begin name
fujita
end name

begin reactions
re1 {1.0}EGFR + {1.0}$EGF = {1.0}EGFEGFR
re12 {1.0}pMEKcyt + {1.0}ERKcyt = {1.0}pMEKERKcyt
re15 {1.0}pTpYERKcyt = {1.0}pTpYERKnuc
re16 {1.0}ERKcyt = {1.0}ERKnuc
re2 {1.0}EGFEGFR = {1.0}degraEGFpEGFR
re22 {1.0}pMEKcyt = {1.0}MEKcyt
re27 {1.0}RasEffector + {1.0}RasGTP = {1.0}RassEffector
re28 {1.0}Sos12 = {1.0}pSos
re3 {1.0}Sos12 + {1.0}EGFEGFR = {1.0}EGFRSos
re30 {1.0}pSos = {1.0}ppSos
re31 {1.0}ppSos = {1.0}pppSos
re32 {1.0}pppSos = {1.0}ppppSos
re4 {1.0}RasGDP = {1.0}RasGTP
re42 {1.0}pMEKERKcyt = {1.0}pMEKpYERK
re43 {1.0}pMEKpYERK = {1.0}pMEKcyt + {1.0}pTpYERKcyt
re44 {1.0}pTpYERKcyt = {1.0}pTERKcyt
re45 {1.0}pTpYERKcyt = {1.0}pYERKcyt
re46 {1.0}pYERKcyt = {1.0}ERKcyt
re47 {1.0}pTERKcyt = {1.0}ERKcyt
re48 {1.0}pYERKcyt = {1.0}pTpYERKcyt
re49 {1.0}pTERKcyt = {1.0}pTpYERKcyt
re5 {1.0}RasGTP = {1.0}RasGDP
re50 {1.0}pYERKcyt = {1.0}pYERKnuc
re51 {1.0}pTERKcyt = {1.0}pTERKnuc
re52 {1.0}pTpYERKnuc = {1.0}pYERKnuc
re53 {1.0}pTpYERKnuc = {1.0}pTERKnuc
re54 {1.0}pYERKnuc = {1.0}ERKnuc
re55 {1.0}pTERKnuc = {1.0}ERKnuc
re56 {1.0}MEKcyt = {1.0}pMEKcyt
re57 {1.0}Shoc2 + {1.0}RasGTP = {1.0}RasShoc2
re58 {1.0}cRaf + {1.0}RasShoc2 = {1.0}RasShoc2cRaf
re6 {1.0}cRaf + {1.0}RasGTP = {1.0}RasRaf
re62 {1.0}PI3K = {1.0}activePI3K
re63 {1.0}Akt = {1.0}pAkt
re64 {1.0}TSC = {1.0}pTSC
re65 {1.0}RhebGTP = {1.0}RhebGDP
re66 {1.0}S6K = {1.0}pS6K
re67 {1.0}RSK = {1.0}pRSK
re68 {1.0}cRaf = {1.0}inactivecRaf
re69 {1.0}EGFEGFR = {1.0}degraEGFpEGFR
re70 {1.0}inactivecRaf = {1.0}cRaf
re9 {1.0}ERKcyt + {1.0}MEKcyt = {1.0}MEKERKcyt
end reactions

begin rate equations
re1 = function1[EGF, EGFR[t], kfEGFEGFR, kphosEGFRmutant]
re12 = c1*function8[ERKcyt[t], c1, kbMEKERK, kfMEKERK, pMEKERKcyt[t], pMEKcyt[t]]
re15 = function9[c2, kexportpTpYERK, kimportpTpYERK, pTpYERKcyt[t], pTpYERKnuc[t]]
re16 = function10[ERKcyt[t], ERKnuc[t], c2, kexportERK, kimportERK]
re2 = c1*function2[EGFEGFR[t], c1, degraEGFpEGFR[t], kbdegra, kfdegra]
re22 = c1*function11[c1, kfdpMEK, pMEKcyt[t]]
re27 = c1*function12[RasEffector[t], RassEffector[t], RasGTP[t], c1, kbRasEffector, kfRasEffector]
re28 = c1*function13[KmpERKcyt, Sos12[t], c1, kbpSos, kcatpERKcyt, kfpSos, pSos[t], pTpYERKcyt[t]]
re3 = c1*function3[EGFRSos[t], EGFRinhibitor[t], EGFEGFR[t], Sos12[t], c1, kbSos, kfSos]
re30 = c1*function14[KmpERKcyt, c1, kbpSos, kcatpERKcyt, kfbppSos, pSos[t], pTpYERKcyt[t], ppSos[t]]
re31 = c1*function15[KmpERKcyt, c1, kbpSos, kcatpERKcyt, kfbpppSos, pTpYERKcyt[t], ppSos[t], pppSos[t]]
re32 = c1*function16[KmpERKcyt, c1, kbpSos, kcatpERKcyt, kfbppppSos, pTpYERKcyt[t], pppSos[t], ppppSos[t]]
re4 = c1*function4[EGFRSos[t], RasGEF[t], RasGDP[t], c1, kfRasGEF, kfSosRas]
re42 = c1*function17[MEKinhibitor[t], c1, kphosnppY, pMEKERKcyt[t]]
re43 = c1*function18[MEKinhibitor[t], c1, kphospYpTpYMEKERK, pMEKpYERK[t]]
re44 = c1*function19[c1, kdphospTpYpTcyt, pTpYERKcyt[t]]
re45 = c1*function20[c1, kdphospTpYpYcyt, pTpYERKcyt[t]]
re46 = c1*function21[c1, kdphospYnpcyt, pYERKcyt[t]]
re47 = c1*function22[c1, kdphospTnpcyt, pTERKcyt[t]]
re48 = c1*function23[MEKinhibitor[t], c1, kphospYpTpY, pMEKcyt[t], pYERKcyt[t]]
re49 = c1*function24[MEKinhibitor[t], c1, kphospTpTpY, pMEKcyt[t], pTERKcyt[t]]
re5 = c1*function5[RasGAP[t], RasGTP[t], c1, kfRasGAP, mutatedRas[t]]
re50 = function25[c2, kexportpYERK, kimportpYERK, pYERKcyt[t], pYERKnuc[t]]
re51 = function26[c2, kexportpTERK, kimportpTERK, pTERKcyt[t], pTERKnuc[t]]
re52 = c2*kdphospTpYpYnuc*pTpYERKnuc[t]
re53 = c2*kdphospTpYpTnuc*pTpYERKnuc[t]
re54 = c2*kdphospYnpnuc*pYERKnuc[t]
re55 = c2*kdphospTnpnuc*pTERKnuc[t]
re56 = c1*function27[BRaf[t], BRafinhibitor[t], MEKcyt[t], RasRaf[t], RasShoc2cRaf[t], c1, kfpMEK, kphosBRafMEK]
re57 = c1*function28[RasGTP[t], RasShoc2[t], Shoc2[t], c1, kbRasShoc2, kfRasShoc2]
re58 = c1*function29[RasShoc2[t], RasShoc2cRaf[t], c1, cRaf[t], kbRasRafShoc2, kfRasRafShoc2]
re6 = c1*function6[RasGTP[t], RasRaf[t], c1, cRaf[t], kbRasRaf, kfRasRaf]
re62 = c1*function30[EGFRinhibitor[t], EGFEGFR[t], PI3K[t], RasGTP[t], activePI3K[t], c1, kactEGFRRasPI3K, kdactPI3K, mutatedPI3K[t]]
re63 = c1*function31[Akt[t], PI3Kinhibitor[t], activePI3K[t], c1, kdphospAkt, kphosPI3KAkt, pAkt[t]]
re64 = c1*function32[TSC[t], c1, kdphospTSC, kphosAktTSC, kphosRSKTSC, pAkt[t], pRSK[t], pTSC[t]]
re65 = c1*function33[RhebGDP[t], RhebGTP[t], TSC[t], c1, kactRheb, kdactTSCRheb]
re66 = c1*function34[RhebGTP[t], S6K[t], c1, kdphospS6K, kphosRhebS6K, pS6K[t]]
re67 = c1*function35[RSK[t], c1, kdphospRSK, kphosERKRSK, pRSK[t], pTpYERKcyt[t]]
re68 = c1*function36[RhebGTP[t], c1, cRaf[t], inactivecRaf[t], kactRhebRaf, kdactRhebRaf]
re69 = c1*function37[EGFEGFR[t], c1, kfdegraERKEGFR, pTpYERKcyt[t]]
re70 = c1*function38[PI3Kinhibitor[t], activePI3K[t], c1, inactivecRaf[t], kactPI3KRaf]
re9 = c1*function7[ERKcyt[t], MEKERKcyt[t], MEKcyt[t], c1, kbMEKERK, kfMEKERK]
end rate equations

begin parameters
KmpERKcyt = 3.0
kactEGFRRasPI3K = 3.0
kactPI3KRaf = 1.8
kactRheb = 0.0021
kactRhebRaf = 0.04
kbMEKERK = 0.27
kbRafMEK = 0.065
kbRasEffector = 0.1
kbRasRaf = 0.0049
kbRasRafShoc2 = 0.049
kbRasShoc2 = 0.1
kbSos = 0.1
kbdegra = 0.001
kbpSos = 0.0025
kcatpERKcyt = 0.075
kdactPI3K = 0.028
kdactRhebRaf = 4.0
kdactTSCRheb = 0.097
kdphospAkt = 0.048
kdphospRSK = 0.3
kdphospS6K = 0.001
kdphospTSC = 0.0088
kdphospTnpcyt = 0.0068
kdphospTnpnuc = 0.0058
kdphospTpYpTcyt = 0.0055
kdphospTpYpTnuc = 0.0038
kdphospTpYpYcyt = 0.004
kdphospTpYpYnuc = 0.0032
kdphospYnpcyt = 0.0067
kdphospYnpnuc = 0.0077
kexportERK = 0.013
kexportpTERK = 0.049
kexportpTpYERK = 0.0076
kexportpYERK = 0.017
kfEGFEGFR = 10.0
kfMEKERK = 0.18
kfRafMEK = 0.65
kfRasEffector = 1.0
kfRasGAP = 0.05
kfRasGEF = "9e-05"
kfRasRaf = 0.049
kfRasRafShoc2 = 0.49
kfRasShoc2 = 1.0
kfSos = 0.1
kfSosRas = 1.0
kfdegra = 0.0014
kfdegraERKEGFR = 0.02
kfdpMEK = 0.0096
kfpMEK = 2.0
kfpSos = 1.0
kfbppSos = 1.0
kfbpppSos = 1.0
kfbppppSos = 1.0
kimportERK = 0.0017
kimportpTERK = 0.0022
kimportpTpYERK = 0.0082
kimportpYERK = 0.0025
kphosAktTSC = 1.2
kphosBRafMEK = 0.01
kphosEGFRmutant = 0.0
kphosERKRSK = 0.7
kphosPI3KAkt = 0.1
kphosRSKTSC = 0.6
kphosRhebS6K = 0.002
kphosnppY = 0.073
kphospTpTpY = 0.02
kphospYpTpY = 0.02
kphospYpTpYMEKERK = 0.05
EGF = 0.0
c1 = 1.0
c2 = 0.2
default = 1.0
end parameters

begin initial conditions
Akt[0] = Akti
BRaf[0] = BRafi
BRafinhibitor[0] = BRafinhibitori
EGFR[0] = EGFRi
EGFRSos[0] = EGFRSosi
EGFRinhibitor[0] = EGFRinhibitori
EGFEGFR[0] = EGFEGFRi
ERKcyt[0] = ERKcyti
ERKnuc[0] = ERKnuci
MEKERKcyt[0] = MEKERKcyti
MEKinhibitor[0] = MEKinhibitori
MEKcyt[0] = MEKcyti
PI3K[0] = PI3Ki
PI3Kinhibitor[0] = PI3Kinhibitori
RSK[0] = RSKi
RasEffector[0] = RasEffectori
RasGAP[0] = RasGAPi
RasGEF[0] = RasGEFi
RasGDP[0] = RasGDPi
RasGTP[0] = RasGTPi
RasRaf[0] = RasRafi
RasShoc2[0] = RasShoc2i
RasShoc2cRaf[0] = RasShoc2cRafi
RassEffector[0] = RassEffectori
RhebGDP[0] = RhebGDPi
RhebGTP[0] = RhebGTPi
S6K[0] = S6Ki
Shoc2[0] = Shoc2i
Sos12[0] = Sos12i
TSC[0] = TSCi
activePI3K[0] = activePI3Ki
cRaf[0] = cRafi
degraEGFpEGFR[0] = degraEGFpEGFRi
inactivecRaf[0] = inactivecRafi
mutatedPI3K[0] = mutatedPI3Ki
mutatedRas[0] = mutatedRasi
pAkt[0] = pAkti
pMEKERKcyt[0] = pMEKERKcyti
pMEKpYERK[0] = pMEKpYERKi
pMEKcyt[0] = pMEKcyti
pRSK[0] = pRSKi
pS6K[0] = pS6Ki
pSos[0] = pSosi
pTERKcyt[0] = pTERKcyti
pTERKnuc[0] = pTERKnuci
pTSC[0] = pTSCi
pTpYERKcyt[0] = pTpYERKcyti
pTpYERKnuc[0] = pTpYERKnuci
pYERKcyt[0] = pYERKcyti
pYERKnuc[0] = pYERKnuci
ppSos[0] = ppSosi
pppSos[0] = pppSosi
ppppSos[0] = ppppSosi
end initial conditions

begin initial values
Akti = 1.0
BRafi = 0.0
BRafinhibitori = 1.0
EGFRi = 0.42
EGFRSosi = 0.0
EGFRinhibitori = 1.0
EGFEGFRi = 0.0
ERKcyti = 0.96
ERKnuci = 0.0
MEKERKcyti = 0.0
MEKinhibitori = 1.0
MEKcyti = 1.4
PI3Ki = 1.0
PI3Kinhibitori = 1.0
RSKi = 1.0
RasEffectori = 2.0
RasGAPi = 1.0
RasGEFi = 1.0
RasGDPi = 0.43
RasGTPi = 0.0
RasRafi = 0.0
RasShoc2i = 0.0
RasShoc2cRafi = 0.0
RassEffectori = 0.0
RhebGDPi = 1.0
RhebGTPi = 0.0
S6Ki = 1.0
Shoc2i = 0.67
Sos12i = 0.12
TSCi = 1.0
activePI3Ki = 0.0
cRafi = 0.013
degraEGFpEGFRi = 0.0
inactivecRafi = 0.0
mutatedPI3Ki = 0.0
mutatedRasi = 0.0
pAkti = 0.0
pMEKERKcyti = 0.0
pMEKpYERKi = 0.0
pMEKcyti = 0.0
pRSKi = 0.0
pS6Ki = 0.0
pSosi = 0.0
pTERKcyti = 0.0
pTERKnuci = 0.0
pTSCi = 0.0
pTpYERKcyti = 0.0
pTpYERKnuci = 0.0
pYERKcyti = 0.0
pYERKnuci = 0.0
ppSosi = 0.0
pppSosi = 0.0
ppppSosi = 0.0
end initial values

begin assignment rules
end assignment rules

begin function definitions
function31[Akt_,PI3Kinhibitor_,activePI3K_,c1_,kdphospAkt_,kphosPI3KAkt_,pAkt_] := (-(kdphospAkt*pAkt) + activePI3K*Akt*c1*kphosPI3KAkt*PI3Kinhibitor)/c1
function11[c1_,kfdpMEK_,pMEKcyt_] := (kfdpMEK*pMEKcyt)/c1
function32[TSC_,c1_,kdphospTSC_,kphosAktTSC_,kphosRSKTSC_,pAkt_,pRSK_,pTSC_] := (-(kdphospTSC*pTSC) + kphosAktTSC*pAkt*TSC + kphosRSKTSC*pRSK*TSC)/c1
function28[RasGTP_,RasShoc2_,Shoc2_,c1_,kbRasShoc2_,kfRasShoc2_] := (-(kbRasShoc2*RasShoc2) + kfRasShoc2*RasGTP*Shoc2)/c1
function25[c2_,kexportpYERK_,kimportpYERK_,pYERKcyt_,pYERKnuc_] := kimportpYERK*pYERKcyt - c2*kexportpYERK*pYERKnuc
function21[c1_,kdphospYnpcyt_,pYERKcyt_] := (kdphospYnpcyt*pYERKcyt)/c1
function19[c1_,kdphospTpYpTcyt_,pTpYERKcyt_] := (kdphospTpYpTcyt*pTpYERKcyt)/c1
function17[MEKinhibitor_,c1_,kphosnppY_,pMEKERKcyt_] := kphosnppY*MEKinhibitor*pMEKERKcyt
function16[KmpERKcyt_,c1_,kbpSos_,kcatpERKcyt_,kfbppppSos_,pTpYERKcyt_,pppSos_,ppppSos_] := (kfbppppSos*(-(kbpSos*ppppSos) + (kcatpERKcyt*pppSos*pTpYERKcyt)/(KmpERKcyt + pppSos)))/c1
function13[KmpERKcyt_,Sos12_,c1_,kbpSos_,kcatpERKcyt_,kfpSos_,pSos_,pTpYERKcyt_] := (-(kbpSos*pSos) + (kcatpERKcyt*kfpSos*pTpYERKcyt*Sos12)/(KmpERKcyt + Sos12))/c1
function9[c2_,kexportpTpYERK_,kimportpTpYERK_,pTpYERKcyt_,pTpYERKnuc_] := kimportpTpYERK*pTpYERKcyt - c2*kexportpTpYERK*pTpYERKnuc
function33[RhebGDP_,RhebGTP_,TSC_,c1_,kactRheb_,kdactTSCRheb_] := (-(kactRheb*RhebGDP) + kdactTSCRheb*RhebGTP*TSC)/c1
function29[RasShoc2_,RasShoc2cRaf_,c1_,cRaf_,kbRasRafShoc2_,kfRasRafShoc2_] := (cRaf*kfRasRafShoc2*RasShoc2 - kbRasRafShoc2*RasShoc2cRaf)/c1
function26[c2_,kexportpTERK_,kimportpTERK_,pTERKcyt_,pTERKnuc_] := kimportpTERK*pTERKcyt - c2*kexportpTERK*pTERKnuc
function24[MEKinhibitor_,c1_,kphospTpTpY_,pMEKcyt_,pTERKcyt_] := kphospTpTpY*MEKinhibitor*pMEKcyt*pTERKcyt
function23[MEKinhibitor_,c1_,kphospYpTpY_,pMEKcyt_,pYERKcyt_] := kphospYpTpY*MEKinhibitor*pMEKcyt*pYERKcyt
function22[c1_,kdphospTnpcyt_,pTERKcyt_] := (kdphospTnpcyt*pTERKcyt)/c1
function20[c1_,kdphospTpYpYcyt_,pTpYERKcyt_] := (kdphospTpYpYcyt*pTpYERKcyt)/c1
function18[MEKinhibitor_,c1_,kphospYpTpYMEKERK_,pMEKpYERK_] := kphospYpTpYMEKERK*MEKinhibitor*pMEKpYERK
function15[KmpERKcyt_,c1_,kbpSos_,kcatpERKcyt_,kfbpppSos_,pTpYERKcyt_,ppSos_,pppSos_] := (kfbpppSos*(-(kbpSos*pppSos) + (kcatpERKcyt*ppSos*pTpYERKcyt)/(KmpERKcyt + ppSos)))/c1
function14[KmpERKcyt_,c1_,kbpSos_,kcatpERKcyt_,kfbppSos_,pSos_,pTpYERKcyt_,ppSos_] := (kfbppSos*(-(kbpSos*ppSos) + (kcatpERKcyt*pSos*pTpYERKcyt)/(KmpERKcyt + pSos)))/c1
function7[ERKcyt_,MEKERKcyt_,MEKcyt_,c1_,kbMEKERK_,kfMEKERK_] := (ERKcyt*kfMEKERK*MEKcyt - kbMEKERK*MEKERKcyt)/c1
function36[RhebGTP_,c1_,cRaf_,inactivecRaf_,kactRhebRaf_,kdactRhebRaf_] := (-(inactivecRaf*kactRhebRaf) + cRaf*kdactRhebRaf*RhebGTP)/c1
function1[EGF_,EGFR_,kfEGFEGFR_,kphosEGFRmutant_] := EGF*EGFR*kfEGFEGFR + EGFR*kphosEGFRmutant
function5[RasGAP_,RasGTP_,c1_,kfRasGAP_,mutatedRas_] := (kfRasGAP*RasGAP*(-mutatedRas + RasGTP))/c1
function10[ERKcyt_,ERKnuc_,c2_,kexportERK_,kimportERK_] := -(c2*ERKnuc*kexportERK) + ERKcyt*kimportERK
function8[ERKcyt_,c1_,kbMEKERK_,kfMEKERK_,pMEKERKcyt_,pMEKcyt_] := (ERKcyt*kfMEKERK*pMEKcyt - kbMEKERK*pMEKERKcyt)/c1
function6[RasGTP_,RasRaf_,c1_,cRaf_,kbRasRaf_,kfRasRaf_] := (cRaf*kfRasRaf*RasGTP - kbRasRaf*RasRaf)/c1
function38[PI3Kinhibitor_,activePI3K_,c1_,inactivecRaf_,kactPI3KRaf_] := activePI3K*inactivecRaf*kactPI3KRaf*PI3Kinhibitor
function35[RSK_,c1_,kdphospRSK_,kphosERKRSK_,pRSK_,pTpYERKcyt_] := (-(kdphospRSK*pRSK) + kphosERKRSK*pTpYERKcyt*RSK)/c1
function37[EGFEGFR_,c1_,kfdegraERKEGFR_,pTpYERKcyt_] := (EGFEGFR*kfdegraERKEGFR*pTpYERKcyt)/c1
function27[BRaf_,BRafinhibitor_,MEKcyt_,RasRaf_,RasShoc2cRaf_,c1_,kfpMEK_,kphosBRafMEK_] := (BRaf*BRafinhibitor*c1*kphosBRafMEK + kfpMEK*MEKcyt*(RasRaf + RasShoc2cRaf))/c1
function4[EGFRSos_,RasGEF_,RasGDP_,c1_,kfRasGEF_,kfSosRas_] := (EGFRSos*kfSosRas*RasGDP + kfRasGEF*RasGEF*RasGDP)/c1
function3[EGFRSos_,EGFRinhibitor_,EGFEGFR_,Sos12_,c1_,kbSos_,kfSos_] := (-(EGFRSos*kbSos) + c1*EGFRinhibitor*EGFEGFR*kfSos*Sos12)/c1
function2[EGFEGFR_,c1_,degraEGFpEGFR_,kbdegra_,kfdegra_] := (-(degraEGFpEGFR*kbdegra) + EGFEGFR*kfdegra)/c1
function12[RasEffector_,RassEffector_,RasGTP_,c1_,kbRasEffector_,kfRasEffector_] := (-(kbRasEffector*RassEffector) + kfRasEffector*RasEffector*RasGTP)/c1
function30[EGFRinhibitor_,EGFEGFR_,PI3K_,RasGTP_,activePI3K_,c1_,kactEGFRRasPI3K_,kdactPI3K_,mutatedPI3K_] := (-(kdactPI3K*(activePI3K - mutatedPI3K)) + c1*EGFRinhibitor*EGFEGFR*kactEGFRRasPI3K*PI3K*RasGTP)/c1
function34[RhebGTP_,S6K_,c1_,kdphospS6K_,kphosRhebS6K_,pS6K_] := (-(kdphospS6K*pS6K) + kphosRhebS6K*RhebGTP*S6K)/c1
end function definitions

begin events
EGFtrig = (t == 6000, {EGF -> 0.0016}, 0)
end events

begin process annotations
end process annotations

begin species annotations
end species annotations

begin units
end units