R-Ras Regulates Migration through an Interaction with Filamin A in Melanoma Cells 英文参考文献.docVIP

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R-Ras Regulates Migration through an Interaction with Filamin A in Melanoma Cells 英文参考文献.doc

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R-Ras Regulates Migration through an Interaction with Filamin A in Melanoma Cells 英文参考文献

R-Ras Regulates Migration through an Interaction with Filamin A in Melanoma Cells JoannaE.Gawecka1,GenevieveS.Griffiths2,BarbroEk-Rylander3,JoeW.Ramos1,MichelleL.Matter2* 1NaturalProductsandCancerBiology,CancerResearchCenterofHawaii,UniversityofHawaiiatManoa,Honolulu,Hawaii,UnitedStatesofAmerica,2DepartmentofCell andMolecularBiology,JohnA.BurnsSchoolofMedicine,UniversityofHawaiiatManoa,Honolulu,Hawaii,UnitedStatesofAmerica,3DivisionofPathology,Department ofLaboratoryMedicine,KarolinskaInstitutet,KarolinskaUniversityHospital,Huddinge,Sweden Abstract Background: Changes in cell adhesion and migration in the tumor microenvironment are key in the initiation and progression of metastasis. R-Ras is one of several small GTPases that regulate cell adhesion and migration on the extracellularmatrix,howeverthemechanismhasnotbeencompletelyelucidated.Usingayeasttwo-hybridapproachwe soughttoidentifynovelR-Rasbindingproteinsthatmightmediateitseffectsonintegrins. Methods and Findings: WeidentifiedFilaminA(FLNa)asacandidateinteractingprotein.FLNaisanactin-bindingscaffold proteinthatalsobindstointegrinb1,b2andb7tailsandisassociatedwithdiversecellprocessesincludingcellmigration. Indeed, M2 melanoma cells require FLNa for motility. We further show that R-Ras and FLNa interact in co- immunoprecipitations and pull-down assays. Deletion of FLNa repeat 3 (FLNaD3) abrogated this interaction. In M2 melanomacellsactiveR-Rasco-localizedwithFLNabutdidnotco-localizewithFLNalackingrepeat3.Thus,activatedR-Ras binds repeat 3 of FLNa. The functional consequence of this interaction was that active R-Ras and FLNa coordinately increasedcellmigration.Incontrast,co-expression ofR-RasandFLNaD3hadasignificantlyreducedeffectonmigration. Whiletherewasenhancementofintegrinactivationandfibronectinmatrixassembly,celladhesionwasnotaltered.Finally, siRNAknockdownofendogenousR-RasimpairedFLNa-dependentfibronectinmatrixassembly. Conclusions: ThesedatasupportamodelinwhichR-Rasfunctionallyassociat