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-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