肿瘤常见信号通路

1JAK-STAT1)JAKSTATJAK-STATJAKSTAT(1)tyrosinekinaseassociatedreceptorJAK-STAT2?7IL-2?7GM-CSF/GHEGFPDGFIFNJAKJAK(2)JAKJanuskinasereceptortyrosinekinase,RTKJAKJAKJanuskinaseJanusJAKSH2JAK4JAK1JAK2JAK3Tyk27JAKJAKhomologydomain,JHJH1JH2JH6JH7(3)STATsignaltransducerandactivatoroftranscriptionSTATSTATSTATSTAT1-STAT6STATN-DNASH3SH2C-SH2SrcSH2GTFLLRFSS2)JAK-STATJAK-STATJAKJAKdockingsiteSH2STATJAKSTATSTATJAKJAKSTATIL-4STAT6IL-12STAT42p531)p53p531979LaneCrawfordSV40SV40T53kDap53TP53[3]p5390p53p53p53DNAp53TP5317P13.1p531114p5316-20kb111012457852.5kbmRNAp53p73p63p532)p53p53DNAp53DNADNADNAp53DNADNAp53mRNAp53p53ubiquitinationp53MDM2p53E3p53p53p53MDM2p53MDM2p53negativefeedbackregulator3)p53p53p53TP5350%51TP53TP53400TP53147TP5395.1%p53DNA175245248249273282p53p53MDM2p300p53p53TP53G:CA:T79%GT1/4TP53G:CT:AGTp53p53p53p53p53p53nutlinsp53MDM23NF-B1975E.A.CarswellL.J.Oldtumournecrosisfactor,TNFTNF1984TNFTNFTNFTNF1)TNFTNFTNF-aTNF-bTNF-aLipopolysaccharides,LPSTNF-blymphotoxin,LTTTNF-bTNF-a2.76kb43TNF-a23376157TNF-aTNF-a2)TNFNF-kBTNF-aTNF-bTNF-TNFTNFreceptor,TNFRTNFTRADDTRADDTRAF2RIPNF-BFADDTNFRTNFNF-kBNF-kBnuclearfactor-kappaB1986BkappaBGGGACTTTCCRel5NF-kB/RelRelAp65RelBC-Relp50/NF-kB1p50/RelAp52/NF-kB2300RelRelhomologydomain,RHDRelNF-kBDNANF-kBNF-kBIkBinhibitoryproteinofNF-kBTNF-aLPSTNFTNFTRADDTRADDTRAFTNFR-associatedfactorRIPreceptorinteractingproteinRIPIKKIkBkinaseNF-kBIKKIKKIKKabgIKKIkBaSer32Ser36bSer19Ser23IkBp50/p65/IkBIkBNF-kBnuclearlocalizationsignals,NLSDNA3)NF-kBNF-kBNF-kBNF-kBc-Relv-RelNF-kBCyclinD1c-MycNF-kBNF-kB75NF-kB2NF-kBICAM-1VCAM-1MMP-9NF-kBVEGFNF-kBCOX2NF-kBIFN-aIFN-bTNF-aIL-2G-CSFGM-CSFEPO6NF-kBNF-kBNF-kBp65p50RNAsiRNANF-kBTNF-aTNFTNF-aTNF-aTNF-aTNF-aIL-2IFN-g4RasPI(3)KmTOR1)RasPI(3)KmTORRasPI(3)KmTORRasPI(3)KmTORRasPI(3)KRasPI(3)KmTOR(1)PI(3)Kphosphatidylinositol-3-kinase-3-p85p110p85p110PIP2phosphatidylinositol4,5-bisphosphatePI3Pphosphatidylinositol3-phosphatePI3PAKTPDK1phosphoinositide-dependentkinase1(2)AKTPKBproteinkinaseBPI3K3AKT1AKT2AKT3(3)mTORmammaliantargetofrapamycin/1991rapamycinTORTORmTORmTORCPI3K/AKTRas/ERKmTORG1EGFreceptortyrosinekinase,RTKRTKGRasPI(3)KRasPI(3)KmTORmTORS6KS6kinase4EBP14Ebindingprotein1ATPmTORmTORTSC1TSC2LKB1mTORTSC1TSC2LKB1mTORPI(3)KRTKsRaf2)Ras-Raf1982R.A.Weinbergc-rasrasratsarcomaRasRasH-rasK-rasN-rasRas21kDap21RasGTP/GDPGTPGDPRasRaf-1[10]RasERK/MAPKRaf/A-rafB-rafC-rafRaf-1RasRTKsGRB2growthfactorreceptor-boundprotein2GRB2RTKSOSRasSOSRasGTPGDPRasRasGTPGDPRasRasRaf1RafMAPKMAPKKMEKMEKERK1/2extracellularsignalregulatedkinaseMAPKERKRafRasERKRasRas60%B-rafB-rafC-rafERKmTORRasRasNF1GAPGTPase-activatingproteinNF1GTPGTPRasRasmiRNAlet-7RasmRNARas3)Ras-PI(3)K20PI(3)K5PI(3)KRTKRasmTOR/AKTPI(3)K10%20%40%50%AKT2PI(3)KPI(3)Kp85?PTENphosphataseandtensinhomologPIP3mTOR4)Ras-RafRas-PI(3)KmTORmTOReverolimusdeforolimustemsirolimus5WntWntWnt1982R.NusseH.E.VarmusWntInt1integration1IntwgwinglessWntH.E.Varmus19891)WntWntWntWntFrizzledCK1DeshevelledGSK3APCAxin-CateninTCF/LEFWntWnt-CateninWnt/PCPplannercellpolaritypathwayGJNKc-JunN-terminalkinaseWnt/Ca2+Ca2+Wnt-CateninWntWnt(1)FrizzledFzdFrzWnt7GFZDNcysteinerichdomain,CRDWnt(2)DishevelledDshDvlDshAPCAxinGSK3-Catenin-CateninTCF/LEF(3)GSK3/WntGSK3-CateninN/-Catenin-TRCPproteasome(4)CK1caseinkinase11-CateninSer45GSK3-CateninThr41Ser37Ser33(5)AxinAPCGSK3CK1-CateninDishevelledPP2Aproteinphosphatase2AwntTCF/LEFGroucho-CateninWnt-CateninCadherin-CateninGSK3WntWntFZDDVLDVLGSK3-Catenin-Catenin-CateninLEF/TCFc-mycCyclinD1WntWntFZDDVL-Catenin-CateninTCF/LEF2)WntWntWnt1993VogelsteinAPCadenomatouspolyposiscoli-Catenin85%APCWnt-CateninAPCAPC-CateninGSK3GSK3-CateninSer/Thr-CateninAPCAPC-Catenin-Catenin-CateninTCF/LEF-Catenin-Catenin-Catenin-Cateninc-mycCyclinD110%-Catenin3500700-Catenin-CateninN-CateninWnt90%WntWntWnt/-CateninWnt6BMP1)BMPBMPbonemorphogeneticproteinTGF-transforminggrowthfactor-BMPBMP/BMPreceptor,BMPRBMPR2IBMPR1SmadBMPTGF-SmadIBMPR1SmadSmad1Smad5Smad8SmadSmad4commonSmadCo-SmadSmadDNA2)BMPcoloncoloniccryptmyofibroblastmuscularismucosaeBMPBMPBMPSmad1Smad5Smad8BMPBMPNogginBMPBMP3)BMP200811511010BMPSmad4TGF-BMPjuvenilepolyposissyndrome,JPS50-200JPS9%-50%50%JPSSmad4BMPR1ABMPBMPBMPJPSSmad70%BMP4)BMPBMPSchwarteSmad4Smad4BMP5Ras2MAPK5.1RasRas.,PDGFR,EGFR(Grb2),src2(SH2)(Shc,Syp),Grb2.,Grb2src3(SH3)mSos1,mSos2,C3G(dynamin).C3GCrkSH3Ras.CrkmSos1Ras.Grb2(Sos)Ras.,SosRas,GTPGDPRas,Ras,GTPGDPRas.RasGTPase,RasGAPs,RasGAPsRas.,Ras.,GTPRas,P120GAP,neurofibrominGAP1m,RasGAPs.5.2Ras5.2.1Ras/Raf,Ras/Raf.GTPGDPRas,Ras,,Raf1,RafMAPK(MAPKK),MAPKKMAPK.MAPK,,.,MAPKFos,JunAP1,mycDNA,.myc,.,DCyclin.DCyclinCyclin(CDK4CDK6),G1S.,Ras/RafG1.,Ras/RafG1.RasRafRaf,,RafRas(SrcPKC),MAPKRas().,.RasCyc2linP21Waf1/cip1,Ras,Cdk2CyclinECdk2CyclinA,DNA.5.2.2Rho/RacRhoGRas,30%Ras,RhoCdc42,Rho,Rac.Cdc42Rac,RacRho.,,,Cdc42RacRho.Rho,P21.RacCdc42MAPK,RhoSrcfos.,RacCdc42JunN,Jun,EIk1ATF2,Rho.RhoP21Waf1/cip1.RhoP21Waf1/cip1,RasS[10],P21Waf1/cip1RhoRasDNA,P21Waf1/cip1Ras.Ras2MAPK.,EGF;EGF,[11].,,ErbB2230%;,EGFR,,,EGFREGFR[12].ras25%,85%40%.ras,11,12,13,18,59,61,RasGAP,,RasGTP,RasRas2GTP,.raf,,Raf,;,Raf