Regulationofthephosphoproteinphosphatase2Asystemanditsmodulationduringoxidativestress:Apotentialtherapeutictarget?I.S.Elgenaidi,J.P.Spiers⁎DepartmentofPharmacologyandTherapeutics,TrinityCollegeDublin,IrelandabstractarticleinfoPhosphoproteinphosphatasesareofgrowinginterestinthepathophysiologyofmanydiseasesandareoftentheneglectedpartnerofproteinkinases.Onefamilymember,PP2A,accountsfordephosphorylationof~55-70%ofallserine/threoninephosphosites.Interestingly,dysregulationofkinasesignallingisahallmarkofmanydiseasesinwhichanincreaseinoxidativestressisalsonoted.Withthisinmind,weassesstheevidencetosupportoxidativestress-mediatedregulationofthePP2AsystemInthisarticle,wefirstpresentanoverviewofthePP2AsystembeforeprovidingananalysisoftheregulationofPP2Abyendogenousinhibitors,posttranslationalmodification,andmiRNA.Next,adetailedcritiqueofdataimplicatingreactiveoxygenspecies,ischaemia,ischaemia-reperfusion,andhypoxiainregulatingthePP2Aholoenzymeandassociatedregulatorsispresented.Finally,thepharmacologicaltargetingofPP2A,itsendoge-nousinhibitors,andenzymesresponsibleforitspost-translationalmodificationarecovered.ThereisextensiveevidencethatoxidativestressmodulatesmultiplecomponentsofthePP2Asystem,however,mostofthedatapertainstothecatalyticsubunitofPP2A.Irrespectiveoftheunderlyingaetiology,freeradical-mediatedattenuationofPP2Aactivityisanemergingtheme.However,inmanyinstances,adichotomyexists,whichrequiresclarificationandmechanisticinsight.Nevertheless,thisraisesthepossibilitythatpharmacologicalactivationofPP2A,eitherthroughsmallmoleculeactivatorsofPP2AorCIP2A/SETantagonistsmaybebeneficialinmodulatingthecellularresponsetooxidativestress.Abetterunderstandingofwhich,willhavewiderangingimplicationsforcancer,heartdiseaseandinflammatoryconditions.©2019ElsevierInc.Allrightsreserved.Keywords::IschaemiaPP2AHIF1αCIP2ASMAPshypoxiamiRNAContents1.Introduction...............................................692.ThePP2Aholoenzyme..........................................693.RegulationofPP2Ac...
