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1、Oncogene(2012)31,1001–1012&2012MacmillanPublishersLimitedAllrightsreserved0950-9232/12www.nature.com/oncORIGINALARTICLEARac1/PAK1cascadecontrolsb-cateninactivationincoloncancercellsGZhu1,YWang1,BHuang1,JLiang1,YDing1,AXu2andWWu11ProteinScienceLaboratoryoftheMinistryofE
2、ducation,SchoolofLifeSciences,TsinghuaUniversity,Beijing,Chinaand2BeijingFriendshipHospital,Beijing,ChinaP21-activatedkinase1(PAK1)isassociatedwithcolonglycogensynthasekinase-3bsequentiallyphosphorylatecancerprogressionandmetastasis,whereasthemolecularN-terminalresidua
3、lsofb-cateninandthiscreatesthemechanismremainselusive.Here,weshowthatdown-recognizingmotiffortheE3-ligaseb-Trcp.APCisalsoregulationofPAK1incoloncancercellsreducestotalcrucialforcaptureofb-catenininthedegradationb-cateninlevel,aswellascellproliferation.Mechanisti-comple
4、xanditbindsb-catenindirectlyviaitscentrallycally,PAK1directlyphosphorylatesb-cateninproteinsatlocalizedarmadillorepeats(Xingetal.,2004).UponSer675siteandthisleadstomorestableandtranscrip-Wntactivation,accumulatedb-cateninentersthetionalactiveb-catenin.Corroboratingthes
5、eresults,PAK1nucleusandbindstotheTCF/LEFfamilytranscrip-isrequiredforfullWntsignaling,andsuperactivationtionalfactorsandinducestheexpressionofitstargetofb-cateninisachievedbysimultaneousknockdowngenes(Moonetal.,2004;Mosimannetal.,2009).Theofadenomatouspolyposiscoliprot
6、einandactivationofkeyeventofbothWntsignalingtransductionandPAK1.Moreover,weshowthatRac1functionsupstreamcancerouscellproliferationistheregulationofb-cateninofPAK1incoloncancercellsandcontributestob-cateninstabilityandactivity.InadditiontoitsN-terminalphosphorylationand
7、accumulation.Weconcludethataresidues,Ser552(Fangetal.,2007)andSer675(HinoRac1/PAK1cascadecontrolsb-cateninS675phosphory-etal.,2005;Taurinetal.,2006)ofb-cateninhavealsolationandfullactivationincoloncancercells.Supportingbeenidentifiedaspotentialphosphorylationsitesandthi
8、sconclusion,overexpressionofPAK1isobservedinmayaffectitssignalingactivityorproteinstability.70%ofcoloncancersamplesan
