信号通路

BCR Signaling Pathway

SignificantprogresshasbeenmadetowardsdelineationoftheintrinsicmolecularprocessesthatregulateBlymphocyteimmunefunction.RecentobservationshaveprovidedaclearerpictureoftheinteractivesignalingpathwaysthatemanatefromthematureBcellantigenreceptor(BCR)complexandthedifferentprecursorcomplexesthatareexpressedduringdevelopment.StudieshavealsorevealedthatthenetfunctionalresponsetoagivenantigenicchallengeisaffectedbythecombinedactionofBCR-dependentsignalingpathways,aswellasthoseoriginatingfromvariouscoreceptorsexpressedbyBcells(e.g.CD19,CD22,FcgRIIbandPIR-B).ItisnowwellestablishedthatreversIBLetyrosinephosphorylationplaysanimportantroleinregulatingBcellBIOLOGy.Inparticular,bindingofantigentotheBCRpromotestheactivationofseveralproteintyrosinekinases(PTK)that,inconjunctionwithproteintyrosinephosphatases(PTP),alterthehomeostasisofreversibletyrosinephosphorylationintherestingBcell.Theneteffectisatransientincreaseinproteintyrosinephosphorylationthatfacilitatesthephosphotyrosinedependentformationofeffectorproteincomplexes,promotestargetingofeffectorproteinstospecificmicroenvironmentswithintheBcellandinitiatesthecatalyticactivationofdownstreameffectorproteins.StudieshavedemonstratedthatSrcfamilyPTKsareactivatedinitiallyandservetophosphorylateCD79aandCD79btherebycreatingphosphotyrosinemotifsthatrecruitdownstreamsignalingproteins.Inparticular,phosphorylationoftheBCRcomplexleadstotherecruitmentandactivationofthePTKSyk,whichinturnpromotesphosphorylationofPLCg,ShcandVav.Additionally,theTecfamilymemberBtkisrecruitedtotheplasmamembranewhereitisinvolvedinactivationofPLCgInitiationofBlymphocyteactivationisdependentonthetyrosinephosphorylation-dependentformationofmulti-moleculareffectorproteincomplexesthatactivatedownstreamsignalingpathways.TheformationofsuchcomplexeswasinitiallyhypothesizedtooccurprimarilyviaeffectorproteinbindingtotheBCRcomplexitself.However,recentstudieshavedemonstratedthatproductivesignalingviatheBCRisinfactdependentontyrosinephosphorylationofoneormoreadapterproteinsthatplayacrucialroleinrecruitmentandorganizationofeffectorproteinsattheplasmamembrane.TheSLP-65/BLNKadapterproteinhasrecentlybeenshowntoplayacrucialroleinrecruitmentandactivationofkeysignaltransducingeffectorproteinsintheBcell.AftertheBCRhasbeenengagedbyantigenandtheactivationresponsehasbeeninitiated,numeroussecondmessengersandintermediatesignaltransducingproteinsareactivated.Theseincludetheproductionoflipidsecondmessengersbyphosphatidylinositol3-kinase,andthePLC-dependenthydrolysisofphosphatidylinositol4,5-bisphosphatetoyielddiacylglyceroland1,4,5-inositoltrisphosphate(IP3).DAGisimportantforactivationofPKCwhereasIP3promotereleaseofcalciumfromtheendoplasmicreticulumandthesubsequentinfluxCa2+fromtheextracellularspace.NumerousintermediatesignalingproteinsarealsoactivatedincludingtheRasandRap1,whicharesmallmolecularweightGTPasesandtheseultimatelyleadtotheactivationofMAPkinasesincludingErk,JNKandp38.TheneteffectofsecondmessengerproductionandactivationofintermediatesignalingproteinsistheconcertedregulationofseveraltranscriptionfactorsthatmediategenetranscriptionintheBcell.

Contributor:GlennCroston,PhD.

REFERENCES:Campbell,K.S.(1999)SignaltransductionfromtheBcellantigen-receptor.Curr.Opin.Immunol.11:256-264.Cornall,R.J.,C.C.Goodnow,andJ.G.Cyster(1999)RegulationofBcellantigenreceptorsignalingbytheLyn/CD22/SHP-1pathway.Curr.Top.Microbiol.Immunol.244:57-68.Gold,M.S.(2000)IntermediarysignalingeffectorscouplingtheB-cellreceptortothenucleus.Curr.Top.Microbiol.Immunol.245:77-134.Justement,L.B.(2000)SignaltransductionviatheB-cellantigenreceptor:theroleofproteintyrosinekinasesandproteintyrosinephosphatases.Curr.Top.Microbiol.Immunol.245:1-51.Kurosaki,T.(1999)GeneticanalysisofBcellantigenreceptorsignaling.Annu.Rev.immunol.17:555-592.PhD.,Kurosaki,T.,andS.Tsukada(2000)BLNK:connectingSykandBtktocalciumsignals.Immunity12:1-5.Wienands,J.(2000)TheB-cellantigenreceptor:Formationofsignalingcomplexesandthefunctionofadaptorproteins.Curr.Top.Microbiol.Immunol.245:53-76.

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