Thenewenglandjournalofmedicinenengljmed379;21nejm.orgNovember22,20182052ReviewArticleThediscoveryofphosphatidylinositol3-kinase(PI3K)changedthewayweviewandunderstandgrowth-factorsignaling.Fromearlyon,itbecameclearthatPI3Kplaysanimportantroleinmanydiseasestates.However,itsdiscoveryasanoncogeneinanagewhencancerbiologywascomingtotheforehascementeditsassociationwithcancer.Undernormalconditions,PI3Kplaysanintegralroleintranslatingextracellulargrowthsignalsintotheintracellularactionsthatfacilitategrowthbycouplingmacromoleculebiosynthesiswiththeinitiationofcell-cycleprogression.CancercellsexploitthecentralpositionofPI3KasaregulatorynodebyevolvingstrategiestoenhancePI3Kactivityatthecellularlevelindependentofsystemicregulation.Inthisregard,thecell“thinks”itisbeingtoldtogrow,wheninfactnogrowthsignalsarepresent.Thisdiscon-nectviolatesanessentialprincipleofmulticellularorganismsandresultsintheuncontrolledcellulargrowththatdefinescancer.TheDiscoveryofanOncogeneIntheevolutionofmulticellularorganisms,somecellslostpartoftheirautonomy.Thesurvivalofthenewensembleofcellswasaidedbythedevelopmentofeffectivenewregulatorymechanisms.Inhumans,theresultisacomplexsystemofendo-crine,paracrine,andautocrinemediatorsthatcontrolcelldifferentiationandcelldivisionbycouplinggrowthandsurvivalwithnutrientavailability.Onefamilyofproteinsthathashelpedfacilitatethecoordinationofcellgrowthinmulticellularorganismsisthetyrosinekinasefamily.Tyrosinekinasesattachphosphategroupstotheaminoacidtyrosineinproteins,controllingkeycellularprocessessuchasthecellcycle,metabolism,andapoptosis.Thesubsetoftyrosinekinaseswithextracellulardomainsthatbindgrowthfactors,whichinturntriggercytosolictyrosinekinaseactivity,arereferredtoasreceptortyrosinekinases(RTKs).Someexamplesincludetheepidermalgrowthfactorreceptor,platelet-derivedgrowthfactorreceptor,andinsulinreceptor.Activationofintracellulartyrosinekinasebythesegrowthfactorsinitiatesacascadeofeventsthatinducesnutrientuptake,macromoleculesynthesis,andproliferation.Thefir...
