PI3K_AKT通路研究

198C.Fumarolaetal./BiochemicalPharmacology90(2014)197–207

Fig.1.ThePI3K/AKT/mTORsignalingcascadeandassociatedinhibitors.

ThePI3K/AKT/mTORnetworkregulatescellgrowth,survival,proliferation,migrationandmetabolism.Aberrationsatdifferentlevelsofthesignalingareimplicatedinlungcancerdevelopmentandprogression.Arrowsrepresentactivation,barsrepresentinhibition.

Differentdrugstargetingthepathwayarebeingdevelopedandareunderclinicalevaluation.Themechanismofactionofcurrentlyavailabletargetedinhibitorsareshown.

isoformsandbringsthemincontactwiththeirlipidsubstratesinthemembrane.PI3Kcanbeactivatedbysignaladapterproteins,suchasinsulinreceptorsubstrate(IRS)-1and-2inadditiontoRTKsthemselves.ClassIPI3KsmightbealsoactivatedbyRAS,throughtheRAS-bindingdomainpresentintheircatalyticsubunits[1].

Thetumorsuppressorgenephosphataseandtensinhomolog(PTEN)inhibitsthePI3KsignalingpathwaybydephosphorylatingPtdIns(3,4,5)P3toPtdIns(4,5)P2.PtdIns(3,4,5)P3attheplasmamembranerecruitsandactivatesanumberofproteinsthatcontainpleckstrinhomologydomains(PHdomains).TheseproteinsincludeAKTandphosphoinositide-dependentproteinkinase-1(PDK1).Afterwards,PDK1phosphorylatesAKT,andothersubstratessuchasserum/glucocorticoid-regulatedkinase1(SGK1),andribosomalS6kinase,90kDa,polypeptide1(RSK1).TobefullyactivatedAKTneedasecondphosphorylationmediatedbymTORC2.AKTactivitymaybenegativelyregulatedbyPHdomainleucine-richrepeatproteinphosphatases(PHLPP1andPHLPP2)thatactbyspeci callydepho-sphorylatingdifferentAKTisoforms[3].

AKTisaserine-threonineproteinkinasewhichexistsinthreeisoforms:AKT1andAKT2,ubiquitouslyexpressed,andAKT3whichispredominantlyexpressedinthebrain,kidneyandheart.

ActivatedAKTphosphorylatesandinhibitsdownstreamsignal-ingproteins,includingglycogensynthasekinase3(GSK3),forkheadboxO(FOXO)transcriptionfactors,andBAD,therebysuppressingapoptoticsignalsandstimulatingcellcycleprogres-sion.Inaddition,AKTindirectlyactivatesmTORC1,amasterregulatorofcellgrowthandmetabolism,byphosphorylatingandinhibitingthetuberoussclerosiscomplex1/2(TSC1/2).

TheTSC1/TSC2complexisacriticalnegativeregulatorofmTORC1,whichexertsGAP(GTPase-activatingprotein)activitytowardsRASRheb(RAShomologueenrichedinbrain),asmallG-proteinthat,initsGTPboundform,functionsasactivatorofmTORC1.

MostofthesignalsthatregulatemTORC1convergetotheTSC1-TSC2complex,suchthatpoorgrowthconditionsactivatethecomplexwhilegrowth-promotingconditionsinhibitit,resultinginmTORC1inhibitionoractivation,respectively[4].Forinstance,energystressinhibitsmTORC1,atleastinpart,throughAMPK-dependentactivatingphosphorylationofTSC2.Ontheotherhand,mitogensactivatemTORC1notonlyviaAKT,butalsoviaERK-1,andRSK-1mediatedinhibitoryphosphorylationofTSC2.Interest-ingly,AKTandERKphosphorylateTSC2ondistinctresidues,leadingtoadditiveeffectsontheinhibitionofTSC2,andhencereinforcingmTORC1signalingcomparedwithinputsignalingthrougheitherpathwayalone.

mTORisanevolutionarilyconservedserine/threoninekinasewhichexistsintwodistinctmultiproteinsignalingcomplexes,mTORC1andmTORC2[5].mTORC1,composedofmTOR,Raptor,mLST8,PRAS40,andDeptor,integratesmultiplesignalsarisingfromtheextracellularenvironment(growthfactors,nutrientsandenergysources)andfromintracellularmetabolicchanges,tocoordinatelyregulatecellgrowth,proliferation,survival,andmetabolism.InparticularmTORstimulatescellgrowthandproliferationbypromotingavarietyofanabolicprocesses,includingbiosynthesisofproteins,lipidsandorganelles,andbylimitingcatabolicprocessessuchasautophagy.AmongthesemultiplemTORC1functions,theregulationoftranslationisthebestcharacterizedinrelationtooncogenesis,andismediatedbytwodownstreameffectors,theeukaryoticinitiationfactor4E(eIF4E)-bindingprotein1(4E-BP1)andthep70ribosomalS6kinase1(p70S6K1,S6K1).4EBP1inhibitstheinitiationofproteintranslationbybindingandinactivatingeIF4E;mTORC1-mediatedphosphorylationof4EBP1promotethedissociationofeIF4E-4EBP1complex,therebyallowingeIF4E-dependenttranslation.S6K1isaserine-threoninekinaseactivatedbymTORC1-mediatedphos-phorylation,whichinturnphosphorylatesthe40Sribosomal