PRESSRELEASE
SheddinglightonthebrakesofAktactivity
Vienna,February2nd2017
ChangesleadingtothehyperactivationoftheproteinkinaseAktareobservedinalmost50%ofall
humantumors.UnderstandingAkt’sregulatorymechanismsisthereforeessentialfordevelopingand
improvingcancertherapies.ResearchersfromtheMaxF.PerutzLaboratories,ajointventureofthe
UniversityofViennaandMedicalUniversityofVienna,proposeacompletelynewmodelofAkt
regulation,limitingitsactivitytodiscretelocationswithinthecell–cellularmembranes.Theresultsare
publishedinthejournalMolecularCell.
Humancancerscanariseduetomanydifferentfactors,bothfromoutsidetheorganismorinsidethecell
itself.Oneproteinthatisoftentimesfoundtobeaffectedbythesefactorsandinvolvedinthemajorityof
cancers,iscalledAkt/ProteinKinaseB.
Aktplaysacentralroleincellularprocessesinvolvinggrowth,survival,andproliferationinresponseto
externalstimuli.
Theoveractivation-orhyperactivation-ofAktisoneofthemostfrequentchangesinhumancancer,andis
observedinabout50%oftumors,helpingcellstogrowanddivideuncontrollably.Itspivotalrolein
contributingtothedelicatebalancebetweenthenormalcellularfunctionsandtumorformationmakesAkt
aprimarysubjectofin-depthstudies,astheunderstandingofhowitsactivityisregulatedcanhelplaythe
firstbrickinthedevelopmentandimprovementofcancertherapies.
Onceactivated,Aktinturnactivatesitstargetsinsidethecellviatheadditionofaphosphate–aprocess
calledphosphorylation.Toavoidhyperactivation,asobservedinmanycancercells,theactivityofAktinside
thecellneedstobetightlycontrolledandremainproportionaltotheexternalsignals–similartoacar’sgas
pedal.Here,theoutcome(speed)hastobeproportionaltotheexternalinput(thefootapplyingpressure
onthepedal).
TheteamsofThomasLeonardandIvanYudushkininvestigatedthemechanismsensuringthatAktdoesnot
gointooverdrive.
“Inourstudy,wehavediscoveredthatAktisonlyactivewhileboundtoasmallmoleculeoncell
membranescalledPIP3.EngagementofPIP3allowsAkttobindandphosphorylateitstargetsandalso
protectsAktfrombeingdeactivatedbyotherproteinsinthecell,calledphosphatases”,co-firstauthorIva
Lučićexplains.“Conversely,whenAktisnotboundtoPIP3,itremainsinactive”.
ThelevelsofPIP3thereforeactasagatekeepertoAkt’sactivity,beingthepressureonthegaspedalinthe
aforementionedanalogy.
Inadditiontoitsproportionalactivation,Aktactivitymustalsobelocallyconfined,asanactivatedAkt
phosphorylatingtargetsindiscriminatelywouldbedetrimentaltothecell’shealth–justasacarspeeding
offwithoutthedriverbehindthewheelislikelytocauseanaccident.
Theresearcherswereabletodemonstrate,forthefirsttime,thatactiveAktisconfinedtocellular
membranes.When“floating”freelyinsidethecell,Aktisinactivatedandunabletophosphorylateany
targets.Co-firstauthorMichaelEbnerfurtherexplains:“Whenlookingincells,wefoundthatactiveAktis
essentiallyamembrane-boundmolecule.ThismeansthatwhileitisnotboundtoPIP3,Aktisshutoffintwo
ways:firstly,whenitfallsoffthemembrane,itadoptsastructurethatpreventsitfrombindingitstargets.
Secondly,Aktisinactivatedbyphosphatases,actingasefficientbrakesonAktactivity.Strikingly,both
MAXF.PERUTZLABORATORIES
ViennaBiocenter(VBC,)Dr.Bohr-Gasse9|1030Wien|Austria
Tel:+431427724014
[email protected]|www.mfpl.ac.at
TheMaxF.PerutzLaboratoriesareajointventureof
PRESSRELEASE
mechanismsarecompromisedbyacancermutation,whichputsAktintooverdriveandmakesitactive
throughoutthecellindependentofPIP3.SuchunrestrictedactivityofAktuncouplessurvival,growthand
divisionofcellsfromgrowthfactorsignals,whichcanultimatelyresultintumorformation”
Theseresultswerecorroboratedbyexperimentsbothintesttubesandinsidelivecells.
Asanextstep,theresearchersintendtodigdeeperandanswermorequestionsaboutAkt’sactivationon
anatomiclevel.Additionally,theywilladdressthequestionofhowthisnewlydiscoveredactivation
mechanismallowsAkttoselectitsspecifictargetsinsideacell.
PublicationinMolecularCell:
MichaelEbner,IvaLučić,ThomasA.LeonardandIvanYudushkin:PI(3,4,5)P3engagementrestrictsAkt
activitytocellularmembranes.MolecularCell,DOI:10.1016/j.molcel.2016.12.028
Scientificcontact
Dr.ThomasLeonard
MaxF.PerutzLaboratories
MedizinischeUniversitätWien
ViennaBiocenter
1030Wien,CampusViennaBiocenter5
+43-1-4277-52205
[email protected]
Dr.IvanYudushkin
MaxF.PerutzLaboratories
MedizinischeUniversitätWien
ViennaBiocenter
1030Wien,CampusViennaBiocenter5
+43-1-4277-61655
[email protected]
PressContact
CaterinaPurini,MSc.
MaxF.PerutzLaboratories
Communications
ViennaBiocenter
1030Wien,Dr.-Bohr-Gasse9
T+43-1-4277-24014
M+43-664-60277-24014
[email protected]
AbouttheMFPL
TheMaxF.PerutzLaboratories(MFPL)areacenterestablishedbytheUniversityofViennaandtheMedical
UniversityofViennatoprovideanenvironmentforexcellent,internationallyrecognizedresearchand
educationinthefieldofMolecularBiology.TheMFPLarelocatedattheViennaBiocenter,oneofthe
largestLifeSciencesclustersinAustria,andhostonaverage60independentresearchgroups,involving
morethan500peoplefrom40nations.
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TheMaxF.PerutzLaboratoriesareajointventureof