Direct Inhibition of GSK3β by the Phosphorylated Cytoplasmic Domain of LRP6 in Wntβ-Catenin Signaling 英文参考文献.docVIP

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Direct Inhibition of GSK3β by the Phosphorylated Cytoplasmic Domain of LRP6 in Wntβ-Catenin Signaling 英文参考文献.doc

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Direct Inhibition of GSK3β by the Phosphorylated Cytoplasmic Domain of LRP6 in Wntβ-Catenin Signaling 英文参考文献

DirectInhibitionofGSK3bbythePhosphorylated CytoplasmicDomainofLRP6inWnt/b-CateninSignaling ShunfuPiao1,Sun-HyeLee2,HyunjoonKim3,SoohwanYum1,JenniferL.Stamos4,YongbinXu1 ,Su-Jin Lee2,JaewonLee1,SangtaekOh5,Jin-KwanHan3,Bum-JoonPark2,WilliamI.Weis4,Nam-ChulHa1* 1College of Pharmacy and Research Institute for DrugDevelopment, Pusan National University,Busan, Korea, 2Department of Molecular Biology,College of Natural Sciences,PusanNationalUniversity,Busan,Korea,3DivisionofMolecularandLifeSciences,POSTECH,Pohang,Korea,4DepartmentsofStructuralBiologyandMolecular CellularPhysiology,StanfordUniversitySchoolofMedicine,Stanford,California,UnitedStatesofAmerica,5PharmcoGenomicsResearchCenter,InjeUniversity,Busan, Korea Abstract Wnt/b-cateninsignalingplaysacentralroleindevelopmentandisalsoinvolvedinadiversearrayofdiseases.Bindingof WntstothecoreceptorsFrizzledandLRP6/5leadstophosphorylationofPPPSPxSmotifsintheLRP6/5intracellularregion andtheinhibitionofGSK3bboundtothescaffoldproteinAxin.However,itremainsunknownhowGSK3bisspecifically inhibiteduponWntstimulation.Here,weshowthatoverexpressionoftheintracellularregionofLRP6containingaSer/Thr rich cluster and aPPPSPxS motif impairs theactivity of GSK3b in cells. Synthetic peptides containing the PPPSPxS motif stronglyinhibitGSK3binvitroonlywhentheyarephosphorylated.MicroinjectionofthesepeptidesintoXenopusembryos confirms that the phosphorylated PPPSPxS motif potentiates Wnt-induced second body axis formation. In addition, we show that the Ser/Thr rich cluster of LRP6 plays an important role in LRP6 binding to GSK3b. These observations demonstrate that phosphorylated LRP6/5 both recruits and directly inhibits GSK3b using two distinct portions of its cytoplasmicsequence,andsuggestanovelmechanismofactivationinthissignalingpathway. Citation:PiaoS,LeeS-H,KimH,YumS,StamosJL,etal.(2008)DirectInhibitionofGSK3bbythePhosphorylatedCytoplasmicDomainofLRP6inWnt/b-Catenin Signaling.PLoSONE3(12):e4046.doi:10.1371/journal.pone.0004046 Editor:Wenqi