信号转导的英文.docx
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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):
1338-9.
MAPKfamilypathway
Proteinkinasesareubiquitousenzymesthatareabletomodulatetheactivitiesofotherproteinsbyaddingphosphategroupstotheirtyrosine
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