begin name beuke16 end name begin reactions Complexassociationc {1.0}p65cytoplasm + {1.0}IkBacytoplasm = {1.0}s19 ComplexdegradationIkBac {1.0}s19 = {1.0}p65cytoplasm ComplexdegradationIkBan {1.0}p65IkBanucleus = {1.0}p65nucleus Complexdegradationp65c {1.0}s19 = {1.0}IkBacytoplasm Complexdegradationp65n {1.0}p65IkBanucleus = {1.0}s11 Complexnuclearshuttle {1.0}p65IkBanucleus = {1.0}s19 IKKphosphorylation {1.0}s14 = {1.0}s15 IkBadegradationc {1.0}IkBacytoplasm = {1.0}$EXTERNAL IkBadegradationn {1.0}s11 = {1.0}$EXTERNAL IkBamRNAdegradationc {1.0}IkBamRNAcytoplasm = {1.0}$EXTERNAL IkBamRNAdegradationn {1.0}IkBamRNAnucleus = {1.0}$EXTERNAL IkBamRNAtransport {1.0}IkBamRNAnucleus = {1.0}IkBamRNAcytoplasm IkBanuclearshuttle {1.0}IkBacytoplasm = {1.0}s11 IkBaphosphorylation {1.0}IkBacytoplasm = {1.0}s5 IkBatranscriptionelongation1 {1.0}IkBapremRNA1 = {1.0}IkBapremRNA2 IkBatranscriptionelongation2 {1.0}IkBapremRNA2 = {1.0}IkBamRNAnucleus IkBatranslation {1.0}IkBamRNAcytoplasm = {1.0}IkBamRNAcytoplasm + {1.0}IkBacytoplasm JNKactivephosphorylation {1.0}JNK = {1.0}JNKP JNKbasalphosphorylation {1.0}JNK = {1.0}JNKP JNKdephosphorylation {1.0}JNKP = {1.0}JNK LPSLSECdegradation {1.0}LPS = {1.0}$EXTERNAL LPSMCdegradation {1.0}LPS = {1.0}$EXTERNAL MSK1activation {1.0}MSK1 = {1.0}MSK1P MSK1deactivation {1.0}MSK1P = {1.0}MSK1 TNFR1shuttle {1.0}TNFR1cytoplasm = {1.0}TNFR1EL TNFaLSECtranscriptionelongation {1.0}TNFapremRNALSEC = {1.0}TNFamRNALSEC TNFaLSECtranscriptioninitiation {1.0}$EXTERNAL = {2.0}TNFapremRNALSEC TNFaLSECtranslation {1.0}TNFamRNALSEC = {1.0}TNFamRNALSEC + {1.0}s16 TNFaMCtranscriptionelongation {1.0}TNFapremRNAMC = {1.0}TNFamRNAMC TNFaMCtranscriptioninitiation {1.0}$EXTERNAL = {2.0}TNFapremRNAMC TNFaMCtranslation {1.0}TNFamRNAMC = {1.0}TNFamRNAMC + {1.0}s16 TNFaTNFR1association {1.0}TNFR1EL + {1.0}s16 = {1.0}TNFaTNFR1EL TNFaTNFR1internalisation {1.0}TNFaTNFR1EL = {1.0}TNFaTNFR1cytoplasm TNFadegradation {1.0}s16 = {1.0}$EXTERNAL TNFainternaldegradation {1.0}TNFaTNFR1cytoplasm = {1.0}TNFR1cytoplasm TNFamRNALSECdegradation {1.0}TNFamRNALSEC = {1.0}$EXTERNAL TNFamRNAMCdegradation {1.0}TNFamRNAMC = {1.0}$EXTERNAL basalIKKbphosphorylation {1.0}s14 = {1.0}s15 p38activephosphorylation {1.0}p38 = {1.0}p38P p38basalphosphorylation {1.0}p38 = {1.0}p38P p38dephosphorylation {1.0}p38P = {1.0}p38 p652Pdegradation {1.0}p652P = {1.0}$EXTERNAL p652Pdephosphorylation0 {1.0}p652P = {1.0}p65nucleus p65Pdegradationc {1.0}s3 = {1.0}$EXTERNAL p65Pdegradationn {1.0}s8 = {1.0}$EXTERNAL p65Pdephosphorylationc {1.0}s8 = {1.0}p65nucleus p65Pdephosphorylationn {1.0}s3 = {1.0}p65cytoplasm p65PphosphorylationMSK1 {1.0}s8 = {1.0}p652P p65nuclearshuttle {1.0}p65cytoplasm = {1.0}p65nucleus p65phosphorylationMSK1 {1.0}p65nucleus = {1.0}p652P p65translation {1.0}$p65mRNA = {1.0}$p65mRNA + {1.0}p65cytoplasm re10 {1.0}$EXTERNAL = {1.0}IkBapremRNA1 re14 {1.0}s5 = {1.0}$EXTERNAL re15 {1.0}s19 = {1.0}s3 + {1.0}s5 re17 {1.0}s15 = {1.0}s14 re19 {1.0}p65nucleus + {1.0}s11 = {1.0}p65IkBanucleus re3 {1.0}s3 = {1.0}s8 end reactions begin rate equations Complexassociationc = default*(IkBap65associationk*IkBacytoplasm[t]*p65cytoplasm[t] - IkBap65dissociationk*s19[t]) ComplexdegradationIkBac = default*IkBadegcomplexcytk*s19[t] ComplexdegradationIkBan = c1*IkBadegcomplexnuck*p65IkBanucleus[t] Complexdegradationp65c = default*p65degradationk*s19[t] Complexdegradationp65n = c1*p65degradationk*p65IkBanucleus[t] Complexnuclearshuttle = IkBap65nuclearexportk*p65IkBanucleus[t] - IkBap65nuclearimportk*s19[t] IKKphosphorylation = default*Catalyticactivationirrev[s14[t], TNFaTNFR1EL[t], IKKbactivephosphorylationkM, IKKbactivephosphorylationvmax, IKKbactivephosphorylationkA] IkBadegradationc = default*IkBadegcytk*IkBacytoplasm[t] IkBadegradationn = c1*IkBadegnuck*s11[t] IkBamRNAdegradationc = default*IkBamRNAdegcytk*IkBamRNAcytoplasm[t] IkBamRNAdegradationn = c1*IkBamRNAdegnuck*IkBamRNAnucleus[t] IkBamRNAtransport = IkBamRNAtransportk*IkBamRNAnucleus[t] IkBanuclearshuttle = IkBanuclearimportk*IkBacytoplasm[t] - IkBanuclearexportk*s11[t] IkBaphosphorylation = default*HenriMichaelisMentenirreversible[IkBacytoplasm[t], IkBaphosphorylationkM, IkBaphosphorylationvmax] IkBatranscriptionelongation1 = c1*IkBatranscriptionelongationkbasal*IkBapremRNA1[t] IkBatranscriptionelongation2 = c1*IkBatranscriptionelongationkbasal*IkBapremRNA2[t] IkBatranslation = default*HenriMichaelisMentenirreversible[IkBamRNAcytoplasm[t], IkBatranslationKm, IkBatranslationvmax] JNKactivephosphorylation = default*HenriMichaelisMentenirreversible[JNK[t], JNKactivephoshorylationKm, JNKactivephosphorylationvmax] JNKbasalphosphorylation = default*JNKbasalphosphorylationk*JNK[t] JNKdephosphorylation = default*JNKdephosphorylationk*JNKP[t] LPSLSECdegradation = EL*LPSLSECdegradationk*LPS[t] LPSMCdegradation = EL*LPSMCdegradationk*LPS[t] MSK1activation = c1*HenriMichaelisMentenirreversible[MSK1[t], MSK1activationkM, MSK1activationvmax] MSK1deactivation = c1*MSK1dephosphorylationk*MSK1P[t] TNFR1shuttle = kTNFR1vessicle2outermembraneshuttle*TNFR1cytoplasm[t] - kTNFR1outermembrane2vessicleshuttle*TNFR1EL[t] TNFaLSECtranscriptionelongation = LSEC*TNFaLSECtranscriptionelongationk*TNFapremRNALSEC[t] TNFaLSECtranscriptioninitiation = LSEC*TNFatranscriptioninitiation[TNFaLSECtranscriptioninitiationkbasal, TNFaLSECtranscriptioninitiationvALPS, LPS[t], TNFaLSECtranscriptioninitiationkALPS] TNFaLSECtranslation = TNFaLSECtranslationk*TNFamRNALSEC[t] TNFaMCtranscriptionelongation = MC*TNFaMCtranscriptionelongationk*TNFapremRNAMC[t] TNFaMCtranscriptioninitiation = MC*TNFatranscriptioninitiation[TNFaMCtranscriptioninitiationkbasal, TNFaMCtranscriptioninitiationvALPS, LPS[t], TNFaMCtranscriptioninitiationkALPS] TNFaMCtranslation = TNFaMCtranslationk*TNFamRNAMC[t] TNFaTNFR1association = EL*(-(kTNFaTNFR1dissociation*TNFaTNFR1EL[t]) + kTNFaTNFR1association*s16[t]*TNFR1EL[t]) TNFaTNFR1internalisation = kTNFaTNFR1internalisation*TNFaTNFR1EL[t] TNFadegradation = EL*TNFadegradationk*s16[t] TNFainternaldegradation = default*kTNFainternaldegradation*TNFaTNFR1cytoplasm[t] TNFamRNALSECdegradation = LSEC*TNFamRNALSECdegradationk*TNFamRNALSEC[t] TNFamRNAMCdegradation = MC*TNFamRNAMCdegradationk*TNFamRNAMC[t] basalIKKbphosphorylation = default*IKKbbasalphosphoylationk*s14[t] p38activephosphorylation = default*HenriMichaelisMentenirreversible[p38[t], p38activephoshorylationKm, p38activephosphorylationvmax] p38basalphosphorylation = default*p38basalphosphorylationk*p38[t] p38dephosphorylation = default*p38dephosphorylationk*p38P[t] p652Pdegradation = c1*p65degradationk*p652P[t] p652Pdephosphorylation0 = c1*p652Pdephosphorylation*p652P[t] p65Pdegradationc = default*p65degradationk*s3[t] p65Pdegradationn = c1*p65degradationk*s8[t] p65Pdephosphorylationc = c1*p65Pdephosphorylationk*s8[t] p65Pdephosphorylationn = default*p65Pdephosphorylationk*s3[t] p65PphosphorylationMSK1 = c1*HenriMichaelisMentenirreversible[s8[t], p65PMSK1phosphrylationkM, p65PMSK1phosphrylationvmax] p65nuclearshuttle = p65nuclearimportk*p65cytoplasm[t] - p65nuclearexportk*p65nucleus[t] p65phosphorylationMSK1 = c1*HenriMichaelisMentenirreversible[p65nucleus[t], p65MSK1phosphorylationkM, p65MSK1phosphrylationvmax] p65translation = default*p65mRNA*p65translationk re10 = c1*activatedTranscription1[IkBatranscriptioninitiationkbasal, IkBatranscriptionkA2p65P, s8[t], IkBatranscriptionkAp65, p65nucleus[t], p652P[t], IkBatranscriptionkA3p652P] re14 = default*IkBapactivedegradationk*s5[t] re15 = default*HenriMichaelisMentenirreversible[s19[t], IkBap65phosphorylationkM, IkBap65phosphorylationvmax] re17 = default*IKKbdephopshorylationk*s15[t] re19 = c1*(-(IkBap65dissociationk*p65IkBanucleus[t]) + IkBap65associationk*p65nucleus[t]*s11[t]) re3 = p65nuclearimportk*s3[t] - p65nuclearexportk*s8[t] end rate equations begin parameters IKKbactivephosphorylationkA = 0.00299747566366216 IKKbactivephosphorylationkM = 5.0 IKKbactivephosphorylationvmax = 644.918247957377 IKKbbasalphosphoylationk = "1.62075185301479e-05" IKKbdephopshorylationk = 2.60841546179819 IkBadegcomplexcytk = "1e-05" IkBadegcomplexnuck = "1.00000000002221e-05" IkBadegcytk = "1.00000000002221e-05" IkBadegnuck = "1e-05" IkBamRNAdegcytk = 0.000238500368797763 IkBamRNAdegnuck = "5e-05" IkBamRNAtransportk = 0.0001 IkBanuclearimportk = 0.005 IkBap65associationk = 0.0179581875147267 IkBap65nuclearexportk = 0.000100000000000222 IkBap65nuclearimportk = 0.00199999999999978 IkBap65phosphorylationkM = 0.5 IkBap65phosphorylationkcat = 119.452309213816 IkBapactivedegradationk = 0.00278036633227308 IkBaphosphorylationkM = 0.1 IkBatranscriptionelongationkbasal = 0.00204052488627245 IkBatranscriptioninitiationkbasal = "1e-06" IkBatranscriptionkA2p65P = 0.000100000000000222 IkBatranscriptionkA3p652P = 0.000100000000000222 IkBatranscriptionkAp65 = 0.632263209679046 IkBatranslationKm = 8.54191840071904 IkBatranslationvmax = 0.000876113149226852 JNKactivephoshorylationKm = 9.53790528349956 JNKactivephosphorylationkcat = 19378.0668283094 JNKbasalphosphorylationk = "4.24244086571766e-06" JNKdephosphorylationk = 0.000758674622149461 LPSLSECdegradationk = 0.000237995625933452 LPSMCdegradationk = 0.000119962880786728 MSK1activationkM = 0.332175 MSK1dephosphorylationk = 0.00911301869355715 MSK1phosphorylationkcat = 0.000524920263298147 TNFaLSECtranscriptionelongationk = "1.00000000022204e-06" TNFaLSECtranscriptioninitiationkALPS = 1.06582483453034 TNFaLSECtranscriptioninitiationkbasal = 0.0 TNFaLSECtranscriptioninitiationvALPS = "1.21810858381465e-05" TNFaLSECtranslationk = "2.16257773268075e-05" TNFaMCtranscriptionelongationk = "1.00000000022204e-06" TNFaMCtranscriptioninitiationkALPS = 0.820846512533503 TNFaMCtranscriptioninitiationkbasal = 0.0 TNFaMCtranscriptioninitiationvALPS = "5.8502901679385e-06" TNFaMCtranslationk = "2.14368005031437e-06" TNFadegradationk = 0.000155219110881789 TNFamRNALSECdegradationk = 0.594858843036592 TNFamRNAMCdegradationk = 0.0518453181918666 kIkBa = 122303.370928952 kIkBaP = 508027.497315407 kIkBamRNA = 10144.1303860642 kJNKP = 9432073.4940875 kMSKP = 34075528.5841576 kTNFR1outermembrane2vessicleshuttle = "1.8e-05" kTNFR1vessicle2outermembraneshuttle = 0.0004 kTNFaTNFR1association = 16.833 kTNFaTNFR1internalisation = 0.00077 kTNFainternaldegradation = "9.03127166797884e-05" kp38P = 149312.531856612 kp65 = 0.102372088824604 kp65P = 2423697.46406852 p38activephoshorylationKm = 0.10266177383089 p38activephosphorylationkcat = 163666.730256547 p38basalphosphorylationk = 0.000367881142669593 p38dephosphorylationk = 0.000499743170517763 p65MSK1phosphorylationkM = 0.90674522655743 p65MSK1phosphrylationkcat = 0.0257010885482558 p65Pdephosphorylationk = 0.000553480398268359 p65degradationk = "1.328912101e-05" p65nuclearimportk = 0.0005 p65translationk = "1.68e-06" p65mRNA = 1.0 EL = "2.59e-06" LSEC = "4.7e-07" MC = "3.5e-07" c1 = "8e-07" default = "1.3e-05" end parameters begin initial conditions IkBacytoplasm[0] = IkBacytoplasmi IkBamRNAcytoplasm[0] = IkBamRNAcytoplasmi IkBamRNAnucleus[0] = IkBamRNAnucleusi IkBapremRNA1[0] = IkBapremRNA1i IkBapremRNA2[0] = IkBapremRNA2i JNK[0] = JNKi JNKP[0] = JNKPi LPS[0] = LPSi MSK1[0] = MSK1i MSK1P[0] = MSK1Pi TNFR1EL[0] = TNFR1ELi TNFR1cytoplasm[0] = TNFR1cytoplasmi TNFaTNFR1EL[0] = TNFaTNFR1ELi TNFaTNFR1cytoplasm[0] = TNFaTNFR1cytoplasmi TNFamRNALSEC[0] = TNFamRNALSECi TNFamRNAMC[0] = TNFamRNAMCi TNFapremRNALSEC[0] = TNFapremRNALSECi TNFapremRNAMC[0] = TNFapremRNAMCi p38[0] = p38i p38P[0] = p38Pi p652P[0] = p652Pi p65IkBanucleus[0] = p65IkBanucleusi p65cytoplasm[0] = p65cytoplasmi p65nucleus[0] = p65nucleusi s11[0] = s11i s14[0] = s14i s15[0] = s15i s16[0] = s16i s19[0] = s19i s3[0] = s3i s5[0] = s5i s8[0] = s8i end initial conditions begin initial values IkBacytoplasmi = 0.569627604156393 IkBamRNAcytoplasmi = 2.76336614851413 IkBamRNAnucleusi = 8.56782999207036e-05 IkBapremRNA1i = 5.2485474918991 IkBapremRNA2i = 5.2485474918991 JNKi = 0.994439184714324 JNKPi = 0.00556081528567571 LPSi = 5.0 MSK1i = 14.9761065220752 MSK1Pi = 0.0238934779247571 TNFR1ELi = 0.00122834645669294 TNFR1cytoplasmi = 5.52755905511824e-05 TNFaTNFR1ELi = 0.0 TNFaTNFR1cytoplasmi = 0.0 TNFamRNALSECi = 0.0 TNFamRNAMCi = 0.0 TNFapremRNALSECi = 0.0 TNFapremRNAMCi = 0.0 p38i = 0.575990279343232 p38Pi = 0.424009720656768 p652Pi = 0.229730530497681 p65IkBanucleusi = 0.847353224350509 p65cytoplasmi = 0.000337415726357701 p65nucleusi = 0.0168664349985797 s11i = 1.13925511245651 s14i = 0.299998135946739 s15i = 1.86405326092334e-06 s16i = 0.0 s19i = 0.0423675493437157 s3i = 0.00435886658608436 s5i = 0.0743812252131838 s8i = 0.217923929080718 end initial values begin assignment rules unscaledp65 := default*(p65cytoplasm[t] + s19[t] + s3[t]) + c1*(p652P[t] + p65IkBanucleus[t] + p65nucleus[t] + s8[t]) JNKactivephosphorylationvmax := JNKactivephosphorylationkcat*TNFaTNFR1EL[t] unscaledIkBamRNA := default*IkBamRNAcytoplasm[t] + c1*IkBamRNAnucleus[t] IkBanuclearexportk := 0.5*IkBanuclearimportk scaledMSKP := kMSKP*unscaledMSKP scaledp65 := kp65*unscaledp65 IkBap65phosphorylationvmax := IkBap65phosphorylationkcat*s15[t] p65MSK1phosphrylationvmax := p65MSK1phosphrylationkcat*MSK1P[t] p65PMSK1phosphrylationkM := p65MSK1phosphorylationkM scaledIkBamRNA := kIkBamRNA*unscaledIkBamRNA unscaledMSKP := c1*MSK1P[t] IkBap65dissociationk := 0.003*IkBap65associationk kTNFaTNFR1dissociation := 0.000019*kTNFaTNFR1association scaledp65P := kp65P*unscaledp65P unscaledp65P := default*s3[t] + c1*s8[t] p65PMSK1phosphrylationvmax := p65PMSK1phosphrylationkcat*MSK1P[t] p65PMSK1phosphrylationkcat := p65MSK1phosphrylationkcat p38activephosphorylationvmax := p38activephosphorylationkcat*TNFaTNFR1EL[t] MSK1activationvmax := MSK1phosphorylationkcat*p38P[t] p65nuclearexportk := 0.02*p65nuclearimportk scaledp38P := kp38P*unscaledp38P unscaledp38P := default*p38P[t] scaledIkBa := kIkBa*unscaledIkBa unscaledIkBa := c1*(p65IkBanucleus[t] + s11[t]) + default*(IkBacytoplasm[t] + s19[t] + s5[t]) scaledIkBaP := kIkBaP*unscaledIkBaP unscaledIkBaP := default*s5[t] IkBaphosphorylationvmax := IkBaphosphorylationkcat*s15[t] IkBaphosphorylationkcat := IkBap65phosphorylationkcat scaledJNKP := kJNKP*unscaledJNKP unscaledJNKP := default*JNKP[t] p652Pdephosphorylation := p65Pdephosphorylationk end assignment rules begin function definitions Catalyticactivationirrev[substrate_,Activator_,Kms_,V_,Ka_] := (Activator*substrate*V)/((Activator + Ka)*(Kms + substrate)) HenriMichaelisMentenirreversible[substrate_,Km_,V_] := (substrate*V)/(Km + substrate) TNFatranscriptioninitiation[kbasal_,vA_,A_,kA_] := kbasal + (A*vA)/(A + kA) activatedTranscription1[k1_,k2_,Modifier_,k3_,Modifier2_,Modifier3_,k4_] := k1 + k2*Modifier + k3*Modifier2 + k4*Modifier3 end function definitions begin events end events begin process annotations end process annotations begin species annotations end species annotations begin units end units