dpAkt initPI45P2BaF3 vPIP3basal 0 initPI3KtBaF3 0 initPTENBaF3 vPI45P2 kshbasal initSHIP1tBaF3 initRpSHIP1 initAkttBaF3 kAkt dpAkt lAkt dpAkt initPI45P2BaF3 vPIP3basal 0 initPI3KtBaF3 0 initPTENBaF3 vPI45P2 kshbasal initSHIP1tBaF3 initRpSHIP1 kAkt dpAkt initPI45P2BaF3 vPIP3basal 0 initPI3KtBaF3 0 initPTENBaF3 vPI45P2 kshbasal initSHIP1tBaF3 initRpSHIP1 initPDK1tBaF3 kPDK1 lPDK1 initPI45P2BaF3 vPIP3basal 0 initPI3KtBaF3 0 initPTENBaF3 vPI45P2 kshbasal initSHIP1tBaF3 initRpSHIP1 kPDK1 vpAkt initPI45P2BaF3 vPIP3basal 0 initPI3KtBaF3 0 initPTENBaF3 vPI45P2 kshbasal initSHIP1tBaF3 initRpSHIP1 initPI45P2BaF3 vPIP3basal 0 initPI3KtBaF3 0 initPTENBaF3 vPI45P2 kshbasal initSHIP1tBaF3 initRpSHIP1 initPDK1tBaF3 kPDK1 lPDK1 initPI45P2BaF3 vPIP3basal 0 initPI3KtBaF3 0 initPTENBaF3 vPI45P2 kshbasal initSHIP1tBaF3 initRpSHIP1 kPDK1 kAkt vpAkt initRastBaF3 kbackRas kbackRas kdRas initRastBaF3 initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initRaftBaF3 initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initMektBaF3 kpMek kpMek kppMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf 2 lppMek kpMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf lpMek initMektBaF3 initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initMektBaF3 kpMek kpMek kppMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf 2 lppMek kpMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf lpMek kppMek lppMek initErktBaF3 initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initMektBaF3 kpMek kpMek kppMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf 2 lppMek kpMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf lpMek kppMek lppMek kpErk kpErk kppErk initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initMektBaF3 kpMek kpMek kppMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf 2 lppMek kpMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf lpMek kppMek lppMek 2 bDUSP3 lppErk kpErk initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initMektBaF3 kpMek kpMek kppMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf 2 lppMek kpMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf lpMek kppMek lppMek bDUSP3 lpErk initErktBaF3 initPI45P2BaF3 vPIP3basal 0 initPI3KtBaF3 0 initPTENBaF3 vPI45P2 kshbasal initSHIP1tBaF3 initRpSHIP1 initPI45P2BaF3 initPI3KtBaF3 initPTENBaF3 initSHIP1tBaF3 initRpSHIP1 initPI45P2BaF3 vPIP3basal 0 initPI3KtBaF3 0 initPTENBaF3 vPI45P2 kshbasal initSHIP1tBaF3 initRpSHIP1 initPDK1tBaF3 kPDK1 lPDK1 initPI45P2BaF3 vPIP3basal 0 initPI3KtBaF3 0 initPTENBaF3 vPI45P2 kshbasal initSHIP1tBaF3 initRpSHIP1 kPDK1 initPDK1tBaF3 initPI45P2BaF3 vPIP3basal 0 initPI3KtBaF3 0 initPTENBaF3 vPI45P2 kshbasal initSHIP1tBaF3 initRpSHIP1 initAkttBaF3 initPI45P2BaF3 vPIP3basal 0 initPI3KtBaF3 0 initPTENBaF3 vPI45P2 kshbasal initSHIP1tBaF3 initRpSHIP1 initPDK1tBaF3 kPDK1 lPDK1 initPI45P2BaF3 vPIP3basal 0 initPI3KtBaF3 0 initPTENBaF3 vPI45P2 kshbasal initSHIP1tBaF3 initRpSHIP1 kPDK1 kAkt vpAkt dpAkt lAkt dpAkt initPI45P2BaF3 vPIP3basal 0 initPI3KtBaF3 0 initPTENBaF3 vPI45P2 kshbasal initSHIP1tBaF3 initRpSHIP1 kAkt dpAkt initPI45P2BaF3 vPIP3basal 0 initPI3KtBaF3 0 initPTENBaF3 vPI45P2 kshbasal initSHIP1tBaF3 initRpSHIP1 initPDK1tBaF3 kPDK1 lPDK1 initPI45P2BaF3 vPIP3basal 0 initPI3KtBaF3 0 initPTENBaF3 vPI45P2 kshbasal initSHIP1tBaF3 initRpSHIP1 kPDK1 vpAkt initPI45P2BaF3 vPIP3basal 0 initPI3KtBaF3 0 initPTENBaF3 vPI45P2 kshbasal initSHIP1tBaF3 initRpSHIP1 initPI45P2BaF3 vPIP3basal 0 initPI3KtBaF3 0 initPTENBaF3 vPI45P2 kshbasal initSHIP1tBaF3 initRpSHIP1 initPDK1tBaF3 kPDK1 lPDK1 initPI45P2BaF3 vPIP3basal 0 initPI3KtBaF3 0 initPTENBaF3 vPI45P2 kshbasal initSHIP1tBaF3 initRpSHIP1 kPDK1 kAkt vpAkt initS6tBaF3 kbacks6 initTORC1 kas6t 0.5 kdphoss6 initTORC1 kas6t 1 RSKin kinrskb 1 Mekin kmekinb 1 kdphoss6 2 initTORC1 2 kas6t 2 2 initTORC1 kas6t kdphoss6 RSKin kdphoss6 2 kinrskb Mekin kdphoss6 2 kmekinb 4 initRSKtb initErktBaF3 initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initMektBaF3 kpMek kpMek kppMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf 2 lppMek kpMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf lpMek kppMek lppMek kpErk kpErk kppErk initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initMektBaF3 kpMek kpMek kppMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf 2 lppMek kpMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf lpMek kppMek lppMek 2 bDUSP3 lppErk kpErk initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initMektBaF3 kpMek kpMek kppMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf 2 lppMek kpMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf lpMek kppMek lppMek bDUSP3 lpErk initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initMektBaF3 kpMek kpMek kppMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf 2 lppMek kpMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf lpMek kppMek lppMek kppErk bDUSP3 lppErk karsk kas6r initTORC1 2 RSKin kas6t 2 kinrskb initTORC1 2 Mekin kas6t 2 kmekinb 2 initTORC1 RSKin kas6t kdphoss6 kinrskb 2 initTORC1 Mekin kas6t kdphoss6 kmekinb RSKin Mekin kdphoss6 2 kinrskb kmekinb initTORC1 2 RSKin Mekin kas6t 2 kinrskb kmekinb 2 initTORC1 RSKin Mekin kas6t kdphoss6 kinrskb kmekinb 1 2 RSKin kdphoss6 kinrskb Mekin kdphoss6 kmekinb initTORC1 RSKin kas6t kinrskb initTORC1 Mekin kas6t kmekinb RSKin Mekin kdphoss6 kinrskb kmekinb initTORC1 RSKin Mekin kas6t kinrskb kmekinb kas6r RSKin kinrskb 1 Mekin kmekinb 1 kas6r kbacks6 kdphoss6 initTORC1 kas6t 0.5 kdphoss6 initTORC1 kas6t 1 RSKin kinrskb 1 Mekin kmekinb 1 kdphoss6 2 initTORC1 2 kas6t 2 2 initTORC1 kas6t kdphoss6 RSKin kdphoss6 2 kinrskb Mekin kdphoss6 2 kmekinb 4 initRSKtb initErktBaF3 initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initMektBaF3 kpMek kpMek kppMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf 2 lppMek kpMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf lpMek kppMek lppMek kpErk kpErk kppErk initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initMektBaF3 kpMek kpMek kppMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf 2 lppMek kpMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf lpMek kppMek lppMek 2 bDUSP3 lppErk kpErk initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initMektBaF3 kpMek kpMek kppMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf 2 lppMek kpMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf lpMek kppMek lppMek bDUSP3 lpErk initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initMektBaF3 kpMek kpMek kppMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf 2 lppMek kpMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf lpMek kppMek lppMek kppErk bDUSP3 lppErk karsk kas6r initTORC1 2 RSKin kas6t 2 kinrskb initTORC1 2 Mekin kas6t 2 kmekinb 2 initTORC1 RSKin kas6t kdphoss6 kinrskb 2 initTORC1 Mekin kas6t kdphoss6 kmekinb RSKin Mekin kdphoss6 2 kinrskb kmekinb initTORC1 2 RSKin Mekin kas6t 2 kinrskb kmekinb 2 initTORC1 RSKin Mekin kas6t kdphoss6 kinrskb kmekinb 1 2 RSKin kdphoss6 kinrskb Mekin kdphoss6 kmekinb initTORC1 RSKin kas6t kinrskb initTORC1 Mekin kas6t kmekinb RSKin Mekin kdphoss6 kinrskb kmekinb initTORC1 RSKin Mekin kas6t kinrskb kmekinb kas6r RSKin kinrskb 1 Mekin kmekinb 1 kas6r initS6tBaF3 initTORC1 initRSKtb initAkttBaF3 0.5 kdphoss6 initTORC1 kas6t 1 RSKin kinrskb 1 Mekin kmekinb 1 kdphoss6 2 initTORC1 2 kas6t 2 2 initTORC1 kas6t kdphoss6 RSKin kdphoss6 2 kinrskb Mekin kdphoss6 2 kmekinb 4 initRSKtb initErktBaF3 initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initMektBaF3 kpMek kpMek kppMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf 2 lppMek kpMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf lpMek kppMek lppMek kpErk kpErk kppErk initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initMektBaF3 kpMek kpMek kppMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf 2 lppMek kpMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf lpMek kppMek lppMek 2 bDUSP3 lppErk kpErk initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initMektBaF3 kpMek kpMek kppMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf 2 lppMek kpMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf lpMek kppMek lppMek bDUSP3 lpErk initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initMektBaF3 kpMek kpMek kppMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf 2 lppMek kpMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf lpMek kppMek lppMek kppErk bDUSP3 lppErk karsk kas6r initTORC1 2 RSKin kas6t 2 kinrskb initTORC1 2 Mekin kas6t 2 kmekinb 2 initTORC1 RSKin kas6t kdphoss6 kinrskb 2 initTORC1 Mekin kas6t kdphoss6 kmekinb RSKin Mekin kdphoss6 2 kinrskb kmekinb initTORC1 2 RSKin Mekin kas6t 2 kinrskb kmekinb 2 initTORC1 RSKin Mekin kas6t kdphoss6 kinrskb kmekinb 1 2 RSKin kdphoss6 kinrskb Mekin kdphoss6 kmekinb initTORC1 RSKin kas6t kinrskb initTORC1 Mekin kas6t kmekinb RSKin Mekin kdphoss6 kinrskb kmekinb initTORC1 RSKin Mekin kas6t kinrskb kmekinb kas6r RSKin kinrskb 1 Mekin kmekinb 1 initErktBaF3 initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initMektBaF3 kpMek kpMek kppMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf 2 lppMek kpMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf lpMek kppMek lppMek kpErk kpErk kppErk initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initMektBaF3 kpMek kpMek kppMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf 2 lppMek kpMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf lpMek kppMek lppMek 2 bDUSP3 lppErk kpErk initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initMektBaF3 kpMek kpMek kppMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf 2 lppMek kpMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf lpMek kppMek lppMek bDUSP3 lpErk initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf initMektBaF3 kpMek kpMek kppMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf 2 lppMek kpMek initRaftBaF3 initRastBaF3 kbackRas kbackRas kdRas kpRaf kpRaf lpRaf lpMek kppMek lppMek kppErk bDUSP3 lppErk 412.8573 pS6 Epodegradation BaF3Epo kSHIP1 SHIP1tBaF3 RpSHIP1 pEpoR RpSHIP1 lSHIP1 RpSHIP1 EpoRactivation1 1 phos2 Ki1 EpoRBaF3 pEpoR 1 kPI3K 1 kPI3K 1 kPI3K kPI3Kras 1 kPI3K kPI3Kras 1 kPI3K 1 kPI3K kPI3Kras 1 BaF3Epo nb ksatb nb BaF3Epo nb vPIP3 PI45P2BaF3 kPI3K 1 kPI3K 1 kPI3K kPI3Kras 1 pEpoR vPIP3 main1 PI45P2BaF3 kPI3K kPI3Kras 1 kPI3K 1 kPI3K kPI3Kras 1 pEpoR kshbasal PIP3 SHIP1tBaF3 RpSHIP1 vPI45P2 PIP3 PTENBaF3 vPI34P2 PIP3 RpSHIP1 kPDK1 PIP3 PDK1tBaF3 PIP3PDK1 lPDK1 PIP3PDK1 kAkt PIP3 AkttBaF3 PIP3Akt pAkt lAkt PIP3Akt vpAkt PIP3Akt PIP3PDK1 Phosphataseactivation1 PhosphatasetBaF3 actPhosphatase pEpoR vpAkt PIP3Akt PIP3PDK1 vpAkt PIP3Akt PIP3PDK1 1 kaktinb Aktin dpAkt pAkt vPIP3basal PI45P2BaF3 PI3KtBaF3 kPI3K 1 kPI3K 1 kPI3K kPI3Kras 1 pEpoR kPI3K kPI3Kras 1 kPI3K 1 kPI3K kPI3Kras 1 pEpoR vPIP3basal main1 PI45P2BaF3 kpes Sostb pSos RpSos ppErk kdpes pSos kSos Sostb RpSos pSos pEpoR RpSos lSos RpSos kpes RpSos ppErk Phosphatasedeactivation1 actPhosphatase kbackRas RastBaF3 GTPRas kPI3K kPI3Kras 1 kPI3K 1 kPI3K kPI3Kras 1 pEpoR kaRas RpSos RastBaF3 GTPRas kPI3K kPI3Kras 1 kPI3K 1 kPI3K kPI3Kras 1 pEpoR kdRas GTPRas kpRaf GTPRas kPI3K kPI3Kras 1 kPI3K 1 kPI3K kPI3Kras 1 pEpoR RaftBaF3 pRaf lpRaf pRaf kpMek pRaf MektBaF3 pMek ppMek lpMek pMek kppMek pRaf pMek lppMek ppMek kpErk ppMek ErktBaF3 pErk ppErk pEpoRdeactivation1 pEpoR actPhosphatase lpErk bDUSP3 pErk kppErk ppMek pErk 1 kmekinb Mekin lppErk bDUSP3 ppErk ppErk pAkt kvpakt pAkt mTORt mTORa TORC1 TORC2 kvppErk RSKa 1 kinrskb RSKin mTORt mTORa TORC1 TORC2 kdactm mTORa kst1 1 kinrapab Rapamycin mTORa TORC1 TORC2 Raptorb TORC1 kdt1 TORC1 Phosact1 pEpoR n1 Ji1 n1 pEpoR n1 kdactm TORC1 kst2 mTORa TORC2 TORC1 Rictorb TORC2 kdt2 TORC2 kdactm TORC2 karsk 1 kinrskb RSKin RSKtb RSKa ppErk kdrsk RSKa kas6t TORC1 S6tBaF3 pS6 kas6r RSKa S6tBaF3 pS6 kbacks6 S6tBaF3 pS6 kdphoss6 pS6 Phosdeact1 phos2 pS6 pbk2correct cycleaktinb pAkt cyclemekinb ppErk maxccb pboffcorrect 60