Reciprocal regulation of ARPP-16 by PKA and MAST-3 kinases provides a cAMP-regulated switch in protein phosphatase 2A inhibition.[2017][Elife][10.7

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1、1Title:ReciprocalregulationofARPP-16byPKAandMAST-3kinasesprovidesacAMP-2regulatedswitchinproteinphosphatase2Ainhibition345612333447Musante,V.,LiL.,Kanyo,J.,Lam,T.T.,Colangelo,C.M.,Cheng,S.K.,Brody,H.,4218Greengard,P.,LeNovèreN.,Nairn,A.C.91011Affiliations:112De

2、partmentofPsychiatry,YaleUniversitySchoolofMedicine,NewHaven,CT06508.213BabrahamInstitute,Cambridge,CB223AT,UnitedKingdom314W.M.KeckBiotechnologyResourceLaboratory,YaleUniversitySchoolMedicine,300George15Street,NewHaven,CT06510.416LaboratoryofMolecularandCellul

3、arNeuroscience,TheRockefellerUniversity,NewYork,NY1710065.118Abstract19ARPP-16,ARPP-19,andENSAareinhibitorsofproteinphosphatasePP2A.ARPP-19and20ENSAphosphorylatedbyGreatwallkinaseinhibitPP2Aduringmitosis.ARPP-16isexpressed21instriatalneuronswherebasalphosphoryl

4、ationbyMAST3kinaseinhibitsPP2Aandregulates22keycomponentsofstriatalsignaling.TheARPP-16/19proteinswerediscoveredassubstrates23forPKA,butthefunctionofPKAphosphorylationisunknown.Wefindthatphosphorylationby24PKAorMAST3mutuallysuppressestheabilityoftheotherkinaset

5、oactonARPP-16.25PhosphorylationbyPKAalsoactstopreventinhibitionofPP2AbyARPP-16phosphorylatedby26MAST3.Moreover,PKAphosphorylatesMAST3atmultiplesitesresultinginitsinhibition.27Mathematicalmodelinghighlightstheroleofthesethreeregulatoryinteractionstocreatea28swit

6、ch-likeresponsetocAMP.Togethertheresultssuggestacomplexantagonisticinterplay29betweenthecontrolofARPP-16byMAST3andPKAthatcreatesamechanismwherebycAMP30mediatesPP2Adisinhibition.31323334235Introduction36ARPP-16andARPP-19wereoriginallyidentifiedtogetherwithDARPP-

7、32andARPP-21asa37groupofcAMP-regulatedphosphoproteins(ARPPs)enrichedinstriatalneurons(Walaasetal.,381983;Giraultetal.,1990;Horiuchietal.,1990).ARPP-16andARPP-19arealternatively39splicedvariants,withARPP-19containing16additionalaminoacidsatitsN-terminus.ARPP-401

8、6/19arealsorelatedtoendosulfine(ENSAorARPP-19e),adistinctgeneproductthatshares41highidentitywiththecommonregionofARPP-16/19butcontainsauniqueN-terminalregion42(Horiuchietal.