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ID:15207402
大小:244.00 KB
页数:4页
时间:2018-08-02
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1、Akt(v-AktMurineThymomaViralOncogene)/PKB(ProteinKinase-B)isaSerine/threonineKinasethatisinvolvedinmediatingvariousbiologicalresponses,suchasinhibitionofApoptosisandstimulationofcellproliferation.Threemammalianisoformsarecurrentlyknown:Akt1/PKB-Alpha,Akt2/PKB-BetaandAkt3/PKB-Gam
2、ma.AllthreeisoformsofAktshareacommonstructureofthreedomains.TheN-terminusoftheproteinisaPH(PleckstrinHomology)domain,whichinteractswithmembranelipidproductssuchasPIP2(Phosphatidylinositol-3,4-Bisphosphate)andPIP3(Phosphatidylinositol-3,4,5-Triphosphate).ThePHdomainisapproximate
3、ly100aminoacidsandplaysaroleinrecognitionbyupstreamkinasesandmembranetranslocationofAkt.ThecenterregionoftheproteinistheKinasedomain,whichhashighsimilaritytootherkinases.Thisdomaincontainsaconservedthreonineresidue,whichneedstobephosphorylatedinordertoactivateAkt.Theapproximate
4、ly40aminoacidsattheC-terminusoftheproteinformaregulatorydomainthatcontainsaprolinerichregionandahydrophobicmotifwithaconservedsequenceofFXX(F/Y)(S/T)(Y/F).Inmammals,thishydrophobicmotifisFPQFSY.TheserineorthreonineresidueinthismotifmustalsobephosphorylatedtoactivateKinaseactivi
5、tyofAkt.Thisisalsoaconservedresidue(Ref.1).ActivationofAktcanbeginwithseveralevents,mainlythebindingofaLigandtoaReceptorinthecellmembrane.MostcommonLigandsactivatingAktincludeGrowthfactors,Cytokines,MitogensandHormones.InsulinandavarietyofGrowthfactorsbindtoRTK(ReceptorTyrosine
6、Kinase)andcauseautophosphorylationoftyrosineresiduesontheintracellulardomainofthereceptor.PI3K(Phosphoinositol3-Kinase)isrecruitedtothephosphotyrosineresidues(consensussequencepYXXM)viaSH2domainsintheregulatorydomain(p85),andisthereforetargetedtotheinnercellmembrane.Bindingofth
7、ep85subunitofPI3KtothephosphorylatedRTKleadstoconformationalchangesinthecatalyticdomainofPI3K(p110)andconsequentkinaseactivation.PI3KcanbeactivatedbyRas.InsulincanalsoactivatePI3KviaIRS1(InsulinReceptorSubstrate-1).GPCR(G-Protein-CoupledReceptor)alsoactivatesPI3KthroughGN-Beta(
8、GuanineNucleotide-BindingProtein-Beta)andGN-Gamma(Guan
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