CXCR4isachemokinereceptorintheGPCRgenefamily,andisexpressedbycellsintheimmunesystemandthecentralnervoussystem.InresponsetobindingitsligandSDF-1(stromalcell-derivedfactor-1),CXCR4triggersthemigrationandrecruitmentofimmunecells.Thisligand-receptorpairmayalsoplayaroleindevelopmentofthenervoussystem.Inadditiontoactingasachemokinereceptor,CXCR4isaco-receptorforentryofHIVintoTcellsandligandsofCXCR4,includingSDF-1mayhelptoblockHIVinfection.Earlyintheinfectionofanindividual,HIVvirusesoftenaretropicfortheCCR5coreceptorthatprovidesformacrophageentry,thenlaterininfectionaretropicforCXCR4andTcellentry.VirusesthataretropicforCXCR4aregenerallysyncitiumforming,causingTcellstoaggregateandbedestroyedatarapidrate.CXCR4inducesdownstreamsignalingbyseveraldifferentpathways.AsaGPCR,CXCR4bindingofSDF-1activatesG-proteinmediatedsignaling,includingdownstreampathwayssuchasras,andPI3kinase.PI3kinaseactivatedbySDF-1andCXCR4playsaroleinlymphocytechemotaxisinresponsetothesesignals.OneendpointofCXCR4signalingistheactivationoftranscriptionfactorssuchasAP-1andchemokineregulatedgenes.JAK/STATsignalingpathwaysalsoappeartoplayaroleinSDF-1/CXCR4signaling.DelineationofthesignalingmechanismsutilizedbyCXCR4mayassistindeterminingtheroleofCXCR4inHIVinfectionandintheimmuneresponse.

Contributor:

REFERENCES:BleulCC,etal.ThelymphocytechemoattractantSDF-1isaligandforLESTR/fusinandblocksHIV-1entry.Nature1996Aug29;382(6594):829-33)ChengZ,etal.b-ArrestinDifferentiallyRegulatestheChemokineReceptorCXCR4-mediatedSignalingandReceptorInternalization,andThisImplicatesMultipleinteractionSitesbetweenb-ArrestinandCXCR4.JBiolChem2000Jan28;pp2476-2485Duttp,etal.StromalCell-DerivedFactor-1aandStemCellFactor/kitLigandShareSignalingPathwaysinHemopoieticProgenitors:APotentialMechanismforCooperativeInductionofChemotaxis.JImmunology,1998161:pp3652-3658Jian-FengWang,In-WooPark,andJeromeE.Groopman.Stromalcell-derivedfactor-1a-stimulatestyrosinephosphorylationofmultiplefocaladhesionproteinsandinducesmigrationofhematopoieticprogenitorcells:rolesofphosphoinositide-3kinaseandproteinkinaseC.Blood,15April2000,95(8),2505-13.LingK,etal.Five-transmembranedomainsappearsufficientforaGprotein-coupledreceptor:Functionalfive-transmembranedomainchemokinereceptors.CellBIOLOGy199996:pp7922-7927MiguelVicente-Manzanares,etal.InvolvementofPhosphatidylinositol3-KinaseinStromalCell-DerivedFactor-1a-InducedLymphocytePolarizationadnChemotaxis.Immunology,1999,163,4001-12.RameshK.Ganju,etal.Thea-Chemokine,StromalCell-derivedFactor-1a,BindstotheTransmembraneG-protein-coupledCXCR-4ReceptorandActivatesMultipleSignalTransductionPathways.BiologicalChemistry,1998,273(36),23169-175.YannisSotsios,GillianC.Whittaker,JohnWestwick,andStephenG.Ward.TheCXCChemokineStromalCell-DerivedFactorActivatesaGi-CoupledPhosphoinositide3-KinaseinTLymphocytes.Immunology,1999,163,5954-63.ZhangXF,etal.Januskinase2isinvolvedinstromalcell-derivedfactor-1alpha-inducedtyrosinephosphorylationoffocaladhesionproteinsandmigrationofhematopoieticprogenitorcells.Blood2001Jun1;97(11):pp3342-3348ZouYR,etal.FunctionofthechemokinereceptorCXCR4inhaematopoiesisandincerebellardevelopment.Nature1998393(6685):pp595-599