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Akt信号通路双向调控细胞自噬的机理研究.docx

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Akt信号通路双向调控细胞自噬的机理研究 Title:DualRegulationofAutophagybyAktsignalingpathway:MechanisticInsights Abstract: Autophagy,ahighlyconservedcellularprocess,playsacriticalroleinmaintainingcellularhomeostasisbyclearingdamagedorganellesandproteins.Dysregulationofautophagyhasbeenimplicatedinvariouspathologicalconditions,includingcancer,neurodegenerativediseases,andmetabolicdisorders.TheAktsignalingpathway,akeyregulatorofcellgrowthandsurvival,hasemergedasamajorregulatorofautophagy.Inthisreview,wewilldiscussthedualregulationofautophagybytheAktsignalingpathwayandtheunderlyingmechanisticinsights. Introduction: Autophagyisacomplexprocessinvolvingthesequestrationofcytosoliccomponentsandtheirsubsequentdeliverytolysosomesfordegradationandrecycling.Thisprocessistightlyregulatedtomaintaincellularhomeostasisandrespondtovariousstressors.TheAktsignalingpathway,alsoknownasthePI3K-Aktpathway,playsacriticalroleincellgrowth,proliferation,andsurvival.Inrecentyears,thelinkbetweenAktsignalingandautophagyhasgainedsignificantattention,asAkthasbeenfoundtobothinhibitandstimulateautophagyunderdifferentcircumstances.TheintricateregulationofautophagybyAktsignalingraisesimportantquestionsabouttheunderlyingmechanismsinvolved. AktSignalingandAutophagyRegulation: Aktisaserine/threoninekinasethatisactivateddownstreamofvariousgrowthfactorsandsurvivalsignals.ActivationofAktleadstothephosphorylationandinactivationofthetuberoussclerosiscomplex2(TSC2),anegativeregulatorofthemammaliantargetofrapamycin(mTOR).mTOR,acriticalregulatorofcellularmetabolism,negativelyregulatesautophagy.Therefore,AktactivationviatheinhibitionofTSC2leadstomTORactivation,resultinginthesuppressionofautophagy.ThisrepresentsoneofthemechanismsbywhichAktnegativelyregulatesautophagy. Ontheotherhand,Akthasalsobeenshowntopositivelyregulateautophagyundercertainconditions.AktsignalinghasbeenfoundtophosphorylateandactivateUnc-51-likeautophagyactivatingkinase1(ULK1),akeyregulatorofautophagyinitiation.PhosphorylationofULK1byAktpromotesautophagyinduction,po