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1、Oncogene(2012)31,1001–1012&2012MacmillanPublishersLimitedAllrightsreserved0950-9232/12www.nature.com/oncORIGINALARTICLEARac1/PAK1cascadecontrolsb-cateninactivationincoloncancercellsGZhu1,YWang1,BHuang1,JLiang1,YDing1,AXu2andWWu11ProteinScienceLaboratoryoftheMinistryofEducation,School
2、ofLifeSciences,TsinghuaUniversity,Beijing,Chinaand2BeijingFriendshipHospital,Beijing,ChinaP21-activatedkinase1(PAK1)isassociatedwithcolonglycogensynthasekinase-3bsequentiallyphosphorylatecancerprogressionandmetastasis,whereasthemolecularN-terminalresidualsofb-cateninandthiscreatesthe
3、mechanismremainselusive.Here,weshowthatdown-recognizingmotiffortheE3-ligaseb-Trcp.APCisalsoregulationofPAK1incoloncancercellsreducestotalcrucialforcaptureofb-catenininthedegradationb-cateninlevel,aswellascellproliferation.Mechanisti-complexanditbindsb-catenindirectlyviaitscentrallyca
4、lly,PAK1directlyphosphorylatesb-cateninproteinsatlocalizedarmadillorepeats(Xingetal.,2004).UponSer675siteandthisleadstomorestableandtranscrip-Wntactivation,accumulatedb-cateninentersthetionalactiveb-catenin.Corroboratingtheseresults,PAK1nucleusandbindstotheTCF/LEFfamilytranscrip-isre
5、quiredforfullWntsignaling,andsuperactivationtionalfactorsandinducestheexpressionofitstargetofb-cateninisachievedbysimultaneousknockdowngenes(Moonetal.,2004;Mosimannetal.,2009).TheofadenomatouspolyposiscoliproteinandactivationofkeyeventofbothWntsignalingtransductionandPAK1.Moreover,we
6、showthatRac1functionsupstreamcancerouscellproliferationistheregulationofb-cateninofPAK1incoloncancercellsandcontributestob-cateninstabilityandactivity.InadditiontoitsN-terminalphosphorylationandaccumulation.Weconcludethataresidues,Ser552(Fangetal.,2007)andSer675(HinoRac1/PAK1cascadec
7、ontrolsb-cateninS675phosphory-etal.,2005;Taurinetal.,2006)ofb-cateninhavealsolationandfullactivationincoloncancercells.Supportingbeenidentifiedaspotentialphosphorylationsitesandthisconclusion,overexpressionofPAK1isobservedinmayaffectitssignalingactivityorproteinstability.70%ofcoloncan
8、cersamplesan
