Analysis of STAT1 Activation by Six FGFR3 Mutants Associated with Skeletal Dysplasia Undermines Dominant Role of STAT1 in FGFR3 Signaling in Cartilage 英文参考文献.docVIP

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Analysis of STAT1 Activation by Six FGFR3 Mutants Associated with Skeletal Dysplasia Undermines Dominant Role of STAT1 in FGFR3 Signaling in Cartilage 英文参考文献.doc

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Analysis of STAT1 Activation by Six FGFR3 Mutants Associated with Skeletal Dysplasia Undermines Dominant Role of STAT1 in FGFR3 Signaling in Cartilage 英文参考文献

AnalysisofSTAT1ActivationbySixFGFR3Mutants AssociatedwithSkeletalDysplasiaUndermines DominantRoleofSTAT1inFGFR3SignalinginCartilage PavelKrejci1,2,3*,LisaSalazar4,TamaraA.Kashiwada4,KatarinaChlebova1,AlenaSalasova1 ,Leslie MichelsThompson4,VitezslavBryja1,2,AloisKozubik1,2,WilliamR.Wilcox3,5 1DepartmentofAnimalPhysiologyandImmunology,InstituteofExperimentalBiology,MasarykUniversity,Brno,CzechRepublic,2DepartmentofCytokinetics,Institute ofBiophysicsASCR,Brno,CzechRepublic,3MedicalGeneticsInstitute,Cedars-SinaiMedicalCenter,LosAngeles,California,UnitedStatesofAmerica,4Departmentof PsychiatryandHumanBehavior,UniversityofCaliforniaIrvine,Irvine,California,UnitedStatesofAmerica,5DepartmentofPediatrics,UniversityofCaliforniaLosAngeles SchoolofMedicine,LosAngeles,California,UnitedStatesofAmerica Abstract ActivatingmutationsinFGFR3tyrosinekinasecauseseveralformsofhumanskeletaldysplasia.Althoughthemechanismsof FGFR3actionincartilagearenotcompletelyunderstood,itisbelievedthattheSTAT1transcriptionfactorplaysacentral roleinpathogenicFGFR3signaling.Here,weanalyzedSTAT1activationbytheN540K,G380R,R248C,Y373C,K650Mand K650E-FGFR3mutantsassociatedwithskeletaldysplasias.Inacell-freekinaseassay,onlyK650MandK650E-FGFR3caused activatorySTAT1(Y701)phosphorylation.Similarly,inRCSchondrocytes,HeLa,and293Tcellularenvironments,onlyK650M andK650E-FGFR3 caused strongSTAT1 activation.Other FGFR3mutantscaused weak(HeLa) orno activation(293T and RCS).ThiscontrastedwithERKMAPkinaseactivation,whichwasstronglyinducedbyallsixmutantsandcorrelatedwiththe inhibition of proliferation in RCS chondrocytes. Thus the ability to activate STAT1 appears restricted to the K650M and K650E-FGFR3mutants,whichhoweveraccountforonlyasmallminorityoftheFGFR3-relatedskeletaldysplasiacases.Other pathwayssuchasERKshouldthereforebeconsideredascentraltopathologicalFGFR3signalingincartilage. Citation: Krejci P, Salazar L, Kashiwada TA,Chlebova K, Salasova A,et al. (2008) AnalysisofSTAT1Activation by SixFGFR3 Mutants Associ