信号转导的英文.docx

信号转导的英文.docx

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信号转导的英文

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GPCRs（G-Protein-CoupledReceptors）andCancer

GPCRs（GuanineNucleotideBinding-ProteinCoupledReceptors）compriselargeanddiversegenefamiliesinfungi,plants,andtheanimalkingdom.Alsotermedserpentinereceptors,GPCRsarepolytopicmembraneproteinsthatshareacommonstructurewithseventransmembranesegments,butsequencesimilarityisminimalamongthemostdistantGPCRs.Theirprincipalfunctionistotransmitinformationabouttheextracellularenvironmenttotheinteriorofthecell,andtheydothisbyinteractingwiththeG-proteins.GPCRsrecognizeavarietyofligandsandstimuliincludingpeptideandnon-peptidehormonesandneurotransmitters,chemokines,prostanoidsandproteinases,biogenicamines,nucleosides,lipids,growthfactors,odorantmoleculesandlight.Thesereceptorsaffectthegenerationofsmallmoleculesthatactasintracellularmediatorsorsecondmessengers,andcanregulateahighlyinterconnectednetworkofbiochemicalroutes.TheintracellularsignalingpathwaysactivatedbyGPCRsignalingincludecAMP（CyclicAdenosineMonophosphate）/PKA（ProteinKinase-A）pathway,Ca2+/PKC（ProteinKinase-C）pathway,Ca2+/NFAT（NuclearFactorofActivatedT-cells）pathway,PLC（Phospholipase-C）pathway,PTK（ProteinTyrosineKinase）pathway,PKC/MEK（MAPK/ERK1）pathway,p43/p44MAPK（MitogenActivatedProteinKinase）pathway,p38MAPpathway,PI3K（Phosphoinositide-3Kinase）pathway,NO-cGMPpathway,Rhopathway,NF-KappaB（NuclearFactor-KappaB）pathwayandJAK（JanusKinase）/STAT（SignalTransducersandActivatorsofTranscriptionFactors）pathway（Ref.1）.

Uponactivation,GPCRsinteractwiththeircognateG-proteins.G-proteinsareheterotrimers（i.e.,madeofthreedifferentsubunits）associatedwiththeinnersurfaceoftheplasmamembrane.Thethreesubunitsare:

G-Alpha,G-BetaandG-Gamma.Whensignaling,theyfunctioninessenceasdimersbecausethesignaliscommunicatedeitherbytheG-AlphasubunitortheG-Beta-Gammacomplex.Currentlythereare20knownG-Alpha,6G-Beta,and11G-Gammasubunits.Onthebasisofsequencesimilarity,theG-Alphasubunitshavebeendividedintofourfamilies:

G-AlphaS,G-AlphaI,G-AlphaQ,andG-Alpha12/13.TheseG-Alphasubunitsregulatetheactivityofseveralsecondmessenger-generatingsystems.Intheinactivestate,G-AlphahasGDPinitsbindingsite.WhenahormoneorotherligandbindstotheassociatedGPCR,anallostericchangetakesplaceinthereceptor.ThistriggersanallostericchangeinG-AlphacausingGDPtoleaveandbereplacedbyGTP.GTPactivatesG-AlphacausingittodissociatefromG-Beta-Gamma（whichremainlinkedasadimer）（Ref.2）.

TheG-Alphasubunithasmanydifferentfunctions,dependingonitsisoform.G-alphasubunitconsistsof4isoforms:

G-AlphaQ,G-AlphaS,G-AlphaIandG-Alpha12/13.G-AlphaQfamilycontrolstheactivityofPhosphatidylinositol-specificPhospholipases,suchasPLC-Beta,whichhydrolyzesPIP2（Phosphatidylinositol4,5-Bisphosphate）togeneratetwo-secondmessengers,IP3（Inositol1,4,5-Trisphosphate）andDAG（Diacylglycerol）.IP3andDAGinturnleadtoanincreaseintheintracellularconcentrationsoffreeCa2+andtheactivationofanumberofProteinKinases,includingPKC（Ref.3）.G-AlphaQ,workingthroughPKCandpossiblydirectly,alsoappearstoregulatevariousisoformsofPLD（Phospholipase-D）.G-AlphaQisreportedtoactivatethetranscriptionfactorNF-KappaBthroughPYK2（Proline-RichTyrosineKinase-2）.ThemembersoftheG-AlphaSfamilyactivateAC（AdenylylCyclase）leadingtotheproductionofcAMPinthecell.cAMPthenbindstotheregulatorysubunitofPKA（ProteinKinase-A）leadingtothedissociationofthecatalyticsubunits.OncethecatalyticsubunitsofPKAdissociate,theybecomeactive.PKAthenleadtothephosphorylationoftheGPCR.OncetheGPCRisphosphorylated,itcanthencoupletoG-AlphaIinsteadofG-AlphaS.G-AlphaIfamilymemberscaninhibitAC,therebycontrollingtheintracellularconcentrationsofcAMP.G-AlphasubunitsoftheG-AlphaIfamily,whichincludesG-AlphaI-1,G-AlphaI-2,G-AlphaI-3,G-AlphaI-O,transducin（G-AlphaI-T）,andgustducin（G-AlphaI-gust）,alsoactivateavarietyofPhospholipasesandPhosphodiesterases,andpromotetheopeningofseveralionchannels.G-AlphaIandG-AlphaI-Ocanregulatesignalsfromc-SrctoSTAT3andtotheRappathways.BothG-AlphaIandG-AlphaQ-coupledreceptorscanpotentlystimulateMAPKactivation（Ref.4）.

G-Beta-GammaSubunitofG-Proteinsdirectlycouplestoatleastfoureffectormolecules:

PLC-Beta,K+channels,AC,andPI3K.OverexpressionofG-Beta-GammasubunitwasfoundtobesufficienttostimulateMAPKs.Furthermore,stimulationofMAPKactivitybycoexpressedG-Beta-GammadimersdidnotrequirePKCactivation,butinvolvedtheactivationofRas.ThesmallG-proteinRasbecomesactivatedwhenitsGEFisrecruitedtothemembrane（viaRTKs,FAK（FocalAdhesionKinase）,etc.）.OnceRasbindsGTP,itcanthenrecruittheserine/threoninekinaseRaftothemembrane.WhenRaftranslocatetothemembrane,itbecomesactivatedandthenphosphorylatesthedualspecificitykinaseMEK.ThisleadstotheactivationofMEK,whichthenphosphorylatesacriticaltyrosineandthreonineonERK（Extracellularsignal-RegulatedKinase）.ERKthenphosphorylatesandactivateothercellularproteins（likep90RSK）aswellastranslocateintothenucleusandphosphorylate/activatetranscriptionfactors（likeElk1）andleadstochangesingeneexpressionandcellcycleprogression.G-Beta-GammaalsobindstoPLC-Beta,whichfacilitatesitsactivationbyG-AlphaQ,andithasbeenshowntoenhanceG-AlphaSactivationofAC.Further,G-Beta-GammaalsointeractswithionchannelsandrecruitsBARK（Beta-AdrenergicReceptorKinase）andPI3K-Gammatothemembrane.G-Beta-Gammacouldleadtotheactivationofthenon-receptortyrosinekinaseSrc.SrcthenleadstothetyrosinephosphorylationoftheadapterproteinSHC.SHCthenrecruittheGRB2（GrowthFactorReceptorBoundProtein-2）-SOS（SonOfSevenless）complextothemembraneviatheSH2domainofGRB2bindingtothePhosphotyrosineonSHC.SOS,aGEFforRas,canthenexchangetheGDPboundtoRastoGTP.OnceRasbindsGTP,itisthenactivated,andtheERKactivationcascadeisinitiated.GPCRsthatcoupletoG-AlphaScouldalsoactivateERKviaG-Beta-Gamma.ThenatureofthesignalingpathwayscontrolledbyG-Alpha12familyofGTPases（GuanosineTriphosphatases）hasjustbeguntobeelucidated.G-Alpha12hasbeenreportedtodirectlyinteractwithaGTPase-activatingproteinforRas,Ras-GAP,andBTK（Bruton'sTyrosineKinase）.Theseobservationsrequireconfirmationandextensiontoestablishthecellularconsequencesinnativesystemsofthesedirectinteractions.G-Alpha12isthoughttostimulatePLD,c-Src,andPKCbyas-yetunidentifiedmechanisms.InmanycasesitappearsthatdifferentmembersoftheMAPKfamily,suchasERK5orJNK（c-JunNH2-terminalKinase）,areactivated.Thisactivationshouldleadtoregulationofgeneexpression.G-Alpha13directlyinteractswithandactivatesaguaninenucleotideexchangefactorfortheGTPaseRho,p115RhoGEF,andthusactivatesRho,leadingtoavarietyofeffectsthatincluderegulationoftheNa+-H+exchanger.ThroughtheactivationofPYK2,G-Alpha13mayengagethePI3KpathwaytoactivatetheproteinkinaseAktandregulateNF-KappaB.HowG-Alpha13activatesPYK2iscurrentlynotunderstood（Ref.5）.

GPCRsmediatehormonalcontrolofnumeroussignalingpathways.Manyofthesepathwaysaredynamicallyregulated.Atthelevelofthereceptor,regulationcanoccurviainhibitionofGPCR/G-Proteincoupling（desensitization）,redistributionofcellsurfacereceptors（trafficking）,andreceptordegradation（down-regulation）.Twoproteinfamilies,GRKs（G-protein-coupledReceptorKinases）andArrestins,playacriticalroleinregulatingtheseprocesses.GRKsspecificallyphosphorylatetheactivatedformofthereceptor,whichinturnpromotesArrestinbinding.ArrestinbindingstericallyinhibitscouplingoftheGPCRtoitsrespectiveGprotein（aprocesstermedreceptordesensitization）andtargetsthereceptorforinternalisationviaclathrin-coatedpits.ByregulatingboththefunctionalstatusandnumberofplasmamembranelocatedGPCRstheGRKsplayapivotalroleinmodulatingGPCR-mediatedsignaltransduction.GPCRsareapharmacologicallyimportantproteinfamilywithapproximately450genesidentifiedtodate.Pathwaysinvolvingthesereceptorsarethetargetsofhundredsofdrugs,includingantihistamines,neuroleptics,antidepressants,andantihypertensives（Ref.6）.

References:

1.FangY,LahiriJ,PicardL.Gprotein-coupledreceptormicroarraysfordrugdiscovery.DrugDiscovToday.2003Aug15;8（16）:

755-61.

2.FangY,LahiriJ,PicardL.Gprotein-coupledreceptormicroarraysfordrugdiscovery.DrugDiscovToday.2003Aug15;8（16）:

755-61.

3.LudwigMG,VanekM,GueriniD,GasserJA,JonesCE,JunkerU,HofstetterH,WolfRM,SeuwenK.Proton-sensingG-protein-coupledreceptors.

Nature.2003Sep4;425（6953）:

93-8.

4.GilchristA,LiA,HammHE.GalphaCOOH-terminalminigenevectorsdissectheterotrimericGproteinsignaling.SciSTKE.2002Feb5;2002（118）:

PL1.

5.GutkindJS.Regulationofmitogen-activatedproteinkinasesignalingnetworksbyGprotein-coupledreceptors.SciSTKE.2000Jul11;2000（40）:

RE1.

6.SahVP,SeasholtzTM,SagiSA,BrownJH.TheroleofRhoinGprotein-coupledreceptorsignaltransduction.AnnuRevPharmacolToxicol.2000;40:

459-89.

7.SpiegelA.CELLSIGNALING:

beta-Arrestin--NotJustforGProtein-CoupledReceptors.Science.2003Sep5;301（5638）:

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MAPKfamilypathway

Proteinkinasesareubiquitousenzymesthatareabletomodulatetheactivitiesofotherproteinsbyaddingphosphategroupstotheirtyrosine