mTOR-Signaling-in-Growth--Metabolism--and-Disease

LeadingEdgeReviewmTORSignalinginGrowth,Metabolism,andDiseaseRobertA.Saxton1,2,3,4andDavidM.Sabatini1,2,3,4,*1WhiteheadInstituteforBiomedicalResearch,455MainStreet,Cambridge,MA02142,USA2DepartmentofBiology,HowardHughesMedicalInstitute,MassachusettsInstituteofTechnology,Cambridge,MA02139,USA3KochInstituteforIntegrativeCancerResearch,77MassachusettsAvenue,Cambridge,MA02139,USA4BroadInstituteofHarvardandMassachusettsInstituteofTechnology,415MainStreet,Cambridge,MA02142,USA*Correspondence:[e-mail](mTOR)coordinateseukaryoticcellgrowthandmetabolismwithenvironmentalinputs,includingnutrientsandgrowthfactors.ExtensiveresearchoverthepasttwodecadeshasestablishedacentralroleformTORinregulatingmanyfundamentalcellpro-cesses,fromproteinsynthesistoautophagy,andderegulatedmTORsignalingisimplicatedintheprogressionofcanceranddiabetes,aswellastheagingprocess.Here,wereviewrecentadvancesinourunderstandingofmTORfunction,regulation,andimportanceinmammalianphysiology.WealsohighlighthowthemTORsignalingnetworkcontributestohumandiseaseanddiscussthecur-rentandfutureprospectsfortherapeuticallytargetingmTORintheclinic.In1964,aCanadianexpeditiontotheisolatedSouthPacificislandofRapaNui(alsoknownasEasterIsland)collectedasetofsoilsampleswiththegoalofidentifyingnovelantimicrobialagents.Inbacteriaisolatedfromoneofthesesamples,Sehgalandcolleaguesdiscoveredacompoundwithremarkableanti-fungal,immunosuppressive,andantitumorproperties(Engetal.,1984;Marteletal.,1977;Ve´zinaetal.,1975).Furtheranal-ysisofthiscompound,namedrapamycinafteritssiteofdiscov-ery(clinicallyreferredtoassirolimus),revealedthatitactsinpartbyformingagainoffunctioncomplexwiththepeptidyl-prolyl-isomeraseFKBP12toinhibitsignaltransductionpathwaysrequiredforcellgrowthandproliferation(Chungetal.,1992).Despitetheseinsights,thefullmechanismofactionofrapa-mycinremainedelusiveuntil1994,whenbiochemicalstudiesidentifiedthemechanistic(formerly‘‘mammalian’’)targetofrapamycin(mTOR)asthedirecttargetoftherapamycin-FKBP12complexinmammals(Brownetal.,1994;Sabatinietal.,1994;Sabersetal.,1995)andrevealedittobethehomologoftheyeastTOR/DRRgenesthathadpreviouslybeenidentifiedingeneticscreensforrapamycinresistance(Cafferkeyetal.,1993;Heitmanetal.,1991;Kunzetal.,1993).Inthemorethan2decadessincethesediscoveries,studiesfromdozensoflabsacrosstheglobehaverevealedthatthemTORproteinkinasenucleatesamajoreukaryoticsignalingnetworkthatcoordinatescellgrowthwithenvironmentalcondi-tionsandplaysafundamentalroleincellandorganismalphysi-ology.ManyaspectsofmTORfunctionandregulationhaveonlyrecentlybeenelucidated,andmanymorequestionsremainun-answered.Inthisreview,weprovideanoverviewofourcurrentunderstandingofthemTORpathwayanditsroleingrowth,metabolism,anddisease.mTORC1andmTORC2mTORisaserine/threonineproteinkinaseinthePI3K-relatedkinase(PIKK)familythatformsthecatalyticsubunitoftwodistinctproteincomplexes,knownasmTORComplex1(mTORC1)and2(mTORC2)(Figure1A).mTORC1isdefinedbyitsthreecorecomponents:mTOR,Raptor(regulatoryproteinassociatedwithmTOR),andmLST8(mammalianlethalwithSec13protein8,alsoknownasGßL)(Figure1B;Kimetal.,2002,2003;Haraetal.,2002).RaptorfacilitatessubstraterecruitmenttomTORC1throughbindingtotheTORsignaling(TOS)motiffoundonseveralcanonicalmTORC1substrates(Nojimaetal.,2003;Schalmetal.,2003)and,asdescribedlater,isrequiredforthecorrectsubcellularlocalizationofmTORC1.mLST8bycontrastassociateswiththecatalyticdomainofmTORC1andmaystabilizethekinaseactivationloop(Yangetal.,2013),thoughgeneticstudiessuggestitisdispensablefortheessentialfunctionsofmTORC1(Guertinetal.,2006).Inadditiontothesethreecorecomponents,mTORC1alsocon-tainsthetwoinhibitorysubunitsPRAS40(proline-richAktsub-strateof40kDa)(Sancaketal.,2007;VanderHaaretal.,2007;Wangetal.,2007)andDEPTOR(DEPdomaincontainingmTORinteractingprotein)(Petersonetal.,2009).StructuralstudiesofmTORC1haveyieldedsignificantinsightsintoitsassembly,function,andperturbationbyrapamycin.Cryo-EMreconstructionsofbothmTORC1andyeastTORC1haverevealedthatthecomplexformsa1-mDa‘‘lozenge’’-shapeddimer,withthedimerizationinterfacecomprisingcon-tactsbetweenthemTORHEATrepeatsaswellasbetweenRaptorandmTOR(Figure1B;Aylettetal.,2016;Bareti
cetal.,2016;Yipetal.,2010).Inaddition,acrystalstructureofthemTORkinasedomainboundtomLST8showedthattherapamy-cin-FKBP12complexbindstotheFRBdomainofmTORtonar-rowthecatalyticcleftandpartiallyoccludesubstratesfromtheactivesite(Yangetal.,2013).Whiletherapamycin-FKBP12complexdirectlyinhibitsmTORC1,mTORC2ischaracterizedbyitsinsensitivitytoacuterapamycintreatment.LikemTORC1,mTORC2alsocontainsmTORandmLST8(Figure1C).InsteadofRaptor,however,960Cell168,March9,2017ª2017ElsevierInc.mTORC2containsRictor(rapamycininsensitivecompanionofmTOR),anunrelatedproteinthatlikelyservesananalogousfunc-tion(Jacintoetal.,2004;Sarbassovetal.,2004).mTORC2alsocontainsDEPTOR(Petersonetal.,2009),aswellastheregulatorysubunitsmSin1(Friasetal.,2006;Jacintoetal.,2006;Yangetal.,2006)andProtor1/2(Pearceetal.,2007;Thediecketal.,2007;Wooe