parallel increase in the number of kinase- and phosphatase- encoding genes. Such diversification appears to have been particularly important in the evolution of protein phosphatase(s) 2A (PP2A), the Fig. 1. Composition of the PP2A holoenzyme. Systematic names are indicated for subject of this review. scaffolding (A), regulatory (B) and catalytic (C) protein subunits. Alternative names are Since protein phosphorylation has profound effects on every aspect indicated in Table 1. of cell biology, precise balance between the activities of kinases and phosphatases is required for the proper regulation of cell function. Strik- this review we will adhere to the systematic names for B subunits. Alter- ingly, such balance is not seen in scientific literature, where published native names are listed in Table 1. articles with “kinase” outnumber those with “phosphatase” in their PP2A profoundly influences all aspects of cell biology, therefore its titles by a factor of almost ten to one. There are several possible explana- function is tightly regulated at several levels. As reviewed extensively tions for such bias. By definition phosphorylation is an energy- elsewhere (Janssens, Longin, & Goris, 2008; Sents, Ivanova, Lambrecht, dependent process requiring the consumption of ATP. For reasons of Haesen, & Janssens, 2013), assembly of holoenzymes is strictly con- energy economy, evolution may have favored use of protein phosphor- trolled to prevent the formation of catalytically active complexes lack- ylation as a means of response to perturbation, and dephosphorylation ing correct substrate specificity. Unpartnered catalytic subunits are as a means of restoring or maintaining equilibrium. This generalization subject to ubiquitination and proteasomal degradation. The protein α4 seems broadly true, although many readers will readily think of excep- (otherwise known as Immunoglobulin Binding Protein 1 or IGBP1) tions. In this perspective, phosphatase activity may be seen as rather both stabilizes and inactivates free C subunits, thereby regulating their non-specific, unregulated, and consequently not very interesting as a availability for assembly into holoenzymes (Kong, Ditsworth, Lindsten, subject of study. Recent advances suggest that these are all misconcep- & Thompson, 2009). The ATP-dependent chaperone phosphotyrosyl tions. Inhibition of kinases to prevent harmful cell activation is more phosphatase activator (encoded by PPP2R4) is required for correct fold- conceptually and practically straightforward than stimulation of phos- ing of the catalytic subunit and incorporation of manganese ions at the phatases to promote restoration of homeostasis.