akt信号转导通路总结

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1、Akt(v-AktMurineThymomaViralOncogene)/PKB(ProteinKinase-B)isaSerine/threonineKinasethatisinvolvedinmediatingvariousbiologicalresponses,suchasinhibitionofApoptosisandstimulationofcellproliferation.Threemammalianisoformsarecurrentlyknown:Akt1/PKB-Alpha,Akt2/PKB-BetaandAk

2、t3/PKB-Gamma.AllthreeisoformsofAktshareacommonstructureofthreedomains.TheN-terminusoftheproteinisaPH(PleckstrinHomology)domain,whichinteractswithmembranelipidproductssuchasPIP2(Phosphatidylinositol-3,4-Bisphosphate)andPIP3(Phosphatidylinositol-3,4,5-Triphosphate).TheP

3、Hdomainisapproximately100aminoacidsandplaysaroleinrecognitionbyupstreamkinasesandmembranetranslocationofAkt.ThecenterregionoftheproteinistheKinasedomain,whichhashighsimilaritytootherkinases.Thisdomaincontainsaconservedthreonineresidue,whichneedstobephosphorylatedinord

4、ertoactivateAkt.Theapproximately40aminoacidsattheC-terminusoftheproteinformaregulatorydomainthatcontainsaprolinerichregionandahydrophobicmotifwithaconservedsequenceofFXX(F/Y)(S/T)(Y/F).Inmammals,thishydrophobicmotifisFPQFSY.Theserineorthreonineresidueinthismotifmustal

5、sobephosphorylatedtoactivateKinaseactivityofAkt.Thisisalsoaconservedresidue(Ref.1).ActivationofAktcanbeginwithseveralevents,mainlythebindingofaLigandtoaReceptorinthecellmembrane.MostcommonLigandsactivatingAktincludeGrowthfactors,Cytokines,MitogensandHormones.Insulinan

6、davarietyofGrowthfactorsbindtoRTK(ReceptorTyrosineKinase)andcauseautophosphorylationoftyrosineresiduesontheintracellulardomainofthereceptor.PI3K(Phosphoinositol3-Kinase)isrecruitedtothephosphotyrosineresidues(consensussequencepYXXM)viaSH2domainsintheregulatorydomain(p

7、85),andisthereforetargetedtotheinnercellmembrane.Bindingofthep85subunitofPI3KtothephosphorylatedRTKleadstoconformationalchangesinthecatalyticdomainofPI3K(p110)andconsequentkinaseactivation.PI3KcanbeactivatedbyRas.InsulincanalsoactivatePI3KviaIRS1(InsulinReceptorSubstr

8、ate-1).GPCR(G-Protein-CoupledReceptor)alsoactivatesPI3KthroughGN-Beta(GuanineNucleotide-BindingProtein-Beta)andGN-Gamma(Guan