mTOR-S6K1信号通路研究进展

20101291ChinJSportsMedJan2010Vol.29No.1mammaliantargetofra-pamycinmTOR、/。mTORS6K1ribosomalproteinS6kinasepolypeptide1、。S6K1S6。mTORS6K1Thr421/Ser4241insulinreceptorsubstrate1IRS-1Ser636/639insulinresistanceIR。mTOR/S6K1IR12。mTOR/S6K1IR、2T2DM。mTOR/S6K1。1mTORmTOR2549290kDa。20HEATmTOR。KinaseDomainFRBFKBP12-RapamycinBindingFKBP12FK506-bind-ingProteinFK506－RapamycinmTORRa-pamycinmTOR。FRBFATFocalAdhesionTargetingDomainmTORFATCFocalAdhesionTargetingDomainofC-terminalmTOR。FATCNRDmTOR。mTORRaptorRegulatory-associatedproteinofTORRictorRapamycin-insensitivecomponentofTOR。mTOR-RaptormTORC1mTOR-RictormTORC2。mTORC1Rapamycin。、S6K1、4E-BP14E-BindingProtein1、。mTORC1mTORC2Rapamycin。mTORC2AktAkt3。PI3K/AktmTORC1mTORC2AktmTORC1mTORC2。2PI3K/AktmTOR/S6K1mTORIR。IGF-1mTOR。IGF-1。IRSIRSSH2SrcHomolo-gy2PI3KP85P110PIP3BPKB/Akt。AktmTORmTORS6K14E-BP14。AktmTORSer2448mTOR5。AktmTORGAPGTPase-Acti-vatingProteinTSC2TuberousSclerosisCom-plex2GTPRhebRasHomologEnrichedinBrain-GTPmTOR。AktTSC2/RhebmTOR。mTORC1PRAS40Proline-richAktSubstrateof40-kDaRaptormTORmTORC1。PRAS40AktAktPRAS40mTORC1mTORC16。3mTORAminoAcidAA、、。111213003812300070mTOR/S6K130871213、[e-mail]022-23010115118··20101291ChinJSportsMedJan2010Vol.29No.1、。AA7。HaraAAmTOR—S6K14E-BP1RapamycinmTORAAS6K18。mTORAATSC1/2。mTORC1TSC1/2Rheb910。NobukuniRNARNAiTSC1/2AAS6K1Rheb-GTP。AAmTOR/S6K1TSC1/2-Rheb11。3PI3K———WortmanninmTORAAS6K1。class1PI3KAANobukuniRNAiClass1PI3KAAS6K1。PKBS6K1。hVps34HumanVacuolarProteinSort-ing34AAS6K1。AAhVps34-3-PI3P。hVps34AAmTOR/S6K1PI3K-PKB-TSC1/2-S6K111。4mTOR/S6K1mTOR/S6K1、812。mTOR、S6K1mRNA13mTOR/S6K1。AMP-activedPro-teinKinaseAMPKAMPAMPK14-16AMPKmTOR12。AMPKmTOR/S6K1。AMPKmTOR/S6K1InokiAMPAMPKTSC2Thr1227Ser1345S6K1Thr389/421Ser424。TSC2RNAiTSC2AMPKS6K117。TSC2AMPKS6K1。AMPKTSC2mTORS6K1。AMPKmTORThr2446S6K112。mTORC1mTORmLST8/GblPRAS40Raptor。RaptormTORHEAT。RaptormTORmTOR、mTORmTOR18。RNAiRaptormTORC1RaptormTORC11920。DanamTORRaptorAMPKmTORC1。RNAiTSC2MEFsMurineEmbryonicFibroblastsAMPKAICARmTORC121TSC2AMPKmTORC1。DanaAMPKRaptorSer722Ser792。TSC2+/+TSC2-/-AMPKmTORRaptorSer722/792AMPKmTORC1。AMPKRaptorSer722/79214-3-3RaptormTORC122。AMPKTSC2RaptormTORC1。22。。S6K123。S6K1PKB/Akt2425Akt2627。PI3K/AktmTORO’NeilPI3K/Akt15minmTOR12hrs。PI3KWortmanninPI3K/AktmTORPI3K/AktmTOR28。ATP/AMPAMPKmTOR。DreyerAMPKmTOR27。AMPKmTOR/S6K1。O’Neil119··20101291ChinJSportsMedJan2010Vol.29No.1DPhospholipaseDPLDPhosphatidicAcidPAmTORDmTOR28。mTORPLDPA。ERK1/2ExtracellularSignal-regulatedKinaseP3829。DeldicqueRNAiC2C12ERK1/2P38S6K1Ser424Thr421S6K1Ser424/Thr421Thr389Thr389S6K130。MitogenActivatedProteinKinaseMAPKERK1/2P38S6K1。ERKmTORMaERKTSC2Ser540Ser664TSC2TSC1-TSC2TSC2mTOR/S6K129。Au-dreyRas/MAPKmTORC1RSK1/2p90RibosomalS6KinasesmTORRaptorRXRXXpS/TArg/Lys-X-Arg/Lys-X-X-pSer/ThrXSer719Ser721Ser722mTORC131。5mTOR、、mTOR。mTORmTORRhebmTORmTOR。mTORmTORmTOR/S6K1IR、T2DM、。61KhamzinaLVeilleuxAMaretteAetal.Increasedaciti-vationofthemammaliantargetofrapamycinpathwayinliverandskeletalmuscleofobeseratspossibleinvolve-mentinobesity-linkedinsulinresistance.Endocrinology200514631473-1481.2UmSHFrigerioFWatanabeMetal.AbsenceofS6K1protectsagainstage-anddiet-inducedobesitywhileen-hancinginsulinsensitivity.Nature20044317007200-205.3SarbassovDDGuertinDAAliSMetal.PhophorylationandregulationofAkt/PKBbytherictor-mTORcomplex.Science200530757121098-101.4AsnaghiLBrunoPPriullaMetal.mTORaproteinki-naseswitchingbetweenlifeanddeath.PharmacolRes2004506545-549.5NaveBTOuwensMWithersDJetal.MammaliantargetofrapamycinisadirecttargetforproteinkinaseBiden-ti?cationofaconvergencepointforopposingeffectsofinsulinandamino-aciddeficiencyonproteintranslation.BiochemJ19993442427-431.6SancakYThoreenCCPetersonTRetal.PRAS40isaninsulin-regulatedinhibitorofthemTORC1proteinkinase.MolCell2007256903-915.7MeijerAJGustafsonLALuikenJJetal.Cellswellingandthesensitivityofautophagicproteolysistoinhibitionbyaminoacidsinisolatedrathepatocytes.EurJBiochem19932152449-454.8HaraKYonezawaKWengQPetal.Aminoacidsuffi-ciencyandmTORregulatep70S6kinaseandelF-4EBP1throughacommoneffectormechanism.JBiolChem19982732314484-94.9GaoXZhangYArrazolaPetal.Tsctumoursuppressorproteinsantagonizeamino-acid-TORsignalling.NatCellBiol200249699-704.10SaucedoLJGaoXChiarelliDAetal.Rhebpromotescellgrowthasacomponentoftheinsulin/TORsignallingnetwork.NatCellBiol200356566-571.11NobukuniTJoaquinMRoccioMetal.AminoacidsmediatemTOR/raptorsignalingthroughactivationofclass3phosphatidylinositol3OH-kinase.ProcNatlAcadSci20051024014238-14243.12ChengSWFryerLGCarlingDetal.Thr2446isanov-elmammaliantargetofrapamycinmTORphosphoryla-tionsiteregulatedbynutrientstatus.JBiolChem20042791615719-15722.13.mTOR/S6K1.2009244297-302.14..200928136-40.15FujijiNHayashiTHirshmanMFetal.Exerciseinducesisoform-specificincreasein5’AMP-activedproteinkinaseactivityinhumanskeletalmuscle.BiochemBiophysResCommun200027331150-1155.16CoffeyVGZhongZShieldAetal.Earlysignalingre-sponsestodivergentexercisestimuliinskeletalmusclefromwell-trainedhuman.FASEBJ2006201190-192.17InokiKZhuTGuanKL.TSC2mediatescellularenergyresponsetocontrolcellg