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.

================  蚂蚁淘在线  ================

免责声明：本文仅代表作者个人观点，与本网无关。其创作性以及文中陈述文字和内容未经本站证实，对本文以及其中全部或者部分内容、文字的真实性、完整性、及时性本站不做任何保证或承诺，请读者仅作参考，并请自行核实相关内容

版权声明：未经蚂蚁淘在线授权不得转载、摘编或利用其他方式使用上述作品。已经经本网授权使用作品的，应该授权范围内使用，并注明“来源：蚂蚁淘在线”。违反上述声明者，本网将追究其相关法律责任。