Raf Kinase Inhibitory Protein Protects Cells against Locostatin-Mediated Inhibition of Migration 英文参考文献.docVIP

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Raf Kinase Inhibitory Protein Protects Cells against Locostatin-Mediated Inhibition of Migration 英文参考文献.doc

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Raf Kinase Inhibitory Protein Protects Cells against Locostatin-Mediated Inhibition of Migration 英文参考文献

RafKinaseInhibitoryProteinProtectsCellsagainst Locostatin-MediatedInhibitionofMigration AnneN.Shemon1,EvaM.Eves1,MatthewC.Clark1,2,GaryHeil3,AlexeyGranovsky1,LingchunZeng1, AkiraImamoto1,ShoheiKoide3.*,MarshaRichRosner1,2. * 1Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, United States of America, 2Department of Neurobiology, Pharmacology and Physiology,UniversityofChicago,Chicago,Illinois,UnitedStatesofAmerica,3DepartmentofBiochemistryandMolecularBiology,UniversityofChicago,Chicago,Illinois, UnitedStatesofAmerica Abstract Background:RafKinaseInhibitoryProtein(RKIP,alsoPEBP1),amemberofthePhosphatidylethanolamineBindingProtein family,negativelyregulatesgrowthfactorsignalingbytheRaf/MAPkinasepathway.Sinceanorganiccompound,locostatin, was reported to bind RKIP and inhibit cell migration by a Raf-dependent mechanism, we addressed the role of RKIP in locostatinfunction. Methods/Findings:WeanalyzedlocostatininteractionwithRKIPandexaminedthebiologicalconsequencesoflocostatin bindingonRKIPfunction.NMRstudiesshowthatalocostatinprecursorbindstotheconservedphosphatidylethanolamine bindingpocketofRKIP.However,drugbindingtothepocketdoesnotpreventRKIPassociationwithitsinhibitorytarget, Raf-1, nor affect RKIP phosphorylation by Protein Kinase C at a regulatory site. Similarly, exposure of wild type, RKIP- depleted HeLa cells or RKIP-deficient (RKIP2/2) mouse embryonic fibroblasts (MEFs) to locostatin has no effect on MAP kinase activation. Locostatin treatment of wild type MEFs causes inhibition of cell migration following wounding. RKIP deficiencyimpairsmigrationfurther,indicatingthatRKIPprotectscellsagainstlocostatin-mediatedinhibitionofmigration. Locostatin treatment of depleted or RKIP2/2 MEFs reveals cytoskeletal disruption and microtubule abnormalities in the spindle. Conclusions/Significance:Theseresultssuggestthatlocostatin’seffectsoncytoskeletalstructureandmigrationarecaused throughmechanismsindependentofitsbindingtoRKIPandRaf/MAPkinas