TheDualRolesoftheAtypicalProteinKinaseCsinCancerMiguelReina-Campos1,MariaT.Diaz-Meco1,JorgeMoscat1,*1CancerMetabolismandSignalingNetworksProgram,SanfordBurnhamPrebysMedicalDiscoveryInstitute,10901N.TorreyPinesRoad,LaJolla,CA92037,USAAbstractAtypicalProteinKinaseC(aPKC)isozymes,PKCλ/ιandPKCζ,arenowconsideredfundamentalregulatorsoftumorigenesis.However,thespecificseparationoffunctionsthatdeterminetheirdifferentrolesincancerisstillbeingunraveled.BothaPKCshavepleiotropiccontext-dependentfunctionsthatcantranslateintotumorpromoterorsuppressivefunctions.Here,wereviewearlyandmorerecentliteraturetodiscusshowthedifferenttumortypes,andtheirmicroenvironments,mightaccountfortheselectivesignalingofeachaPKCisotype.Thisisofclinicalrelevancebecauseabetterunderstandingoftherolesofthesekinasesisessentialforthedesignofnewanti-cancertreatments.IntroductionTheextendedproteinkinaseC(PKC)familycomprisesthreesubfamilies:theatypical(aPKCs;PKCζandPKCλ/ι),theconventional(cPKCs;PKCα,PKCβ,andPKCγ),andthenovel(nPKCs;PKCδ,PKCε,PKCη,andPKCθ)(GrinerandKazanietz,2007;NewtonandBrognard,2017).TheaPKCsdifferfromtheothermembersoftheextendedPKCfamilyinthattheylackfunctionalC2andC1domains,whichaccountsfortheirinsensitivitytoCa2+anddiacylglycerol(DAG)(Onoetal.,1988;Onoetal.,1989).Incontrast,theaPKCsharboraPhoxandBem1(PB1)domain,whichisahighlyconservedproteininteractionmodulethatgovernstheirbindingtootherPB1-containingproteinssuchasthepolarityregulatorPAR6(Moscatetal.,2006;Moscatetal.,2009),ortheautophagyreceptorandsignalingadaptorp62(MoscatandDiazMeco,2009;Moscatetal.,2016;Reina-Camposetal.,2018)(Figure1;Box1).Fromtheverybeginning,theaPKCshavebeenimplicatedinthecontrolofcriticalcellularfunctionsimportantincancer(Diaz-MecoandMoscat,2012;MoscatandDiaz-Meco,2000).However,establishingthespecificrolesforeachaPKCintumortransformationhasbeenchallenging.Thisismostlyduetothehighdegreeofsequence*Correspondence:jmoscat@sbpdiscovery.org.AUTHORCONTRIBUTIONSM.R.-C.,M.T.D.-M.,andJ.M.conceivedandwrotetheman...
