ReviewTheImportanceofKinase–PhosphataseIntegration:LessonsfromMitosisLendertGelens,1,*JunbinQian,2MathieuBollen,2andAdrianT.Saurin3,*Kinasesandphosphatasesworkantagonisticallytocontrolthebehaviourofindividualsubstratemolecules.Thiscanbeincorrectlyextrapolatedtoimplythattheyalsoworkantagonisticallyonthesignalsorprocessesthatthesemoleculescontrol.Infact,inmanysituationskinasesandphosphatasesworktogethertopositivelydrivesignalresponses.Weexplainhowthis‘coopera-tivity’iscriticalforsettingtheamplitude,localisation,timing[268_TD$DIF],andshapeofphosphorylationsignals.Weusemitosistoillustratewhythesepropertiesareimportantforcontrollingmitoticentry,sisterchromatidcohesion,kinetochore–microtubuleattachments,thespindleassemblycheckpoint,mitoticspindleelongation[269_TD$DIF],andmitoticexit.Theseexamplesprovidearationaletoexplainhowcomplexsignallingbehaviourcouldrelyonsimilartypesofintegrationwithinmanyotherbiologicalprocesses.IntroductionThetraditionalviewofproteinphosphorylationisthatkinasesandphosphatasesworkantag-onisticallytoswitchindividualsignalsonoroff.Itisanimagethataccuratelydescribestheinnerworkingsofallproteinphosphorylationnetworksattheirmostfundamentallevel[271_TD$DIF];anindividualsubstratemoleculeorresidue.Theproblemisthatthisbasicbuildingblock,whichismerelyasimplebinaryswitch,isusedbycellstooutputresponsesthatarefarmorecomplexthanthat.Thiscomplexityarisesbecauseeachindividualmoleculeisoftenpresentinthousandsofidenticalcopiesthatmustworktogetherintimeandspacetocollectivelydefinetheresponse.Imagineeachcopyasaseparatelight,andthenvisualisethedifferentpatternsorintensitiesthatcouldbeoutputwithinthecellandhowthiscouldchangeovertime.Pulses,waves,flickeringpatterns,andgradientsoflightperhapsburstingintolifeinspecificplacesatcertaintimes.Itdependsonwhatthesignalrequires:kinasesandphosphatasesmayworkinoppositiontoflickeachlightonandoff,buttheyalsoworkverymuchtogethertodirectthebiggerpictureanddefinehowthestoryunfolds.Thisreviewusesspecificexamplesfromthefieldofmitos...
