Combinatorial Interventions for Control Tasks in Large-Scale Signaling Networks
Paola Vera-Licona
Computational Systems Medicine Research Group Center for Quantitative Medicine Cell Biology Department Institute for Systems Genomics
Follow me on http://twitter.com/compsysmed LBP@ LPS@
LPS + LBP <==> LPS:LBP IL-1beta-p17:IL-1RI:IL-1RAcP:MyD88:tollip:IRAK-4:(IRAK-1{pT209}{pT387}{p}n)2@
IL-1beta-p17:IL-1RI:IL-1RAcP:MyD88:tollip:IRAK-4:(IRAK-1{pT209}{pT387})2 + n ATP --> IL-1beta-p17:IL-1RI:IL-1RAcP:MyD88:tollip:IRAK-4:(IRAK-1{pT209}{pT387}{p}n)2 ST2:TIRAP@ + n ADP
ST2 + TIRAP IL-1beta-p17:IL-1RI:IL-1RAcP:MyD88:tollip:IRAK-4:(IRAK-1{pT209}{pT387})2@ <==> ST2:TIRAP
IL-1beta-p17:IL-1RI:IL-1RAcP:MyD88:tollip:IRAK-4:(IRAK-1{pT209})2 + 2 ATP --> IL-1beta-p17:IL-1RI:IL-1RAcP:MyD88:tollip:IRAK-4:(IRAK-1{pT209}{pT387})2 + 2 ADP ST2@ EGF:(ErbB1{pY})2:eps15{pY}:AP2:clathrin:dynamin --> EGF:(ErbB1{pY})2:eps15{pY}:AP2:clathrin:dynamin LPS:LBP@ IL-1beta-p17:IL-1RI:IL-1RAcP:MyD88:tollip:IRAK-4:(IRAK-1{pT209})2@ IL-1RA@
IL-1RII@ IL-1beta-p17:IL-1RI:IL-1RAcP:MyD88:tollip:IRAK-4:(IRAK-1)2 + 2 ATP --> IL-1beta-p17:IL-1RI:IL-1RAcP:MyD88:tollip:IRAK-4:(IRAK-1{pT209})2 TIRAP@ + 2 ADP CD14@
IL-1beta-p17:IL-1RI:IL-1RAcP:MyD88:tollip:IRAK-4:(IRAK-1)2@
IL-1beta-p17 + EGF:(ErbB1{pY})2:eps15{pY}:AP2:clathrin:dynamin@ IL-1RI:IL-1RAcP:MyD88:tollip:IRAK-4:(IRAK-1)2 ST2 + MyD88 <==> ST2:MyD88@IL-1beta-p17:IL-1RII:IL-1RAcP@ <==> IL-1beta-p17:IL-1RI:IL-1RAcP:MyD88:tollip:IRAK-4:(IRAK-1)2 MD-2@TLR4@ ST2:MyD88 Paola Vera-LiconaVera-Licona – Computational ResearchIL-1RI + IL-1RA clathrin@ GroupSystems Biology & <==> dynamin@ IL-1RI:IL-1RA AP2@ IL-1beta-p17 + IL-1RI:IL-1RA@ IL-1RII + IL-1RAcP <==> IL-1beta-p17:IL-1RII:IL-1RAcP LPS:LBP + CD14 <==> TLR4 + MD-2 + LPS:LBP:CD14 TIRAP <==> TLR4:MD-2:TIRAP IRF-7{p}:IRF-3{p}:CBP:p300 --> IRF-7{p}:IRF-3{p}:CBP:p300
TLR4 + MD-2 + MyD88 <==> EGF:(ErbB1{pY})2:eps15{pY} TLR4:MD-2:MyD88 + AP2 + clathrin + dynamin <==> p50:RelA-p65:IkappaB-alpha@ EGF:(ErbB1{pY})2:eps15{pY}:AP2:clathrin:dynamin IL-1RI:IL-1RAcP:MyD88:tollip:IRAK-4:(IRAK-1)2@
IL-1beta-p17@ tollip@ MyD88@ IL-1RI@ IL-1RAcP@
SIRT1@ IRF-7{p}:IRF-3{p}:CBP:p300@ (NGF)2:(p75NTR)2:TRAF6:IRAK-1{pT66}:p62:PKCiota:IKK-alpha{p}:IKK-beta{p}:(IKK-gamma{p})2@ AR (NR3C4){aceK630}{aceK632}{aceK633}:SIRT1@acetyl@ AR PKCiota@ ComputationalBioinformatics(NR3C4){aceK630}{aceK632}{aceK633}:SIRT1 SystemsIKK-alpha{p}:IKK-beta{p}:(IKK-gamma{p})2@ Medicine --> AR TLR4:MD-2:TIRAP@ p50:RelA-p65:IkappaB-alpha (NR3C4):SIRT1 + ATP --IKK-alpha{p}:IKK-beta{p}:(IKK-gamma{p})2--> + 3 acetyl (NGF)2:(p75NTR)2:TRAF6:IRAK-1{pT66}:p62:PKCiota:IKK-alpha{p}:IKK-beta{p}:(IKK-gamma{p})2 p50:RelA-p65:IkappaB-alpha{p} <==> + ADP (NGF)2:(p75NTR)2:TRAF6:IRAK-1{pT66}:p62:PKCiota LPS:LBP:CD14@(NGF)2:(p75NTR)2:TRAF6:IRAK-1{pT66}:p62:PKCiota:IKK-alpha:IKK-beta:(IKK-gamma)2 (NGF)2:(p75NTR)2:TRAF6:IRAK-1:p62:PKCiota@ + IL-1RI + endophilin@ TLR4:MD-2:MyD88@+ 4 ATP --> IKK-alpha{p}:IKK-beta{p}:(IKK-gamma{p})2 IL-1RAcP + (NGF)2:(p75NTR)2:TRAF6:IRAK-1{pT66}:p62:PKCiota:IKK-alpha{p}:IKK-beta{p}:(IKK-gamma{p})2 MyD88 + tollip Rap2B:GDP@ (NGF)2:(p75NTR)2:TRAF6:IRAK-1:p62:PKCiota + 4 ADP + IRAK-4 + 2 + ATP --> IRAK-1 <==> (NGF)2:(p75NTR)2:TRAF6:IRAK-1{pT66}:p62:PKCiota IL-1RI:IL-1RAcP:MyD88:tollip:IRAK-4:(IRAK-1)2 TRAM:TRIF:TBK1:IKK-i{pS172}:IRF-3:IRF-7:CBP:p300 + ADP AR + ATP --> (NR3C4){aceK630}{aceK632}{aceK633} TRAM:TRIF:TBK1:IKK-i{pS172} RhoA:GTP@ + SIRT1 <==> TRAM:TRIF:TBK1:IKK-i + IL-1beta-p17 + AR + ATP --> (NGF)2:(p75NTR)2:TRAF6:IRAK-1:p62 TBK1:TRIF:IKK-i{pS172}:IRF-7:IRF-3:CBP:p300IRF-7{p}:IRF-3{p}:CBP:p300 IL-1RI + (NR3C4){aceK630}{aceK632}{aceK633}:SIRT1TRAM:TRIF:TBK1:IKK-i{pS172} + PKCiota + ATP -->+ ADP+ ADP IL-1RAcP + <==> TBK1:TRIF:IKK-i{pS172} MyD88 <==> EGF:(ErbB1{pY})2:eps15{pY}@(NGF)2:(p75NTR)2:TRAF6:IRAK-1:p62:PKCiota + IL-1beta-p17:IL-1RI:IL-1RAcP:MyD88 IRF-7{p}:IRF-3{p}:CBP:p300 + ADP AR PC@ (NR3C4):SIRT1@
tollip:IRAK-1@ Center for Quantitative Medicine, Cellp50:RelA-p65:IkappaB-alpha{p}@ Biology Department IRAK-4@EGF:(ErbB1{pY})2:c-Cbl:CIN85:endophilin@ Rap2B:GDP + TRAM:TRIF:TBK1:IKK-i@ (NGF)2:(p75NTR)2:TRAF6:IRAK-1{pT66}:p62:PKCiota@ EGF:(ErbB1{pY})2:c-Cbl:CIN85 + endophilin GTP Smad3@ --GRP3{pY}--> TBK1:TRIF:IKK-i SMRT@ <==> RhoA:GTP NCOR1@ Rap2B:GTP + + ATP --> (NGF)2:(p75NTR)2:TRAF6:IRAK-1{pT66}:p62:PKCiota:IKK-alpha:IKK-beta:(IKK-gamma)2@ EGF:(ErbB1{pY})2:c-Cbl:CIN85:endophilin --p190RhoGAP{pY}--> GDP TBK1:TRIF:IKK-i{pS172} RhoA:GDP + p Rap2B:GTP@ LPS:LBP:CD14 + + ADP TLR4:MD-2:TIRAP <==> RhoA:GDP@ LPS:LBP:CD14:TLR4:MD-2:TIRAP TRAM:TRIF:TBK1:IKK-i{pS172}@ LPS:LBP:CD14 + TLR4:MD-2:MyD88 <==> choline@ LPS:LBP:CD14:TLR4:MD-2:MyD88 PIAS3:STAT5A@ TRAM:TRIF:TBK1:IKK-i{pS172}:IRF-3:IRF-7:CBP:p300@ Fe65@ TBK1:TRIF:IKK-i@ tollip:IRAK-1 + TBK1:TRIF:IKK-i{pS172}:IRF-7:IRF-3:CBP:p300@ IRAK-4 + 2 ATP TANK@ PC TBK1:TRIF:IKK-i{pS172}@ --> AR --EGF:(ErbB1{pY})2:ARF4:GTP:pld2--> tollip:IRAK-1{pS376}{pT387}:IRAK-4 IRAK-1@ PA + choline (NR3C4){aceK630}{aceK632}{aceK633}@ + 2 ADP IKK-alpha@ LPS:LBP:CD14:TLR4:MD-2:TIRAP:TRAM:TRIF:TBK1:IKK-i IKK-gamma@ Smad3 + AR (NGF)2:(p75NTR)2:TRAF6:IRAK-1:p62@ <==> (NR3C4):SIRT1 TBK1:TRIF:IKK-i{pS172}:TANK:IKK-alpha:IKK-beta:(IKK-gamma)2 BRG1@ IKK-beta@ LPS:LBP:CD14:TLR4:MD-2:TIRAP + 2 ATP --> PIAS3@ + HDAC1 + IRAK-1 + 2 ATP PA@ BAF47@ + TBK1:TRIF:IKK-i{pS172}:TANK:IKK-alpha:IKK-beta{pS177}{pS181}:(IKK-gamma)2 SMRT + NCOR1 --IRAK-4--> p190RhoGAP{pY}@ TRAM:TRIF:TBK1:IKK-i TBK1:TRIF:IKK-i{pS172}:TANK:IKK-alpha:IKK-beta:(IKK-gamma)2@ + 2 ADP prolactin:CypB <==> IRAK-1{pS376}{pT387} BAF155@ + PIAS3:STAT5A TRAM@ Smad3:AR + 2 ADP IRF-3@ <==> (NR3C4):SIRT1:HDAC1:SMRT:NCOR1IRF-7@ prolactin:CypB:STAT5A GRP3{pY}@ CBP@ IkappaB-alpha{p}@ + PIAS3 LPS:LBP:CD14:TLR4:MD-2:TIRAP:TRAM:TRIF:TBK1:IKK-i@ Smad3:AR EGF:(ErbB1{pY})2:eps15 p50:RelA-p65:IkappaB-alpha{p} prolactin:CypB (NR3C4):SIRT1:HDAC1:SMRT:NCOR1@(NGF)2:(p75NTR)2:TRAF6:IRAK-1{pT66}:p62:PKCiota + ATP --> <==> EGF:(ErbB1{pY})2:c-Cbl:CIN85@ prolactin:CypB:STAT5A@--> + EGF:(ErbB1{pY})2:eps15{pY} p50:RelA-p65 + IKK-alpha:IKK-beta:(IKK-gamma)2 prolactin:CypB Sprouty2@ CIN85@ NRIF@ + ADP IkappaB-alpha{p} prolactin:CypB <==> APP-p3@ --> LPS:LBP:CD14:TLR4:MD-2:TIRAP:TRAM:TRIF@ (NGF)2:(p75NTR)2:TRAF6:IRAK-1{pT66}:p62:PKCiota:IKK-alpha:IKK-beta:(IKK-gamma)2 AICD59@ prolactin:CypB TBK1:TRIF:IKK-i{pS172}:TANK:IKK-alpha:IKK-beta{pS177}{pS181}:(IKK-gamma)2@ TBK1:TRIF:IKK-i{pS172} Tip60 + Fe65 + gamma-secretase@ GRP3@ IL-1beta-p17:IL-1RI:IL-1RAcP:MyD88@ Pyk2@ + TANK + AICD59 <==> IKK-alpha:IKK-beta:(IKK-gamma)2 Tip60:Fe65:AICD59 Tip60:Fe65:AICD59@ p75NTR-ICD{palC}@ dsRNA:TLR3:TRIF:TBK1:IKK-i IKK-alpha + <==> (NGF)2:(p75NTR)2:TRAF6:IRAK-1@ BAF47 + <==> IKK-beta + 2 TBK1:TRIF:IKK-i{pS172}:TANK:IKK-alpha:IKK-beta:(IKK-gamma)2TRAM:TRIF:TBK1:IKK-i{pS172} BAF155 + BRG1 dsRNA:TLR3@dsRNA:TLR3 + IKK-gamma + IRF-3 + IRF-7 p75NTR-CTF{palC} + TBK1:TRIF:IKK-i <==> TBK1:TRIF:IKK-i{pS172}+ CBP + p300 synaptotagmin-11@ --gamma-secretase--> Pellino1:IRAK-4@ p53:importin-alpha (p53{pS15}{pT18}{pS20}{pS392}{ace})4 IKK-alpha:IKK-beta:(IKK-gamma)2 + IRF-7 + IRF-3<==> parkin@ p75NTR-ICD{palC} EGF:(ErbB1{pY})2:Src:mDia1:SPIN90:p190RhoGAP LPS:LBP:CD14:TLR4:MD-2:TIRAP --> <==> TRAM:TRIF:TBK1:IKK-i{pS172}:IRF-3:IRF-7:CBP:p300+ CBP + p300 + protein Jak2@ + 2 NTP --> p190RhoGAP@ + TRAM + TRIF p53:importin-alpha BAF47:BAF155:BRG1:(p53{pS15}{pT18}{pS20}{pS392}{ace})4 <==> remnants EGF:(ErbB1{pY})2:ARF4:GTP:pld2@ prolactin:CypB@ EGF:(ErbB1{pY})2:Src:mDia1:SPIN90{pY} <==> + TBK1:TRIF:IKK-i{pS172}:IRF-7:IRF-3:CBP:p300Pellino1:IRAK-4:IRAK-1{pS376}{pT387}{p}n:TRAF6:TAB2 LPS:LBP:CD14:TLR4:MD-2:TIRAP:TRAM:TRIF p50:RelA-p65 BAF47:BAF155:BRG1:(p53{pS15}{pT18}{pS20}{pS392}{ace})4@p190RhoGAP{pY} <==> LPS:LBP:CD14:TLR4:MD-2:TIRAP@ --> + 2 NDP LPS:LBP:CD14:TLR4:MD-2:TIRAP:TRAM:TRIF IRAK-1{pS376}{pT387}{p}n:TRAF6:TAB2AR tollip:IRAK-1{pS376}{pT387}:IRAK-4@ p50:RelA-p65 Data-Driven Static and Dynamical+ TBK1 + IKK-i (NR3C4){aceK630}{aceK632}{aceK633}:p300 + APP-C83 <==> AR <==> Hic-5{p}:Pyk2@ Pellino1:IRAK-4 --gamma-secretase-->--gamma-secretase--> EGF:(ErbB1{pY})2:Src:mDia1:SPIN90:p190RhoGAP@ (NR3C4){aceK630}{aceK632}{aceK633} LPS:LBP:CD14:TLR4:MD-2:TIRAP:TRAM:TRIF:TBK1:IKK-i AICDepsilonAICD59 + + CypB@ Hic-5:Pyk2 + + p300 EGF:(ErbB1{pY})2:c-Cblp75NTR-ICD{palC} APP-p3 (NGF)2:(p75NTR)2:TRAF6:IRAK-1 Jak2 + PRLR-L GRP3 + ATP ATP --> + NRIF <==> mDia1@ LPS:LBP:CD14:TLR4:MD-2:MyD88@ + CIN85 <==> APP-C99 + p62 <==> --EGF:(ErbB1{pY})2:Src--> Hic-5{p}:Pyk2 + IRAK-1{pS376}{pT387}@ p75NTR-ICD{palC}:NRIF IkappaB-alpha, <==> EGF:(ErbB1{pY})2:c-Cbl:CIN85--gamma-secretase--> EGF:(ErbB1{pY})2:c-Cbl:CIN85 (NGF)2:(p75NTR)2:TRAF6(NGF)2:(p75NTR)2:TRAF6:IRAK-1:p62 Vav-2@ SPIN90@ GRP3{pY} + ADP ADP EGF:(ErbB1{pY})2:c-Cbl IkappaB-beta:p50:RelA-p65 PRLR-L:Jak2 AICD59 + + IRAK-1 SM@ + Sprouty2 AICDepsilon@EGF:(ErbB1{pY}{ub}n)2:c-Cbl:UbcH7:CIN85{ub}@+ UbcH7 + + ATP Hic-5:Pyk2@ EGF:(ErbB1{pY})2:c-Cbl:Sprouty2{pY}@ Abeta40 <==> <==> ubiquitin --> Controllability--TBK1:TRIF:IKK-i{pS172}:TANK:IKK-alpha:IKK-beta{pS177}{pS181}:(IKK-gamma)2--> of Large Scale Networks (NGF)2:(p75NTR)2:TRAF6:IRAK-1 EGF:(ErbB1{pY})2:c-Cbl:Sprouty2{pY} EGF:(ErbB1{pY}{ub}n)2:c-Cbl:UbcH7:CIN85{ub} IkappaB-alpha, EGF:(ErbB1{pY})2:Src Hic-5 + Pyk2 IkappaB-beta{pS}:p50:RelA-p65 + mDia1 + hnRNPA1@ <==> + ADP SPIN90 + Hic-5:Pyk2 Abeta40@ PRLR-L@ UbcH7{ub(1)} + p190RhoGAP synaptotagmin-11{ub(n)}@ <==> AR synaptotagmin-11 p53:importin-alpha@ (NR3C4){aceK630}{aceK632}{aceK633}:p300@ + n ubiquitin EGF:(ErbB1{pY})2:Src:mDia1:SPIN90:p190RhoGAP HDAC1@ prolactin + IRAK-1{pS376}{pT387}{p}n:TRAF6:TAB2@ --parkin--> UbcH7 + p50:RelA-p65@ CypB <==> DET1@ VEGF-A@ prolactin:CypB CUL4A@ synaptotagmin-11{ub(n)} STAT1alpha{pY}:STAT3{pY} DDB1@ --> importin-alpha@ EGF:(ErbB1{pY})2:ARF4:GTP Pellino1:IRAK-4:IRAK-1{pS376}{pT387}{p}n:TRAF6:TAB2@ EGF:(ErbB1{pY})2:eps15@ STAT1alpha{pY}:STAT3{pY} NT-3@ TRAF6:UbcH7{ub(1)}:p75NTR:(NGF-p13)2:trkA{pY490}:p62 + Unc18A:pld2 EGF:(ErbB1{pY})2:SrcdsRNA:TLR3:TRIF:TBK1:IKK-i@ Roc1@ Tip60@ p75NTR-CTF{palC}@ SM p75NTR-ICD{palC}:NRIF{ub{K63}(n)K19}:p62 --> <==> PRLR-L:Jak2@ + mDia1 + --N-SMase--> --> TRAF6:UbcH7:p75NTR:(NGF-p13)2:trkA{pY490}{ub{K63}(1)K485}p62 EGF:(ErbB1{pY})2:ARF4:GTP:pld2 trkC@ Modelling SPIN90 + Vav-2 p75NTR-ICD{palC}:NRIF{ub{K63}(n)K19}:p62 ceramide EGF:(ErbB1{pY})2:Src:mDia1:SPIN90{pY}@ (p53{pS15}{pT18}{pS20}{pS392}{ace})4@ Rhox5@IKK-alpha:IKK-beta:(IKK-gamma)2@AR <==> TBK1@ TRIF@ + Unc18A IKK-i@ (NR3C4):Epicardin:HDAC1 AR TRAF6:UbcH7{ub(1)}:p75NTR:(NGF-p13)2:trkA{pY490}:p62@ AR Pellino1@ EGF:(ErbB1{pY})2:Src:mDia1:SPIN90:Vav-2 --/ Rhox5 (NR3C4):Epicardin MO000017728->MO000169115 (NR3C4):Epicardin:HDAC1@AR (NR3C4):ARA54+ HDAC1 <==> AR + hnRNPA1 ceramide@ 2 VEGF-A (NR3C4):Epicardin:HDAC1 IRAK-2@ <==> AR IRAK-1{pS376}{pT387}{p}n:TRAF6:TAB2IRAK-1{pS376}{pT387}{p}n@ p75NTR-ICD{palC}:NRIF:TRAF6 IkappaB-alpha, Nrdp1@ <==> (NR3C4):ARA54:hnRNPA1 --> --n IkappaB-beta:p50:RelA-p65@ IL-1beta-p17:IL-1RI:IL-1RAcP:MyD88 VEGF-A:VEGF-A IRAK-1{pS376}{pT387}{p}n UbcH7{ub(1)}--> + ● palmityl-CoA@ + TRAF6:TAB2 p75NTR-ICD{palC}:NRIF{ub{K63}(n)K19}:TRAF6 tollip:IRAK-1{pS376}{pT387}:IRAK-4 EGF:(ErbB1{pY})2:Src:mDia1:SPIN90:Vav-2@ + IRAK-2 HDAC1:AR plk3@ 2 NT-3 + 2 trkC <==> (NR3C4):Tip60@ AR HDAC1:AR APP-C83@ <==> p300@IL-1beta-p17:IL-1RI:IL-1RAcP:MyD88:tollip:IRAK-1{pS376}{pT387}:IRAK-4:IRAK-2 IkappaB-alpha, p53{ub(1)K370}{ub(1)K372} TLR3@ EGF:(ErbB1{pY})2:Src@ (NR3C4):p300(NR3C4){ace}:Tip60@ + p75NTR-ICD{palC}:NRIF@ CascadingPIRH2@ Failures (NT-3)2:(trkC)2 LPS:LBP:CD14:TLR4:MD-2:MyD88 Roc1 + CUL4A 3 acetyl-CoA IkappaB-beta{pS}:p50:RelA-p65@ --> + DDB1 + DET1 + TRAF6:UbcH7:p75NTR:(NGF-p13)2:trkA{pY490}{ub{K63}(1)K485}p62@eps15@ dsRNA@ MO000043847->MO000118480--> ARHDAC1:AR STAT1alpha{pY}:STAT3{pY}@ p53{ub(1)K370}{ub(1)K372} prolactin + 2 IRAK-1{pS376}{pT387} EGF:(ErbB1{pY})2:c-Cbl@ p53 + + COP1LPS:LBP:CD14:TLR4:MD-2:MyD88:IRAK-1{pS376}{pT387} <==> (NR3C4){aceK630}{aceK632}{aceK633}:p300 (NR3C4):Tip60 UbcH7@ PRLR-L:Jak2 <==> importin-alpha (STAT1alpha{pY})2 Fam@ Roc1:CUL4A:DDB1:DET1:COP1 + TRAF6:TAB2 + 3 CoA+ acetyl-CoA setd7@ <==> LPS:LBP:CD14:TLR4:MD-2:MyD88:IRAK-1{pS376}{pT387} <==> --> NADH@ + ATP --> --> HDAC1:AR EGF:(ErbB1{pY})2:Src{pY}:Pyk2{pY}:STAT3@ Unc18A:pld2@Unc18A@ prolactin:(PRLR-L:Jak2)2 Hic-5@ p53:importin-alpha (STAT1alpha{pY})2 LPS:LBP:CD14:TLR4:MD-2:MyD88 (NR3C4){ace}:Tip60 APP-C99@ p62@ prolactin@ EGF:(ErbB1{pY})2:Src:Pyk2:STAT3 + + CoA EGF:(ErbB1{pY})2:ARF4:GTP@ ErbB3{ub}@ ceramide --> prlr@ LPS:LBP:CD14:TLR4:MD-2:TIRAP + 2 ATP --> IkappaB-alpha, VEGF-A:VEGF-A@ IRAK-1{pS376}{pT387}{p}n:TRAF6:TAB2 AR p75NTR-ICD{palC}:NRIF{ub{K63}(n)K19}:p62@ JNK1{pT183}{pY185} p/CAF@ + IRAK-2 COP1@ IkappaB-beta:p50:RelA-p65 p62 + N-SMase@ IL-1beta-p17:IL-1RI:IL-1RAcP:MyD88:tollip:IRAK-1{pS376}{pT387}:IRAK-4:IRAK-2+ ADP (NR3C4):p300@ EGF:(ErbB1{pY})2:Src{pY}:Pyk2{pY}:STAT3 (Reverse Engineering) <==> + TRAF6:TAB2 MO000043846->MO000118484 + 2 ADP + ATP p75NTR:(NGF-p13)2:trkA{pY490} p53{ub(1)K370} Ubc5{ub(1)} + LPS:LBP:CD14:TLR4:MD-2:TIRAP:IRAK-2AR + Pellino1 + --IKK-alpha{p}:IKK-beta{p}:(IKK-gamma)2--> + --> TAF(II)31@ p75NTR-ICD{palC}:NRIF:TRAF6@ ARF4:GDP@ ErbB3 + beta-catenin{pS33}{pS45}{ub(n)}:CKI-alpha, (NR3C4):ARA54:hnRNPA1@ ATP --> p75NTR-ICD{palC}:NRIF{ub{K63}(n)K19}:TRAF6@UbcH7{ub(1)}@ IkappaB-alpha, TRAF6:UbcH7{ub(1)} p53{ub(1)K370} n ubiquitin + insulin@ ubiquitin VEGFR-2@ CKI-delta:axin1{p}:APC{p}:GSK3beta:beta-TrCP1:Cul-1{nedd}:Skp1 dsRNA:TLR3:TRIF IL-1beta-p17:IL-1RI:IL-1RAcP:MyD88:tollip:IRAK-2 IkappaB-beta{pS}:p50:RelA-p65● (NGF)2:(p75NTR)2:TRAF6@ <==> beta-catenin{pS33}{pS45}:axin1{p}:CKI-alpha, AR --Nrdp1--> CKI-delta:APC{p}:GSK3beta:beta-TrCP1:Cul-1{nedd}:Skp1 + Fam <==> InsR@ + TBK1 + IKK-i + + ADP TRAF6:UbcH7{ub(1)}:p75NTR:(NGF-p13)2:trkA{pY490}:p62STAT3{pY}@ p75NTR-CTF + Ubc5 + --> APC{p}:axin1{p}:GSK3beta:CKI-alpha, EGF:(ErbB1{pY})2:Src:mDia1:SPIN90:Vav-2 <==> (NR3C4):ARA54@Pellino1:IRAK-4:IRAK-1{pS376}{pT387}{p}n:TRAF6:TAB2 AR p53{ub(n)}@ 4 IKK-alpha:IKK-beta:(IKK-gamma)2 IL-1beta-p17:IL-1RI:IL-1RAcP:MyD88:tollip:IRAK-2@ ErbB3{ub} CKI-delta:beta-catenin{pS33}{pS45}{ub(n)}:Fam:beta-TrCP1:Cul-1{nedd}:Skp1 + 2 NTP --> atad2@ dsRNA:TLR3:TRIF:TBK1:IKK-i (NR3C4):Epicardin@+ ADP palmityl-CoA beta-catenin{pS33}{pS45}{ub(n)}:CKI-alpha, p53{pS15}{pT18}{pS20}{pS392}{ace} + ATP HDAC1 + AR --> EGF:(ErbB1{pY})2:Src:mDia1:SPIN90{pY} AR (STAT1alpha{pY})2@ CKI-delta:axin1{p}:APC{p}:GSK3beta:beta-TrCP1:Cul-1{nedd}:Skp1 <==> --TRAF6{ub(n)}:TAB2:TAK1:TAB1--> (NR3C4) + p75NTR-CTF{palC} Cul-1{nedd} + + Vav-2{pY} + 2 dsRNA + TLR3 (NR3C4):ARA54 Ubc5{ub(1)} +Optimal Combinations of InterventionAPC{p}:axin1{p}:GSK3beta:CKI-alpha, (p53{pS15}{pT18}{pS20}{pS392}{ace})4IKK-alpha:IKK-beta{p}:(IKK-gamma)2 Tip60 <==> IkappaB-alpha, ErbB3@ prolactin:(PRLR-L:Jak2)2@ NDP + TRIF <==> --> KLK3 p53 + n + CoA Ubc5{ub(1)} + + ADP ARA54@ HDAC1:AR IkappaB-beta{pS}:p50:RelA-p65 CKI-delta:beta-catenin{pS33}{pS45}{ub(n)}:Fam:beta-TrCP1:Cul-1{nedd}:Skp1@ Syk@ dsRNA:TLR3:TRIFIKK-alpha:IKK-beta:(IKK-gamma)2 p53 + n (NT-3)2:(trkC)2@ beta-catenin{pS33}{pS45}:axin1{p}:CKI-alpha, TRAF6:TAB2@ ubiquitin APC:axin1:beta-catenin{pS45}:CKI-alpha, + ATP (NR3C4):Tip60 alphaAPPs@ p53{pS20}@ p53 + ATP ubiquitin + n ubiquitin CKI-delta:APC{p}:GSK3beta:beta-TrCP1:Cul-1{nedd}:Skp1@ --COP1--> CKI-delta:GSK3beta SLP-65@ --TRAF6{ub}:TAK1{p}:TAB1{p}:TAB2:PKR--> KLK3@TRAF6:TAK1:TAB1:TAB2:PKR Asp2@ --plk3--> --Ubc5,Cdc34--> Ubc5 + --PIRH2--> p53{ub(1)K370}{ub(1)K372}@ NADH + CtBP2 + ATP --> ADP IKK-alpha:IKK-beta{p}:(IKK-gamma)2p110alpha:p85alpha:AR + 2 ATP --> APP-C83@ EGF:(ErbB1{pY})2 p53{pS20} + Ubc5 + IkappaB-alpha,IkappaB-alpha, p53{ub(n)} p53{ub(n)} AKT-1{pT308}{pS473}:mdm2{pS166}{pS186}{pS188}@<==> p/CAF + VEGF-A:VEGF-A + + ADP (NR3C4):Src + TRAF6:TAK1{p}:TAB1{p}:TAB2:PKR + eps15 <==>TRAF6:UbcH7{ub(1)}@ ADP p53{ub(n)} IkappaB-beta{pS}{ub(n)}:Cul-1{nedd}IkappaB-beta{pS}{ub(n)}:Cul-1{nedd}@ p85alpha@ acetyl-CoA@ --26S p75NTR:(NGF-p13)2:trkA{pY490}@ NADH:CtBP2 TAF(II)31 <==> + 2 VEGFR-2 APC:axin1:beta-catenin{pS33}{pS45}:CKI-alpha, ATP --> + 2 ADP Epicardin@ CoA@ EGF:(ErbB1{pY})2:eps15 + p50:RelA-p65 APC:axin1:beta-catenin{pS33}{pS45}:CKI-alpha, mdm2{pS166}{pS188}:YY1:p53@ proteasome--> AKT-1{pT308}{pS473}:AR p/CAF:TAF(II)31 <==> beta-catenin{pS33}{pS45}{ub(n)}:CKI-alpha,CKI-delta:GSK3beta APC:axin1:beta-catenin{pS45}:CKI-alpha, Src:p110alpha:p85alpha{pY}:AR p110alpha@ alphaAPPs@ setd7 --> p53 STAT1alpha{pY} CKI-delta:GSK3beta@ p110alpha:p85alpha:AR mdm2{pS166}{pS188}:YY1@ protein (NR3C4){pS213}{pS791}{ub(n)}:mdm2{pS166}{pS186}{pS188}p53{ub{K48}(n)K} (VEGF-A:VEGFR-2)2 CKI-delta:axin1{p}:APC{p}:GSK3beta:beta-TrCP1:Cul-1{nedd}:Skp1@ CKI-delta:GSK3beta@ (NR3C4) + ADP p110alpha:p85alpha:AR SHP-1@ + STAT3{pY} beta-TrCP1@ (NR3C4)@ p75NTR:NGF-p13@ remnants + n --26S --26S NADH:CtBP2@ IGF1R@ (NR3C4):Src@ TRAF6:UbcH7:p75NTR:(NGF-p13)2:trkA{pY490}{ub{K63}(1)K485}p62 mdm2{pS166}{pS188}:YY1<==> Cul-1{nedd}@ APC:axin1:beta-catenin{pS33}{pS45}:CKI-alpha, prolactin + 2 IKK-alpha:IKK-beta{p}:(IKK-gamma)2@ EGF:(ErbB1{pY})2:Src{pY}:Pyk2{pY}:STAT3Pyk2{pY}@ YY1@ ubiquitin proteasome-->proteasome--> C3d:antigen:BCR{p}:CD19{p}:CD21:CD81 --nEGF:(ErbB1{pY})2:Src:Pyk2:STAT3@ + p53 STAT1alpha{pY}:STAT3{pY}<==> JNK1{pT183}{pY185}@ p53{ub{K48}(n)K382}{ub{K48}(4)K386} CKI-delta:GSK3beta prlr <==>insulin + InsR AR (NR3C4) + E1{ub(1)}@+ ATP --> p53{ub(1)K370}@ AKT-1{pT308}{pS473}:mdm2{pS166}{pS186}{pS188}protein 5alphaDHT:AR Lyn, Fyn, Blk@ + 2 Syk <==> UbcH7{ub(1)}--> mdm2{pS166}{pS188}:YY1:p53 --26S + beta-TrCP1 prolactin:(prlr)2<==> p300 <==> AR EGF:(ErbB1{pY})2 Unc18A + pld2 remnants + protein (NR3C4){sumoK386}{sumoK520}:PIAS1:Ubc9@ C3d:antigen:BCR{p}:(Syk)2:CD19{p}:CD21:CD81 p75NTR:NGF-p13 p53{ub{K48}(n)K}@ proteasome--> + Cul-1{nedd} CD19:CD21:CD81@ insulin:InsR Roc1:CUL4A:DDB1:DET1:COP1@ (NR3C4):p300 + Src{pY} + EGF:(ErbB1{pY})2 Ubc5{ub(1)}@ Cdc25A{pS75}{pS78}{pS81}{pS123}{pT506}{ub(n)}<==> remnants + n AR + p62 + TRAF6 protein + Skp1 <==> atad2:(AR IKK-alpha:IKK-beta:(IKK-gamma)2 Pyk2{pY} + + ARF4:GDP + Ubc5@ --26SUnc18A:pld2 ubiquitin sumo1@ (NR3C4):Hic-5@ + UbcH7 + remnants beta-catenin{pS33}{pS45}:axin1{p}:CKI-alpha, SPI1@ (NR3C4))2:(5alphaDHT)2 + ATP STAT3{pY} + GTP <==> p53{ub(1)K370}:mdm2{pS166}{pS188}:Ubc5A{ub(1)}@proteasome--> (NGF)2:(p75NTR)2 5alphaDHT:AR AR (NR3C4) + p75NTR-ICD{palC}:NRIFIKK-alpha{p}:IKK-beta{p}:(IKK-gamma)2@p75NTR-ICD{palC}:NRIF{ub{K63}(n)K19}:TRAF6 NGF-p13:trkA{pY490}{ub{K63}(n)K485} protein CKI-delta:APC{p}:GSK3beta:beta-TrCP1:Cul-1{nedd}:Skp1 APC:axin1:beta-catenin:CKI-alpha, --> IGF1R --TRAF6:SITPEC:MEKK1--> EGF:(ErbB1{pY})2 NGF-p13:trkA{pY490}{ub{K63}(n)K485}@ ADP Src{pY}@EGF:(ErbB1{pY})2:ARF4:GTPYY1:p53@ --> N-SMase (NR3C4):PIAS1:Ubc9 C3d:antigen:BCR Hic-5ARA54:hnRNPA1@ <==> AR + TRAF6 <==> + p62 <==> E1{ub(1)} + 2 remnants + n CKI-delta:GSK3beta MO000038486->MO000000144 SLP-65 + NTP IRS2@ IKK-alpha:IKK-beta{p}:(IKK-gamma)2TRAF6:TAK1:TAB1:TAB2:PKR@ + Src <==> Pyk2@ + GDP AKT-1{pT308}{pS473}:AR + 2 sumo1 --> C3d:antigen@ + atad2:(AR AR(NR3C4):Hic-5 p75NTR-ICD{palC}:NRIF:TRAF6p75NTR-ICD{palC}:NRIF{ub{K63}(n)K19}:p62 UbcH7 --> E1 STAT1alpha{pY} ubiquitin + ATP --> ADP C3d:antigen:BCR@ C3d:antigen:BCR{p}:(Syk)2:CD19{p}:CD21:CD81@ --C3d:antigen:BCR{p}:(Syk{p})2:CD19{p}:CD21:CD81--> Src:p110alpha:p85alpha{pY}:AR + ADP AR (NR3C4)EGF:(ErbB1{pY})2:Src + (NR3C4){pS213}{pS791}{ub(n)}:mdm2{pS166}{pS186}{pS188}@ 5alphaDHT:AR CD19:CD21:CD81 (NR3C4))2:(5alphaDHT)2 (NR3C4):ARA54:hnRNPA1 + TRAF6 + UbcH7{ub(1)} <==> Ubc5A{ub(1)}@ + prolactin:(PRLR-L:Jak2)2 SLP-65{pY} + (NR3C4)@ ARA54 <==>Src + p53{ub{K48}(n)K382}{ub{K48}(4)K386}@ (NR3C4){sumoK386}{sumoK520}:PIAS1:Ubc95alphaDHT:AR APC{p}@ C3d:antigen + <==> --> IRS2 <==> AR AR (NR3C4) + YY1 + p53 (STAT1alpha{pY})2 beta-catenin{pS33}{pS45}{ub(n)}:CKI-alpha, APC:axin1:beta-catenin{pS45}:CKI-alpha, BCR <==> C3d:antigen:BCR:CD19:CD21:CD81 + 4 ATP --> NDP atad2:(AR p110alpha:p85alpha:ARAR MO000016672->MO000122316 (NR3C4):PIAS2-alpha:Ubc9 C3d:antigen:BCR:CD19:CD21:CD81 atad2:(AR (NR3C4) +Epicardin <==> <==> YY1:p53 p53:mdm2{pS166}{pS188}:Ubc5A{ub(1)}@ CKI-delta:axin1{p}:APC{p}:GSK3beta:beta-TrCP1:Cul-1{nedd}:Skp1 CKI-delta:GSK3beta C3d:antigen:BCR C3d:antigen:BCR:CD19:CD21:CD81@ + NTP --Lyn, prolactin:(PRLR-L:Jak2{pY1007}{pY1008})2 (NR3C4))2:(5alphaDHT)2@ (NR3C4):ARA54AR (NR3C4) <==> Cdc25A{pS75}{pS78}{pS81}{pS123}{pT506}{ub(n)}@ p75NTR-CTF@ + 2 sumo1 --> BCR@ (NR3C4))2:(5alphaDHT)2 TRAF6:TAK1{p}:TAB1{p}:TAB2:PKR@ ARA54:hnRNPA1 TRAF6 + <==> APC{p} + Fyn, Blk--> + 4 ADP BIRC5@ (NR3C4):Epicardinp110alphap110alpha:p85alpha:AR + p75NTR:(NGF-p13)2:trkA 5alphaDHT:AR --> BIRC5 UbcH7{ub(1)} mdm2:p/CAF:TAF(II)31 (NT-3)2:(trkC)2 axin1{p} + C3d:antigen:BCR{p}:CD19{p}:CD21:CD81 p85alpha +(NR3C4):Src AR EGF-ECD:ErbB1-p170{pY869}{pY915}{pY944}{pY1016}{pY1092}{pY1110}{pY1125}{pY1172}{pY1197}:ErbB2{pY}:Src{p}@APP695 EGF:(ErbB1{pY})2:Src:STAT1alpha@ MO000020022->MO000044258 p53{ub(1)K386}@ + ATP --> beta-catenin{pS33}{pS45}{ub(n)}@ (NR3C4){sumoK386}{sumoK520}:PIAS2-alpha:Ubc9 C3d:antigen:BCR{p}:(Syk)2:CD19{p}:CD21:CD81 <==> + n ubiquitin + 2 ATP --> beta-catenin{pS33}{pS45}{ub(n)} + NDP (NR3C4) <==> --adam10--> p75NTR:(NGF-p13)2:trkA{pY490}beta-catenin{pS33}{pS45}{ub(n)} + 2 NTP --> TRAF6:UbcH7{ub(1)} MO000017622->MO000000218 (NT-3)2:(trkC{pY516})2 + beta-TrCP1 + p110alpha:p85alpha:AR alphaAPPs + mdm2{pS166}{pS188}:YY1:p53 --> + ADP C3d:antigen:BCR{p}:(Syk{p})2:CD19{p}:CD21:CD81 atad2:(AR APP695 Cdc34@ --26S + 2 ADP CKI-alpha, atad2 + (AR (NR3C4)EGF:(ErbB1{pY})2 APP-C83 + n mdm2:p/CAF{ub(n)}:TAF(II)31 5alphaDHT:AR + 2 NDP (NR3C4))2:(5alphaDHT)2 --Asp2--> proteasome--> 5alphaDHT:AR CKI-delta + (NR3C4))2:(5alphaDHT)2C3d:antigen:BCR{p}:(Syk{p})2:c-Cbl:CD19{p}:CD21:CD81@ IKK-alpha:IKK-beta{p}:(IKK-gamma)2Ubc13:Uev1@ + c-Cbl <==> EGF:(ErbB1{pY})2 p53{ub(1)K370}:mdm2{pS166}{pS188}:Ubc5A{ub(1)}Ubc5A{ub(1)} (VEGF-A:VEGFR-2)2@proteasome@ (NR3C4){sumoK386}{sumoK520}:PIAS2-alpha:Ubc9@ C3d:antigen:BCR{p}:CD19{p}:CD21:CD81@Lyn@ --> SGK1 APPp100 + EGF-ECD:ErbB1-p170:ErbB2:SrcGab-2@ E1{ub(1)} + protein (NR3C4):PIAS1:Ubc9@ Cul-1{nedd} + <==> + ATP EGF:(ErbB1{pY})2:c-Cbl --SHP-1--> mdm2{pS166}{pS188} --> --> CtBP2@ beta-catenin{ub} Fbw7@ APP-C99 + 11 ATP --> Ubc5 --> E1 + c-Jun{p}{ub(n)} p53{ub(1)K370} 26S remnants + n atad2:(AR --TRAF6:SITPEC:MEKK1--> EGF:(ErbB1)2 + CtBP2:mdm2:p53@+ YY1 <==>p53{ub(1)K370}{ub(1)K372} p53{ub{K48}(n)K} p/CAF:TAF(II)31@ PIAS1@ GSK3beta + p53{pS15}{pT18}{pS20}{pS392}{ace}@ EGF-ECD:ErbB1-p170{pY869}{pY915}{pY944}{pY1016}{pY1092}{pY1110}{pY1125}{pY1172}{pY1197}:ErbB2{pY}:Src{p}Ubc5{ub(1)} --26S + ubiquitin --proteasome--> TRAF6{ub(n)}:TAB2:TAK1:TAB1@ IKK-alpha{p}:IKK-beta{p}:(IKK-gamma)2 2 p mdm2{pS166}{pS188}:YY1 + + proteasome@ Skp1 (NR3C4))2:(5alphaDHT)2 LPS:LBP:CD14:TLR4:MD-2:MyD88:IRAK-1{pS376}{pT387}@APP + 11 ADP p53{ub(1)K386} 5alphaDHT:AR protein axin1{p}@ proteasome-->mdm2{pS166}{pS188} mdm2{pS166}{pS188}mdm2{pS166}{pS188} MITF{pS} + SPI1 + ADP --adam10--> TRAF6:TAB2 + p53:mdm2{pS166}{pS188}:Ubc5A{ub(1)}+ 4 (NR3C4):PIAS2-alpha:Ubc9@remnants + adam10@ protein + Ubc5A{ub(1)}+ Ubc5A AKT-1{pT308}{pS473}:AR C3d:antigen:BCR{p}:(Syk{p})2:CD19{p}:CD21:CD81SGK1@ IL-1beta-p17:IL-1RI:IL-1RAcP:MyD88:tollip:IRAK-1{pS376}{pT387}:IRAK-4:IRAK-2@alphaAPPs + n ubiquitin + +--> YY1 + Ubc5A ubiquitin <==> insulin:InsR{pY}:APS remnants + n <==>mdm2{pS166}{pS188} CtBP2:mdm2@ (NR3C4){pS213}{pS791}:mdm2{pS166}{pS186}{pS188} Skp1@ + c-Cbl <==> ATP APPp100@ p53{ub(1)K370} LMW-PTP@ MITF{pS}:SPI1 APP-C83 EGF:(ErbB1{pY})2:Src:STAT1alpha EGF:(ErbB1)2 + p53{ub(1)K370}:mdm2{pS166}{pS188}:Ubc5A{ub(1)}ubiquitinCtBP2:mdm2p53 + + + n + n ubiquitin C3d:antigen:BCR{p}:(Syk{p})2:c-Cbl:CD19{p}:CD21:CD81 + NTP --> Pyk2 + + dsRNA:TLR3:TRIF:TRAF6:TAK1:TAB1:TAB2 --E1,Ubc13:Uev1--> + ATP --> ATPCdc25A{pS75}{pS78}{pS81}{pS123}{pT506} --> mdm2{pS166}{pS188}p53p53:mdm2{pS166}{pS188}:Ubc5A{ub(1)} <==> Ubc5A{ub(1)} insulin:InsR{pY}:APS{pY} EGF:(ErbB1{pY})2 EGF-ECD:ErbB1-p170:ErbB2:Src@ --> TACE@ TAB2@ + PKR <==> p53{pS15}{pT18}{pS20}TRAF6{ub(n)}:TAB2 EGF:(ErbB1{pY})2 p53 + ATP CtBP2:mdm2:p53+ Ubc5A{ub(1)}mdm2{pS166}{pS188} --> + NDP p62Dok-1@ + Src + STAT3 EGF:(ErbB1{pY})2 + n ubiquitin --> Wee1{pS53}{pS123}{ub(n)} AKT-1{pT308}{pS473}:AR beta-catenin{ub}@ APC:axin1:beta-catenin:CKI-alpha, C3d:antigen:BCR{p}:(Syk{p})2:CD19{p}:CD21:CD81@ dsRNA:TLR3:TRIF:TRAF6:TAK1:TAB1:TAB2@ + acetyl-CoA + ADP (NGF)2:(p75NTR)2 --JNK1{pT183}{pY185}--> <==> + Ubc5A HIF-1alpha{hydP}{ub(n)} MITF{pS}:SPI1@ Vav-2{pY}@ dsRNA:TLR3:TRIF + Src + --E1,Ubc5,beta-TrCP1:Skp1:Cul-1{nedd}:Roc1-->+ ADP p53{ub{K48}(n)K382}{ub{K48}(4)K386}p53{ub(1)K386} (NR3C4){pS213}{pS791}{ub(n)}:mdm2{pS166}{pS186}{pS188}mdm2:p/CAF{ub(n)}:TAF(II)31@mdm2:p/CAF:TAF(II)31@ CKI-delta:GSK3beta@ insulin:InsR@ TRAF6{ub(n)}:TAB2@ <==> --26S --proteasome--> TAB1@ + --p300--> STAT1alpha{pY}+ TRAF6 <==> Cdc25A{pS75}{pS78}{pS81}{pS123}{pT506}{ub(n)}p53{p} + ADPp53:mdm2{pS166}{pS188}:Ubc5A{ub(1)} + + 4 Ubc9 + PIAS1 + C3d:antigen:BCR{p}:CD19{p}:CD21:CD81 SLP-65{pY}@ dsRNA:TLR3:TRIF@ EGF:(ErbB1{pY})2:Src:Pyk2:STAT3 proteasome--> protein p53{pS15}{pT18}{pS20}{ace} (NGF)2:(p75NTR)2:TRAF6c-Jun{p}{ub(n)}@ CKI-alpha, TRAF6:TAK1:TAB1:TAB2:PKR + ADP EGF mdm2{pS166}{pS188}mdm2{pS166}{pS188} protein 5alphaDHT:ARUbc9 + + Lyn <==> + CoA EGF:(ErbB1{pY})2 remnants + n CKI-delta@APC:beta-catenin{ub}:Ebi:Siah1:SIAHBP1:Skp1:Ubc9@ APC:beta-catenin:Ebi:Siah1:SIAHBP1:Skp1:Ubc9 EGF-ECD:ErbB1-p170:ErbB2 --adam10--> + Ubc5A+ n Ubc5A (NR3C4)PIAS2-alpha <==> + PIAS2-alpha@ C3d:antigen:BCR{p}:CD19{p}:CD21:CD81:Lyn PTP1B{pY}@ + Src + EGF:(ErbB1)2@ remnants + n ubiquitin + ubiquitin --> prolactin:(prlr)2@ LPS:LBP:CD14:TLR4:MD-2:TIRAP:IRAK-2@ + Src <==> EGF-ECD + mdm2{pS166}{pS188} 5alphaDHT:AR5alphaDHT:AR TRAF6{ub}:TAK1{p}:TAB1{p}:TAB2:PKR@ STAT1alpha Ubc5{ub(1)} + ubiquitin APC:beta-catenin{ub}:Ebi:Siah1:SIAHBP1:Skp1:Ubc9 TRAF6:TAK1{p}:TAB1{p}:TAB2:PKR protein --> (NR3C4):PIAS1:Ubc9 APC:beta-catenin{ub}:Ebi:Siah1:SIAHBP1:Skp1:Ubc9 GSK3beta@ EGF-ECD:ErbB1-p170:ErbB2:Src<==> mdm2 --> 5alphaDHT:AR (NR3C4) <==> AKT-1, AKT-2 c-Cbl@ + ubiquitin + remnants STAT1alpha{pY}@ mdm2{pS166}{pS188} (NGF)2:(p75NTR)2@ HIF-1alpha{hydP}@ <==> Ubc9 + EGF:(ErbB1{pY})2:Src:STAT1alpha Ubc5 + (NR3C4)@ 5alphaDHT:AR Hsp27@ + NTP Grb10@ insulin:InsR{pY}:APS{pY}@ ATP prolactin:(prlr{pY})2:SHP-2{pY} Siah1 + prolactin:(prlr)2 PKCtheta --> mdm2{ub(n)} (VEGF-A:VEGFR-2{pY})2 (NR3C4):PIAS2-alpha:Ubc9 Siah1@ AKT-1{p},--Src:p110alpha:p85alpha{pY}:AR TRAF6{ub(n)}:TAB2 CAP@ --E1,Ubc13:Uev1--> + Gab-2 + NTP EGF-ECD:ErbB1-p170:ErbB2 SIAHBP1 + Skp1 IKK-alpha{p}:IKK-beta{p}:(IKK-gamma)2 (VEGF-A:VEGFR-2)2--LMW-PTP--> prolactin:(PRLR-L:Jak2{pY1007}{pY1008})2@ AKT-2{p}@ (NR3C4)--> + TAK1 + TAB1 + Src <==> TRAF6{ub}:TAK1{p}:TAB1{p}:TAB2:PKR Src@ --> 5alphaDHT + Ubc5A@ + Ebi + APC + c-Jun{ub(n)}@ CKII-alpha:CKII-alpha2:(CKII-beta)2:Cdc68:SSRP1@ c-Jun{p} + n + 2 ATP --> (VEGF-A:VEGFR-2)2 Ubc9@ Ebi@ tec@ <==> prolactin:(prlr)2:Src prolactin:(prlr{pY})2:SHP-2{pY}@ AR (NR3C4) EGF-ECD:ErbB1-p170:ErbB2@mdm2{ub(n)}@ rpl11@ + 2 ATP --> APC:axin1:beta-catenin:GSK3beta@ AKT-1{p}, + ADP ubiquitin prolactin:(prlr{pY})2:SHP-2{pY}:Gab-2{pY} EGF-ECD:ErbB1-p170{pY}:ErbB2{pY}HAUSP@ + 2 p beta-catenin{ub} TopoI@ (VEGF-A:VEGFR-2{pY})2 p75NTR:(NGF-p13)2:trkA@ c-Jun + n AKT-2{p} + NDPTRAF6{ub(n)}:TAB2:TAK1:TAB1 --E1,Cdc34,Fbw7--> + NDP <==> + 2 ADP ErbB3@ insulin:InsR{pY}:(Jak1)2:(SOCS-3)2@ FAK1@ + 2 ADP SIAHBP1@ APC:axin1:beta-catenin:GSK3beta ubiquitin c-Jun{p}{ub(n)} 5alphaDHT:AR cIAP-2{ub(n)} MAPKAPK-5 JNK1{pT183}{pY185}:MKK7@ pld2@ HIF-1alpha{hydP}:p53:mdm2@ 2 BDNF:p75NTR (NT-3)2:(trkC{pY516})2@ + --Roc1:CUL4A:DDB1:DET1:COP1--> AR (NR3C4)@ EGF:(ErbB1{pY})2@ (NR3C4) --26S axin1@ APC:axin1:beta-catenin:GSK3beta:CKI-epsilon:Dvl{p}APC:axin1:beta-catenin:GSK3beta:CKI-epsilon:Dvl{p}@ --> Hsp27 Jak1@ 5alphaDHT@ cIAP-1{ub(n)} --TACE--> 2 APC:beta-catenin:Ebi:Siah1:SIAHBP1:Skp1:Ubc9@APC + axin1 + CKI-epsilon:Dvl{p} c-Jun{ub(n)} proteasome--> HIF-1alpha{hydP}{ub(n)}@ + Frat1 <==> CKI-epsilon:Dvl{p}@ prolactin:(prlr)2 EGF-ECD@ --26S mdm2:p/CAF{ub(n)}:TAF(II)31CtBP2 + mdm2 BDNF:p75NTR-ECD APC@ beta-catenin + <==> protein APC:axin1:beta-catenin:CKI-epsilon:Dvl{p}:Frat1:GSK3beta prolactin:(PRLR-L:Jak2{pY1007}{pY1008})2 + SHP-2 + 3 CDKN1A@ proteasome--> <==>--26S + 2 PML@ CKI-alpha, APC:axin1:beta-catenin:CKI-epsilon:Dvl{p}:Frat1:GSK3beta@ APC:axin1:beta-catenin:GSK3beta:CKI-epsilon:Dvl{p} insulin:InsR{pY}:(Jak1)2 EGF:(ErbB1{pY})2 remnants + n mdm2 + + n ATP --> dsRNA:TLR3:TRIF NTP --> protein CtBP2:mdm2proteasome--> PML{p}@p75NTR-CTF CKI-delta + + 2 SOCS-3 insulin:InsR{pY}:APS@ + p62Dok-1 beta-TrCP1:Skp1:Cul-1{nedd}:Roc1@ p/CAF:TAF(II)31 APC:axin1:beta-catenin:CKI-epsilon:Dvl{p}:Frat1:GSK3beta Frat1@ prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008})2 Btk@ + TRAF6 + prolactin:(prlr{pY})2:SHP-2{pY} ubiquitinremnants + n mdm2 + Siah1 + GSK3beta MKK6b{p}@<==>C3d:antigen:BCR{p}:CD19{p}:CD21:CD81:Lyn@ 2 AR (NR3C4) + AKT-1{pT308}{pS473}:AR <==> PACE@ <==> APC + + n ADP MITF{pS}@ prolactin:(prlr)2:Src@ TAK1 + TAB1 + + 3 NDP <==> ubiquitin protein BDNF:p75NTR-ECD@ SIAHBP1 + Skp1 MAPKAPK-5@ SOCS-3@ insulin:InsR{pY}:(Jak1)2:(SOCS-3)2 STAT5B{pY679}{pY699}{pY724}@ (NR3C4){pS213}{pS791}:mdm2{pS166}{pS186}{pS188}@mdm2:p/CAF:TAF(II)31 <==> TAB2 <==> 2 5alphaDHT EGF:(ErbB1{pY})2:p62Dok-1 Cdc25A{pS75}{pS78}{pS81}{pS123}{pT506}@ + Ebi + axin1 + SOCS-1@ prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008})2:SOCS-3@ (TRAF2)2:(ASK1{p})2@ p53 --> Wee1{pS53}{pS123}{ub(n)}@ remnants + n APC:axin1:beta-catenin:CKI-alpha, dsRNA:TLR3:TRIF:TRAF6:TAK1:TAB1:TAB2 <==> (AR prolactin:(prlr{pY})2:SHP-2{pY}:Gab-2{pY}@ IRS-2@ beta-catenin + beta-catenin + TRAF6@ CDKN1A EGF@ HIF-1alpha{hydP} ubiquitin NGF --PACE--> CKI-delta:GSK3beta (NR3C4))2:(5alphaDHT)2 E1@ STAT1alpha@ STAT1alpha + NGF-p17@ APC + Ubc9 CKI-epsilon + insulin:InsR{pY} + p53 + mdm2 c-Myc@ NGF-p13 + MKK6 + ATP ATP <==> Dvl{p} + Frat1 + prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008}:STAT5B)2 prolactin:(prlr)2 --PTP1B{pY}--> <==> mdm2{ub(n)} NGF-p17 + prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008}:STAT5B{pY699})2@ c-Jun{pS63}{pS73}@ --TRAF6{ub(n)}:TAB2:TAK1:TAB1-->STAT5B + 3 NTP insulin:InsR{pY}:(Jak1)2@ PKR@ Dvl{p}@ GSK3beta + Fyn + c-Cbl Btk + insulin:InsR + p --(VEGF-A:VEGFR-2{pY})2-->HIF-1alpha{hydP}:p53:mdm2 NGF@ APC:beta-catenin:Ebi:Siah1:SIAHBP1:Skp1:Ubc9 + 2 ATP --> prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008})2 --prolactin:(prlr)2:Src--> insulin:InsR + insulin:InsR{pY}:Grb10@ insulin:InsR{pY}:APS{pY} HIF-1alpha{hydP}:p53:mdm2--HAUSP--> protein prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008})2 p38beta2 --> MITF@ MKK6{p} + ADP <==> SLP-65{pY} p53{pS15}{pT18}{pS20}{ace}APP@ mdm2{pS166}{pS188}@ STAT1alpha{pY} + n ubiquitinrpl11 + PML{p} NRG --> c-Myc CIS@ prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008}:STAT5B{pY699})2 + SOCS-3 STAT5B{pY679}{pY699}{pY724} Btk:SLP-65{pY} ATP --> + CAP + c-Cbl mdm2 + n remnants + SOCS-1 MAPKAPK-5 prolactin:(prlr)2:Fyn:c-Cbl<==> + ATP STAT3@ + ADP --> + mdm2 <==> PML + ATP + 2 ADP <==> beta-arrestin2:ASK1:MKK4{p}:JNK3{p}@ + NTP insulin:InsR{pY}insulin:InsR{pY} <==> ubiquitin MEF-2C{p}@ prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008}:STAT5B)2@ + 3 NDP Btk:SLP-65{pY} --CKII-alpha:CKII-alpha2:(CKII-beta)2:Cdc68:SSRP1-->prolactin:(prlr)2:Src HIF-1alpha{hydP}{ub(n)}rpl11:PML{p}:mdm2 2 NGF + 2 <==> --C3d:antigen:BCR{p}:(Syk{p})2:CD19{p}:CD21:CD81-->prolactin:(prlr)2 + Grb10 <==> c-Jun{p} + --ATR--> NRG@ prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008})2:SOCS-3 MO000016959->MO000016960 beta-arrestin2:ASK1:MKK4{p}:JNK3 + ADP p53{pS15}{pT18}{pS20}{pS392}{ace}+ FAK1 <==>insulin:InsR{pY}:APS{pY}:CAP:c-Cbl + p53 + mdm2 p75NTR <==> prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008})2:SOCS-1prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008})2 MKK6 + ATP + tecBtk{pY551}:SLP-65{pY} + Vav insulin:InsR{pY}:Grb10 TRAF6:SITPEC:MEKK1@ TopoI <==> PML{p} + ADP + ATP --> c-Jun + 2 ATP prolactin:(prlr)2:Src:FAK1+ ADP MO000021757->MO000071119 2 ErbB1 + EGF rpl11:PML{p}:mdm2@ (NGF)2:(p75NTR)2 Nedd4-2:trkA{ub(1)}n@ + CIS <==> --TRAF6{ub}:TAK1{p}:TAB1{p}:TAB2:PKR--> <==> + NDP c-Jun{p}:TopoI EGF-ECD:ErbB1-p170{pY}:ErbB2{pY}@ beta-arrestin2:ASK1:MKK4{p}:JNK3{p}--JNK1{pT183}{pY185}:MKK7--> <==> IRS-2 + ATP prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008})2:CIS MRF4@ MKK6{p} + ADP prolactin:(prlr)2:tec:Vav insulin:InsR{pY} PDGF 2 ATP + + ADP c-Jun{pS63}{pS73} p53{p}@ EGF:(ErbB1)2 --prolactin:(prlr{pY}:Jak2{pY1007})2--> MEF-2C + ATP p38beta2@prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008})2 + 2 Jak1 <==> prolactin:(prlr)2:Fyn:c-Cbl@ AA:(PDGFRalpha{pY572})2:Src@ (VEGF-A:VEGFR-2{pY})2@ MEF-2C@ + 2 ADP EGF-ECD + IRS-2{pY} + ADP --ERK5--> prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008}:STAT5A)2 prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008})2:SOCS-1@p38beta2 --> + 2 STAT5B PGC-1{p}:PPARgamma insulin:InsR{pY}:(Jak1)2 (AR ErbB1-p170@ c-Jun + ATP insulin:InsR{pY}:(Jak1)2 p53{pS15}{pT18}{pS20}@ ErbB1-p170 + MEF-2C{p} + --> MEF-2C prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008})2@ <==> (NR1C3)@ (NR3C4))2:(5alphaDHT)2@ SHP-2@ CKI-epsilon@ p38beta + ATP --beta-arrestin2:ASK1:MKK4{p}:JNK3{p}-->+ 2 ATP --> p53@ PDGF prolactin:(prlr{pY}:Jak2{pY1007})2 ErbB2 <==> Cas@ NGF-p13@ Nedd4-2:trkA + TBP@ ADP prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008}:STAT5A{pY694})2 prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008}:STAT5B)2 MKK6 + ATP c-Jun{p}@ prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008}:STAT5A)2@prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008}:STAT5B{pY699})2 --MKK6b{p}--> Btk:SLP-65{pY} c-Jun{p} + ADP insulin:InsR{pY}:(Jak1{pY})2 c-Jun{p}:TopoI@ AA:(PDGFRalpha{pY})2 --SHP-2--> EGF-ECD:ErbB1-p170:ErbB2 n ubiquitin --> + 2 ADP prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008})2:CIS@ PGC-1{p}p38beta@ + --(TRAF2)2:(ASK1{p})2--> <==> STAT5B@ p38beta{p} + + NTP + 2 ADP EGF:(ErbB1{pY})2:p62Dok-1@ + Src <==> AKT-1{pT308}{pS473}:AR prolactin:(prlr:Jak2)2 EGF:ErbB1:ErbB2@ EGF:ErbB1:ErbB2 Nedd4-2:trkA{ub(1)}n Bcl-3@ prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008})2 MKK6{p} + ADP prolactin:(prlr)2:tec:Vav@ insulin:InsR{pY} ERK5{pT}{pY}@ ERK5@ prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008})2 p38beta2 --> PPARgamma APP695@ PDGF AKT-1{pT308}{pS473}:AR + 2 ATPNRG:ErbB2:ErbB3@ --> p75NTR + 2 + 2 STAT5A ADP --C3d:antigen:BCR{p}:CD19{p}:CD21:CD81:Lyn--> + IRS-1, IRS-2 (NR3C4){pS213}{pS791}@ + p CrkII, CrkL@ + 2 MEF-2A (NR1C3) <==> (NR3C4){pS213}{pS791} EGF:ErbB1{pY}:ErbB2{pY} NGF-p13 + trkA Reptin52@ <==> Btk{pY551}:SLP-65{pY} <==> AA:(PDGFRalpha{pY572})2:Src prolactin:(prlr{pY})2:SHP-2{pY}:Gab-2{pY}:p110@ (NT-3)2:(trkC{pY516})2 2 NGF-p13 TCF + STAT5B{pY699} PGC-1{p}:PPARgamma MAPKAPK2{p}@ insulin:InsR{pY} + + 2 ADP <==> prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008}:STAT5A)2 + NDP insulin:InsR{pY}:IRS-1, EGF --> ErbB1 + Shc-1 <==> NRG + ErbB2 + <==> beta-catenin + prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008}:STAT5A{pY694})2 (NR1C3) Rac1:GDP + GTPc-Jun + 2 ATP AKT-1, AKT-2@ + APS <==> PKCtheta@ STAT5@ Wee1{pS53}{pS123}PDGFcIAP-2{ub(n)}@ mdm2{pS166}{pS186}{pS188} p75NTR:(NGF-p13)2:trkA Bcl-3 + (p50)2 prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008}:STAT5A{pY694})2@ IRS-2 prolactin:(prlr)2:Fyn:c-Cbl prolactin:(prlr{pY})2:SHP-2{pY}:Gab-2{pY} (NT-3)2:(trkC{pY516})2:Shc-1 ErbB3 <==> (NT-3)2:(trkC{pY516})2:Shc-1@ (NGF-p13)2 Pontin52 + <==> MO000013133->MO000166928 --Vav-2{pY}-->--MKK7{p}:JNK1{pT183}{pY185}--> STAT1alpha + AA:(PDGFRalpha{pY720})2:SHP-2{pY}@+ n ubiquitin Nedd4-2:trkA@ + beta-catenin Pontin52@ (p50)2@ ERK5 + 2 ATP insulin:InsR{pY}:APS + ATP --> cIAP-1{ub(n)}@ <==>+ p110 <==> EGF + ErbB1 + prolactin:(prlr{pY}:Jak2{pY1007})2@ NRG:ErbB2:ErbB3 Reptin52 + TBP prolactin:(PRLR-L{pY}n:Jak2{pY1007}{pY1008})2 STAT5A{pS}@ Rac1:GTP + GDPc-Jun{pS63}{pS73} ATP --E1,Ubc5A,beta-TrCP1:Skp1:Cul-1{nedd}:Roc1-->AKT-1{pT308}{pS473}:AR prolactin:(prlr:Jak2)2@ prolactin:(prlr:Jak2)2 + Reptin52 --MKK5{p}--> STAT5A@ PGC-1{p}@ MAPKAPK2 + insulin:InsR{pY}insulin:InsR{pY}:STAT5B@ TAK1@ prolactin:(prlr)2:Fyn:c-Cbl{pY731} prolactin:(prlr{pY})2:SHP-2{pY}:Gab-2{pY}:p110 ErbB2 <==> (NGF-p13)2:(trkA)2 BDNF:p75NTR:caveolin-1beta@ TCF:beta-catenin:Pontin52:Reptin52:TBP@<==> + 2 + 2 ADP MITF + ATP AR --PDGFBB:(PDGFRbeta{pY})2--> Wee1{pS53}{pS123}{ub(n)} PDGF + 4 ATP --> ERK5{pT}{pY} + MEF-2A@ ATP + STAT5B + ADP Cdc25A{pS75}{pS123}{pT506}PDGF (NR3C4){pS213}{pS791}:mdm2{pS166}{pS186}{pS188} EGF:ErbB1:ErbB2 + 2 ATP --> TCF:beta-catenin:Pontin52:Reptin52:TBP<==> STAT5A{pY694} MLCK@ --p38alpha{p}--> (NR3C4):AKT-1{pT308}{pS473} STAT1alpha{pY} AA:(PDGFRalpha{pY})2prolactin:(prlr{pY}:Jak2{pY1007})2 Bcl-3:(p50)2:beta-catenin:Reptin52@ 2 ADP beta-arrestin2:ASK1:MKK4{p}:JNK3@ --p38beta{p}--> <==> AKT-1:AR PDGFBB:(PDGFRbeta{pY579})2:Src@ AA:(PDGFRalpha{pY})2+ 2 ATP --> (NGF-p13)2:(trkA{pY490})2 caveolin-1beta@ Bcl-3:(p50)2:beta-catenin:Reptin52 MITF{pS} + ADP c-Jun + ATP PDGFBB:(PDGFRbeta{pY})2 + ADP + 4 ADP Nedd4-2@ beta-catenin@ Bcl-3:(p50)2:beta-catenin:Reptin52 Rac1:GDP@MAPKAPK2{p} + insulin:InsR{pY}:STAT5B (NR3C4){pS213}@ + ATP --> ADP Cdc25A{pS75}{pS78}{pS81}{pS123}{pT506}+ SHP-2 + ATP + CrkII, CrkL + + 2 ADP CKI-epsilon:Dvl@ (STAT5B{pY699})2 MKK6bMKK6 --> --> Fyn@ --JNK1, + Src <==> c-Jun{p}:TopoI Nedd4-2 + trkA 2 STAT5A + ATP AKT-1:AR + + -->2 ADP PDGF MO000016681->MO000107670 Cas + ATP --> --/ CD82 STAT5B{pY699}@ --> (STAT5B{pY699})2@ p38betap38beta2 ADP HPK1 --> TAK1 insulin:InsR{pY}:IRS-1, PDGFBB:(PDGFRbeta{pY579})2:Src mdm2@ ATR@ BDNF:p75NTR + CKI-epsilon + STAT5B{pY699} JNK2{p}--> (NR3C4) + ATP prolactin:(prlr)2:Src:FAK1@ AKT-1{pT308}{pS473}:AR --> ErbB1 PDGF (NGF-p13)2:(trkA{pY490})2@ <==> CD82@ (STAT5B{pY699})2 --p65PAK:Rac1:GTP--> MO000000022->MO000016959 MKK6 --> IRS-2@ AA:(PDGFRalpha{pY720})2:SHP-2{pY} IRS-2{pY}@ caveolin-1beta Dvl:Fz <==> <==> MLC{p}@ MRF4{pS}@ c-Jun{p} + ADP (NR3C4){pS213}{pS791} EGF:(ErbB1{pY})2 (VEGF-A:VEGFR-2{pY})2AA:(PDGFRalpha{pY762})2:CrkII, Nedd4-2:trkA STAT5A{pS} + p38gammaMO000019005->MO000019006 --> AKT-1:AR + ADP Chk1@ PDGF (STAT5B{pY699})2 TAK1 + 2 ATP PDGFBB:(PDGFRbeta{pY})2:PKR@ + Shc-1 + + Shc-1 + ATP <==> CKI-epsilon:Dvl STAT5A{pY694}@ ADP MLCK + ATP insulin:InsR{pY}:(Jak1{pY})2@(NR3C4){pS213} AA:(PDGFRalpha{pY762})2:CrkII,CrkL:Cas{p} + --HIP-55{pY334}{pY344}:HPK1-->MRF4 + ATP IRS-1, IRS-2@ SHIP2 <==> EGF:(ErbB1{pY})2:PLCgamma1{pY} --> BDNF:p75NTR:caveolin-1beta (NGF-p13)2@ + Fz STAT5B{pY699} MLCK{p}@ + ADP CrkL:Cas{p}@ ADP NRG:ErbB2:ErbB3(NT-3)2:(trkC{pY516})2:Shc-1 trkA@ (STAT5B{pY699})2 --p65PAK:Rac1:GTP--> p38gamma@ MKK6{p}@ TAK1{pS}{pT} + TRAF6 + SITPEC + pld2 <==> MKK5{p}@ + --p38alpha{p}--> AKT-1:AR PDGFBB:(PDGFRbeta{pY})2 EGF:(ErbB1{pY})2:Shc-1:SHIP2 (VEGF-A:VEGFR-2{pY})2:Shc-1{pY} + ATP --> IRS-1@ --> CISH MLCK{p} + ADP MKK6 --> p38 2 ADP + MEKK1 EGF-ECD:ErbB1-p170{pY}:ErbB2{pY} + 9 ATP --> 9 STAT5A{pY694} MKK6 + ATP MRF4{pS} + ADP c-Jun + ATP TRAF6 + SITPEC prolactin:(prlr)2:Src:FAK1 EGF:(ErbB1{pY})2:PLCgamma1{pY}:pld2ErbB1 --> Shc-1 + ADP (NGF-p13)2:(trkA{pY490})2:Shc-1@ (NGF-p13)2 + 2 MLC + ATP p38beta{p}@ Btk:SLP-65{pY}@ LAT{p}:Grap2:SLP-76{p}:SLAP-130:Nck-1:Vavinsulin:InsR{pY}@(NR3C4)@ --LPS:LBP:CD14:TLR4:MD-2:MyD88:IRAK-1{pS376}{pT387}--> + PKR <==> + PLCgamma ADP(NT-3)2:(trkC{pY516})2:Shc-1{pY} + <==> MO000038358->MO000016960 --TAO2--> --JNK2{p}--> Btk{pY551}:SLP-65{pY}@ --> PKCtheta + MEKK1 PDGFBB:(PDGFRbeta{pY})2:PKR + ATP --> (NGF-p13)2:(trkA{pY490})2 + ADP trkA <==> --MLCK{p}--> MO000038363->MO000038365 c-Jun@ EGF:(ErbB1{pY})2:p62Dok-1:Nck-1:p65PAK@ TRAF6 +TRAF6:SITPEC:MEKK1 SITPEC EGF:(ErbB1{pY})2 UbcH6@ <==> NRG:ErbB2{pY1139}{pY1222}{pY1248}:ErbB3{pY1054}{pY1197}{pY1222}{pY1260}{pY1276}{pY1289}EGF:ErbB1{pY}:ErbB2{pY}@ STAT5B{pY699}:STAT5A{pY694} MO000038358->MO000004690MKK6{p} + ADP Rac1:GDP + GTP JIP1:HPK1:MLK3{p}:MKK7{p}:JNK1{p}:APP{pT743}:KNS2@c-Jun{p} + ADP AKT-1--dsRNA:TLR3:TRIF--> + AR TRAF6 + SITPEC prolactin:(prlr)2:Src:FAK1{pY}n + Shc-1 <==> (NGF-p13)2:(trkA)2 2 (STAT5B{pY699})2 MLC{p} + ADP MKK7{p}:JNK1{pT183}{pY185}@ MKK6 + ATP (NR3C4) <==> + MEKK1 + PLCgamma1 EGF-ECD:ErbB1-p170{pY}:ErbB2{pY}:PLCgamma (NGF)2 + 2 trkA --prolactin:(prlr)2:tec:Vav--> PGC-1 + ATP JIP1:HPK1:MLK3{p}:MKK7{p}:JNK1{p}:APP:KNS2 TRAF6:SITPEC:MEKK1 + MEKK1 + ADP (NGF-p13)2:(trkA{pY490})2:Shc-1 BDNF:p75NTR@(NGF-p13)2:(trkA{pY490})2:Shc-1 (NGF)2@ alpha catenin-1 STAT5A{pY694} KNS2@ --LPS:LBP:CD14:TLR4:MD-2:TIRAP:IRAK-2-->STAT3{pS}@ prolactin:(prlr)2:Fyn:c-Cbl{pY731}@IRS-1, + ATP --> <==> --> CSN2 p65PAK:Rac1:GTP@ --TAK1{pS}{pT}--> Rac1:GTP + GDP --p38alpha{p}--> STAT1@ insulin:InsR{pY}:STAT5B p53{pS33}@ SITPEC@AKT-1:AR--IL-1beta-p17:IL-1RI:IL-1RAcP:MyD88:tollip:IRAK-1{pS376}{pT387}:IRAK-4:IRAK-2--> EGF-ECD:ErbB1-p170{pY}:ErbB2{pY}:PLCgamma@ + ATP --> + beta-catenin <==> CISH@ MKK6@ + ATP --> TRAF6:SITPEC:MEKK1 IRS-1, IRS-2{pY} EGF:(ErbB1{pY})2:PLCgamma1{pY} prolactin:(prlr{pY}:Jak2{pY1007})2 (NGF-p13)2:(trkA)2@ PPARgamma MKK6{p} + ADP (NR3C4) STAT3 + ATPTRAF6:SITPEC:MEKK1 insulin:InsR{pY}:APS{pY}:CAP:c-Cbl@ IRS-2{pY}:SHP-2@ (NGF-p13)2:(trkA{pY490})2:Shc-1{pY} (NGF:trkA)2 + E-cadherinalpha catenin-1 + Yes{pY}:Fyn, Fz@ PGC-1{p} + ADP JIP1:HPK1:MLK3{p}:MKK7{p}:JNK1{p}:APP{pT743}:KNS2+ ATP --> insulin:InsR{pY} p53 + ATP + 1 Shc-1 + 4 (STAT5A{pY694})2 Rac1:GDP + GTP --MSK1{pS}--> + SHP-2 <==> + ADP + beta-catenin Fer{pY}:p120CAS{pY}@ (NR1C3)@ ATF-2{p}@ + ADPinsulin:InsR{pY} EGF:(ErbB1{pY})2:p62Dok-1 STAT5 + ATP --Chk1{pS317}{pS345}--> NTP --> 1 (VEGF-A:VEGFR-2{pY})2:Shc-1{pY}@ IRS-1 + ATP + ADP Yes{pY}:Fyn, --Btk:SLP-65{pY}:Vav:Nck-1--> (AR + Shc-1IRS-1, <==> Chk1 + 2 ATP (VEGF-A:VEGFR-2{pY})2 + E-cadherin + STAT5B{pY699}:STAT5A{pY694} MLC@ MO000000022->MO000004690 p38beta --> Mnk1@ + STAT5B{pY} + + Nck-1 + STAT3{pS} + --PDGFBB:(PDGFRbeta{pY})2--> RasGAP{pY}@ (NGF-p13)2:(trkA{pY785})2:PLCgamma1 --prolactin:(prlr{pY}:Jak2{pY1007})2--> (NGF-p13)2:(trkA)2p75NTR@ Fer{pY}:p120CAS{pY} MKK5 + ATP Ccnd1@ (NR3C4){pS650})2:(5alphaDHT)2@JIP1:HPK1:MLK3{p}:MKK7{p}:JNK1{p}:APP:KNS2@ p53{pS20}{pT81}@ insulin:InsR{pY}:Shc-1IRS-2{pY}:SHP-2STAT5{pY}@ p53{pS15}{pS20}{pS37} --ATR--> prolactin:(prlr{pY}:Jak2{pY1007})2:Shc-1{pY}+ p85 + p110 STAT5B{pY699}:STAT5A{pY694}@ ATF-2 MKK6 + ATP HPK1@ Rac1:GTP + GDP ADP p65PAK <==> ADP STAT5{pY} + p53{pS15}{pS20}{pS37}@ (VEGF-A:VEGFR-2{pY})2+ ATP --> IRS-1{pY} + ADP + 4 ATP --> <==> alphaplakoglobin alpha MEKK2{p}@ --MEKK2{p}--> --> Ccnd1 JIP1:HPK1:MLK3{p}:MKK7{p}:JNK1:APP:KNS2(AR p53 + ATP + ADP Chk1{pS317}{pS345} ++ 1ATP NDP --> PDGF STAT5B{pY699}:STAT5A{pY694} (STAT5A{pY694})2 --Rac1:GTP:MEKK4-->HIP-55{pY334}{pY344}:HPK1@ PDGFBB:(PDGFRbeta{pY})2:RasGAP{pY} (NGF-p13)2:(trkA{pY785})2:PLCgamma1{pY}+ ATP + (NGF-p13)2:(trkA{pY490}{pY785})2 <==> alpha MKK5{p} + ADP +(NR3C4))2:(5alphaDHT)2 ATP --> --p38alpha{p}-->EGF:(ErbB1{pY})2:p62Dok-1:Nck-1:p65PAK PLCgamma2@ AR ADP + 2 ADP ErbB1@ catenin-1:beta-catenin:E-cadherin:Yes{pY}:Fyn, catenin-1:beta-catenin:E-cadherin:Yes{pY}:Fyn, alpha --> CISH --SHP-2--> PLCgamma(VEGF-A:VEGFR-2{pY})2:p85{p}:p110+ ADP --> AA:(PDGFRalpha)2 + 4 ADP catenin-1:beta-catenin:E-cadherin:plakoglobin --> MKK6{p} + ADP Rac1:GDP + GTP Btk:SLP-65{pY}:Vav:Nck-1@+ ATP c-Jun + ATP p53{pS33} + (NR3C4):AKT-1{pT308}{pS473}@ EGF:(ErbB1{pY})2 Fer{pY}:p120CAS{pY} Fer{pY}:p120CAS{pY}@ catenin-1:beta-catenin:E-cadherin:Yes{pY}:Fyn, JIP1:HPK1:MLK3{p}:MKK7{p}:JNK1{p}:APP:KNS2 insulin:InsR{pY}:IRS-1, p53 + ATP ADP + + ADP + 2 ATP --> alpha catenin-1 STAT5B{pY699}:STAT5A{pY694} STAT5B{pY699}:STAT5A{pY694} --LAT{p}:Grap2:SLP-76{p}:SLAP-130:Nck-1:Vav--> Vav@ --JNK1, JNK2, PDGFBB:(PDGFRbeta{pY})2 + Shc-1 + PDGF Dvl:Fz@ + ADP--JNK1{p}--> p53 + 2 ATP ADP IRS-2 + ATP DAG:PKCalpha --plk1--> Shc-1@ IRS-2{pY} + (NGF-p13)2:(trkA{pY785})2:PLCgamma1{pY}@PDGF + beta-catenin Fer{pY}:p120CAS{pY} CSN2@ MAPKAPK2@JNK1, JNK2{p}@ Rac1:GTP + GDP JNK3{p}--> p53{pS15}{pT18}{pS20}{ace}@ p53 + ATP + RasGAP{pY} + prolactin:(prlr)2:Src:FAK1{pY}n@ AA:(PDGFRalpha{pY})2@ (VEGF-A:VEGFR-2{pY})2:PLCgamma{pY} --> CSN2 amphiphysin1{p}@ p65PAK + JIP1:HPK1:MLK3{p}:MKK7{p}:JNK1:APP:KNS2@(AR --> --> PKCtheta p53{p} + ADP Grb-2 + Sos + p85:p110 (NGF-p13)2:(trkA{pY490}{pY785})2@ + E-cadherin + alpha + ATP --> MKK6b@ --JNK2{p}--> APS@ Smac:cIAP-2Smac:cIAP-1 + + p SHIP2{pY}@ AA:(PDGFRalpha{pY})2 (NGF-p13)2:(trkA)2 PDGF MKK5@ p38alpha, MO000041391->MO000038350Rac1:GTP (NR3C4){pS650})2:(5alphaDHT)2 c-Jun{p} + ADP TRAF6:SITPEC:MEKK1 IRS-1, IRS-2 + --Chk2{pT68}--> ATP <==> <==> NRG:ErbB2{pY1139}{pY1222}{pY1248}:ErbB3{pY1054}{pY1197}{pY1222}{pY1260}{pY1276}{pY1289}@ PI3K-C2beta@ plakoglobin@ alpha JIP1:HPK1:MLK3{p}:MKK7:JNK1:APP:KNS2 p53{pS20}{pT81} insulin:InsR{pY} n ubiquitin + 2 ADP + 2 ATP --> AA:(PDGFRalpha)2@ p120CAS + catenin-1:beta-catenin:E-cadherin:plakoglobin@ MEKK4@ NRF-1@p38beta2@ Elk-1, ATF-2, + MKK4 + ATP p53{pS15}{pT18}{pS20} n ubiquitin p110@ ErbB2@ beta-arrestin2:ASK1:MKK4:JNK3 MKK6{p} <==> + ATP --> + ADP + IRS-1, --E1,UbcH6--> Shc-1 --> SHIP2 EGF:(ErbB1{pY})2:Shc-1{pY}:Grb-2:Sos IRS-2{pY}:p85:p110 plakoglobin catenin-1:beta-catenin{pY142}:E-cadherin:Yes{pY}:Fyn, (STAT5A{pY694})2@ TAO2@ p38gamma --> PGC-1 --> MBP{p}@ + 2 ADP JNK1, JNK2, --insulin:InsR{pY}:(Jak1{pY})2--> + ADP --E1,UbcH6--> (NGF-p13)2:(trkA{pY785})2 (NGF:trkA)2@ NUDEL{p}@ p65PAK:Rac1:GTP Btk:SLP-65{pY} IRS-2{pY} + ADP + ADP ErbB1 --> <==> alpha Fer{pY}:p120CAS{pY} alpha Wnt + Fz <==> amphiphysin1 + Fyn + NTP ATF-2 + ATP --> NRF-1--PP2Calpha--> ATF-2 + ATP JIP1:HPK1:MLK3{p}:MKK7{p}:JNK1:APP:KNS2 insulin:InsR{pY}:APS{pY}:CAP:c-Cbl cIAP-2{ub(n)}cIAP-1{ub(n)} + + mdm2{pS166}{pS186}{pS188}@ (NGF-p13)2:(trkA{pY785})2:PLCgamma1@ Shc-1 --> + 2 ADP + Nck-1 + Vav JNK3 + JSAP1 IRS-1, IRS-2{pY} Grb-2 prolactin:(prlr{pY}:Jak2{pY1007})2:Shc-1{pY}@ PI3K-C2alpha@ + ADP catenin-1:beta-catenin:E-cadherin:plakoglobin Fz:Wnt --Csk--> beta-arrestin2:ASK1:MKK4{p}:JNK3 MKK6 + pPGC-1@ + ADP LAT{p}:Grap2:SLP-76{p}:SLAP-130:Nck-1:Vav@ + SHIP2 <==> SmacSmac Grb-2 PDGF AA + 2 catenin-1:beta-catenin:E-cadherin:plakoglobin:p120CAS ATP --p38alpha{p}--> MO000056264->MO000017411 <==> + ADP EGF:ErbB1{pY}:ErbB2{pY} + 2 ATP (STAT5A{pY694})2 amphiphysin1@ Fyn{p} + NDP + ADP JNK3 --> c-Jun JIP1:HPK1:MLK3{p}:MKK7:JNK1:APP:KNS2@ <==> insulin:InsR{pY}:APS{pY}:CAP:c-Cbl:SHIP2 prolactin:(prlr)2:Fyn:c-Cbl{pY731} IRS-2{pY}:p85:p110@ PDGFRalpha Dvl + Fz:Wnt --Rac1:GTP:Cdk5:CDK5R1p35--> ATF-2{p} + ADP MEKK1:MKK4:JNK1, Cdc25A{pS75}{pS123}{pT506}@ + Grb-2 + PDGF AA@ 2 PDGF A --> --protein Dvl@ --> (STAT5A{pY694})2 Btk:SLP-65{pY}:Vav:Nck-1 p85@ <==> PDGF amphiphysin1{p} JIP1:HPK1:MLK3:MKK7:JNK1:APP:KNS2 JNK2, + p85:p110 PI3K-C2alpha + PDGF AA PDGF A@ <==> Dvl:Fz + (STAT5A{pY694})2 --> CSN2 alpha catenin-1 tyrosine NUDEL+ ADP + ATP Cdk5:CDK5R1p35@ p38@ Rac1:GTP + STAT5B{pY}@+ ATP --> p38alpha, Btk{pY551}:SLP-65{pY} <==> PI3K-C2beta AA:(PDGFRalpha)2 Wnt TAK1{pS}{pT}@ JNK3:JSAP1 + (NT-3)2:(trkC{pY516})2:Shc-1{pY}@ IRS-1, + beta-catenin alpha kinases--> Fz:Wnt@ Rac1:GTP:Cdk5:CDK5R1p35@ JIP1:HPK1:MLK3{p}:MKK7:JNK1:APP:KNS2p38beta2 + ATP STAT1 + ATP + PLCgamma2 prolactin:(prlr)2:Fyn:c-Cbl{pY731}:p85:p110 (NGF-p13)2:(trkA{pY785})2@ <==> alpha --Rac1:GTP:Cdk5:CDK5R1p35--> MEKK4 <==> MKK6 + ATP TRAF6 + SITPEC insulin:InsR{pY}:Shc-1@ IRS-2{pY}{pS}:p85{pS}:p110:14-3-3beta@ + E-cadherin catenin-1:beta-catenin{pY142}:E-cadherin:Yes{pY}:Fyn, alpha NUDEL{p} + ADP Rac1:GTP:MEKK4 + ADP --MKK6{p}--> --p38alpha, IGF-1@ MSK1 + ATP + NTP --> (BDNF-p14)2:(trkB{pY490})2EGF:ErbB1{pY}:ErbB2{pY}:Grb-2:PI3K-C2alpha:PI3K-C2beta (NGF-p13)2:(trkA{pY490})2:Shc-1{pY}@ alpha alpha catenin-1:beta-catenin{pY142}:E-cadherin:Yes{pY}:Fyn, PPARgamma --MLK2--> Mnk1 + ATP IRS-1{pY}:p85:p110@ <==> alpha Fer{pY}:p120CAS{pY} catenin-1:beta-catenin{pY}:E-cadherin:plakoglobin{pY} NUDEL@ Rac1:GTP + JIP1:HPK1:MLK3:MKK7:JNK1:APP:KNS2@p38alpha, p38beta2{p}--> --p38beta{p}--> Btk{pY551}:SLP-65{pY}:PLCgamma2{pY} insulin:InsR{pY}:Shc-1 + Shc-1 <==> catenin-1@ catenin-1:beta-catenin:E-cadherin:plakoglobin:p120CAS@ Fer{pY}:p120CAS{pY}@ (NR1C3) + ATP MKK6{p} + ADP JIP1 + HPK1 +--p38alpha{p}--> SHIP2@ EGF:(ErbB1{pY})2:PLCgamma1{pY}@ NRG:ErbB2{pY1139}{pY1222}{pY1248}:ErbB3{pY1054}{pY1197}{pY1222}{pY1260}{pY1276}{pY1289} 2 p75NTR catenin-1:beta-catenin:E-cadherin E-cadherin@ <==> alpha + 2 ADP Cdk5:CDK5R1p35 p38beta2{p} + STAT1{pS}p38alpha{p}@ + MSK1{pS} + ADP + NDP EGF:(ErbB1{pY})2:Shc-1:SHIP2@ + SHIP2{pY} (BDNF-p14)2:(trkB{pY490})2:Shc-1 MKK7{p}:JNK1 + --JNK1{p}--> ATF-2 + ATP MO000041391->MO000038348MLK3 + MKK7 Mnk1{p} + ADPp38alpha + ATP p65PAK@ PDGFBB:(PDGFRbeta{pY})2 + Sos + p110 + 14-3-3beta@ <==> catenin-1 + <==> ADP ADP (NGF-p13)2:(trkA{pY785})2 <==> PDGF IRS-1, p38 --> pax6 2 ATP --> PPARgamma --JNK1{p}--> + JNK1 + APP + --MKK6{p}--> STAT1{pS}@ + p110 + p85 PLCgamma@ prolactin:(prlr)2:Src:FAK1{pY}n p85 + 2 Grb-2 (p75NTR)2 beta-catenin{pY142}:E-cadherin:Yes{pY}:Fyn, Rac1:GTP:Cdk5:CDK5R1p35 + PLCgamma1 insulin:InsR{pY}:Shc-1:SHIP2{pY} AA:(PDGFRalpha{pY})2 (NGF-p13)2:(trkA{pY785})2:PLCgamma1{pY} IRS-2{pY}{pS}:p85{pS}:p110 alpha MKK7{p}:JNK1{pT183}{pY185}HIP-55{pY334}{pY344} (NR1C3){pS} + ATF-2{p} + ADP KNS2 <==> p38alpha{p} + Chk1{pS317}{pS345}@Smac:cIAP-2@ <==> + Grb-2 + Sos + Shc-1 <==> Fer{pY}:p120CAS{pY} Wnt@ MEKK1:MKK4:JNK1, <==> + p85 + p110PDGFIRS-1{pY} + (VEGF-A:VEGFR-2{pY})2:Shc-1{pY} + 14-3-3beta catenin-1:beta-catenin{pY}:E-cadherin:plakoglobin{pY}@ + 2 ADP JIP1:HPK1:MLK3:MKK7:JNK1:APP:KNS2 JNK2{p}@ AR (NR3C4) + Smac:cIAP-1@ PDGFBB:(PDGFRbeta{pY740}{pY751})2:p85:p110 NRG:ErbB2{pY1139}{pY1222}{pY1248}:ErbB3{pY1054}{pY1197}{pY1222}{pY1260}{pY1276}{pY1289}:Sos:(Grb-2)2:Shc-1:p110:p85<==> <==> + HPK1 <==> ADP ADP JNK2, Btk:SLP-65{pY} (NGF-p13)2:(trkA{pY785})2:PLCgamma1 <==>AA:(PDGFRalpha{pY})2 PDGF + Grb-2 + Sos <==> IRS-1, STAT5B{pY}:STAT5B{pY} AKT-1{pT308}{pS473} prolactin:(prlr)2:Src:FAK1{pY}n:Grb-2:Sos p85:p110 (NGF-p13)2:(trkA{pY785})2 HIP-55{pY334}{pY344}:HPK1 JNK3:JSAP1@ + Grb-2:Sos{p} (VEGF-A:VEGFR-2{pY})2:Shc-1{pY}:Grb-2:Sos@--> beta-catenin{pY142}:E-cadherin:Yes{pY}:Fyn,p120CAS@ alpha PPARgamma Rac1:GTP@ cIAP-2@ AA:(PDGFRalpha{pY731}{pY742})2:p85:p110+ Shc-1<==> + + IRS-2{pY}{pS}:p85{pS}:p110:14-3-3beta --> JSAP1@ <==> <==> AR EGF:(ErbB1{pY})2:PLCgamma1{pY}:pld2@ catenin-1:beta-catenin:E-cadherin:plakoglobin:p120CAS (NR1C3){pS}@ Grb-2IRS-1{pY}:p85:p110 + Sos (VEGF-A:VEGFR-2{pY})2:Shc-1{pY}:Grb-2:SosPLCgamma1{pY} IRS-1{pY}@ Fer{pY}:p120CAS{pY}@ STAT5B{pY}:STAT5B{pY} Cdk5@ Rac1:GTP:POSH:MLK3:MKK4, Elk-1, ATF-2, Btk:SLP-65{pY}:Grb-2:Sos{p} (NR3C4):AKT-1{pT308}{pS473} MO000000102->MO000017617 PDGFBB:(PDGFRbeta{pY})2:RasGAP{pY}@ IRS-1, + ATP --protein pax6@ MKK6 -->MKK6 --> MSK1 + ATP Nck-1 + mdm2 + 2 ATP p85:p110@ <==> PDGF EGF:ErbB1{pY}:ErbB2{pY}:Grb-2:PI3K-C2alpha:PI3K-C2beta@ STAT5B{pY}:STAT5B{pY}@ MKK7:JNK1,ATF-2@ p38delta MBP + ATPMO000038357->MO000038368 PDGFBB:(PDGFRbeta{pY})2@ IRS-2{pY}{pS}:p85{pS}:p110@ tyrosine p38alphaJNK2 --> c-Jun TAK1 --> MKK4 IGF-1 --> --p38alpha{p}--> Nck-1@ p65PAK + --AKT-1{pT308}{pS473}--> AA:(PDGFRalpha{pY})2:Shc-1:Grb-2:Sos Grb-2@ (p75NTR)2 + alpha JNK2 + ATP -->Rac1:GTP:MEKK4@ --p38alpha, (BDNF-p14)2:(trkB{pY490})2@PDGFRalpha@ kinases--> RXR-alpha{pY248}@2 STAT5B{pY} AKT-1 MSK1{pS} + ADP PDGFBB:(PDGFRbeta{pY})2 mdm2{pS166}{pS188} (NGF:trkA)2 alpha catenin-1:beta-catenin{pY}:E-cadherin:plakoglobin{pY} Rac1:GTP + p38beta2{p}--> IRS-1, IRS-1, (NGF-p13)2:(trkA{pY490})2:Shc-1{pY} alpha <==> p38alpha --> --> insulin:InsR{pY}:APS{pY}:CAP:c-Cbl:SHIP2@+ 2 ADP cIAP-1@ <==> catenin-1:beta-catenin{pY}:E-cadherin:plakoglobin{pY}:p120CAS + LAR <==> Cdk5 --/ JNK3 POSH + MLK3 + Elk-1, ATF-2, p73alpha@ PDGFBB:(PDGFRbeta{pY})2:Nck-1{pY}:p65PAK@ IRS-2{pY}@ IRS-1, IRS-2{pY} IRS-2{pY}:p85:p110 + Grb-2 <==> catenin-1:beta-catenin{pY}:E-cadherin:plakoglobin{pY}:p120CAS STAT5B{pY}:STAT5B{pY} MAPKAPK2 PDGFBB:(PDGFRbeta{pY})2:Nck-1{pY}:p65PAK prolactin:(prlr{pY}:Jak2{pY1007})2:Shc-1{pY} (p75NTR:NGF:trkA)2 <==> alpha alpha RXR-alpha@ ASK1 --> MKK6MKK4, MKK7{p} MKK6b --> insulin:InsR{pY}:APS{pY}:CAP:c-Cbl ATM@+ p85:p110 + ATP --> MO000038358->MO000016958 MBP{p} + ADPJNK1, JNK2, + Grb-2 + Sos (NGF-p13)2:(trkA{pY490})2:Shc-1{pY}:Grb-2 catenin-1 +plakoglobin{pY}@ + ADP catenin-1:beta-catenin{pY}:E-cadherin:plakoglobin{pY}:LAR MKK3 + 2 ATP + JNK1, JNK2{p} p38alpha + ATP --> PLCgamma1@ IRS-1, Csk@ RXR-alpha + JNK3@ Cdc25C + ATP DAG:PKCalpha@ <==> IRS-1, Wee1{pS53}{pS123}@ (VEGF-A:VEGFR-2{pY})2:p85{p}:p110@ <==> PtdIns(4)P@ beta-catenin{pY}@beta-catenin{pY} --TAO2--> + ADP p38alphaMO000038270->MO000017818 + ATP SLAP-130@ insulin:InsR{pY} PDGFBB:(PDGFRbeta{pY})2 IRS-2{pY}{pS}:p85{pS}:p110 (NT-3)2:(trkC{pY516})2:Shc-1{pY} ATP MO000038340->MO000038350 Cdc25C + ATP Cdc25C{pS216}@ --Chk1{pS317}{pS345}--> IRS-2{pY}:p85:p110 prolactin:(prlr{pY}:Jak2{pY1007})2:Shc-1{pY}:Grb-2:Sos (p75NTR:NGF:trkA)2@ + E-cadherin + MKK3{pS189}{pT193} --MKK3{pS189}{pT193}--> + APS + PDGFBB:(PDGFRbeta{pY})2+ Shc-1 + PtdIns(4)P+ ADP + + Grb-2 <==> LAR@ Rac1:GTP:POSH:MLK3:MKK4,--JNK1{p}--> p38alpha --> Rac1:GTP:MEKK1 --p38alpha{p}--> Cdc25C{pS216} Grb-2 --> Sos p120CAS + alpha Fyn{p}@ + 2 ADP p38alpha{p} + CAP:c-Cbl{pY} + + RasGAP + Grb-2 + Sos (VEGF-A:VEGFR-2{pY})2:PLCgamma{pY}@ ATP (NT-3)2:(trkC{pY516})2:Shc-1{pY}:Grb-2 Fer, Fyn + MKK7:JNK1, RXR-alpha{pY248} JNK3@ Cdc25C{pS216}PDK1{pS}@ + ADP plakoglobin{pY} Yes{pY}:Fyn, PP2Calpha@ADP PGC-1 + JNK1, JNK2, Rac1:GTP:MEKK1@ MSK1{pS}@ ADP ATP --> <==> prolactin:(prlr)2:Src:FAK1{pY}n:Grb-2:Sos@--EGF:ErbB1{pY}:ErbB2{pY}:Grb-2:PI3K-C2alpha:PI3K-C2beta--> (p75NTR)2@ p120CAS <==> catenin-1:beta-catenin{pY}:E-cadherin:plakoglobin{pY}:LAR@ JNK2@ + ADP beta-arrestin2:ASK1:MKK4:JNK3@ p38alpha + ATP MEKK1:MKK4:JNK1, + ADP APP695 + ATP Fer:p120CAS@ MO000000022->MO000016958 JNK3 + JSAP1 + PDGFBB:(PDGFRbeta{pY579}{pY740}{pY751}{pY771}{pY716}{pY775})2:Shc-1{pY317}:Grb-2:SosPDGFBB:(PDGFRbeta{pY})2:RasGAP{pY} PtdIns(3,4)P2 + (p75NTR:NGF:trkA)2 Fer, MO000000022->MO000016961JNK2{p} --MKK4{pS221}{pT225}--> JNK2, PDGFBB:(PDGFRbeta)2--cyclinB:Cdk1--> PDGFBB + Rac1:GTP + 2 MKK4 --> insulin:InsR{pY}:Shc-1+ ADP IRS-1, ADP (BDNF-p14)2:(trkB)2 + ATP --> Fyn:p120CAS --MKP-5--> p38alpha{p} + JNK3:JSAP1 + 4 fer@ + ATP --> APP695{pT668}mdm2 + 3 ATP prolactin:(prlr)2:Fyn:c-Cbl{pY731}:p85:p110@ insulin:InsR{pY}:Shc-1:SHIP2{pY}@ TAO1@ MLK3 <==> DLK:MKK7:JNK2:JIP1Mnk1{p}@ JNK1 --> c-JunMEKK1:MKK4:JNK1, IRS-1, IRS-2{pY} Smac + cIAP-2 Cdc25A + 3 IRS-2{pY}:p85:p110@ PDGFRalpha + PDGFBB:PDGFRalpha:PDGFRbeta@ + ATP --> (p75NTR:NGF:trkA{pY490})2 alpha alpha Fer, JNK2 + p ADP Cdc25B + ATP PDGFBB:(PDGFRbeta{pY})2--AKT-1{pT308}{pS473}--> + ADP + NTP --> BDNF + p75NTR alpha Rac1:GTP:(MLK3)2 + 2 ATP --> p38alphaJNK1{p}@MO000038318->MO000000062 --> JNK2,ATP --> Cdc25B + ATP Btk:SLP-65{pY}:Grb-2:Sos{p}@ <==> ATP PDGFRbeta (BDNF-p14)2:(trkB{pY490})2 + ADP catenin-1:beta-catenin:E-cadherin@ catenin-1:beta-catenin{pY}:E-cadherin:plakoglobin{pY}:LAR M3/6 --/ JNK3 Rac1:GTP + Grap2 + LAT{p} + Nck-1 <==> Cdc25C--Chk1{pS317}{pS345}--> + ATP Smac + cIAP-1 insulin:InsR{pY}:Shc-1{pY} <==> catenin-1:beta-catenin{pY}:E-cadherin:plakoglobin{pY}:p120CAS@ Fyn:p120CAS:Yes MKK3 + ATP DLK + MKK7{p} MEKK3 --> JNK3:JSAP1MEKK1{pT} + + MSK1@ Btk{pY551}:SLP-65{pY}:PLCgamma2{pY}@ + ADP Smac:cIAP-2mdm2{pS166}{pS186}{pS188}Chk2 + ATP PDGF <==> + ADP --> alpha POSH@ ATF-2 p38alpha,MEKK1 <==> + Nck-1 + --p38alpha{p}--> IRS-1, --Chk2{pT68}--> --Chk1{pS317}{pS345}--> <==> + NDP + ATP --> --TAO1--> JNK2 + ATP MKK6 MKK4{pS221}{pT225} Cdc25B{pS} + + 3 ADP AA:(PDGFRalpha{pY})2 PDGFBB:PDGFRalpha:PDGFRbeta BDNF:p75NTR Fer, Fyn@ MKP-5@ + JNK2{p} + Rac1:GTP p38beta2{p}@Rac1:GTP:MEKK1 Cdc25B{pS} + IRS-2{pY}:Nck-1 Cdc25C{pS216} --ATM-->Cdc25A{pS75}{pS123}{pT506} Smac:cIAP-1 (BDNF-p14)2:(trkB{pY490})2:Shc-1@ PDGFBB:PDGFRalpha:PDGFRbeta catenin-1:beta-catenin:E-cadherin:plakoglobin:LARYes{pY}:Fyn, MKK3{pS189}{pT193}@ --MKK7{p}--> JNK2 + ATP MO000038340->MO000038348MEKK1{pT}@+ JNK1, JNK2, SLAP-130 + AKT-1 + NTP ADP + PLCgamma + PDGFBB:(PDGFRbeta{pY579}{pY740}{pY751}{pY771}{pY716}{pY775})2:Shc-1{pY317}:Grb-2:Sos@ MKK3{pS189}{pT193} ADP p38delta --> AKT-1@ ADP plk1@ Chk2{pT68} + + 3 ADP + n ATP --> (p75NTR:NGF:trkA{pY490})2@ + p Fer:p120CAS + JNK2{p} + ADP MKK4 + ATP SLP-76{p} + Vav --PDK1{pS}--> + ADP PDGFBB:(PDGFRbeta{pY})2 PIP3 <==> Sos@ Fer, + ADP Rac1:GTP:(MLK3)2@ ATF-2 --MKK4{pS221}{pT225}--> JNK3{p} + JSAP1 ADP PDGF PDGFB@ PDGFBB:PDGFRalpha{pY}n:PDGFRbeta{pY771}{pY}n --TAK1{pS}{pT}--> <==> AKT-1{pT308} + PLCgamma + PDGFBB@ ADP JNK2{p} + ADP MO000038270->MO000016903 + 4 ADP p73alpha + YAP Chk2{pT68}@ PDGFBB:(PDGFRbeta{pY740}{pY751})2:p85:p110@PDGF PtdIns(3,4)P2@ PDGF AA:(PDGFRalpha{pY})2:Shc-1:Grb-2:Sos@ 2 PDGFB --> + n ADP Fyn:p120CAS@ JNK2 --> ATF-2 MKK4{pS221}{pT225} LAT{p}:Grap2:SLP-76{p}:SLAP-130:Nck-1:Vav PIP3 + ATP --> JNK1, JNK2, JNK1, JNK2, <==> + NDP AA:(PDGFRalpha{pY988}{pY1018})2:PLCgamma{pY}:PIP3AA:(PDGFRalpha{pY731}{pY742})2:p85:p110@ PDGFBB DCoHm:HNF-1alpha@ + ADP PDGFBB:(PDGFRbeta{pY})2:PLCgamma{pY}:PIP3 NRG:ErbB2{pY1139}{pY1222}{pY1248}:ErbB3{pY1054}{pY1197}{pY1222}{pY1260}{pY1276}{pY1289}:Sos:(Grb-2)2:Shc-1:p110:p85@ alpha MKK7{p}:JNK1@ JNK3 + ATP JNK3{p}@ p73alpha:YAP PIP3 prolactin:(prlr{pY}:Jak2{pY1007})2:Shc-1{pY}:Grb-2:Sos@ Fer, Rac1:GTPJIP1@ + Cdc25B + ATP Ras:GTP PDGFRbeta@ catenin-1:beta-catenin:E-cadherin:plakoglobin:LAR@ --MKK4, SHIP2 --/ PIP3 + ADP--EGF:(ErbB1{pY})2:Shc-1:SHIP2--> PDGFBB + 2 PDGFBB:PDGFRalpha{pY}n:PDGFRbeta{pY771}{pY}n PDGFBB:PDGFRalpha{pY}n:PDGFRbeta{pY771}{pY}n@ Fyn:p120CAS:Yes@ MKK3 + 2 ATP POSH + MLK3 + Cdc25B{pS}@ --Chk2{pT68}--> PIP3 PLCgamma1{pY}@ MKK7{p}--> PtdIns(3,4)P2 + PDGFRbetaEGF:(ErbB1{pY})2:Shc-1{pY}:Grb-2:Sos@ --PDGFBB:(PDGFRbeta{pY})2:RasGAP{pY}--> + RasGAP + --MLK2--> p73alpha:YAP@ Grap2@ MKK4, MKK7 + M3/6@ MKP-5 --/ MKK4 + 2JNK1, ATP JNK2, Cdc25B{pS} + --insulin:InsR{pY}:APS{pY}:CAP:c-Cbl:SHIP2-->p <==> Ras:GDP + p RasGAP@ DCoHm@ Itk@ MO000000108->MO000016681 ATP --> MKK3:Dyrk1B + MKK3{pS189}{pT193} JNK1, JNK2 MLK2@ --Rac1:GTP:MEKK4-->JNK3{p} + ADP ADP PDGFBB:(PDGFRbeta{pY})2 PtdIns(3,4)P2 + p38alpha PDGFBB:(PDGFRbeta)2 PDGFBB:PDGFRalpha{pY}n:PDGFRbeta{pY771}{pY}n:RasGAP{pY} Yes + Fer, DCoHm:HNF-1alpha + 2 ADP DLK:MKK7:JNK2:JIP1@ <==> MLK3@ MKK4{pS221}{pT225} + fer + ATP --> p (BDNF-p14)2:(trkB)2@ Rac1:GTP:(MLK3)2 MKK4, Elk-1, ATF-2, + ADP Fyn:p120CAS <==> Rac1:GTP:POSH:MLK3:MKK4, + 2 ADP p73alpha:YAP PDGFBB:(PDGFRbeta{pY})2:fer{pY} Lck + NTP + ATP --> MKK7{p}@ M3/6 --/ MBP@ Cdc25A{pS123}@ MO000000108->MO000018279PIP2 <==> Fer, MKK3:Dyrk1B:DCoHm:HNF-1alpha MKK3:Dyrk1B:DCoHm:HNF-1alpha MKK7:JNK1, --> Tp73 AKT-1{pT308}@ + ADP --Csk--> MKK3:Dyrk1B:DCoHm:HNF-1alpha@ Rac1:GTP:(MLK3{p})2 p38alpha p38delta@ AKT-1 --/ ASK1 --EGF:(ErbB1{pY})2:PLCgamma1{pY}--> Fyn:p120CAS:Yes MKK3:Dyrk1B@ Dyrk1B@ + ATP -->MKK3 + Dyrk1B JNK2 p38alpha@ PDGFBB:(PDGFRbeta)2@ (NGF-p13)2:(trkA{pY490})2:Shc-1{pY}:Grb-2@ Lck{p} + NDP + 2 ADP HIP-55{pY334}{pY344}@ MKK3 --> JNK1 --> ATF-2 PLCgamma1 + Cdc25A + ATP Ras:GDP + GTP DAG + IP3 Ras:GDP + GTP MKK3 + Dyrk1B<==> MKK3@ Ras:GDP + GTP DLK@ p38alpha MKK4{pS221}{pT225} LAT{p} + Grap2 --Chk2{pT68}--> --Btk:SLP-65{pY}:Grb-2:Sos{p}--> --prolactin:(prlr)2:Src:FAK1{pY}n:Grb-2:Sos--> Lck@ + DCoHmMKK3:Dyrk1B + DAG + PIP2--PDGFBB:(PDGFRbeta{pY579}{pY740}{pY751}{pY771}{pY716}{pY775})2:Shc-1{pY317}:Grb-2:Sos--> MKP-7 --/ beta-arrestin2 Tp73@ Grb-2:Sos{p}@ Cdc25C@ Cdc25A{pS123} Chk2@ Ras:GTP + GDP alpha HNF-1alpha{pS249} MO000000023->MO000017818 --PP2Calpha--> MO000038270->MO000007822 + SLP-76{p} + MEKK1@ PKCalpha PIP3PIP2 + ATP --EGF:(ErbB1{pY})2:PLCgamma1{pY}:pld2--> Ras:GTP + GDPRas:GTP + GDP (NT-3)2:(trkC{pY516})2:Shc-1{pY}:Grb-2@ p38alpha + ASK1 + MKK4 PDGFBB:(PDGFRbeta{pY})2:PLCgamma{pY}:PIP3@ catenin-1:beta-catenin:E-cadherin TCR + Fyn{p} MKK4 + 2 p Itk <==> + ADP <==> --insulin:InsR{pY}:Shc-1:SHIP2{pY}-->--p85:p110--> DAG + IP3 + ADP + JNK3 <==> GCK --> MLK3 PDGF + MAGI-2:PTEN <==> JNK2 + JIP1 + MKK4{pS221}{pT225}@ PLCgamma1:LAT{p}:Grap2:SLP-76{p}:Itk DAG:PKCalpha PtdIns(3,4)P2PIP3 + ADP+ PIP2 + ATP Ras:GDP + GTP Yes@ MKP-7@ beta-arrestin2:ASK1:MKK4:JNK3 PDGFBB:(PDGFRbeta{pY})2 AA:(PDGFRalpha{pY988}{pY1018})2:PLCgamma{pY}:PIP3@ + vinculin TCR:Fyn{p} doublecortin GCK@ IRS-1, IRS-2{pY} p --(VEGF-A:VEGFR-2{pY})2:p85{p}:p110--> --PDGF (BDNF-p14)2:(trkB)2 MO000038594->MO000038595 JNK2 --> MLK2 JNK2@ --CD148--> vinculin:alpha <==> doublecortin@JNK2:JIP1:doublecortin@ JNK2:JIP1:doublecortin<==> + Grb-2:Sos PIP3 + ADP + ARMS <==> HNF-1alpha{pS249}@ Trx1{oxC}@ JNK1 + ATP GCK + 2 MEKK1 PDGFBB:(PDGFRbeta)2 PIP2 AA:(PDGFRalpha{pY})2:Shc-1:Grb-2:Sos-->Ras:GDP + GTP catenin-1:beta-catenin:E-cadherin:MAGI-2:PTEN@vinculin:alpha (BDNF-p14)2 + TCR@ MKK7{p}@ beta-arrestin2@ <==> IRS-1, PIP2 + ATP (BDNF-p14)2:(trkB{pY490})2:Shc-1 (BDNF-p14)2:(trkB)2:ARMS MKK4, MKK7 + +JNK2:JIP1:doublecortin ATP --> JNK2 DLK + MKK7 + MLK2 --> MKK4 --MKK4{p}--> <==> + 2 p Smac@ PIP2 + ATP --(VEGF-A:VEGFR-2{pY})2:PLCgamma{pY}--> --prolactin:(prlr{pY}:Jak2{pY1007})2:Shc-1{pY}:Grb-2:Sos-->Ras:GTP + GDP p53{pS15}{pS37} catenin-1:beta-catenin:E-cadherin:MAGI-2:PTEN vinculin@ ARMS@ JNK1 + ATP APP695{pT668}@PKCalpha@ + Grb-2 + PDGFBB:PDGFRalpha{pY}n:PDGFRbeta{pY771}{pY}n:RasGAP{pY}@ 2 trkB <==> ATPASK1 --> MKK3 + JIP1 + JNK1{p} + ADP MSK1 + 2 ATP IRS-2{pY}:Grb-2:Sos PIP2 --IRS-1, Ras:GTP + GDP + ATP CKI-delta@ JNK2 + JIP1 MKK7 --> --MKK4{pS221}{pT225}-->MKK4 + 2MLK3 ATP --> MKK4 GCK:(MEKK1)2 --prolactin:(prlr)2:Fyn:c-Cbl{pY731}:p85:p110--> IP3 + DAG Ras:GTP + Sos (BDNF-p14)2:(trkB)2 --Rac1:GTP:(MLK3{p})2--> doublecortin{pT321}{pT331}{pS334} --ERK1{pT}{pY}--> --Btk{pY551}:SLP-65{pY}:PLCgamma2{pY}-->IRS-2{pY}:p85:p110--> insulin:InsR{pY}:Shc-1{pY}@ --CKI-delta--> ASK1@ <==> JLP:MEKK3:MKK4{pS221}{pT225}:JNK1p38delta JNK1{p} + ADP--MLK2--> MEKK1 --> YAP@ PIP3 + ADP <==> MKK4, MKK7{p} + ADP PIP3 + AKT-1 AKT-1{pT308} DAG + IP3 PIP3 + ADP p53{pS15}{pS18}{pS37} trkB@ DLK:MKK7:JNK2:JIP1 + ATP --> JLP MKK4 --> MKK7 Cdc25B@ MSK1{pS}{pT} + PIP2 + ATPp53 + 2 ATP p53{pS15}{pS37}@ MKK3 + 2 ATP MKK4{pS221}{pT225} <==> + ATP (BDNF-p14)2:(trkB{pY490})2:Shc-1:Grb-2:Sos:Ras:GTP Trx1{reC}2:ASK1 + ADP MKP-7 --/ JNK2 + MEKK3 + 2 ADP --PDGF + ADP --MEKK3-->EIF-4E + ATP + 2 ADP p38alpha PIP3:AKT-1 PIP2 + ATP --DNA-PKcs:Ku70:Ku80--> Ras:GDP@ glucose@ --> Trx1{oxC} EIF-4E{pS}@ MLK2 --> MKK7MKK4{pS221}{pT225} --PKCalpha--> AA:(PDGFRalpha{pY731}{pY742})2:p85:p110--> PIP2 MKK3{pS189}{pT193}--Mnk1{p}--> MKK7{p} + JNK1 MKK4 --> JNK2 --PDGFBB:(PDGFRbeta{pY740}{pY751})2:p85:p110-->p53{pS15}{pS37} PIP2 p53:Bcl-x@ MAGI-2:PTEN@ + ASK1 doublecortin{pT321}{pT331}{pS334}@ ADP + --PLCgamma1{pY}--> Ras:GDP + GTP Rac1:GTP:(MLK3{p})2@ EIF-4E{pS}+ 2 ADP + +<==> JNK1{p} + PIP3 + ADP PIP3 + ADP + 2 ADP Trx1{reC}2:ASK1@ Trx1{reC}2 + Grx --/ ASK1 Elk-1 + ATP IRS-1,AKT-1{pT308}{pS473} --PDGFBB:(PDGFRbeta{pY})2:PLCgamma{pY}:PIP3--> --RasGRP:DAG--> DLK --> MKK7 MKK7{p}:JNK1ADP MO000000023->MO000016903ASK1 --> MKK4 14-3-3:Cdc25B{pS}@ DAG + IP3 Ras:GTP ADP MKK4@ IP3 + DAG NRG:ErbB2{pY1139}{pY1222}{pY1248}:ErbB3{pY1054}{pY1197}{pY1222}{pY1260}{pY1276}{pY1289}:Sos:(Grb-2)2:Shc-1:p110:p85p53 + Bcl-x p53{pS15}{pS18}{pS37}@ ASK1 <==> MLK3 --> MKK7 MEKK2:MKK7:JNK1 --p38alpha, IRS-2{pY}:Nck-1@ --PDGFBB:PDGFRalpha{pY}n:PDGFRbeta{pY771}{pY}n:RasGAP{pY}-->Ras:GTP + GDP Trx1{reC}2:ASK1ASK1{pS967} ASK1:DUSP19:MKK7 14-3-3 + MSK1{pS}{pT}@ <==> + 2 ATP --> + 2 ATP --> p38beta2{p}--> Ras:GDP + p PTEN + MAGI-2 Grx@ --> ASK1 + p MO000041390->MO000016903MKK4, MKK7@ Cdc25B{pS} CaMKII{p}@ NRG:ErbB2{pY1139}{pY1222}{pY1248}:ErbB3{pY1054}{pY1197}{pY1222}{pY1260}{pY1276}{pY1289}:Sos:(Grb-2)2:Shc-1{pY}:p110:p85{pY}Ras:GTP@p53:Bcl-x glucose + ATP --> MEKK2 + Elk-1{p} + ADP PLCgamma1:LAT{p}:Grap2:SLP-76{p}:Itk@ Chk2 + ATP <==> Cdc25A@ + 2 ADP RasGRP:DAG@ <==>--GLUT4--> MAGI-2@ (BDNF-p14)2:(trkB)2:ARMS@ ASK1 + DUSP19 MKK7@ SLP-76{p}@GCK:(MEKK1)2@ --DNA-PKcs:Ku70:Ku80--> Sos --> H-Ras golgin-160 + MKK7{p} + MKK4{p}@ Elk-1 + NTP Wee1:14-3-3beta@ (NGF-p13)2:(trkA{pY490})2:Shc-1{pY}:Grb-2 MAGI-2:PTENglucose + MKK7{p} + MO000038593->MO000016917 MKK4 + ATP 14-3-3:Cdc25B{pS} Ras:GDP + GTP ATP Trx1{reC}2@ PP5 --/ ASK1 MKK7 --> JNK2 JNK1{p} + 2 ADP --JNK1, JNK2, Chk2{pT68} + + Sos + ADP MKK4 + ATP --GCK:(MEKK1{pT})2--> CREB-341 + ADP --LAT{p}:Grb-2:Sos{p}--> --Rac1:GTP:(MLK3{p})2--> JNK3{p}--> EGFR --> (NT-3)2:(trkC{pY516})2:Shc-1{pY}:Grb-2Ras:GTP <==> ASK1{pS967}@ ASK1 --> MKK7 --AIP1:ASK1--> MKK4{pS221}{pT225} MO000038318->MO000020748 ATP PLCgamma1:LAT{p}:Grap2:SLP-76{p}:Itk Ras:GTP + GDP PIP2 --PDGF golgin-160{p} + p38deltap38alpha --> --> Elk-1{p} + NDP MEKK1 (NGF-p13)2:(trkA{pY490})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP+ Sos + PTEN@ MKK4{pS221}{pT225} MKK4+ ADP + 2 ATP MKP-4 --/ --MSK1{pS}--> + NTP --> AA:(PDGFRalpha{pY988}{pY1018})2:PLCgamma{pY}:PIP3--> Lck{p}@ ADP MBP MBP Wee1{pS53}@ Ras:GTP <==> JNK@ + ADP --MEKK2--> p38alpha YAPCREB-341{p} + ATP +PLCgamma1{p}:LAT{p}:Grap2:SLP-76{p}:Itk Ras:GDPIP3@ + GTPIP3 + DAG Grb-2:Sos@ Wee1{pS53} + (NT-3)2:(trkC{pY516})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP GLUT4@ MO000000023->MO000007822MKK4{pS221}{pT225} MKK4 --> JNK1 --AKT-1{pT308}{pS473}-->ADP + NDP CREB1{pS133}@ ATP --IRS-1,PIP3 --PTEN--> RasGRP + DAG RasGRP@ ASK1 + DUSP19 YAP{pS127} + (BDNF-p14)2@ golgin-160@ PP5@ AIP1 + ASK1 MO000038593->MO000016916 + 2 ADP JNK1@ JNK2 --> MBP LAT{p}@ YAP{pS127}@ CREB-341{p}@ Cdc25C + ATP Wee1 + ATP --cyclinB:Cdk1{pT161}-->PIP2@ IRS-2{pY}:Grb-2:Sos-->PIP2 + p <==> + MKK7 <==> PDGFBB:(PDGFRbeta{pY})2:fer{pY}@ADP Cdc25C + ATP golgin-160{p}@ <==> MEKK3@ MKP-X --/ MKK4 + ATP Raf-1{p}@ --cyclinB:Cdk1{pY15}--> --plk1-->CAP:c-Cbl{pY}@ PIP2 Wee1{pS53}{pS123} Ras:GTP + GDP RasGRP:DAG ASK1:DUSP19:MKK7 GCK:(MEKK1)2 MKP-1 --/ --CaMKII{p}--> LAT{p}:Grb-2:Sos{p}@Smac --/ JNK1, JNK2@ AIP1:ASK1@ p38alpha --MEKK1{p}-->14-3-3:YAP{pS127}@ Cdc25C{p} + Wee1{pS53} + CREB1 + ATP PIP3@ --PLCgamma1{p}:LAT{p}:Grap2:SLP-76{p}:Itk--> DAG@ AIP1:ASK1 JLP:MEKK3:MKK4{pS221}{pT225}:JNK1@ + 2 ATP --> p38alpha Cdc25C{p} + flotillin-1 + IRS-1, + ADP Ras:GTP + Raf{p}@ MKK4{p} + ADP Cdc25CADP + NTP ADP ML-IAP--MSK1{pS}{pT}--> DAG + IP3 H-Ras:GDP + BDNF@ MO000041390->MO000007822 JLP + MEKK3 + GCK:(MEKK1{pT})2 ADP CAP:c-Cbl{pY} IRS-2{pY}:Grb-2:Sos@ Raf{p} <==> TC10:GTP --> JLP@ --cyclinA:Cdk1{pY15}--> CREB1{pS133} + cyclinB:Cdk1 + GTP Rac1 --> JNK DUSP19@ MKK4 + JNK1 + 2 ADP 14-3-3 + Cdc25B + ATP <==> Ras:GTP:Raf{p} GLUT4 HIP-55 + 2 ATP Cdc25C{p} + ADP ATP --EGF:(ErbB1{pY})2:Shc-1{pY}:Grb-2:Sos--> (BDNF-p14)2:(trkB)2:ARMS <==> YAP{pS127} --cyclinB:Cdk1{pY15}--> PLCgamma1{p}:LAT{p}:Grap2:SLP-76{p}:Itk@ flotillin-1:CAP:c-Cbl{pY} TCR:Fyn{p}@ --MHC class MKK7 --> JNK1 NDP --Wee1:14-3-3beta-->PIP3 --> AKT H-Ras:GTP + 2 BDNF <==> + ATP --> ASK1:DUSP19:MKK7@ MEKK3 --> JLP:MEKK3:MKK4:JNK1 <==> Cdc25B + ATP Cdc25B{p} + II:antigen:TCR{p}:Fyn:ZAP-70{p}--> cyclinB:Cdk1{pY15} GDP (BDNF)2 (BDNF-p14)2:(trkB)2:ARMS{pY} AIP1@ MKK7 14-3-3:YAP{pS127} LAT{p} + --Raf-1{p}--> Cdc25BADP + ATP MEKK1 + ATP cyclinB:Cdk1{pY15}@ flotillin-1:CAP:c-Cbl{pY}@DAG + PKC (BDNF)2 HIP-55{pY334}{pY344} PIP3:AKT-1@ + ADP + ADP GCK:(MEKK1{pT})2@ Cdc25B{p} + --cyclinA:Cdk1{pY15}--> insulin:InsR{pY}:Shc-1{pY}<==> DAG:PKC flotillin-1:CAP:c-Cbl{pY} MEKK2:MKK7:JNK1@ Grb-2:Sos{p} --PKCdelta--> flotillin-1@ Ras:GDP + GTP (BDNF)2@ --plasmin--> 2 Rac1@ + 2 ADP CD148@ MEKK1{p}@ + CrkII:C3G MEKK2 + MKK7 PLCgamma1{p}:LAT{p}:Grap2:SLP-76{p}:Itk<==> ADP Cdc25B{p} + MEKK1{p} + + Grb-2:Sos --insulin:InsR{pY}:Shc-1{pY}:Grb-2:Sos--> BDNF-p24 + AKT@ TC10:GTP@ + JNK1 <==> SLP-76 + NTP LAT{p}:Grb-2:Sos{p}--CD148--> Elk-1{p}@ ADP ADP <==> <==> BDNF-p24@ (BDNF-p14)2 JNK1 --> MBP ERK1{pT}{pY}@ Ras:GTP + GDP Tiam-1 --> MEKK2:MKK7:JNK1 --MHC class PIP3:AKT-1{pS473} insulin:InsR{pY}:Shc-1{pY}:Grb-2:Sos flotillin-1:CAP:c-Cbl{pY}:CrkII:C3G MEKK2 --> PLCgamma1:LAT{p}:Grap2:SLP-76{p}:Itk AKT-1{pT308}{pS473}@ cyclinB:Cdk1@ CrkII:C3G@flotillin-1:CAP:c-Cbl{pY}:CrkII:C3G@ Rac1 II:antigen:TCR{p}:Fyn:ZAP-70{p}--> + p + ATP MKK7 SLP-76{p} + (BDNF)2 --> plasmin@ AlgorithmLAT + NTP Development--PIP3:PDK1{pS241}--> Pin1:APP695{pT668}@ NRG:ErbB2{pY1139}{pY1222}{pY1248}:ErbB3{pY1054}{pY1197}{pY1222}{pY1260}{pY1276}{pY1289}:Sos:(Grb-2)2:Shc-1{pY}:p110:p85{pY}@DAG:PKC@ andH-Ras:GDP@ TC10:GDP + NDP --MHC class EGFR@ (BDNF)2 CD8 + Lck{p} Tiam-1@ HIP-55@ JLP:MEKK3:MKK4:JNK1@ SLP-76 + NTP AKT-1{pT308}{pS473} GTP II:antigen:TCR{p}:Fyn:ZAP-70{p}--> cyclinB:Cdk1{pY15} Pin1 + <==> NDKA@ NDKA --/ JLP:MEKK3:MKK4:JNK1 --MHC class + PIP3 + ADP --flotillin-1:CAP:c-Cbl{pY}:CrkII:C3G--> LAT{p} + NDP MKP-1 --/ JNK1 cyclinB:Cdk1{pY15}--Cdc25C{p}--> APP695{pT668} CD8@ CD8:Lck{p} Tiam-1 + NTP --> I:antigen:TCR{p}:Fyn:ZAP-70{p}-->MEKK2@ Cdc25B + ATP TC10:GTP + p53{pS15}{pT18}{pS20}{ace}Elk-1@ --Cdc25B{p}-->cyclinB:Cdk1 + <==> CD4 + Lck{p} JLP:MEKK3:MKK4{pS221}{pT225}:JNK1 SLP-76{p} + PIP3:AKT-1 + --cyclinA:Cdk2{pY15}--> cyclinB:Cdk1{pT14}{pY15}@ GDP MBP@ 4 + ATP cyclinB:Cdk1 + p Pin1:APP695{pT668} <==> + NDP NDP NTP Cdc25B{p} + PIP2 + ATP EIF-4E@ LAT + NTP 14-3-3@ p53{pS15}{pT18}{pS20}{pS315}{ace} --cyclinA:Cdk2--> p eNOS + ATP CD4:Lck{p} --pdpk2--> p53{pS15}{pT18}{pS20}{pS315}{ace}@ ADP IRS-1, --NRG:ErbB2{pY1139}{pY1222}{pY1248}:ErbB3{pY1054}{pY1197}{pY1222}{pY1260}{pY1276}{pY1289}:Sos:(Grb-2)2:Shc-1{pY}:p110:p85{pY}--> --MHC class (p53{pS15}{pT18}{pS20}{pS315}{ace})4@MKP-4@ p53{pS15}{pT18}{pS20}{pS315}{ace} --AKT-1{pT308}{pS473}--> eNOS@ PIP3:AKT-1{pS473} <==> IRS-1,IRS-2{pY}:Nck-1:PRK2@ ADP + PIP3 IP3 + IP3R TC10:GDP@ I:antigen:TCR{p}:Fyn:ZAP-70{p}--> PIP3:AKT-1{pS473}@ + ADP eNOS{pS1177} cyclinB:Cdk1 + + NDP (p53{pS15}{pT18}{pS20}{pS315}{ace})4 Elk-1 + ATP IRS-2{pY}:Nck-1 <==> IP3R:IP3 IP3R@ CD4@ MHC class LAT{p} + NDP + ADP 2 ATP --ERK1{pT202}{pY204}--> + PRK2 <==> Ras:GTP:Raf{p}@ II:antigen:TCR{p}:Fyn:ZAP-70{p} pdpk2@ --pkmyt1--> (BDNF-p14)2:(trkB)2:ARMS{pY}@ SLP-76@ ML-IAP@ Elk-1{p} + ADP IRS-1, Raf + Ras:GTP H-Ras@ Bcl-x@ --CD148--> cyclinB:Cdk1{pT14}{pY15} MHC class cyclinA:Cdk1{pY15}@ <==> Ras:GTP:Raf@ MHC class IRS-2{pY}:Nck-1:PRK2 cyclinE:Cdk2{pY15} (BDNF-p14)2:(trkB{pY490})2:Shc-1:Grb-2:Sos:Ras:GTP@ II:antigen:TCR{p}:Fyn:ZAP-70{p}@ Elk-1 + ATP + 2 ADP Ras:GTP:Raf DAG --> II:antigen:TCR{p}:Fyn:ZAP-70 CREB1 + ATP + Cdc25A DNA-PKcs:Ku70:Ku80@ cortactin{pY}@ MKP-X@ --ERK2{pT185}{pY187}--> Rap1:GTP + p --AKT-1{pT308}{pS473}--> <==> H-Ras:GDP + MHC class PIP3:PDK1{pS241}@ Elk-1{p} + ADP DAG:PKCdelta MKP-1@ CREB1{pS} + CREB1@ eNOS{pS1177}@ GTP I:antigen:TCR{p}:Fyn:ZAP-70{p} PIP3:AKT-1 + cortactin + ATP Elk-1 + NTP cyclinE:Cdk2{pY15}:Cdc25A <==> DAG + LAT@ FOXO3a + 3 ADP DAG + PKCdelta --NRG:ErbB2{pY1139}{pY1222}{pY1248}:ErbB3{pY1054}{pY1197}{pY1222}{pY1260}{pY1276}{pY1289}:Sos:(Grb-2)2:Shc-1{pY}:p110:p85{pY}--> --CD148--> ATP--PDGFBB:(PDGFRbeta{pY})2:fer{pY}--> Cdc25C{p}@ --ERK{p}--> PKCdelta 14-3-3zeta{pS184}@ ATP <==> H-Ras:GTP + MHC class --mTOR:mLST8:rictor:SIN1:Protor-1-->cortactin{pY} + Elk-1{p} + NDP --AKT-1{pT308}{pS473}--> Cdc25B{p}@ DAG:PKCdelta GDP PIP3:AKT-1{pS473} ADP I:antigen:TCR{p}:Fyn:ZAP-70 14-3-3sigma{pS186}@ FOXO3a{pT32}{pS253}{pS315} MEKK3 --> + ADP GSK3 + ATP TCR:Fyn{p} + p FOXO3a + ATP+ ADP MKK4 CREB1--AKT-1{pT308}{pS473}--> --> FOS (NGF-p13)2:(trkA{pY490})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP@ --CD45--> 14-3-3zeta:Bax MEKK1 --> --AKT-1{pT308}{pS473}--> BDNF --> ERK1 NADP+@ pkmyt1 + ATP PKCdelta@GSK3{pS} + ADP NO@ TCR:Fyn + p + ATP MEKK2 --> MKK4 FOXO3a{p} + cyclinB + Cdk1 insulin:InsR{pY}:Shc-1{pY}:Grb-2:Sos@ L-arginine + --AKT{p}--> 14-3-3sigma:Bax ERK1{pT202}{pY204}@ (NT-3)2:(trkC{pY516})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP@3/2 O2 + 3/2 pkmyt1@ Software--JNK1--> MKK4 ADP Implementation<==> pkmyt1{pS} + AKT{p}@ + ATP ERK1 + 2 ATP cyclinB@ MHC class 14-3-3zeta{pS184} mTOR + ATP bad{pS75}:Bcl-xL cyclinB:Cdk1 NADPH + 3/2 pkmyt1ADP + ATP PIP3 + --MEK1{p}--> L-arginine@ I:antigen:TCR{p}:Fyn:ZAP-70{p}@ --JNK1-->+ Bax + ADP --AKT-1{pT308}{pS473}--> + ATP H+ --RSK2--> pkmyt1{pS}@ MHC class 14-3-3sigma{pS186} mTOR{pS} + --AKT-1{pT308}{pS473}--> Caspase-9{pS196}@ PIP3:PDK1{pS241}PDK1{pS241} CREB-341@ ERK1{pT}{pY} +GSK3{pS}@ --eNOS{pS1177}--> pkmyt1{pS} + CD8:Lck{p}@ mTOR{pS}:4E-BP1:EIF-4E:raptor@ bad:Bcl-xL + <==> FOS@ II:antigen:TCR{p}:Fyn:ZAP-70@ + Bax + ADP ADP bad{pS75}{pS99}:Bcl-xL Caspase-9 + --> cyclinA:Cdk1{pY15} 2 ADP L-citrulline + 2 O2@ ADP MHC class MO000000074->MO000017354 FOXO3a{pT32}{pS253}{pS315}@ ATP GSK3@ pkmyt1 + ATP + ADP ATP PIP3:PDK1{pS241}PDK1{pS241} + foxo4 + 3 ATP --Cdc25C{p}--> H2O + NO + (BDNF-p14)2:(trkB)2:ARMS{pY} II:antigen:TCR{p}:Fyn:ZAP-70 MO000000074->MO000022455 --AKT-1{pT308}{pS473}--> ERK1 --> MBP PKCdelta-CF:DNA-PKcs@ DNA-PKcs + --cyclinB:Cdk1{pT161}--> RSK2@ --AKT-1{pT308}{pS473}--> PIP3 MKP-4 --/ ERK1 --AKT-1{pT308}{pS473}--> cyclinA:Cdk1 + L-citrulline@3/2 NADP+ + CrkL <==> + NTP --MHC Ku70 + Ku80DAG:PKCdelta@ pkmyt1{p} + CD4:Lck{p}@ mTOR{pS}:4E-BP1:EIF-4E:raptor bad{pS75}:Bcl-xL Caspase-9{pS196} Elk-1 + ATP p H-Ras:GTP@ H2O@ NADPH@ (BDNF-p14)2:(trkB)2:ARMS{pY}:CrkL class foxo4{pT28}{pS193}{pS258} <==> ADP + ATP --> + ADP + ADP --ERK2{p}--> cyclinA:Cdk1 + II:antigen:CD4:Lck--> + 3 ADP ERK2{pT185}{pY187}@ CREB1{pS}@ DNA-PKcs:Ku70:Ku80 DNA-PKcs@ mTOR{pS} + 4E-BP1{p}@ bad{pS75}:Bcl-xL@ bad + ATP Elk-1{pS} + ADPElk-1 + ATP ATP --Wee1--> PIP2 + ATP CrkL@ MHC class DNA-PKcs:Ku70:Ku80 cyclinB:Cdk1{pT161}@ 4E-BP1{p} + --AKT-1{pT308}{pS473}-->ML-IAP --/ --ERK1{p}-->PFK2 + ATP cyclinA:Cdk1{pY15} --HB-EGF-ECD:(ErbB4{pY})2:p101:p110gamma--> MEK + NTP II:antigen:TCR{p}:Fyn:ZAP-70{p} ERK1:MP1:MEK1{pS218}{pS222} + PKCdelta-CF cyclinA:Cdk1 + EIF-4E + raptor bad{pS99}Caspase-9 + Elk-1{pS}--AKT-1{pT308}{pS473}--> + ADP Wee1@ + ADP PIP3 + ADP gys1 + NTP --Ras:GTP:Raf{p}--> Rap1:GTP@ + NDP ERK2 --> MBP + 2 ATP --> <==> ATP MHC class + ADP ADP PFK2{pS} + ADP foxo4@ pkmyt1{p}@ --GSK3--> MEK{p} + NDP MP1 + PKCdelta-CF:DNA-PKcs --pkmyt1--> IP3R:IP3@ I:antigen:TCR{p}:Fyn:ZAP-70@ gys1{p} + NDP H+@ (BDNF-p14)2:(trkB)2:ARMS{pY}:CrkL@ CD45@ Smac:XIAP@ MEK1{pS218}{pS222}ERK{p}@ + Ku80 + Ku70 cyclinA:Cdk1{pT14}{pY15} MHC class FOXO1A + ATP Elk-1{pS}@ p27Kip1 + ATP cyclinE:Cdk2{pY15}:Cdc25A@ (BDNF-p14)2:(trkB)2:ARMS{pY}:CrkL:C3G mTOR{pS}@ bad{pS99}@ cyclinA:Cdk2{pY15}@ + cytosolic + ADP II:antigen:TCR{p}:Fyn FOXO3a@ --AKT-1{pT308}{pS473}--> --AKT-1{pT308}{pS473}-->p27Kip1 + 3 Smac + + Rap1:GTP MKP-X --/ ERK2 ERK1{pT202}{pY204} phospholipase + ZAP-70 mTOR:mLST8:rictor:SIN1:Protor-1@ FOXO1A{p} + MKP-1 --/ ERK2 PDE-3B + ATP p27Kip1{pT157}ATP Cytochrome <==> (BDNF-p14)2:(trkB)2:ARMS{pY}:CrkL mTOR{pS} + + ADP + 2 ADP A2{p}@ MEK2@ <==> MHC 2 14-3-3zeta + ADP --AKT-1{pT308}{pS473}--> --AKT-1{pT308}{pS473}--> C:(Apaf-1)2:dATP:(Caspase-9)2:XIAP:proCaspase-3 Pin1@ (BDNF-p14)2:(trkB)2:ARMS{pY}:CrkL:C3G:Rap1:GTP (BDNF-p14)2:(trkB)2:ARMS{pY}:CrkL:C3G@ + C3G <==> MHC class 4E-BP1:EIF-4E MEKK1 --> Raf --> MEK2 gys1@ class FOXO3a{pT32}{pS253}{pS315} PDE-3B{pS} + p27Kip1{pT157}@p27Kip1{pS10}{pT187}{pT198} <==> cytosolic (BDNF-p14)2:(trkB{pY490})2:Shc-1:Grb-2:Sos:Ras:GTP:Raf-1:MEK1{p}cyclinA:Cdk1{pT14}{pY15}@ H-Ras --> (BDNF-p14)2:(trkB)2:ARMS{pY}:CrkL:C3G I:antigen:TCR{p}:Fyn:ZAP-70 + raptor <==> 14-3-3zeta:Bax@ p21Cip1 + ATP II:antigen:TCR{p}:Fyn:ZAP-70 <==> ADP PDE-3B{pS}@MEK1 + 3 ADP Smac:XIAP + phospholipase <==> + NTP --MHC mTOR{pS}:4E-BP1:EIF-4E:raptor FOXO3a{p}@ --AKT-1{pT308}{pS473}--> ERK + NTP Raf-1 gys1{p}@ (14-3-3zeta)2:FOXO3a{pT32}{pS253}{pS315} Cytochrome A2 insulin:InsR{pY}:Shc-1{pY}:Grb-2:Sos+ NTP (BDNF-p14)2:(trkB{pY490})2:Shc-1:Grb-2:Sos:Ras:GTP MEK{p}@ class (14-3-3zeta)2:FOXO3a{pT32}{pS253}{pS315}@ p21Cip1{pT145} CREB1 + ATP --MEK{p}--> cyclinE:Cdk2{pY15}@ C:(Apaf-1)2:dATP:(Caspase-9)2 MEK2ERK1:MP1:MEK1{pS218}{pS222}@ --> ERK1 --ERK{p}--> + ATP + MEK1{p} + (BDNF-p14)2:(trkB)2:ARMS{pY}:CrkL:C3G:Rap1:GTP:B-Raf@ C3G@ I:antigen:CD8:Lck--> 14-3-3zeta@ p27Kip1{pS10}{pT187}{pT198}@ + ADP PRK2@ --RSK{p}--> ERK{p} + NDP (BDNF-p14)2:(trkB{pY490})2:Shc-1:Grb-2:Sos:Ras:GTPRaf@ MEK@ (BDNF-p14)2:(trkB)2:ARMS{pY}:CrkL:C3G:Rap1:GTP@ 14-3-3sigma:Bax@ + Caspase-3 + MEK1{p}@ cytosolic --ERK{p}--> Raf-1 gys1{p} MHC class CREB1{pS} + + Raf-1 <==> bad{pS75}{pS99}:Bcl-xL@ p21Cip1{pT145}@ protein phospholipaseinsulin:InsR{pY}:Shc-1{pY}:Grb-2:Sos{p} Bcl-x + Bak Bcl-x:Bak@ --PP1--> gys1 CD8:Lck{p} I:antigen:TCR{p}:Fyn:ZAP-70{p} p27Kip1{pS10}{pT187}{pT198} ADP (BDNF-p14)2:(trkB{pY490})2:Shc-1:Grb-2:Sos:Ras:GTP:Raf-1 MHC class cortactin@ remnants cyclinA:Cdk1@ A2{p} + NDP + ADP <==> + p --CD45--> + NDP + 14-3-3tau ERK2 + 2 ATP (NGF-p13)2:(trkA{pY490})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP:Raf-1:MEK1{pS} TCR:Fyn@ II:antigen:CD4:Lck@MHC class MHC class cyclinB:Cdk1 + Ku70@ Bcl-x:Bak 4E-BP1:EIF-4E@ 14-3-3zeta + 14-3-3tau@ <==> --MEK1{pS218}{pS222}--> insulin:InsR{pY}:Shc-1{pY}:Grb-2:Sos <==> PKC --> Raf CD8:Lck + p II:antigen:TCR{p}:Fyn@ I:antigen:TCR{p}:Fyn mTOR{pS} + NTP --CAK--> H-Ras:GTP:Raf-1:MEK1Ku80@ MEK + ATP (BDNF-p14)2:(trkB)2:ARMS{pY}:CrkL:C3G:Rap1:GTP Bax <==> p27Kip1{pS10}{pT187}{pT198}:14-3-3tau ERK2{pT185}{pY187} + ATP (NGF-p13)2:(trkA{pY490})2:Shc-1{pY}:Grb-2:Sos:Ras:GTPDAG:PKCdelta + CD4:Lck{p} + ZAP-70 raptor + MEK1{pS218}{pS222}@cyclinB:Cdk1{pT161} H-Ras:GTP:Raf-1:MEK1+ ATP -->(NT-3)2:(trkC{pY516})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP:Raf-1:MEK1{pS} --PKCdelta:DAG:Raf-1--> PP1@ + B-Raf <==> ZAP-70@ 14-3-3zeta:Bax 2 14-3-3zeta + + 2 ADP MEK2 --> ERK2 --RSK{p}--> + Raf-1(NGF-p13)2:(trkA{pY490})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP + Raf-1 <==> --CD45--> <==> MHC MP1@ + NDPCdk1@ H-Ras:GTP+ 2 ATP + --> <==> MEK{p} + ADP (BDNF-p14)2:(trkB)2:ARMS{pY}:CrkL:C3G:Rap1:GTP:B-Raf MHC class p70S6K1 <==> MEKK3@ foxo4{pT28}{pS193}{pS258} ERK1@ insulin:InsR{pY}:Shc-1{pY}:Grb-2:Sos{p} MEK1{pS} PKCdelta:DAG:Raf-1+ Raf-1 <==> CD4:Lck + p class mTOR{pS}:raptor:p70S6K1 ERK2 + ATP Raf-1H-Ras:GTP + + (NT-3)2:(trkC{pY516})2:Shc-1{pY}:Grb-2:Sos:Ras:GTPcytosolic II:antigen:TCR:Fyn <==> PDE-3B@ + ADP (NGF-p13)2:(trkA{pY490})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP:Raf-1 Raf-1 + I:antigen:TCR{p}:Fyn:ZAP-70 raptor@ MEKK2@ --MEK1{p}--> PKCdelta-CF@ MEK1{p} +Raf-1 ADP + phospholipase+ Raf-1(NT-3)2:(trkC{pY516})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP + PKCdelta:DAG:Raf-1@ + NTP --MHC (14-3-3zeta)2:foxo4{pT28}{pS193}{pS258} Rap1:GTP Bax@p27Kip1{pS10}{pT187}{pT198}:14-3-3tau@ MEK1{p}:MP1:ERK1 ERK1 + MP1 + MEK1{pS218}{pS222}insulin:InsR{pY}:Shc-1{pY}:Grb-2:Sos{p}@ A2@ MEK1{pS} + Raf-1 <==> class ERK2{p} + ADP B-Raf@ cyclinA:Cdk2{pY15} + ATP --> MEK1{pS218}{pS222} + 2 ADP (NT-3)2:(trkC{pY516})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP:Raf-1 <==> II:antigen:CD4:Lck--> 14-3-3sigma + MEK1{p} + MP1 MEK1{pS}@ Raf-1:Rap1:GTP FOXO1A@ cyclinA:Cdk2{pY15}--Cdc25C{p}--> MEK1{p} + MP1 <==> MHC class mTOR{pS}:raptor:p70S6K1 ERK2{p}@foxo4{pT28}{pS193}{pS258}@ + ERK1 <==> Bax <==> --Cdc25B{p}-->cyclinA:Cdk2 + ERK2 + ATP+ ERK1{p} + ERK1:MP1:MEK1{pS218}{pS222} ERK@ II:antigen:TCR{p}:Fyn + ATP --> mTOR@ FOXO3a + ATP MEK1{p}:MP1:ERK1 DNA-PKcs:Ku70:Ku80 CD4:Lck@ 14-3-3sigma:Bax (14-3-3zeta)2:foxo4{pT28}{pS193}{pS258}@cyclinA:Cdk2 + p RSK + --MEK1{pS}-->NTP ADPERK1 + ATP p70S6K1@ mTOR{pS} + --SGK-1{pT256}--> FOXO1A{p}@ PDK1{pS241}@ cyclinE:Cdk2{pY15}:Cdc25A --Caspase-3--> (BDNF-p14)2:(trkB{pY490})2:Shc-1:Grb-2:Sos:Ras:GTP:Raf-1:MEK1{p}@ + NDP Caspase-9@ p --ERK{p}-->ERK2{p} + ADP --MEK1{pS}--> MO000000011->MO000004670 H-Ras:GTP + MHC class p70S6K1{pT389}mTOR + mLST8 FOXO3a{p} + PFK2{pS}@ + ATP --> Ku70 + Ku80 + Raf-1:Rap1:GTP@ RSK{p} + NDP ERK1{p} + ADP Raf-1 + MEK1 MHC class II:antigen + + raptor+ rictor + ADP + SIN1 ADP bad:Bcl-xL@ ERK1{p}@ cyclinE:Cdk2{pY15}:Cdc25A{p} protein PFK2@ MO000000108->MO000016673 <==> II:antigen:TCR:Fyn@ CD4:Lck <==> MHC class + Protor-1 cyclinA:Cdk2 + + ADP remnants Ca mTOR{pS}:raptor:p70S6K1@ MO000000011->MO000004676 PKCdelta H-Ras:GTP:Raf-1:MEK1@ MHC class I:antigen:CD8:Lck@MHC class <==> ATP --Wee1--> ERK2@ H-Ras:GTP:Raf-1:MEK1 HB-EGF-ECD:(ErbB4{pY})2:p101:p110gamma@ --IP3R:IP3--> MHC class bad@ --Caspase-3--> (NGF-p13)2:(trkA{pY490})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP:Raf-1:MEK1{pS}@ II:antigen + I:antigen:TCR{p}:Fyn@ 14-3-3sigma@ Tau + ATP Ca CD8:Lck@ II:antigen:CD4:Lck mTOR:mLST8:rictor:SIN1:Protor-1 cyclinA:Cdk2{pY15} PFK2 + ATP TCR:Fyn <==> bad{pS75}{pS99}:Bcl-xL 14-3-3tau + PKCdelta-CF --Cdk1--> + ADP --RSK{p}--> MHC class + (14-3-3tau)2 Bax <==> MKP-3 --/ ERK1 Raf --> MEK1 Tau{pT231} + PFK2{pS}CREB-341 + ADP Pin1 + II:antigen:TCR:FynMHC class MHC class <==> FOXO1A + ATP 14-3-3tau:Bax PFK2 + ATP MEK1{p}:MP1:ERK1@ ADP RSK{p}@ Tau{pT231} I:antigen + rictor@ bad{pS75}{pS99}:Bcl-xL:(14-3-3tau)2 --SGK-1{pT256}--> --WISK{p}--> --Caspase-3--> MHC class I:antigen:TCR:Fyn (NT-3)2:(trkC{pY516})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP:Raf-1:MEK1{pS}@ TCR:Fyn <==> FOXO1A{p} + PFK2{pS} + ADP CREB-341-p30 Pin1:Tau <==><==> I:antigen + + NTP --MHC (BDNF-p14)2:(trkB{pY490})2:Shc-1:Grb-2:Sos:Ras:GTP:Raf-1@ MHC class ADP + protein Pin1 + Pin1:Tau{pT231}Tau CD8:Lck <==> class Protor-1@ I:antigen:TCR:Fyn WISK + ATP MO000045192->MO000038692 remnants I:antigen:CD8:Lck--> MKK4beta@ Raf-1@ MHC class MHC class p70S6K1{pT389}@ RSK@ MHC class mLST8@ --PDK1{pS241}--> CREB-341-p30@ (NGF-p13)2:(trkA{pY490})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP:Raf-1@ I:antigen:TCR:Fyn@ I:antigen:CD8:Lck WISK{p}@ I:antigen:TCR{p}:Fyn cortactin + ATP WISK{p} + ADP MKK4 --/ NR1B2 MO000045192->MO000038672 cyclinE:Cdk2 + Cytochrome cyclinA + Cdk1 PKCzeta + ATP bad + ATP calpain-2 + ATP + NDP --ERK1{p}, ATP --Wee1--> C:(Apaf-1)2:dATP:(Caspase-9)2:XIAP:proCaspase-3@ <==> Tau{pT231}@ E2F:DP:pRb + Target Identification (Breast Cancer,--PDK1{pS241}--> GPCR--WISK{p}--> --ERK1{p}-->PRK2 cyclinA:Cdk1 + ERK2{p}--> NR1B2-isoform2@ 14-3-3tau:Bax@ cyclinE:Cdk2{pY15} cyclinA:Cdk1 (BDNF-p14)2:(trkB{pY490})2:Shc-1:Grb-2:Sos:Ras:GTP:Raf-1:MEK1ATP (14-3-3tau)2@ PKCzeta{pT410} bad{p} + ADP PFK2 + ATP calpain-2{pS}--Caspase-3--> + ATP --CAK--> cortactin{pS405}{pS418} + ADP (NT-3)2:(trkC{pY516})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP:Raf-1@--cyclinB:Cdk1{pT161}--> SIN1@ + ADP --p70S6K1{pT229}{pT389}--> ADP protein cyclinA:Cdk1{pT161} + ATP --> bad{p}@ FOXO1A + ATP MKP-3@ E2F:DP + pRb{p} + ADP PFK2{pS} + ADP remnants + ADP (BDNF-p14)2:(trkB{pY490})2:Shc-1:Grb-2:Sos:Ras:GTP:Raf-1:MEK1{p} --WISK{p}-->p70S6K1{pT389} MEKK3 --> MHC class p27Kip1@ + ADP + ADP FOXO1A{p} + + ATP MEK1 (NGF-p13)2:(trkA{pY490})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP:Raf-1:MEK1 II:antigen@ SGK-1 + ATP ADP--PDK1{pS241}--> MathematicsTau@ + ATP --> & Computational SGK-1{pT256}@ MEKK2 --> MEK1@ WISK@ --PDK1{pS241}--> p70S6K1{pT229}{pT389}CARD4:proCaspase-9 14-3-3tau:Bax (BDNF-p14)2:(trkB{pY490})2:Shc-1:Grb-2:Sos:Ras:GTP:Raf-1(NGF-p13)2:(trkA{pY490})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP:Raf-1 MO000000051->MO000022259 MEK1 (NGF-p13)2:(trkA{pY490})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP:Raf-1:MEK1{pS} SGK-1{pT256} --> CARD4 + --Caspase-3--> ABP-280 + ATP + MEK1+ MEK1 <==> <==> MHC class + ADP cyclinE:Cdk2{pY15}:Cdc25A{p}@ + ADP + ADP Caspase-9 Bax + protein (BDNF-p14)2:(trkB{pY490})2:Shc-1:Grb-2:Sos:Ras:GTP:Raf-1:MEK1(NGF-p13)2:(trkA{pY490})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP:Raf-1:MEK1--RSK{p}--> I:antigen@ remnants calpain-2{pS}@ ABP-280{pS2152} bad{pS75}{pS99}:Bcl-xL:(14-3-3tau)2@ PKCzeta@ Cytochrome (NGF-p13)2:(trkA{pY490})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP:Raf-1:MEK1@ ERK1{p}, Cytochrome rps6 + ATP calpain-2@ + ADP (BDNF-p14)2:(trkB{pY490})2:Shc-1:Grb-2:Sos:Ras:GTP:Raf-1:MEK1@ Bak@ C:(Apaf-1)2:dATP:(Caspase-9)2@ (NT-3)2:(trkC{pY516})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP:Raf-1:MEK1 ERK2{p}@ C:(Apaf-1)2:dATP:(Caspase-9)2 --RSK{p}--> (NT-3)2:(trkC{pY516})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP:Raf-1Tau + ATP --> <==> 2 rps6{p} + ADP cortactin{pS405}{pS418}@ + MEK1--calpain-2{pS}--> <==> (NT-3)2:(trkC{pY516})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP:Raf-1:MEK1{pS} Caspase-9 + MEKK1@ cyclinA:Cdk2 + p21Cip1@ ABP-280{pS2152}@(NT-3)2:(trkC{pY516})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP:Raf-1:MEK1 protein + ADP PKCzeta{pT410}@ bad + Bcl-xL Cytochrome p27Kip1 <==> remnants HB-EGF-ECD:(ErbB4{pY})2 <==> C:(Apaf-1)2:dATP Cytochrome cyclinA:Cdk2:p27Kip1 cyclinA:Cdk1{pT161}@ rps6@ + p101 + PDK1 + ATP bad:Bcl-xL C:(Apaf-1)2:dATP:(proCaspase-9)2 p27Kip1 + ATP Ca@ RSK1@ (NT-3)2:(trkC{pY516})2:Shc-1{pY}:Grb-2:Sos:Ras:GTP:Raf-1:MEK1@ p110gamma --> cyclinA:Cdk2:p27Kip1@--> --KIS--> proteins and infertility)Nedd4-2{pS}@ rps6 + ATP <==> SGK-1{pT256}:Nedd4-2:ENaC PDK1{pS241} + p70S6K1{pT229}{pT389}@ Cytochrome MHC class I + cortactin{pS405}{pS418}:N-WASP@ cyclinA:Cdk2:p27Kip1 p27Kip1{pS10} + ATP --> ADP C:(Apaf-1)2:dATP:(Caspase-9)2--p70S6K1{pT229}{pT389}--> cyclinA:Cdk2 + + ADP HB-EGF-ECD:(ErbB4{pY})2:p101:p110gamma antigenMHC <==> class II + + ATP --> rps6{p}@ SGK-1{pT256}SGK-1{pT256} + protein rps6{p} + ADP p21Cip1 <==> Pin1:Tau{pT231}@ ABP-280@ MHCantigen class <==> cyclinA:Cdk2:p27Kip1{pT187}cyclinA:Cdk2:p107@ Pin1:Tau@ + Nedd4-2{pS} remnants cyclinA:Cdk2:p21Cip1 PLA2{p} + Ca I:antigenMHC class SGK-1@ + ADP N-WASP + Nedd4-2:ENaC+ ENaC + ADP <==> II:antigen Cytochrome cortactin{pS405}{pS418} ENaC@<==> cyclinE:Cdk2 + p27Kip1{pS10}@ PLA2{p}:Ca bad{pS75}{pS99}:Bcl-xL:(14-3-3tau)2 Cks1 + Cytochrome C:(Apaf-1)2:dATP:(Caspase-9)2 pRb{p}@ <==> SGK-1{pT256}:Nedd4-2:ENaC proCaspase-7 p27Kip1 <==> antigen@ C:(Apaf-1)2:dATP:(proCaspase-9)2@ + proCaspase-3 cyclinD:Cdk6:p27Kip1@PCNA + E2F:DP:pRb + p110gamma@ + ATP ERK1{p}, CARD4:proCaspase-9@ cyclinA:Cdk2:p27Kip1{pT187}cyclinA:Cdk2 + cyclinA:Cdk2@ cyclinE:Cdk2:p27Kip1 cortactin{pS405}{pS418}:N-WASP CARD4@ --Cytochrome p21Cip1 <==> MHC class I@ --PKAc--> IRAP + ATP ERK2{p} + RSK1 + SCF-Skp2 + n p107 <==> cyclinA:Cdk2:p21Cip1@ + XIAP <==> NTP PLA2{p}@ cyclinA:Cdk2:p27Kip1{pT187}@ C:(Apaf-1)2:dATP:(Caspase-9)2--> PCNA:p21Cip1 PLA2{p}:Ca@ bad{pS75}{pS99}{pS118}:Bcl-xL:(14-3-3tau)2 --PKCzeta{pT410}--> <==> ERK1{p}, ubiquitin --> cyclinA:Cdk2:p107 Cytochrome --cyclinA:Cdk1{pT161}--> Caspase-7 + cyclinE:Cdk2:p27Kip1@ cyclinE:Cdk2{pY15}:Cdc25A{p} p101@ + ADP IRAP{pS} + ADP ERK1{p}, ERK2{p}:RSK1 cyclinA:Cdk2 + cyclinE:Cdk2:p27Kip1 C:(Apaf-1)2:dATP:(Caspase-9)2:XIAP:proCaspase-3 E2F:DP + pRb{p} Biology Cytochrome protein cyclinD:Cdk6 + KIS@ MHC class II@ SGK-1{pT256}:Nedd4-2:ENaC@ ERK2{p}:RSK1{pS380}{pT573} p27Kip1{pT187}{ub(n)} --> + NDP C:(Apaf-1)2:dATP@ + ATP --> remnants p27Kip1 <==> cyclinD:Cdk6:p21Cip1@ --> ERK1{p}, + MEK1@ cyclinE:Cdk2 + CAK@ apc Nedd4-2:ENaC@ cyclinE:Cdk2:p27Kip1{pT187} proCaspase-3 cyclinD:Cdk6:p27Kip1 Bcl-xL@ ERK2{p} + Cks1:SCF-Skp2 Cdc25A{p} + p cyclinE:Cdk2 + E2F:DP:pRb@ --PLA2{p}:Ca--> + ADP Caspase-3@ PCNA:p21Cip1@ RSK1{pS380}{pT573} p21Cip1 <==> --Cytochrome arachidonic acid IRAP{pS}@ Cdc25A{p}@cyclinE:Cdk2:p21Cip1C:(Apaf-1)2:dATP:(Caspase-9)2--> cyclinA@ N-WASP@ apc@ cyclinE:Cdk2:p27Kip1{pT187}@ cyclinE:Cdk2:p107@ Caspase-3 + cyclinD:Cdk6 + Cytochrome proCaspase-7@ p21Cip1 <==> CARD4 + protein cyclinA:Cdk2 + cyclinD:Cdk4:p27Kip1@ PCNA@ p27Kip1{pT187}{ub(n)}@ C:(Apaf-1)2:dATP Cot --> MKK4 p107@proCaspase-9Cks1 + remnants ATP --CAK--> cyclinD:Cdk6:p21Cip1 PKAc@ + proCaspase-9<==> E2F:DP@ arachidonic Cks1:SCF-Skp2@ cyclinE:Cdk2:p27Kip1{pT187} cyclinE:Cdk2:p21Cip1@ cyclinA:Cdk2{pT160} XIAP@ IRAP@ CARD4:proCaspase-9<==> acid@ Cks1@ + SCF-Skp2 + n MEK1 --> ERK1 + ADP cyclinD:Cdk4 + Cytochrome ubiquitin --> cyclinE:Cdk2 + p27Kip1 <==> SCF-Skp2@ C:(Apaf-1)2:dATP:(proCaspase-9)2 cyclinE:Cdk2 + p107 <==> cyclinD:Cdk4:p27Kip1 cyclinD:Cdk4:p21Cip1@ p27Kip1{pT187}{ub(n)} cyclinE:Cdk2:p107 Raf-1 --> MEK1 2 Bak + tBid bad{pS75}{pS99}{pS118}:Bcl-xL:(14-3-3tau)2 ERK1{p}, E2F:DP:pRb + + proCaspase-7 cyclinA + Cdk2 SRF <==> <==> ERK2{p}:RSK1@ MKK4 --/ ATP bad{pS75}{pS99}{pS118}:Bcl-xL:(14-3-3tau)2@ PDK1@ Cks1:SCF-Skp2 --(Caspase-10)2--> <==>--Caspase-3--> Pin1:Tau{pT231}cyclinD:Cdk4 + (Bak)2:tBid bad{pS75}{pS99}{pS118}:(14-3-3tau)2 RXR-alpha --cyclinA:Cdk2{pT160}--> Caspase-7 + cyclinA:Cdk2protein --PP2A--> p +p21Cip1 <==> + Bcl-xL ERK1{p}, E2F:DP + pRb{p} RSK1{pS380}{pT573}@ protein remnants Pin1:TaucyclinD:Cdk4:p21Cip1 ERK2{p}:RSK1{pS380}{pT573}@ cyclinE:Cdk2@ MEK1 --> ERK2 + ADP KAP --/remnants (Caspase-10)2@ cyclinE:Cdk2 + calcineurin + Apaf-1:dATP + Caspase-7@ cyclinD:Cdk6 + cyclinA:Cdk2 proCaspase-3Cytochrome C ATP --CAK--> ErbB4@ calmodulin + Cytochrome C Cytochrome C@Cdc42 --> Cdc42 (Bak)2:tBid@ ATP --CAK--> SRF@ --(Caspase-10)2-->--(Bak)2:tBid-->cyclinE:Cdk2{pT160} Ca <==> SRF MEKK1 --Caspase-3--> cyclinD:Cdk6{pT177} HB-EGF-ECD:(ErbB4{pY})2@ E2F:DP:pRb + bad{pS75}{pS99}{pS118}:(14-3-3tau)2@ <==> proCaspase-9@ Caspase-3 + + ADP E2F:DP:pRb + calcineurin:calmodulin:Ca --Caspase-7--> Cytochrome C protein + ADP ATP Cytochrome p65PAK --> cyclinA:Cdk2 protein Mcl-1L 2 ATP protein Rad21 Cot --> MEK1 remnants --cyclinD:Cdk4{pT172}--> calmodulin@ C:(Apaf-1)2:dATP MKK4 --/ pRb remnants proCaspase-3@ --Caspase-3--> Caspase-3-p20:Caspase-3-p12 cyclinD:Cdk4 + --cyclinD:Cdk6{pT177}--> remnants --Caspase-3--> E2F:DP + ATP E2F:DP:pRb{p} + MLH1protein -->cyclinA:Cdk2{pT160}@ 2 ATP --CAK--> MO000031330->MO000031372 E2F:DP:pRb{p} + protein proCaspase-6 (Bak)2:tBid --> --cyclinA:Cdk2{pT160}--> ADP Rac1 --> MEKK1 --Caspase-3-->remnants Caspase-3 + cyclinD:Cdk4{pT172} ADP ERK1{p}, cyclinA:Cdk2 remnants --Caspase-3-->numa1 (Bak)2:tBid E2F{p}:DP + calcineurin@ MEKK1 --> protein cyclinA + protein + ADP PDK1 + ERK2{p}:RSK1 + --/ p73beta --Caspase-3,Caspase-6-->Caspase-6 cyclinD:Cdk6@ ADP RSK1{pT573}:ERK1{p}, IKK-beta remnants Cdk2{pT160} remnants RSK1{pS380}{pT573} ATP --> E2F5 proCaspase-3:Hsp10:Hsp60protein ERK2{p} + ATP E2f7E2F4 <==> <==> RSK1{pT573}:ERK1{p}, Wee1 --/ E2F2 Cdk2 + ATP --Caspase-6-->remnants --> ADP + TFDP2 cyclinA:Cdk2{pT160} PDK1:RSK1{pS380}{pT573} ERK2{p} + ADP NR2F2 E2F3 --CAK--> ERK1{p}, cyclinA:Cdk2 IRF6 Caspase-3 + E2F{p}:DP@ TFDP1 Cdk2{pT160} + Hsp10 + Hsp60 ERK2{p}:RSK1{pS380}{pT573} GABPA MEKK1 --> cyclinE + Cdk2 DEDD:Keratin-18ADP tBid@ NR2F1 STAT3 (Apo2L:DR5:FADD)3@ --Caspase-3--> Cdk6 + ATP EBF2 GSK3betaIRF4 --> <==> E2F:DP:pRb{p}@ Ben@ (Apo2L:DR5:FADD:proCaspase-10)6 DEDD + protein E2F:DP:pRb{p} + --CAK--> MEKK1 cyclinE:Cdk2 IRF2 p65PAK --> remnants ATP Cdk6{pT177} + cyclinD:Cdk4{pT172}@ PDK1:RSK1{pS221}{pS380}{pS563}{pT573} EBF3 Rad21@ --> 2 Cdc42@ Apaf-1:dATP@ MEK1 --cyclinE:Cdk2{pT160}--> ADP --> PDK1 + IRF8 cyclinE:Cdk2 (Apo2L:DR5:FADD)3 CAD:ICAD proCaspase-2 p107:E2F-4:DP-1 cyclinD:Cdk6{pT177}@ RSK1{pT573}:ERK1{p}, E2F:DP + proCaspase-6@ RSK1{pS221}{pS380}{pS563}{pT573} NR5A2 SFPQ --/ pRb Cot-58kDa@ + 3 --Caspase-3--> --Caspase-3--> + ATP ERK2{p}@ IRF1 pRb{p}n + ADP cyclinA:Cdk2{pT160}:KAP@ NR1I2 MECP-2@ (Caspase-10)2 PP2A@ CAD + protein proCaspase-3 + Caspase-2 --cyclinA:Cdk2{pT160}--> IRF5 TCF7L1 PRC1 ● PCNA ZBTB16 + protein 2 proCaspase-3 E2F-4:DP-1 + Rad21 Wee1 --/ remnants Hsp10 + Hsp60pRb{p}n@ E2F-4:DP-1@ E4F1 Cdk2@ <==> numa1@ p107{p} + ADP --Caspase-7--> cyclinE:Cdk2 BUB1B PPP1CA remnants <==> calcineurin:calmodulin:Ca@ car CKAP5 CDC20 Mcl-1L@(proCaspase-3)2 cyclinA:Cdk2{pT160} PDK1:RSK1{pS380}{pT573}@ protein B-Myb@ TRIP13 HSF2 proCaspase-3:Hsp10:Hsp60 CCNB2 LMOD1 PP2A --/ Caspase-2@ + KAP <==> remnants YWHAH Abl + p107:E2F-4:DP-1 H2AFZ KAP@ cyclinA:Cdk2 IRF-3@ ERK2 --> MEK1 Hsp60@ cyclinA:Cdk2{pT160}:KAP proCaspase-9Graph MLH1@ theory cyclinD:Cdk4{pT172} + ATP HNRNPAB CKS2 ECT2-isoform1@ <==> Caspase-3-p20:Caspase-3-p12@ --calcineurin:calmodulin:Ca--> ACTB TPX2 PPP2CA BimEL{p} proCaspase-3:Hsp10:Hsp60@ Caspase-6@ p107:E2F-4:DP-1@ --cyclinD:Cdk4{pT172}--> AURKA MEK1 --> Abl:proCaspase-9 cyclinD:Cdk4 + DPP3 --Caspase-3--> cyclinD:Cdk4@ E2F-4:DP-1 + CEP55 PPP1R2 p p73beta@ ATF-a@ GSK3beta cyclinE@ Hsp10@ p107{p} + ADP e2f-1 MgcRacGAP@PPP1R11 STAT4@ BimEL-p22 + p107{p}@ srebp-2 cyclinE:Cdk2{pT160}@ TOP2AFOXO4 MSH6 ISGF3G protein cyclinD:Cdk4 cyclinA:Cdk2{pT160} srebp-1aKLF4 BAZ1A cyclinA:Cdk2{pT160}:p130@ HB-EGF-ECD:(ErbB4)2 PDK1:RSK1{pS221}{pS380}{pS563}{pT573}@ Apaf-1 + dATP remnants Abl:proCaspase-9@ --/ pRb + p130 <==> + 2 ATP --> Bid ATF-2-xbb4@ATFa-isoform3@ prbSTAT5B@ Cdk2{pT160}@ <==> GABPB1 CREM-Ia@ XBP1 CFL1 FXYD1 cyclinA:Cdk2{pT160}:p130 HB-EGF-ECD:(ErbB4{pY})2 --(Caspase-8)2--> PDK1:RSK1{pS380}{pT573} ICER-xbb1@ Apaf-1:dATP ATF-2-isoform1@ SPAG5 POLE3 cyclinD+ 2 ADP + Cdk6 tBid + protein + ATP --> LEF1 MEF2A CCNB1 <==> RXR-alpha@MEF2D MgcRacGAP --/ remnants PDK1:RSK1{pS380}{pS563}{pT573} ATFa-isoform1@cyclinA:Cdk2 TUBA1CSMARCA5 LXRalpha-isoform1@ FOXN1ZFP161 Cdc42 Abl:proCaspase-9 (proCaspase-3)2@ cyclinD:Cdk6 + ADP RSK1{pS221}{pS380}{pS563}{pT573}@ --> p53mef2c/delta8 cyclinE:Cdk2{pT160} (Apo2L:DR5:FADD:proCaspase-10)6@ calmodulin:Ca@ + ATP --> DEDD@ Cdk6{pT177}@ cyclinD + NF-AT2{p} + ATF-3@ E2F-1 --> pRb LXR-beta@ ECT2 --> Cdc42 --PP2A-->Cdc42-isoform2@ MAD2L1 Abl:proCaspase-9{pY153} DEDD:Keratin-18@ Cdk6{pT177} calcineurin:calmodulin:Ca CREM-Ib@ rxr-betaATF-1@ cyclinE:Cdk2 + cyclinE + ● + ADP <==> Bid@ --> PDK1:RSK1{pS380}{pS563}{pT573} pRb --/ E2F-1 pitx1@ ECT2 --> Rac1 Cdk2{pT160} CREB-A@ ELK4 ATF-4@ IKK-beta --> p calcineurin:NF-AT2 + ATP --> p63alpha@ HDAC5 <==> Cdk2{pT160} cyclinD:Cdk6{pT177} NFYC IRF-3 KAP@ + PDK1:RSK1{pS221}{pS380}{pS563}{pT573} SRC-1 --> CAR ELF2 Fli-1@ cyclinE:Cdk2{pT160} --PP2C--> dATP@ ELF1 NFYB (proCaspase-3)2 calmodulin:Ca + ADP p73gamma@ (NR1I3) Cdk2 + p proCaspase-10 Caspase-8 DeltaNp73alpha@ p300 --> E2F-1 VDR EBF1 Abl:proCaspase-9{pY153}@ --(Caspase-8)2--> + p PDK1:RSK1{pS380}{pS563}{pT573}@ ETV6ELF4 c-Ets-1@ Cdk2{pT160} CAD:ICAD@ --Caspase-6--> --Caspase-6--> p300 --> ERG ETS2 hsf1-l Combinatorics 2 Apaf-1@ SREBP-1c@ ATF6@c-Myb-isoform1@ --KAP:HTm4--> CAD@ Caspase-10 Caspase-8 + SREBP-2 ATF5@ NFYA Caspase-3-p20:Caspase-3-p12 CKS2 CTF-1@ IRF-7A@ Cdk2 + p protein p300 --> p73 CREB-B@ BCL-6@ NF-1A@ elk1-isoform1 Ikaros-1@ Raf-1 --/ pRb cyclinE:Cdk2{pT160} Cdk6@ Gfi1@ Abl@ remnants Wee1@ HELIOS@ + p130 <==> CDP-isoform1@gfi1b@ net Cdc42 --> Elk-1 Cot --> ERK1 CTF-2@ c-Fos@ c-MAF-isoform2@ Rac1-isoform1@ cyclinE:Cdk2{pT160}:p130 cyclinD:Cdk4:p19INK4d@ p300 --> p65PAK-isoform1@ NF-AT2{p}@ MEF-2C@ATM --> E2F-1 PRDM1 STAT2-isoform1@ Caspase-10@ c-Fos + ATP SREBP-1 STAT6-isoform1@ SRF@ RRM2 Cdc42 --> c-Jun --RSK1{pS221}{pS380}{pS563}{pT573}--> HNRNPF IKK-beta@ Rac1 --> Cdc42 cyclinD:Cdk4 + p73delta@ c-Jun@ STAT1beta@ Cdc42 --> proCaspase-2@ c-Fos{pS362}{pS374} p63gamma@ HSPA8 cyclinE:Cdk2{pT160}:p130@ p19INK4d + ADP p65PAK BimEL-p22@ p130@ PP2C@ p300 --> <==> cyclinD + Cdk4 MgcRacGAP{p} Rac1 --> Elk-1 cyclinD:Cdk4:p19INK4d ATMMEF-2C --> CREB1 ERK1 --> Raf-1-isoform1@ HB-EGF-ECD:(ErbB4)2@ DEDD + <==> --PP2A--> c-Ets-2 Keratin-18 cyclinD:Cdk4 Cdk6{pT177} MgcRacGAP + p STAT5A@ ERK1 --> ERK1@ --PP2C--> (Caspase-8)2@ Caspase-8@ c-Fos{pS362}{pS374}@ p300 --> p63 VDR --> STAT6-xbb1@ ● <==> Abl RXR-alpha --> c-Ets-1 --(Caspase-8)2-->Cdk6 + p cyclinD@ proCaspase-10@ calcineurin:NF-AT2@ VDRRXR-alpha --> ERK1 --> c-Myb DEDD:Keratin-18 E2F-1 --> p53VDR TCF-4E@ Abl-p120 + SRC-1 --> VDR RXR-beta 14-3-3zeta@ HB-EGF-ECD + GSK3beta --> BimEL{p}@ ERK2 --> 2 ErbB4 <==> protein Caspase-8@ Tome-1 --/ ERK1 -->ERK1 Elk-1 & Rac1 --> p15INK4b:Cdk6@ E2F-1 STAT3-isoform1@ p65PAK --> remnants CKII-alpha:CKII-alpha2:(CKII-beta)2 c-Ets-2 GSK3beta --/ p65PAK HB-EGF-ECD:(ErbB4)2 Hippi:Hip-1 + c-Fos@ Wee1DeltaNp63alpha@ NR1B1-isoform1@ ERK2 --> c-Myb SRC-1A@ ERK2 --> HSF1 Raf-1 Polynomial dynamical systemsCaspase-8 --> ATF-1p300 --> BCL-6 ERK1 --> c-Jun p16INK4a:Cdk6@ c-Ets-1 KAP:HTm4@ CAD + ICAD (FasL:Fas:FADD:FAF1:Caspase-8)6 (FasL:Fas:FADD)6 <==> GSK3beta@ p15INK4b + PPARgamma <==> p18INK4c:Cdk6@ --> 4 Caspase-8 + 6 FAF1 + 6 Hippi:Hip-1:Caspase-8 limk1 --> ERK2 --> Elk-1 Cdk6 <==> RIP140 --/ (NR1C3) & p300 ERK2 --> Net CAD:ICAD (FasL:Fas:FADD)6 --> 2 Caspase-8c-FLIP-L-p43 + CREB1 p65PAK --> p19INK4d + p15INK4b:Cdk6p16INK4a + RAR-alpha --/ c-Fos ERK2@ Caspase-8 + <==> Caspase-8 STAT5A Cdk6 <==> Cdk6 <==> + 6 FAF1 + 3 (FasL:Fas:FADD)6 PP2A --> Raf-1 p18INK4c + (FasL:Fas:FADD:FAF1:Caspase-8)6 huntingtin:Hip-1@ FasL@ (NR1B1) p19INK4d:Cdk6 p16INK4a:Cdk6 (Caspase-8)2 + protein+ 3 (FasL:Fas:FADD:FAF1:Caspase-8)6@ <==> 6 FasL + 6 Fas ERK1 --/ Raf-1 p19INK4d:Cdk6@Cdk6 <==> Hippi:Hip-1@ CKII-alpha --> (c-FLIP-L-p43)3:(FADD:Fas:FasL)6:(proCaspase-10)3@protein remnants c-FLIP-L-p43:Caspase-8Hippi:Hip-1:Caspase-8@ Hippi:Hip-1 + <==> p18INK4c:Cdk6 c-FLIP-L-p43 + VDR c-Myb --> p53 remnants calcineurin:NF-AT2 huntingtin (FasL:Fas)6 ATM@ PP2A@ STAT1 --> ERK1 --> STAT1 (FasL:Fas:FADD:CRADD:RIP)6 3 p65PAK --> --> <==> Hippi + RIP140@ STAT2 ERK2 --> c-Jun ERK2 --> + 6 proCaspase-10 FAF1@ Fas@ RSK2 -->RSK2 ATF-1 --> ATF-4 limk1 calcineurin:NF-AT2 p53-isoform1@ p53 --/ NetRSK2 --> CREB1 p65PAK ERK2 --/ Raf-1 proCaspase-2 <==> huntingtin:Hip-1 Keratin-18@ (Caspase-8-p43:Caspase-8-p10)2:(FADD:FasL:Fas)6:(c-FLIP-L-p43)2 STAT1 --> <==> (c-FLIP-L-p43)3:(FADD:Fas:FasL)6:(proCaspase-10)3 (FasL:Fas)6@ Hippi + Hip-1 Tome-1@ estradiol --> STAT1alpha@ BimEL-p22:Bcl-2@ --> huntingtin@ RSK2 --> HSF1 STAT1 Bmx --> (FasL:Fas:FADD:CRADD:RIP:proCaspase-2)6 p300 --> SRC-1 cyclinB1:Cdk1 p53 --/ STAT1 pRb (TNF-alpha)3:(TNFR1)3:(TRADD)2:(CRADD)2:(RIP)2 (FasL:Fas)6 + 6 <==> Wee1 --> Cdk1 ATM{pS1981} Cdk1 --> CDP p65PAK ● p19INK4d@ (Caspase-8-p26:Caspase-8-p24)2:(FADD:FasL:Fas)6:(c-FLIP-L-p43)2(FasL:Fas:FADD)6@ c-FLIP-L-p43:Caspase-8@ --/ Wee1 p300 --> pRb --/ RACK1 GSK3beta --> ERK2 --> STAT3 + 2 FADD <==> Hippi:Hip-1 --PP2A--> + 2 Caspase-8 Hippi@ RIP140 c-Jun BimEL-p22 + proCaspase-2 (FasL:Fas:FADD)6 ATM + p Abl-p120@ cyclinD:Cdk4:p16INK4a:p34SEI-1@ + protein p53beta@ ERK2 --> p53 Bcl-2 <==> <==> Cdk1 --> c-Jun remnants Delta40p53@ BimEL-p22:Bcl-2 (TNF-alpha)3:(TNFR1)3:(TRADD)2:(CRADD)2:(RIP)2:(proCaspase-2)2 c-FLIP-L-p43@ Pin1 --> Wee1 VDR-M4@ GSK3beta --/ ERK2 --> STAT1 Optimization methodsCdk4@ cyclinD + 2 p53 limk1-isoform1@ ERK1 --> RSK2 p16INK4a:Cdk4 (Caspase-8-p26:Caspase-8-p24)2:(FADD:FasL:Fas)6:(c-FLIP-L-p43)2@ c-FLIP-L-p43:Caspase-8 FADD@ Hip-1@ TCF-4B@ estradiol --> ICAD@ + p34SEI-1 p15INK4b@ + PP2A --> PKCalpha --/ Bmx --> STAT3 IRAK-1 --> c-Fos Cdk1 --> <==> (FasL:Fas:FADD)6 GSK3beta HSF1 p65PAK CKII-alpha:CKII-alpha2:(CKII-beta)2@ IRF-7 Lck --> STAT5A cyclinD:Cdk4:p16INK4a:p34SEI-1 <==> p300@ Syk --> Rac1 alpha-tubulinp53{pS15} HePTP --/ ERK2 (c-FLIP-L-p43:Caspase-8)2:(FasL:Fas:FADD)6 CKII-beta --> 1:BimEL + ATP p16INK4a@ p300 --> p53 --PP2A--> p53 Lck --> ERK1 TCF-4 --> BimEl{p} + JKAP --> ERK2 p18INK4c@ (FasL:Fas:FADD:CRADD:RIP)6@ (Caspase-8-p43:Caspase-8-p10)2:(FADD:FasL:Fas)6:(c-FLIP-L-p43)2@ + ATP Lck -->ERK2 STAT3 --> RSK2 (FasL:Fas:FADD:CRADD:RIP:proCaspase-2)6@ alpha-tubulin 1 Syk --> STAT5A PKCalpha --> + ADP GSK3beta --> STAT2 --> STAT3Bmx --> --> Cdk1-isoform1@ Jak2 --> STAT6 Raf-1 Abl-p120 --> p53{pS315} Pin1:Cdc25C{p} IRAK-1 --> APP IFNAR2 lepr-BSTAT1alpha p19INK4d + TCF-4-isoform8@ Fes --> STAT5A Syk --> STAT3 Abl-p120p15INK4b + (c-FLIP-L-p43:Caspase-8)2:(FasL:Fas:FADD)6@ --Cdc14A--> --PP2A--> Pin1PKCbeta STAT3 --> Cdk4 <==> 5-HT-2A -->Src --> IKK-beta Cdk4 <==> p53 + pAPP695 --> p53 + Cdc25C + p VDR ● ERK1 --> Syk p19INK4d:Cdk4 (FasL:Fas:FADD)6 Src --> STAT1 (c-FLIP-L-p43:Caspase-8)2:(FasL:Fas:FADD)6 Fes --> STAT3 PDGFRalphaPKCalphaSTAT3 --> p15INK4b:Cdk4 CKII-alpha@ Tyk2Jak1 --> -->STAT2 STAT6 Jak2 --> STAT1ERK2 --> (TNF-alpha)3:(TNFR1)3:(TRADD)2:(CRADD)2:(RIP)2:(proCaspase-2)2@ + 6 CRADD + 6 --> TC-PTP --> GSK3beta --> STAT1 RIP <==> RSK2 --> p53 Tyk2 --> STAT1 C/EBPalpha Src --> Raf-1 ERK1 --/ p16INK4a + (Caspase-8-p43:Caspase-8-p10)2:(FADD:FasL:Fas)6:(c-FLIP-L-p43)2 STAT1 CypB --> Jak2 --> p18INK4c + (TNF-alpha)3:(TNFR1)3:(TRADD)2:(CRADD)2:(RIP)2@ estradiol --> betaARK-1Jak2 --> Raf-1 Cdk4 <==> (FasL:Fas:FADD:CRADD:RIP)6 14-3-3zeta --> STAT5A STAT5A SHP-2 --> Bcl-2@ Cdk4 <==> p53 Jak1 --> STAT2 Bmx@ p19INK4d:Cdk4@ p16INK4a:Cdk4 PKCalpha --> RACK1 -->RSK2@ IL-5Rbeta-isoform1 STAT1 Network Theory p18INK4c:Cdk4 p34SEI-1@ (FasL:Fas:FADD:CRADD:RIP:proCaspase-2)6 STAT1alpha Src PDGFRalpha--> STAT3 ERK1 --> SHP-2 p15INK4b:Cdk4@ p53 --> STAT3 Jak2 --> STAT3 --> Fes --> p16INK4a:Cdk4@ (FasL:Fas:FADD:CRADD:RIP)6 CXCR2(h){p} TC-PTP --> Tyk2 -->Jak1 STAT3 --> HEPTP@ CKII-alpha + STAT1alpha + 3 cyclinB1:Cdk1@ Cdk1 --> p300 --PP2A(h)--> STAT3 STAT5A CKII-alpha2 + 2 (Caspase-2)2 + CXCR2(h)PKCbeta + p --> p18INK4c:Cdk4@ CKII-beta Jak1 --> STAT3 protein alpha-tubulin Cdk1 --> p53 ERK2{pT185}{pY187}ERK2 + 2 ATP JKAP@ <==> CTLA-4 --> Src --> remnants alpha-tubulin1:BimEL@ CKII-beta --DUSP5-->--> CKII-alpha:CKII-alpha2:(CKII-beta)2 PP2A STAT1alpha Jak2 --> (TNF-alpha)3:(TNFR1)3:(TRADD)2:(CRADD)2:(RIP)2:(proCaspase-2)2 1@ IRAK-1b@ ERK2{pT185}{pY187}ERK2 + 2 p STAT1alpha --> + 2 ADP (TNF-alpha)3:(TNFR1)3:(TRADD)2:(CRADD)2:(RIP)2(TNF-alpha:TNFR1)3:(TRADD)2 RIP@ IRAK-1c@ Cdk1 --> Lck SHP-2 --> + (Caspase-2)2 Pin1@ IRAK-1a@ c-Jun --> ErbB1 Lck-L@ + 2 CRADD + 2 Jak1 --> STAT5A + protein CRADD@ Cdc14A2@ Cdk1 --> APP RIP <==> CKII-beta --> STAT1alpha remnants APP695@ VEGFR-2 --> (TNF-alpha)3:(TNFR1)3:(TRADD)2:(CRADD)2:(RIP)2 CKII-alpha estradiol@ C/EBPalpha --/ STAT1alphaPDGFRbeta --> CKII-beta@ pkmyt1 --> Cdk1 STAT3 Cdk1Cdk1 --> C/EBPalpha@ pkmyt1 PDGFRbeta --> (Caspase-2)2@ RACK1@ STAT1alpha ERK2 --> ErbB1 alpha-tubulin 1 lepr-B@ + BimEL <==> Syk-isoform1@ HB-EGF-ECD@ cyclinH --> RSK2 --/ SHP-1PKCalpha@ --> alpha-tubulin Cdk1 pkmyt1 STAT3 1:BimEL 5-HT-2A@ CXCR2{p}@ Fes@ (TNF-alpha:TNFR1)3:(TRADD)2@ IRAK-1 --> IRAK-1 Lck --> Syk Pin1 --> APP TC-PTPa@ cyclinB1:Cdk1 CXCR2@ --/ p73alpha Pin1 --> TC-PTPb@IFNAR2-isoform1@ p73alpha PKCbeta2@ IL-5Rbeta-isoform1@ Pin1 --> pkmyt1@ PKCbeta1@ BimEL@ Src-isoform1@ pkmyt1 Jak1 --> Lck betaARK-1@ CypB@ PDGFRalpha@ p300 --> Src --> RACK1 Jak2@ lepr-B --> Jak2 p73alpha RACK1 --/ CTLA-4@ Tyk2@ Syk -->Src Src --> Syk Jak2 --> lepr-B p73alpha Cdk1 --> ErbB2 5-HT-2A --> ErbB2 --> Cdk1estradiol --> Jak2 ERK2{pT185}{pY187} SHP2-isoform2@ HB-EGF --MDC9--> cyclinH@ Jak1 --> Syk HB-EGF-ECD + ERK2{pT185}{pY187}@ HB-EGF Src{pY} --stromelysin1-->protein remnants Jak1@ --SHP-2--> p HB-EGF-ECD HB-EGF-ECD + Src --> --> ErbB1 protein p73alpha@ + SrcJak2 --> IFNRI --> VEGFR-2@ betaARK-1 IL-5Rbeta --> remnants Src IL-5Rbeta-isoform1--> SHP-2 RACK1 Jak2 --> SHP-2 PKCalpha --> CTLA-4 CTLA-4 --> estradiol --/ TC-PTP --> Jak1 SHP-1 --/ Syk SHP-1 CTLA-4 --> SHP-2 Jak2 --> SHP-2 ErbB2 PDGFRalpha CXCR2(h) + IFNAR2 --> Jak1 Jak2 --> Src SHP-2 --> Jak2 PR65(h) <==> Src --> Jak1 --> VEGFR-2 --> CXCR2(h):PR65(h) TC-PTP --> ERK2{pT185}{pY187} IL-5Rbeta-isoform1 SHP-2 PDGFRalpha ErbB1 PDGFRbeta --> betaARK-1--> --> SHP-2 CD22 --> Syk IL-4R --> Fes Src Jak1 --> Jak2 ErbB1 --> Src PDGFRbeta CXCR2:PR65@ PDGFRbeta@ HB-EGF@ SHP-2 --> IFNalpha1 --> betaARK-1 --> SOCS-1 --/ Jak2 IFNRI --> Tyk2 PDGFRbetaPDGFRbeta --> MDC9@ IFNAR2 ErbB1 SHP-2 IL-3R -->Jak2 Jak2 --> tec Src --> ErbB1 ErbB2 --> Src Jak2 --> ErbB1 GM-CSFR --> AT1A --> Src tec --> Jak2Jak2 --> GHR Jak2 --> ErbB2 IL-3R --> Tyk2 IL-5R --> Jak2Jak2 GM-CSFR --> GHR --> Jak2 stromelysin1@ PKCalpha --/ IFNRII --> Jak2 SIT --> SHP-2 SHP-1 --> Tyk2 Tyk2 Src --> ErbB2 InsR IL-5R --> Tyk2IL-4R --> Jak2 ErbB1 + ATP SHP-1L@ SHP-1 --/ Jak2 SHP1-isoform2@ AT1A --> Tyk2 SLAM --> SHP-2 IFNRI --> Jak1 --Src--> AT1A -->Jak2 Jak2 --> IRS-2 PKCbeta --/ PDGFB --> IFNalpha1 --> ErbB1{pY} + ErbB1-p170@ InsR PDGFRalpha Tyk2 --> IRS-2 ADP Epo:(EpoR{pY}:Jak2{pY1007})2 SHP-2 LMW-PTP --> Jak1 -->--SHP-1--> tec Jak2 --> IRS-2 --> SHP-2 PR65@ SOCS-3 --/ Jak2 PDGFRalpha Epo + 2 SOCS-3 IL-4R --> Jak1 IFNRI@ IFNRII --> Jak1 EpoR{pY} + 2 prolactin --> SHP-1 --> Jak2 + 2 p CypB PIR-B --> SHP-2 ERK2{pT185}{pY187} Jak1 --> IRS-2 VEGFR-2 --> SHP-1 --/ Jak1 SHP-1 SOCS-3Jak1 --> --/ Jak1 InsR --> Jak2 SOCS-3 IL-7Ralpha --> Jak1{pY} Jak1 + ATP -->IFNalpha1@ gp130 -->IL-9R Jak1 OSMRbeta--> Jak1 Jak1--> --CD45--> p + IL-3R@ SOCS-1@ Jak1 Jak1{pY} Jak1+ ADP InsR --> Jak1 GM-CSFR@ YB-1 --> IL-4R@ ERK2{pT185}{pY187} IL-5R@ tec@ PDGFRbeta +PDGFB --> SIT@ ErbB2@ ATP --> PDGFRbeta AT1A@ PDGFRbeta{pY} PDGFRbeta{pY} IFNRII@ ErbB1 --> ErbB2--RPTPalpha--> GHR@ + ADP SLAM-isoform1@ PDGFRbeta + p CD22@ SHP-1 --/ ErbB1
CD22SHP-1 --> SHP-1 --/ CD22PIR-B --> SHP-1 IRS-2@ ErbB1{pY} ErbB1{pY}@ --Cdc25A--> PDGFB@ ErbB1 + p
Epo:(EpoR{pY}:Jak2{pY1007})2@ InsR-B@InsR-A@ PIR-B@ YB-1 --> ErbB1BTC --> ErbB1 SOCS-3@
ErbB1{pY}ErbB1 + ATP LMW-PTP-isoform1@ amphiregulin-NTFc-Cbl & CIN85 --Cdc25A-->--> ErbB1{pY} --> ErbB1--/ ErbB1 ErbB1TGFalpha+ +ADP p --> Group website: http://compsysmed.org ErbB1 Jak1{pY}@ GHR --> IRS-2 PDGFRbeta{pY}@gp130-isoform1@ IL-7Ralpha@ prolactin@ IL-9R@ OSMRbeta@ YB-1@ ErbB1{pY1092}{pY1197}{pY1016} --PTPRK--> NRG2 --> ErbB2 BTC --> ErbB2 YB-1B@ ErbB1 + p YB-1 --> ErbB2 InsR --> IRS-2 FOXP3 --/ ErbB2 DP97 --> ErbB2
InsR --> SOCS-3 --/ InsR InsR --> InsR SOCS-3 BTC@ LMW-PTP --> InsR prolactin --/ SOCS-3
prolactin --> Jak1{pY}
NRG --> ErbB2 Caspase-8 --> ErbB2 amphiregulin-NTF@ ErbB1{pY}@ CIN85@
NRG2@ TGFalpha@
FOXP3@ ErbB1{pY1092}{pY1197}{pY1016}@PTPRK@ DP97-xbb2@
NRG1-beta2@ NRG1-beta1@ NRG1-GGF2@ TGFalpha --> NRG1-alpha1A@NRG1-beta3@ ErbB1{pY}
Caspase-8b@ Caspase-8a@
FAF1 --> Caspase-8 Outline of Presentation
Part I: Breaking down the title of this talk ✦ Signal transduction networks ✦ Network controllability ✦ Targeted network controllability
Part II: Let’s solve the problem together! ✦ Little example
Part III: OCSANA ✦ Introduction ✦ What does combinatorics and algebra got to do with it? ✦ How OCSANA works
Part IV: Application Example to breast cancer ✦ Intro ✦ Results
Conclusions and Future Work
3 Part I: Breaking down the title of this talk
4 Signaling Networks
- Biological network mediating between genes, the environment and the phenotype
- Crucial for the understanding of cell response to external and internal perturbations.
Phenotype1 Phenotype2 Controllability of Complex Systems
Cornelius et al. Realistic control of network dynamics. Nature Comms., 2014
(a) Network portrait. The goal is to drive the network to a desired state by perturbing nodes in a control set. (b) State space portrait. In the absence of control, the network at an initial state x0 evolves to an undesirable equilibrium xu in the n-dimensional state space (red curve). By perturbing the initial state (orange arrow), the network reaches a new state that evolves to the desired target state x* (blue curve). (c) Constraints. In general, there will be constraints on the types of compensatory perturbations that one can make. (d, e) Iterative construction of compensatory perturbations. Signaling Networks
- Large complex networks (thousands of components)
- Non-linear interactions among components
- Is full controllability achievable? biologically feasible?
Phenotype1 Phenotype2 Signaling Networks
- Klamt (Minimal Cut Sets, Metabolic Networks)
- Barabasi, Zhou, etc (Cascading Failures, Target Control)
- Albert et al. (stable motifs, Signaling Networks)
Phenotype1 Phenotype2 Targeted Control Tasks in Signaling Networks
Vera-Licona et al. Institut Curie & Servier Scientific Report, 2013. Targeted Control Tasks in Signaling Networks
Source Nodes
Vera-Licona et al. Institut Curie & Servier Scientific Report, 2013. Targeted Control Tasks in Signaling Networks
Source Nodes
Target Nodes
Vera-Licona et al. Institut Curie & Servier Scientific Report, 2013. Targeted Control Tasks in Signaling Networks
Source Nodes
Target Nodes
Vera-Licona et al. Institut Curie & Servier Scientific Report, 2013. Targeted Control Tasks in Signaling Networks
Source Nodes
Target Nodes
Vera-Licona et al. Institut Curie & Servier Scientific Report, 2013. Targeted Control Tasks in Signaling Networks
Source Nodes
Target Nodes
Vera-Licona et al. Institut Curie & Servier Scientific Report, 2013. Targeted Control Tasks in Signaling Networks
Source Nodes
Target Nodes
Vera-Licona et al. Institut Curie & Servier Scientific Report, 2013. Targeted Control Tasks in Signaling Networks
Source Nodes
Target Nodes Side-Effects
Vera-Licona et al. Institut Curie & Servier Scientific Report, 2013. Targeted Control Tasks in Signaling Networks
Source Nodes
Target Nodes Side-Effects
Vera-Licona et al. Institut Curie & Servier Scientific Report, 2013. Targeted Control Tasks in Signaling Networks
Source Nodes
Target Nodes Side-Effects
Vera-Licona et al. Institut Curie & Servier Scientific Report, 2013. Targeted Control Tasks in Signaling Networks
Source Nodes
Target Nodes Side-Effects
Vera-Licona et al. Institut Curie & - Which Combination of Interventions (CI) Servier Scientific Report, 2013. is more optimal? Prioritization of CIs Part II: Let’s solve the problem together! Minimal Combinations of Interventions (Signed Digraphs) Minimal Combinations of Interventions (Signed Digraphs) Minimal Combinations of Interventions (Signed Digraphs) Minimal Combinations of Interventions (Signed Digraphs) Minimal Combinations of Interventions (Signed Digraphs) Minimal Combinations of Interventions (Signed Digraphs) Minimal Combinations of Interventions (Signed Digraphs) Minimal Combinations of Interventions Minimal Combinations of Interventions Minimal Combinations of Interventions Minimal Combinations of Interventions Minimal Combinations of Interventions
I1-> B-> C -> O1 Minimal Combinations of Interventions
I1-> B-> C -> O1 Minimal Combinations of Interventions
I1-> B-> C -> O1 Minimal Combinations of Interventions
I1-> B-> C -> O1 Minimal Combinations of Interventions
I1-> B-> C -> O1 Minimal Combinations of Interventions
I1-> B-> C -> O1
I1-| E -> C -> O1 Minimal Combinations of Interventions
I1-> B-> C -> O1
I1-| E -> C -> O1 Minimal Combinations of Interventions
I1-> B-> C -> O1
I1-| E -> C -> O1 Minimal Combinations of Interventions
I1-> B-> C -> O1
I1-| E -> C -> O1 Minimal Combinations of Interventions
I1-> B-> C -> O1
I1-| E -> C -> O1 Minimal Combinations of Interventions
I1-> B-> C -> O1
I1-| E -> C -> O1
I2-> E -> C -> O1 Minimal Combinations of Interventions (CIs)
I1-> B-> C -> O1
I1-| E -> C -> O1
I2-> E -> C -> O1 Minimal Combinations of Interventions (CIs)
I1-> B-> C -> O1
I1-| E -> C -> O1
I2-> E -> C -> O1
Intervene (Knockout or Over-express) at least one time each one of these elementary paths Minimal Combinations of Interventions (CIs)
I1-> B-> C -> O1
I1-| E -> C -> O1
I2-> E -> C -> O1
Intervene (Knockout or Over-express) at least one time each one of these elementary paths
Interventions of size 1: {C} Minimal Combinations of Interventions (CIs)
I1-> B-> C -> O1
I1-| E -> C -> O1
I2-> E -> C -> O1
Intervene (Knockout or Over-express) at least one time each one of these elementary paths
Interventions of size 1: {C}
Interventions of size 2: {B,E}, {I1, E}, {I2,B}, {I1,I2} Minimal Combinations of Interventions (CIs)
I1-> B-> C -> O1
I1-| E -> C -> O1
I2-> E -> C -> O1
Intervene (Knockout or Over-express) at least one time each one of these elementary paths
Interventions of size 1: {C}
Interventions of size 2: {B,E}, {I1, E}, {I2,B}, {I1,I2}
“Minimal” in the sense that no subset of an intervention set can be an intervention set itself. Minimal Combinations of Interventions (CIs)
I1-> B-> C -> O1
I1-| E -> C -> O1
I2-> E -> C -> O1
Intervene (Knockout or Over-express) at least one time each one of these elementary paths
Interventions of size 1: {C}
Interventions of size 2: {B,E}, {I1, E}, {I2,B}, {I1,I2}
“Minimal” in the sense that no subset of an intervention set can be an intervention set itself. Minimal Combinations of Interventions (CIs)
I1-> B-> C -> O1
I1-| E -> C -> O1
I2-> E -> C -> O1
Intervene (Knockout or Over-express) at least one time each one of these elementary paths
Interventions of size 1: {C}
Interventions of size 2: {B,E}, {I1, E}, {I2,B}, {I1,I2}
“Minimal” in the sense that no subset of an intervention set can be an intervention set itself. Minimal Combinations of Interventions (CIs)
I1-> B-> C -> O1
I1-| E -> C -> O1
I2-> E -> C -> O1
Intervene (Knockout or Over-express) at least one time each one of these elementary paths
Interventions of size 1: {C}
Interventions of size 2: {B,E}, {I1, E}, {I2,B}, {I1,I2}
“Minimal” in the sense that no subset of an intervention set can be an intervention set itself. Minimal Combinations of Interventions Part III: OCSANA
17
Minimal Combinations of Interventions
Although some in silico strategies have been proposed [1,2,3,4], scalability and prioritization of the CIs remain as important limitations to their full applicability.
OCSANA has been designed as a systemic method designed to identify and rank optimal combinations of interventions (CIs) that intervene, the elementary path between specified source and targets nodes to obtain a desired behavior in the network while minimizing side-effects on pre-specified non-target paths for large size signal transduction networks.
[1] Klamt, S., Saez-Rodriguez, J., Lindquist, J.A., Sorger P. (2006) A methodology for the structural and functional analysis of signaling and regulatory networks. BMC Bioinformatics, 7(56).
[2] Haus UU, Klamt S, Stephen T (2008) Computing knock-out strategies in metabolic networks, J. Comput Biol, 15, 259-268.
[3]Samaga, R., Von Kamp, A., Klamt S. (2010) Computing Combinatorial Intervention Strategies and Failure Modes in Signaling Networks. Journal of Computational Biology, 17(1): 39-53.
[4]Yan, H., Zhang, B., Li, S., Zhao, Q. (2010) A formal model for analyzing drug combination effects and its application in TNF-alpha-induced NFkappaB pathway. BMC Syst Biol, 4:50
Minimal Combinations of Interventions
I1-> B-> C -> O1
I1-| E -> C -> O1
I2-> E -> C -> O1
Interventions of size 1: {C}
Interventions of size 2: {B,E}, {I1, E}, {I2,B}, {I1,I2} Minimal Combinations of Interventions
I1-> B-> C -> O1
I1-| E -> C -> O1
I2-> E -> C -> O1
Interventions of size 1: {C}
Interventions of size 2: {B,E}, {I1, E}, {I2,B}, {I1,I2} Minimal Combinations of Interventions
I1-> B-> C -> O1 Find Elementary Paths
I1-| E -> C -> O1
I2-> E -> C -> O1
Interventions of size 1: {C}
Interventions of size 2: {B,E}, {I1, E}, {I2,B}, {I1,I2} Minimal Combinations of Interventions
I1-> B-> C -> O1 Find Elementary Paths
I1-| E -> C -> O1
I2-> E -> C -> O1
Interventions of size 1: {C}
Interventions of size 2: {B,E}, {I1, E}, {I2,B}, {I1,I2} Minimal Combinations of Interventions
I1-> B-> C -> O1 Find Elementary Paths
I1-| E -> C -> O1
I2-> E -> C -> O1
Interventions of size 1: {C} Minimal Intervention Sets
Interventions of size 2: {B,E}, {I1, E}, {I2,B}, {I1,I2} Minimal Combinations of Interventions
I1-> B-> C -> O1
I1-| E -> C -> O1
I2-> E -> C -> O1
Interventions of size 1: {C} Minimal Intervention Sets Interventions of size 2: {B,E}, {I1, E}, {I2,B}, {I1,I2} Minimal Combinations of Interventions
I1-> B-> C -> O1 === {I1, B, C, O1}
I1-| E -> C -> O1 === {I1, E, C, O1}
I2-> E -> C -> O1 === {I2, E, C, O1} Minimal Combinations of Interventions
I1-> B-> C -> O1 === {I1, B, C, O1}
I1-| E -> C -> O1 === {I1, E, C, O1}
I2-> E -> C -> O1 === {I2, E, C, O1}
“Hit” (intersect) at least one time each one of these elementary paths Minimal Combinations of Interventions
I1-> B-> C -> O1 === {I1, B, C, O1}
I1-| E -> C -> O1 === {I1, E, C, O1}
I2-> E -> C -> O1 === {I2, E, C, O1}
“Hit” (intersect) at least one time each one of these elementary paths
Interventions of size 1: {C} Minimal Combinations of Interventions
I1-> B-> C -> O1 === {I1, B, C, O1}
I1-| E -> C -> O1 === {I1, E, C, O1}
I2-> E -> C -> O1 === {I2, E, C, O1}
“Hit” (intersect) at least one time each one of these elementary paths
Interventions of size 1: {C}
Interventions of size 2: {B,E}, {I1, E}, {I2,B}, {I1,I2} Minimal Combinations of Interventions
I1-> B-> C -> O1 === {I1, B, C, O1}
I1-| E -> C -> O1 === {I1, E, C, O1}
I2-> E -> C -> O1 === {I2, E, C, O1}
“Hit” (intersect) at least one time each one of these elementary paths Minimal Hitting Set Problem Interventions of size 1: {C}
Interventions of size 2: {B,E}, {I1, E}, {I2,B}, {I1,I2} Minimal Transversal Boolean Dualization Minimal Hitting Set Problem for Hypergraphs
Maximal Elements Minimal Transversal Boolean Dualization Minimal Hitting Set Problem Graph Theory for Hypergraphs
Maximal Elements Minimal Transversal Boolean Dualization Algebra Minimal Hitting Set Problem Graph Theory for Hypergraphs
Maximal Elements Minimal Transversal Boolean Dualization Algebra Minimal Hitting Set Problem Graph Theory for Hypergraphs
Machine Learning
Maximal Elements Artificial Intelligence
Minimal Transversal Boolean Dualization Algebra Minimal Hitting Set Problem Graph Theory for Hypergraphs
Machine Learning
Maximal Elements Artificial Intelligence
Minimal Transversal Boolean Dualization Algebra Minimal Hitting Set Problem Graph Theory for Hypergraphs
Machine Learning
Maximal Elements Artificial Intelligence
Minimal Transversal Boolean Dualization Algebra Minimal Hitting Set Problem Graph Theory for Hypergraphs
Machine Learning
Maximal Elements Artificial Intelligence
Minimal Transversal Boolean Dualization Algebra Minimal Hitting Set Problem Graph Theory for Hypergraphs
Machine Learning
Maximal Elements Artificial Intelligence
Minimal Transversal Boolean Dualization Algebra Minimal Hitting Set Problem Graph Theory for Hypergraphs
Machine Learning
Maximal Elements Given a collection of sets C, to find minimal hitting sets ““Hi” is a classical problem in Combinatorics called “The Minimal Hitting Set Problem”. This is an NP-Complete problem
Artificial Intelligence
Minimal Transversal Boolean Dualization Algebra Minimal Hitting Set Problem Graph Theory for Hypergraphs
Machine Learning
Maximal Elements Minimal Hitting Set Problem Problem 1: Finding Minimal Hitting Sets
Several known algorithms:
Sequential Method [Berge 1989] FK-Algorithm [Fredman, Khachiyan 1996] DL-Algorithm [Dong, Li 1999] KS-Algorithm Kavvadias, Stravropoulos 199] Multiplication Method [Takata 2002] BMR-Algorithm [Bailey, Ramamohanarao 2003] Partial Enumerative Solutions [Vera-Licona,2013; Klamt, 2014] Minimal Hitting Set Problem Problem 1: Finding Minimal Hitting Sets
Several known algorithms:
Sequential Method [Berge 1989] FK-Algorithm [Fredman, Khachiyan 1996] DL-Algorithm [Dong, Li 1999] KS-Algorithm Kavvadias, Stravropoulos 199] Multiplication Method [Takata 2002] BMR-Algorithm [Bailey, Ramamohanarao 2003] Partial Enumerative Solutions [Vera-Licona,2013; Klamt, 2014] Minimal Hitting Set Problem Problem 1: Finding Minimal Hitting Sets
Several known algorithms:
Sequential Method [Berge 1989] FK-Algorithm [Fredman, Khachiyan 1996] DL-Algorithm [Dong, Li 1999] KS-Algorithm Kavvadias, Stravropoulos 199] Multiplication Method [Takata 2002] BMR-Algorithm [Bailey, Ramamohanarao 2003] Partial Enumerative Solutions [Vera-Licona,2013; Klamt, 2014] Problem 2: How to choose from the identified MIs? Which one(s) is better and why?
We score MHSs by first, scoring each one of its nodes.
The scoring is based on:
(i) The lengths of the paths from the node of interest to the targets,
(ii) The type of effect on target nodes (e.g. activation/inhibition effect),
(iii) Side effects with respect to off-target nodes,
(iv) The number of elementary paths in which the node participates and
(v) The number of targets that such node can reach simultaneously. Problem 2: How to choose from the identified MIs? Which one(s) is better and why?
We introduce a score for nodes according to the effect on the target node O1. Let’s suppose that we have m source paths sinking in O1.
1 s (n)= (i) , where (i) is the sign of the O1 length of path i i=1,m X ith path starting from node n
1 s (C)=(+) =1 O1 1 1 s (B)=(+) =0.5 O1 2 1 s (E)=(+) =0.5 O1 2 1 1 s (I1) = (+) +( ) =0 O1 3 3 1 s (I2) = (+) =0.33 O1 3 Problem 2: How to choose from the identified MIs? Which one(s) is better and why?
Additionally, we introduce a penalty score for the source nodes, according to their effect on all unwanted target nodes:
pO2(C)=0 1 r p (B)=0 p (n)= s (x), where U is the set of unwanted targeted O2 O1 r Ui i i=1 p (E)=1/3=0.33 X O2 nodes and r = U path starting from node n p (I1) = 1/4 | i| O2 pO2(I2) = +1/4
Thus the total score of each one of the source nodes x to O1 are scored as S (x)=s (x) p (x) O1 Ui O1 S (C)=1 0=1 O1 S (B)=1/2 0=0.5 O1 S (E)=1/2 1/3=.166 O1 S (I1) = 0 ( )1/4=.25 O1 S (I2) = 1/3 1/4=0.083 O1 Problem 2: How to choose from the identified MIs? Which one(s) is better and why?
Optimal minimal intervention sets according to their score is: Minimal Hitting Set Problem Problem 3: Scalability of the Method
Several known algorithms: Exact Solution Sequential Method [Berge 1989] FK-Algorithm [Fredman, Khachiyan 1996] DL-Algorithm [Dong, Li 1999] KS-Algorithm Kavvadias, Stravropoulos 199] Multiplication Method [Takata 2002] BMR-Algorithm [Bailey, Ramamohanarao 2003] Partial Enumerative Solutions [Vera-Licona,2013]
Selective Enumeration (Greedy Algorithm) Minimal Hitting Set Problem Problem 3: Scalability of the Method
Several known algorithms: Exact Solution Sequential Method [Berge 1989] FK-Algorithm [Fredman, Khachiyan 1996] DL-Algorithm [Dong, Li 1999] KS-Algorithm Kavvadias, Stravropoulos 199] Multiplication Method [Takata 2002] BMR-Algorithm [Bailey, Ramamohanarao 2003] Partial Enumerative Solutions [Vera-Licona,2013]
Selective Enumeration (Greedy Algorithm) Minimal Hitting Set Problem Problem 3: Scalability of the Method
Several known algorithms: Exact Solution Sequential Method [Berge 1989] FK-Algorithm [Fredman, Khachiyan 1996] DL-Algorithm [Dong, Li 1999] KS-Algorithm Kavvadias, Stravropoulos 199] Multiplication Method [Takata 2002] BMR-Algorithm [Bailey, Ramamohanarao 2003] Partial Enumerative Solutions [Vera-Licona,2013]
Selective Enumeration (Greedy Algorithm) Outline of Algorithm to Compute Minimal Combinations of Interventions
Input/mandatory: A network (signed digraph), a set of source nodes, target nodes and a set of parameters. Input/optional: A set of complementary nodes assigned as off-target nodes (i.e. side effects).
Output: Prioritized list of optimal CIs.
1. Pre-processing step: Compute the collection of elementary paths, that is, paths from source nodes to target nodes according to the selected parameters for the path analysis.
2. Score the nodes present in the elementary paths and sort them in a descending order.
3. Compute the so-called minimal hitting sets (MHSs) for the elementary paths according to the selected algorithm approach and sort them according to OCSANA’s score.
This sorted list ofMHSs is the sought list of prioritized optimal CIs. Outline of Algorithm to Compute Minimal Combinations of Interventions Part IV: Application Example to breast cancer
33 Introduction: HER2-positive Breast Cancer
✦ HER2 (also known as ErbB2 or Her2/neu) stands for Human Epidermal Growth Factor Receptor 2.
✦ Each normal breast cell contains copies of the HER2 gene which encodes the HER2 protein (also called HER2 receptor).
✦ HER2 is a member of the HER receptor tyrosine kinase family, which includes three other members: Epidermal growth factor receptor (EGFR or HER1), HER3 and HER4.
✦ HER2, the preferred heterodimerization partner of the other HER receptors, does not have a ligand and is activated by
✦ overexpression and homodimerization, or
✦ ligand-mediated stimulation of another HER
receptor by heterodimerization. Genentech BioOncology Introduction: HER2-positive Breast Cancer
✦ In HER2+ breast cancer, the cancer cells have an abnormally high number of HER2 genes per cell thus a higher number of HER2 protein on the surface of these cancer cells. This is called HER2 protein over-expression (HER2+).
✦ Approximately 20% of breast cancer patients have tumors that are HER2+ . This abnormality in HER2 production can occur in many other types of cancer. Approved Targeted-Therapies for Her2+ Breast Cancer
✦ These targeted therapies have shown significant clinical benefit.
✦ However, a large percentage of patients with advanced HER2+ BC eventually relapse after treatment, suggesting that tumors acquire or intrinsically possess mechanisms for escape from HER2 inhibition. Example: Combinations of Targeted Therapies in Breast Cancer
The pipeline of network analysis consists of 4 main steps:
4. Construction of combinations of interventions with OCSANA and identification of optimal therapeutic interventions.
3. Identification of a Core Signal Transduction Network of Dysregulated Pathways in HER2+ BC. Assembling of a comprehensive network for the set of functionally enriched genes, their transcription factor and master regulators.
2. Identification of transcription factors and master regulators responsible for the expression patterns observed in the functionally enriched gene set identified on step 1.
1. Protein-protein interaction (PPI) network analysis for the identification of Functionally Enriched Gene Set in HER2+ BC. Example: Combinations of Targeted Therapies in Breast Cancer
The pipeline of network analysis consists of 4 main steps:
4. Construction of combinations of interventions with OCSANA and identification of optimal therapeutic interventions.
3. Identification of a Core Signal Transduction Network of Dysregulated Pathways in HER2+ BC. Assembling of a comprehensive network for the set of functionally enriched genes, their transcription factor and master regulators.
2. Identification of transcription factors and master regulators responsible for the expression patterns observed in the functionally enriched gene set identified on step 1.
1. Protein-protein interaction (PPI) network analysis for the identification of Functionally Enriched Gene Set in HER2+ BC.
Stage I Functionally enriched set of genes Example: Combinations of Targeted Therapies in Breast Cancer
The pipeline of network analysis consists of 4 main steps:
4. Construction of combinations of interventions with OCSANA and identification of optimal therapeutic interventions.
3. Identification of a Core Signal Transduction Network of Dysregulated Pathways in HER2+ BC. Assembling of a comprehensive network for the set of functionally enriched genes, their transcription factor and master regulators.
2. Identification of transcription factors and master TF TF TF regulators responsible for the expression patterns observed Stage 2 List of in the functionally enriched gene set identified on step 1. overrepresented TFs
1. Protein-protein interaction (PPI) network analysis for the identification of Functionally Enriched Gene Set in HER2+ BC.
Stage I Functionally enriched set of genes Example: Combinations of Targeted Therapies in Breast Cancer
The pipeline of network analysis consists of 4 main steps:
4. Construction of combinations of interventions with OCSANA and identification of optimal therapeutic interventions.
Stage 3 Mapping on MR canonical pathways 3. Identification of a Core Signal Transduction Network + Identification of of Dysregulated Pathways in HER2+ BC. Assembling of a Master Regulators comprehensive network for the set of functionally enriched MR genes, their transcription factor and master regulators. MR
2. Identification of transcription factors and master TF TF TF regulators responsible for the expression patterns observed Stage 2 List of in the functionally enriched gene set identified on step 1. overrepresented TFs
1. Protein-protein interaction (PPI) network analysis for the identification of Functionally Enriched Gene Set in HER2+ BC.
Stage I Functionally enriched set of genes Example: Combinations of Targeted Therapies in Breast Cancer
Stage 4 Identification of The pipeline of network analysis consists of 4 main steps: Optimal OCSANA Combinations of Interventions from Network Analysis 4. Construction of combinations of interventions with OCSANA and identification of optimal therapeutic interventions. Vera-Licona et al. OCSANA: optimal combinations of interventions from Stage 3 network analysis. Bioinformatics, 2013. Mapping on MR canonical pathways 3. Identification of a Core Signal Transduction Network + Identification of of Dysregulated Pathways in HER2+ BC. Assembling of a Master Regulators comprehensive network for the set of functionally enriched MR genes, their transcription factor and master regulators. MR
2. Identification of transcription factors and master TF TF TF regulators responsible for the expression patterns observed Stage 2 List of in the functionally enriched gene set identified on step 1. overrepresented TFs
1. Protein-protein interaction (PPI) network analysis for the identification of Functionally Enriched Gene Set in HER2+ BC.
Stage I Functionally enriched set of genes Family of HER receptors and associated activating ligands.
Fralick M, Hilton JF, Bouganim N, Clemons M, Amir E. Dual Blockade of HER2 — Twice as Good or Twice as Toxic? Clinical Oncology, 2012: 24(9), 593 - 603. Family of HER receptors and associated activating ligands.
Fralick M, Hilton JF, Bouganim N, Clemons M, Amir E. Dual Blockade of HER2 — Twice as Good or Twice as Toxic? Clinical Oncology, 2012: 24(9), 593 - 603. Family of HER receptors and associated activating ligands.
Fralick M, Hilton JF, Bouganim N, Clemons M, Amir E. Dual Blockade of HER2 — Twice as Good or Twice as Toxic? Clinical Oncology, 2012: 24(9), 593 - 603. Family of HER receptors and associated activating ligands.
Fralick M, Hilton JF, Bouganim N, Clemons M, Amir E. Dual Blockade of HER2 — Twice as Good or Twice as Toxic? Clinical Oncology, 2012: 24(9), 593 - 603. Family of HER receptors and associated activating ligands.
Fralick M, Hilton JF, Bouganim N, Clemons M, Amir E. Dual Blockade of HER2 — Twice as Good or Twice as Toxic? Clinical Oncology, 2012: 24(9), 593 - 603. Family of HER receptors and associated activating ligands.
Fralick M, Hilton JF, Bouganim N, Clemons M, Amir E. Dual Blockade of HER2 — Twice as Good or Twice as Toxic? Clinical Oncology, 2012: 24(9), 593 - 603. Family of HER receptors and associated activating ligands.
Fralick M, Hilton JF, Bouganim N, Clemons M, Amir E. Dual Blockade of HER2 — Twice as Good or Twice as Toxic? Clinical Oncology, 2012: 24(9), 593 - 603. Family of HER receptors and associated activating ligands.
Fralick M, Hilton JF, Bouganim N, Clemons M, Amir E. Dual Blockade of HER2 — Twice as Good or Twice as Toxic? Clinical Oncology, 2012: 24(9), 593 - 603. Family of HER receptors and associated activating ligands.
Fralick M, Hilton JF, Bouganim N, Clemons M, Amir E. Dual Blockade of HER2 — Twice as Good or Twice as Toxic? Clinical Oncology, 2012: 24(9), 593 - 603. Family of HER receptors and associated activating ligands.
Fralick M, Hilton JF, Bouganim N, Clemons M, Amir E. Dual Blockade of HER2 — Twice as Good or Twice as Toxic? Clinical Oncology, 2012: 24(9), 593 - 603. Family of HER receptors and associated activating ligands.
Fralick M, Hilton JF, Bouganim N, Clemons M, Amir E. Dual Blockade of HER2 — Twice as Good or Twice as Toxic? Clinical Oncology, 2012: 24(9), 593 - 603. Family of HER receptors and associated activating ligands.
Fralick M, Hilton JF, Bouganim N, Clemons M, Amir E. Dual Blockade of HER2 — Twice as Good or Twice as Toxic? Clinical Oncology, 2012: 24(9), 593 - 603. Family of HER receptors and associated activating ligands.
Fralick M, Hilton JF, Bouganim N, Clemons M, Amir E. Dual Blockade of HER2 — Twice as Good or Twice as Toxic? Clinical Oncology, 2012: 24(9), 593 - 603. Family of HER receptors and associated activating ligands.
Fralick M, Hilton JF, Bouganim N, Clemons M, Amir E. Dual Blockade of HER2 — Twice as Good or Twice as Toxic? Clinical Oncology, 2012: 24(9), 593 - 603. Family of HER receptors and associated activating ligands.
Fralick M, Hilton JF, Bouganim N, Clemons M, Amir E. Dual Blockade of HER2 — Twice as Good or Twice as Toxic? Clinical Oncology, 2012: 24(9), 593 - 603. Family of HER receptors and associated activating ligands.
Fralick M, Hilton JF, Bouganim N, Clemons M, Amir E. Dual Blockade of HER2 — Twice as Good or Twice as Toxic? Clinical Oncology, 2012: 24(9), 593 - 603. Family of HER receptors and associated activating ligands.
Fralick M, Hilton JF, Bouganim N, Clemons M, Amir E. Dual Blockade of HER2 — Twice as Good or Twice as Toxic? Clinical Oncology, 2012: 24(9), 593 - 603. Stage IV: Identification of Optimal Combinations of Interventions from Network Analysis with OCSANA Stage IV: Identification of Optimal Combinations of Interventions from Network Analysis with OCSANA
1) Does ErbB2 has access to all the OFTEN genes that are highly dysregulated in HER2? YES. Thus it is natural to consider it as THE guilty gene causing the disease. Found 3657 elementary paths and 208 elementary nodes if we consider ANSIP of length at most 10. Stage IV: Identification of Optimal Combinations of Interventions from Network Analysis with OCSANA
1) Does ErbB2 has access to all the OFTEN genes that are highly dysregulated in HER2? YES. Thus it is natural to consider it as THE guilty gene causing the disease. Found 3657 elementary paths and 208 elementary nodes if we consider ANSIP of length at most 10.
2) Considering only ErbB2 as THE guilty gene (thus considering it as the only one source node), is it possible to find CIs such that ALL the pathways to OFTEN dysregulated genes in HER2+ BC? YES. Found 17 optimal CIs. The only CI of size 1 is ErbB2 itself and the other CIs require to be of size at least 3.
However we know that this view of the problem might be reduced as resistance to treatment targeting ErbB2 alone, might occur. Stage IV: Identification of Optimal Combinations of Interventions from Network Analysis with OCSANA
1) Does ErbB2 has access to all the OFTEN genes that are highly dysregulated in HER2? YES. Thus it is natural to consider it as THE guilty gene causing the disease. Found 3657 elementary paths and 208 elementary nodes if we consider ANSIP of length at most 10.
2) Considering only ErbB2 as THE guilty gene (thus considering it as the only one source node), is it possible to find CIs such that ALL the pathways to OFTEN dysregulated genes in HER2+ BC? YES. Found 17 optimal CIs. The only CI of size 1 is ErbB2 itself and the other CIs require to be of size at least 3.
However we know that this view of the problem might be reduced as resistance to treatment targeting ErbB2 alone, might occur.
3) Considering all the MRs as source nodes, is it possible to find CIs < 6 such that ALL the pathways to OFTEN dysregulated genes in HER2+ BC? Found 380942 elementary paths and 588 elementary nodes to be blocked simultaneously. Stage IV: Identification of Optimal Combinations of Interventions from Network Analysis with OCSANA
1) Does ErbB2 has access to all the OFTEN genes that are highly dysregulated in HER2? YES. Thus it is natural to consider it as THE guilty gene causing the disease. Found 3657 elementary paths and 208 elementary nodes if we consider ANSIP of length at most 10.
2) Considering only ErbB2 as THE guilty gene (thus considering it as the only one source node), is it possible to find CIs such that ALL the pathways to OFTEN dysregulated genes in HER2+ BC? YES. Found 17 optimal CIs. The only CI of size 1 is ErbB2 itself and the other CIs require to be of size at least 3.
However we know that this view of the problem might be reduced as resistance to treatment targeting ErbB2 alone, might occur.
3) Considering all the MRs as source nodes, is it possible to find CIs < 6 such that ALL the pathways to OFTEN dysregulated genes in HER2+ BC? Found 380942 elementary paths and 588 elementary nodes to be blocked simultaneously.
NO! Stage IV: Identification of Optimal Combinations of Interventions from Network Analysis with OCSANA
1) Does ErbB2 has access to all the OFTEN genes that are highly dysregulated in HER2? YES. Thus it is natural to consider it as THE guilty gene causing the disease. Found 3657 elementary paths and 208 elementary nodes if we consider ANSIP of length at most 10.
2) Considering only ErbB2 as THE guilty gene (thus considering it as the only one source node), is it possible to find CIs such that ALL the pathways to OFTEN dysregulated genes in HER2+ BC? YES. Found 17 optimal CIs. The only CI of size 1 is ErbB2 itself and the other CIs require to be of size at least 3.
However we know that this view of the problem might be reduced as resistance to treatment targeting ErbB2 alone, might occur.
3) Considering all the MRs as source nodes, is it possible to find CIs < 6 such that ALL the pathways to OFTEN dysregulated genes in HER2+ BC? Found 380942 elementary paths and 588 elementary nodes to be blocked simultaneously.
NO!
4) We simulated an scenario where both drugs, Trastuzumab and Lapatinib are combined. We aim to reveal complementary intervention strategies to ensure all the pathways are intervened.
We applied OCSANA algorithm to our network top 3 master regulators. Found 36 CIs of size at least three. Here is and example with one of the most prevalent interventions suggested:
Intervention Set Size Score [SRC, PIP3, ERK2] 3 6654.37 Literature Validation (PIP3)
Upon inhibition of PI3K, the cell can maintain some level of PIP3 through partial restoration of HER3 phosphorylation which may limit the net inhibitory effect of the PI3K inhibitor thus suggesting that additional blockage of PIP3 is indeed necessary (for example via the antagonist PTEN).
Additionally in [Abramson et al. CCR 2011:17(5)] is suggested, as with one of our predicted combinations that, to inhibit the HER2 network and its output PI3K/Akt another rational therapeutic combination is trastuzumab or lapatinib plus a HER3 or an AKT inhibitor. Literature Validation (SRC)
In this work the authors showed how SRC, a non-membrane tyrosine kinase, is a common signaling node in trastuzumab resistance caused by different mechanisms in HER2-positive breast cancers. A SRC inhibitor restored trastuzumab sensitivity in vitro and in mouse tumor models, suggesting a new way to tackle drug resistance in breast tumors. Literature Validation (ERK) Current & Future Work
• Data Integration into Cellular Signaling Networks for Combinations of Targeted Therapies in Disease Networks • Integration of high through-put data to better prioritize combinations of interventions
• Integration of data from drugome and drug-target interactions
• Dynamical Modeling
• Implement signal propagation functions into network’s edges to better quantify information transduction in signaling networks (signal propagation).
43 Acknowledgements
Institut Curie Emmanuel Barillot Eric Bonnet Andrei Zinovyev
44