Modulation of Interleukin-1 Transcriptional Response by the Interaction between VRK2 and the JIP1 Scaffold Protein 英文参考文献.docVIP

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Modulation of Interleukin-1 Transcriptional Response by the Interaction between VRK2 and the JIP1 Scaffold Protein 英文参考文献.doc

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Modulation of Interleukin-1 Transcriptional Response by the Interaction between VRK2 and the JIP1 Scaffold Protein 英文参考文献

ModulationofInterleukin-1TranscriptionalResponseby theInteractionbetweenVRK2andtheJIP1Scaffold Protein SandraBlanco,MartaSanz-Garc?′a,ClaudioR.Santos,PedroA.Lazo* Programa de Oncolog?′a Traslacional, Instituto de Biolog?′a Molecular y Celular del Ca′ncer, Consejo Superior de Investigaciones Cient?′ficas (CSIC), Universidad de Salamanca,Salamanca,Spain Abstract Background:Cellularbiologicalresponsestospecificstimulationaredeterminedbyabalanceamongsignalingpathways. Proteininteractionsarelikelytomodulatethesepathways.Vaccinia-relatedkinase-2(VRK2)isanovelhumankinasethatcan modulatedifferentsignalingpathways. Principal Findings: We report that in vivo, the activity of JIP1-JNK complexes is downregulated by VRK2 in response to interleukin-1b.AlsothereductionofendogenousVRK2withshRNAincreasesthetranscriptionalresponsetoIL-1b.TheJIP1 scaffoldproteinassemblesthreeconsecutivemembersofagivenMAPKpathwayformingsignalingcomplexesandtheir signalcanbemodulatedbyinteractions withregulatoryproteins thatremaintobeidentified. Knocking-downJIP1 with siRNAresultedineliminationoftheAP1transcriptionalresponsetoIL-1b.VRK2,amemberofnovelSer-Thrkinasefamily,is able to stably interact with JIP1, TAK1 and MKK7, but not JNK, and can be isolated forming oligomeric complexes with different proportions of TAK1, MKK7b1 and JNK. JIP1 assembles all these proteins in an oligomeric signalosome. VRK2 binding to the JIP1 signalosome prevents the association of JNK and results in a reduction in its phosphorylation and downregulationofAP1-dependenttranscription. Conclusions/Significance:ThisworksuggeststhattheintracellularlevelofVRK2proteincanmodulatetheflowthrougha signaling pathwayandalter the responsefrom areceptor thatcan bedistributed by morethan onepathway, andthus contribute tothe cellular specificity of the response by forming alternative signaling complexes. Furthermore, theeffect might be more general and affect other signaling routes assembled on the JIP1 scaffold protein for which a mo