BioModels Database logo

BioModels Database

spacer

BIOMD0000000568 - Mueller2015 - Hepatocyte proliferation, T160 phosphorylation of CDK2

 

 |   |   |  Send feedback
Reference Publication
Publication ID: 25771250
Mueller S, Huard J, Waldow K, Huang X, D'Alessandro LA, Bohl S, Börner K, Grimm D, Klamt S, Klingmüller U, Schilling M.
T160-phosphorylated CDK2 defines threshold for HGF-dependent proliferation in primary hepatocytes.
Mol. Syst. Biol. 2015 Jan; 11(1): 795
Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany.  [more]
Model
Original Model: BIOMD0000000568.origin
Submitter: Marcel Schilling
Submission ID: MODEL1502090000
Submission Date: 09 Feb 2015 15:56:06 UTC
Last Modification Date: 20 Mar 2015 15:41:33 UTC
Creation Date: 19 Mar 2015 16:40:19 UTC
Encoders:  Audald Lloret i Villas
   Marcel Schilling
set #1
bqbiol:hasVersion Human Disease Ontology liver disease
set #2
bqbiol:isVersionOf Gene Ontology hepatocyte proliferation
set #3
bqbiol:hasTaxon Taxonomy Mus musculus
Notes
Mueller2015 - Hepatocyte proliferation, T160 phosphorylation of CDK2

This model is described in the article:

Mueller S, Huard J, Waldow K, Huang X, D'Alessandro LA, Bohl S, Börner K, Grimm D, Klamt S, Klingmüller U, Schilling M.
Mol. Syst. Biol. 2015; 11(3): 795

Abstract:

Liver regeneration is a tightly controlled process mainly achieved by proliferation of usually quiescent hepatocytes. The specific molecular mechanisms ensuring cell division only in response to proliferative signals such as hepatocyte growth factor (HGF) are not fully understood. Here, we combined quantitative time-resolved analysis of primary mouse hepatocyte proliferation at the single cell and at the population level with mathematical modeling. We showed that numerous G1/S transition components are activated upon hepatocyte isolation whereas DNA replication only occurs upon additional HGF stimulation. In response to HGF, Cyclin:CDK complex formation was increased, p21 rather than p27 was regulated, and Rb expression was enhanced. Quantification of protein levels at the restriction point showed an excess of CDK2 over CDK4 and limiting amounts of the transcription factor E2F-1. Analysis with our mathematical model revealed that T160 phosphorylation of CDK2 correlated best with growth factor-dependent proliferation, which we validated experimentally on both the population and the single cell level. In conclusion, we identified CDK2 phosphorylation as a gate-keeping mechanism to maintain hepatocyte quiescence in the absence of HGF.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 25771250 Submission Date: 09 Feb 2015 15:56:06 UTC Last Modification Date: 20 Mar 2015 15:41:33 UTC Creation Date: 19 Mar 2015 16:40:19 UTC
Mathematical expressions
Reactions
reaction_1 reaction_2 reaction_3 reaction_4
reaction_5 reaction_6 reaction_7 reaction_8
reaction_9 reaction_10 reaction_11 reaction_12
reaction_13 reaction_14 reaction_15 reaction_16
reaction_17 reaction_18 reaction_19 reaction_20
reaction_21 reaction_22 reaction_23 reaction_24
reaction_25 reaction_26 reaction_27 reaction_28
reaction_29 reaction_30 reaction_31 reaction_32
reaction_33 reaction_34 reaction_35 reaction_36
reaction_37 reaction_38 reaction_39 reaction_40
reaction_41 reaction_42 reaction_43 reaction_44
reaction_45 reaction_46 reaction_47 reaction_48
reaction_49 reaction_50 reaction_51 reaction_52
reaction_53 reaction_54 reaction_55 reaction_56
reaction_57 reaction_58 reaction_59 reaction_60
reaction_61 reaction_62 reaction_63 reaction_64
reaction_65 reaction_66 reaction_67 reaction_68
reaction_69      
Rules
Assignment Rule (variable: CDK2P21) Assignment Rule (variable: TotE2F) Assignment Rule (variable: HGF) Assignment Rule (variable: inhp53)
Assignment Rule (variable: inhERK) Assignment Rule (variable: inhAKT) Assignment Rule (variable: inhc4d1) Assignment Rule (variable: TotCycECDK2)
Assignment Rule (variable: TotCDK2T160) Assignment Rule (variable: TotCycDCDK4) Assignment Rule (variable: TotP21) Assignment Rule (variable: TotRb)
Assignment Rule (variable: PhosRbS788) Assignment Rule (variable: PhosRbS800) Assignment Rule (variable: DNAContent) Assignment Rule (variable: Vratio)
Assignment Rule (variable: erk) Assignment Rule (variable: akt) Assignment Rule (variable: gsk3b) Assignment Rule (variable: tf)
Assignment Rule (variable: tfp21) Assignment Rule (variable: kp_c2cak) Assignment Rule (variable: kd_p21c4) Assignment Rule (variable: kd_p21c2)
Assignment Rule (variable: kimport) Assignment Rule (variable: kdeg_e2ffree) Assignment Rule (variable: kdeg_rbfree) Assignment Rule (variable: kd_rbe2f)
Assignment Rule (variable: kd_rbpe2f) Assignment Rule (variable: kcatp_rbc4)    
Physical entities
Compartments Species
Cytoplasm @cyto::C2E(T160~U,b) @cyto::C4D1(b) @cyto::p21(b)
@cyto::C4D1(b!1).p21(b!1) @cyto::C2E(T160~U,b!1).p21(b!1) HGF
inhp53 inhERK inhAKT
inhc4d1    
Nucleus TotCycECDK2 TotCDK2T160 TotCycDCDK4
TotP21 CDK2P21 TotE2F
TotRb PhosRbS788 PhosRbS800
DNAContent @nuc::C2E(T160~P,b!1).p21(b!1) @nuc::C2E(T160~P,b)
@nuc::C2E(T160~U,b!1).p21(b!1) @nuc::C2E(T160~U,b) @nuc::C4D1(b!1).p21(b!1)
@nuc::C4D1(b) @nuc::dnapre() @nuc::dnapre1()
@nuc::dnapre2() @nuc::dnapre3() @nuc::dnapre4()
@nuc::e2f(b!1).rb(S788~P,S800~U,b!1) @nuc::e2f(b!1).rb(S788~U,S800~U,b!1) @nuc::e2f(b)
@nuc::p21(b) @nuc::rb(S788~P,S800~P,b) @nuc::rb(S788~P,S800~U,b)
@nuc::rb(S788~U,S800~U,b) @nuc::dnapre5()  
Global parameters
Vnuc Vcyto perk nerk
pakt nakt aerk aakt
atf ks_c4 kdeg_c4 kdeg_c4gsk3b
ks_c2myc ks_c2e2f kdeg_c2c2gsk3b kdeg_c2gsk3b
kdeg_c2 kdp_c2cak kc2cak ks_p21p53
ks_p21e2f kdeg_p21erkskp2 kdeg_p21c2skp2 kdeg_p21skp2
kdeg_p21gsk3b kdeg_p21erk Kd_p21c4 kb_p21c4
Kd_p21c2 kb_p21c2 ki kinh_p21akt
ks_e2fe2f ks_e2fmyc kdege2fplus kdeg_e2fbound
ks_rb ks_rbe2f kdeg_rbp21 kdeg_rbbound
kdegrbplus kb_rbe2f Kd_rb_e2f kb_rbpe2f
Kd_rbp_e2f kcatprbc4 kcatp_rbc2 kcatdp_rbc2
kcatdp_rbc4 kinh_pp1 Km_dprb Km_prb
nrb k_dna k_delay Vratio
erk akt gsk3b tf
tfp21 kp_c2cak kd_p21c4 kd_p21c2
kimport kdeg_e2ffree kdeg_rbfree kd_rbe2f
kd_rbpe2f kcatp_rbc4 scale_TotcycDCDK4 scale_TotcycECDK2
scale_Totp21CDK2 scale_TotCDK2T160 scale_TotRb scale_PhosRbS788
scale_PhosRbS800 scale_Totp21 scale_TotE2F  
Reactions (69)
 
 reaction_1  → [@cyto::C4D1(b)];  
 
 reaction_2  → [@cyto::C2E(T160~U,b)];   {@nuc::e2f(b)} , {@nuc::e2f(b!1).rb(S788~P,S800~U,b!1)}
 
 reaction_3 [@nuc::C2E(T160~U,b!1).p21(b!1)] → [@nuc::p21(b)];   {@nuc::C2E(T160~U,b!1).p21(b!1)}
 
 reaction_4 [@cyto::C2E(T160~U,b)] → ;   {@cyto::C2E(T160~U,b)}
 
 reaction_5  → [@cyto::p21(b)];   {@nuc::e2f(b)}
 
 reaction_6 [@nuc::C2E(T160~U,b!1).p21(b!1)] → [@nuc::p21(b)] + [@nuc::C2E(T160~U,b)];   {@nuc::C2E(T160~U,b!1).p21(b!1)}
 
 reaction_7 [@nuc::C2E(T160~U,b!1).p21(b!1)] → [@nuc::C2E(T160~U,b)];   {@nuc::C2E(T160~P,b)} , {@nuc::e2f(b)} , {@nuc::C2E(T160~U,b!1).p21(b!1)}
 
 reaction_8  → [@nuc::rb(S788~U,S800~U,b)];   {@nuc::e2f(b)}
 
 reaction_9 [@nuc::rb(S788~U,S800~U,b)] → ;   {@nuc::rb(S788~U,S800~U,b)}
 
 reaction_10 [@nuc::e2f(b!1).rb(S788~U,S800~U,b!1)] → [@nuc::e2f(b)];   {@nuc::e2f(b!1).rb(S788~U,S800~U,b!1)}
 
 reaction_11 [@nuc::rb(S788~U,S800~U,b)] → ;   {@nuc::p21(b)} , {@nuc::rb(S788~U,S800~U,b)}
 
 reaction_12 [@nuc::e2f(b!1).rb(S788~U,S800~U,b!1)] → [@nuc::e2f(b)];   {@nuc::p21(b)} , {@nuc::e2f(b!1).rb(S788~U,S800~U,b!1)}
 
 reaction_13  → [@nuc::e2f(b)];   {@nuc::e2f(b)}
 
 reaction_14 [@nuc::e2f(b!1).rb(S788~U,S800~U,b!1)] → [@nuc::rb(S788~U,S800~U,b)];   {@nuc::e2f(b!1).rb(S788~U,S800~U,b!1)}
 
 reaction_15 [@nuc::e2f(b!1).rb(S788~U,S800~U,b!1)] → [@nuc::rb(S788~U,S800~U,b)] + [@nuc::e2f(b)];   {@nuc::e2f(b!1).rb(S788~U,S800~U,b!1)}
 
 reaction_16 [@nuc::rb(S788~U,S800~U,b)] → [@nuc::rb(S788~P,S800~U,b)];   {@nuc::C4D1(b!1).p21(b!1)} , {@nuc::rb(S788~U,S800~U,b)}
 
 reaction_17 [@nuc::e2f(b!1).rb(S788~U,S800~U,b!1)] → [@nuc::e2f(b!1).rb(S788~P,S800~U,b!1)];   {@nuc::C4D1(b!1).p21(b!1)} , {@nuc::e2f(b!1).rb(S788~U,S800~U,b!1)}
 
 reaction_18 [@nuc::dnapre()] → [@nuc::dnapre1()];   {@nuc::C2E(T160~P,b)} , {@nuc::e2f(b)} , {@nuc::dnapre()}
 
 reaction_19 [@cyto::C4D1(b)] → ;   {@cyto::C4D1(b)}
 
 reaction_20 [@nuc::C2E(T160~U,b)] → ;   {@nuc::C2E(T160~U,b)}
 
 reaction_21 [@nuc::C2E(T160~U,b)] → [@nuc::C2E(T160~P,b)];   {@nuc::C2E(T160~U,b)}
 
 reaction_22 [@cyto::C4D1(b)] + [@cyto::p21(b)] → [@cyto::C4D1(b!1).p21(b!1)];   {@cyto::C4D1(b)} , {@cyto::p21(b)}
 
 reaction_23 [@cyto::C2E(T160~U,b)] + [@cyto::p21(b)] → [@cyto::C2E(T160~U,b!1).p21(b!1)];   {@cyto::C2E(T160~U,b)} , {@cyto::p21(b)}
 
 reaction_24 [@nuc::p21(b)] + [@nuc::C2E(T160~U,b)] → [@nuc::C2E(T160~U,b!1).p21(b!1)];   {@nuc::p21(b)} , {@nuc::C2E(T160~U,b)}
 
 reaction_25 [@cyto::p21(b)] → [@nuc::p21(b)];   {@cyto::p21(b)}
 
 reaction_26 [@cyto::p21(b)] ↔ ;   {@cyto::p21(b)}
 
 reaction_27 [@nuc::p21(b)] → ;   {@nuc::p21(b)}
 
 reaction_28 [@cyto::p21(b)] → ;   {@cyto::p21(b)}
 
 reaction_29 [@nuc::rb(S788~P,S800~U,b)] → ;   {@nuc::rb(S788~P,S800~U,b)}
 
 reaction_30 [@nuc::e2f(b!1).rb(S788~P,S800~U,b!1)] → [@nuc::e2f(b)];   {@nuc::e2f(b!1).rb(S788~P,S800~U,b!1)}
 
 reaction_31 [@nuc::rb(S788~P,S800~U,b)] → ;   {@nuc::p21(b)} , {@nuc::rb(S788~P,S800~U,b)}
 
 reaction_32 [@nuc::e2f(b!1).rb(S788~P,S800~U,b!1)] → [@nuc::e2f(b)];   {@nuc::p21(b)} , {@nuc::e2f(b!1).rb(S788~P,S800~U,b!1)}
 
 reaction_33 [@nuc::e2f(b)] → ;   {@nuc::e2f(b)}
 
 reaction_34 [@nuc::e2f(b!1).rb(S788~P,S800~U,b!1)] → [@nuc::rb(S788~P,S800~U,b)];   {@nuc::e2f(b!1).rb(S788~P,S800~U,b!1)}
 
 reaction_35 [@nuc::rb(S788~U,S800~U,b)] + [@nuc::e2f(b)] → [@nuc::e2f(b!1).rb(S788~U,S800~U,b!1)];   {@nuc::rb(S788~U,S800~U,b)} , {@nuc::e2f(b)}
 
 reaction_36 [@nuc::e2f(b)] + [@nuc::rb(S788~P,S800~U,b)] → [@nuc::e2f(b!1).rb(S788~P,S800~U,b!1)];   {@nuc::e2f(b)} , {@nuc::rb(S788~P,S800~U,b)}
 
 reaction_37 [@nuc::e2f(b!1).rb(S788~P,S800~U,b!1)] → [@nuc::e2f(b)] + [@nuc::rb(S788~P,S800~U,b)];   {@nuc::e2f(b!1).rb(S788~P,S800~U,b!1)}
 
 reaction_38 [@nuc::rb(S788~P,S800~U,b)] → [@nuc::rb(S788~P,S800~P,b)];   {@nuc::C2E(T160~P,b)} , {@nuc::rb(S788~P,S800~U,b)}
 
 reaction_39 [@nuc::e2f(b!1).rb(S788~P,S800~U,b!1)] → [@nuc::e2f(b)] + [@nuc::rb(S788~P,S800~P,b)];   {@nuc::C2E(T160~P,b)} , {@nuc::e2f(b!1).rb(S788~P,S800~U,b!1)}
 
 reaction_40 [@nuc::rb(S788~P,S800~U,b)] → [@nuc::rb(S788~U,S800~U,b)];   {@nuc::C2E(T160~P,b)} , {@nuc::rb(S788~P,S800~U,b)}
 
 reaction_41 [@nuc::e2f(b!1).rb(S788~P,S800~U,b!1)] → [@nuc::e2f(b!1).rb(S788~U,S800~U,b!1)];   {@nuc::C2E(T160~P,b)} , {@nuc::e2f(b!1).rb(S788~P,S800~U,b!1)}
 
 reaction_42 [@nuc::dnapre1()] → [@nuc::dnapre2()];   {@nuc::dnapre1()}
 
 reaction_43 [@cyto::C4D1(b!1).p21(b!1)] → [@cyto::p21(b)];   {@cyto::C4D1(b!1).p21(b!1)}
 
 reaction_44 [@nuc::C2E(T160~P,b)] → ;   {@nuc::C2E(T160~P,b)}
 
 reaction_45 [@cyto::C2E(T160~U,b!1).p21(b!1)] → [@cyto::p21(b)];   {@cyto::C2E(T160~U,b!1).p21(b!1)}
 
 reaction_46 [@nuc::C2E(T160~P,b)] → ;   {@nuc::C2E(T160~P,b)}
 
 reaction_47 [@nuc::C2E(T160~P,b)] → [@nuc::C2E(T160~U,b)];   {@nuc::C2E(T160~P,b)}
 
 reaction_48 [@cyto::C4D1(b!1).p21(b!1)] → [@cyto::C4D1(b)] + [@cyto::p21(b)];   {@cyto::C4D1(b!1).p21(b!1)}
 
 reaction_49 [@nuc::p21(b)] + [@nuc::C2E(T160~P,b)] → [@nuc::C2E(T160~P,b!1).p21(b!1)];   {@nuc::p21(b)} , {@nuc::C2E(T160~P,b)}
 
 reaction_50 [@cyto::C2E(T160~U,b!1).p21(b!1)] → [@cyto::C2E(T160~U,b)] + [@cyto::p21(b)];   {@cyto::C2E(T160~U,b!1).p21(b!1)}
 
 reaction_51 [@cyto::C4D1(b!1).p21(b!1)] → [@nuc::C4D1(b!1).p21(b!1)];   {@cyto::C4D1(b!1).p21(b!1)}
 
 reaction_52 [@cyto::C2E(T160~U,b!1).p21(b!1)] → [@nuc::C2E(T160~U,b!1).p21(b!1)];   {@cyto::C2E(T160~U,b!1).p21(b!1)}
 
 reaction_53 [@cyto::C4D1(b!1).p21(b!1)] ↔ ;   {@cyto::C4D1(b!1).p21(b!1)}
 
 reaction_54 [@cyto::C2E(T160~U,b!1).p21(b!1)] ↔ ;   {@cyto::C2E(T160~U,b!1).p21(b!1)}
 
 reaction_55 [@nuc::rb(S788~P,S800~P,b)] → ;   {@nuc::rb(S788~P,S800~P,b)}
 
 reaction_56 [@nuc::rb(S788~P,S800~P,b)] → ;   {@nuc::p21(b)} , {@nuc::rb(S788~P,S800~P,b)}
 
 reaction_57 [@nuc::rb(S788~P,S800~P,b)] → [@nuc::rb(S788~P,S800~U,b)];   {@nuc::C2E(T160~P,b)} , {@nuc::rb(S788~P,S800~P,b)}
 
 reaction_58 [@nuc::dnapre2()] → [@nuc::dnapre3()];   {@nuc::dnapre2()}
 
 reaction_59 [@nuc::C4D1(b!1).p21(b!1)] → ;   {@nuc::C4D1(b!1).p21(b!1)}
 
 reaction_60 [@nuc::C2E(T160~P,b!1).p21(b!1)] → [@nuc::p21(b)];   {@nuc::C2E(T160~P,b!1).p21(b!1)}
 
 reaction_61 [@nuc::C4D1(b!1).p21(b!1)] → [@nuc::p21(b)] + [@nuc::C4D1(b)];   {@nuc::C4D1(b!1).p21(b!1)}
 
 reaction_62 [@nuc::C2E(T160~P,b!1).p21(b!1)] → [@nuc::p21(b)] + [@nuc::C2E(T160~P,b)];   {@nuc::C2E(T160~P,b!1).p21(b!1)}
 
 reaction_63 [@nuc::C2E(T160~P,b!1).p21(b!1)] → [@nuc::C2E(T160~P,b)];   {@nuc::C2E(T160~P,b)} , {@nuc::e2f(b)} , {@nuc::C2E(T160~P,b!1).p21(b!1)}
 
 reaction_64 [@nuc::C4D1(b!1).p21(b!1)] → [@nuc::C4D1(b)];   {@nuc::C2E(T160~P,b)} , {@nuc::e2f(b)} , {@nuc::C4D1(b!1).p21(b!1)}
 
 reaction_65 [@nuc::dnapre3()] → [@nuc::dnapre4()];   {@nuc::dnapre3()}
 
 reaction_66 [@nuc::C4D1(b)] → ;   {@nuc::C4D1(b)}
 
 reaction_67 [@nuc::p21(b)] + [@nuc::C4D1(b)] → [@nuc::C4D1(b!1).p21(b!1)];   {@nuc::p21(b)} , {@nuc::C4D1(b)}
 
 reaction_68 [@nuc::dnapre4()] → [@nuc::dnapre5()];   {@nuc::dnapre4()}
 
 reaction_69 [@nuc::dnapre5()] → ;   {@nuc::dnapre5()}
 
Rules (30)
 
 Assignment Rule (name: ObsCDK2P21_obs) CDK2P21 = scale_Totp21CDK2*(Vnuc*(S3+S23)+Vcyto*S20)/(Vnuc+Vcyto)
 
 Assignment Rule (name: ObsTotE2F_obs) TotE2F = (scale_TotE2F+scale_TotRb)*Vnuc*(S2+S14+S16)/(Vnuc+Vcyto)
 
 Assignment Rule (name: hgf) HGF = piecewise(0, (time < (-1)), piecewise(0, (time < 24), 1))
 
 Assignment Rule (name: inhp53) inhp53 = piecewise(0, (time < (-1)), piecewise(0, (time < 0), 0))
 
 Assignment Rule (name: inherk) inhERK = piecewise(0, (time < (-1)), piecewise(0, (time < 0), 0))
 
 Assignment Rule (name: inhakt) inhAKT = piecewise(0, (time < (-1)), piecewise(0, (time < 0), 0))
 
 Assignment Rule (name: inhc4d1) inhc4d1 = piecewise(0, (time < (-1)), piecewise(0, (time < 0), 0))
 
 Assignment Rule (name: ObsTotCycECDK2_obs) TotCycECDK2 = scale_TotcycECDK2*(Vnuc*(S3+S13+S18+S23)+Vcyto*(S4+S20))/(Vnuc+Vcyto)
 
 Assignment Rule (name: ObsTotCDK2T160_obs) TotCDK2T160 = scale_TotCDK2T160*Vnuc*(S18+S23)/(Vnuc+Vcyto)
 
 Assignment Rule (name: ObsTotCycDCDK4_obs) TotCycDCDK4 = scale_TotcycDCDK4*(Vnuc*S24+Vcyto*S19)/(Vnuc+Vcyto)
 
 Assignment Rule (name: ObsTotP21_obs) TotP21 = scale_Totp21*(Vnuc*(S3+S11+S23+S24)+Vcyto*(S12+S19+S20))/(Vnuc+Vcyto)
 
 Assignment Rule (name: ObsTotRb_obs) TotRb = scale_TotRb*Vnuc*(S1+S2+S15+S16+S21)/(Vnuc+Vcyto)
 
 Assignment Rule (name: ObsPhosRbS788_obs) PhosRbS788 = scale_PhosRbS788*Vnuc*(S15+S16+S21)/(Vnuc+Vcyto)
 
 Assignment Rule (name: ObsPhosRbS800_obs) PhosRbS800 = scale_PhosRbS800*Vnuc*S21/(Vnuc+Vcyto)
 
 Assignment Rule (name: ObsDNAContent_obs) DNAContent = 2-(S5+S17+S22+S25+S27+S28)
 
 Assignment Rule (name: Vratio) Vratio = Vnuc/Vcyto
 
 Assignment Rule (name: erk) erk = (1-inherk)*((1-aerk)*(perk^nerk+1)*hgf^nerk/(hgf^nerk+perk^nerk)+aerk)
 
 Assignment Rule (name: akt) akt = (1-inhakt)*((1-aakt)*(pakt^nakt+1)*hgf^nakt/(hgf^nakt+pakt^nakt)+aakt)
 
 Assignment Rule (name: gsk3b) gsk3b = 1-akt
 
 Assignment Rule (name: tf) tf = (1-atf)*erk*(1-gsk3b)+atf
 
 Assignment Rule (name: tfp21) tfp21 = (1-inhp53)*tf
 
 Assignment Rule (name: kp_c2cak) kp_c2cak = kdp_c2cak+kc2cak
 
 Assignment Rule (name: kd_p21c4) kd_p21c4 = Kd_p21c4*kb_p21c4
 
 Assignment Rule (name: kd_p21c2) kd_p21c2 = Kd_p21c2*kb_p21c2
 
 Assignment Rule (name: kimport) kimport = ki/(1+kinh_p21akt*akt)
 
 Assignment Rule (name: kdeg_e2ffree) kdeg_e2ffree = kdeg_e2fbound+kdege2fplus
 
 Assignment Rule (name: kdeg_rbfree) kdeg_rbfree = kdeg_rbbound+kdegrbplus
 
 Assignment Rule (name: kd_rbe2f) kd_rbe2f = kb_rbe2f*Kd_rb_e2f
 
 Assignment Rule (name: kd_rbpe2f) kd_rbpe2f = kb_rbpe2f*Kd_rbp_e2f
 
 Assignment Rule (name: kcatp_rbc4) kcatp_rbc4 = kcatprbc4*(1-inhc4d1)
 
Functions (69)
 
 Function for reaction_1 lambda(cell, ks_c4, tf, ks_c4*tf/cell)
 
 Function for reaction_2 lambda(S14, S16, cell, ks_c2e2f, ks_c2myc, tf, (ks_c2myc*tf+ks_c2e2f*(S14+S16))/cell)
 
 Function for reaction_58 lambda(S22, cell, k_delay, k_delay*S22/cell)
 
 Function for reaction_59 lambda(S24, cell, kdeg_c4, kdeg_c4*S24/cell)
 
 Function for reaction_3 lambda(S3, cell, gsk3b, kdeg_c2, kdeg_c2gsk3b, (kdeg_c2+kdeg_c2gsk3b*gsk3b)*S3/cell)
 
 Function for reaction_4 lambda(S4, cell, gsk3b, kdeg_c2, kdeg_c2gsk3b, (kdeg_c2+kdeg_c2gsk3b*gsk3b)*S4/cell)
 
 Function for reaction_5 lambda(S14, cell, ks_p21e2f, ks_p21p53, tfp21, (ks_p21p53+ks_p21e2f*S14)*tfp21/cell)
 
 Function for reaction_6 lambda(S3, cell, kd_p21c2, kd_p21c2*S3/cell)
 
 Function for reaction_7 lambda(S14, S18, S3, cell, erk, kdeg_p21c2skp2, kdeg_p21erkskp2, kdeg_p21skp2, (kdeg_p21erkskp2*erk+kdeg_p21c2skp2*S18+kdeg_p21skp2)*S14*S3/cell)
 
 Function for reaction_8 lambda(S14, cell, ks_rb, ks_rbe2f, (ks_rb+ks_rbe2f*S14)/cell)
 
 Function for reaction_9 lambda(S1, cell, kdeg_rbfree, kdeg_rbfree*S1/cell)
 
 Function for reaction_10 lambda(S2, cell, kdeg_rbbound, kdeg_rbbound*S2/cell)
 
 Function for reaction_11 lambda(S1, S11, cell, kdeg_rbp21, kdeg_rbp21*S11*S1/cell)
 
 Function for reaction_12 lambda(S11, S2, cell, kdeg_rbp21, kdeg_rbp21*S11*S2/cell)
 
 Function for reaction_13 lambda(S14, cell, ks_e2fe2f, ks_e2fmyc, tf, (ks_e2fe2f*S14+ks_e2fmyc)*tf/cell)
 
 Function for reaction_14 lambda(S2, cell, kdeg_e2fbound, kdeg_e2fbound*S2/cell)
 
 Function for reaction_15 lambda(S2, cell, kd_rbe2f, kd_rbe2f*S2/cell)
 
 Function for reaction_16 lambda(Km_prb, S1, S24, cell, kcatp_rbc4, nrb, kcatp_rbc4*S24*S1^nrb/(Km_prb^nrb+S1^nrb)/cell)
 
 Function for reaction_17 lambda(Km_prb, S2, S24, cell, kcatp_rbc4, nrb, kcatp_rbc4*S24*S2^nrb/(Km_prb^nrb+S2^nrb)/cell)
 
 Function for reaction_18 lambda(S14, S18, S5, cell, k_dna, k_dna*S18*S14*S5/cell)
 
 Function for reaction_19 lambda(S10, cell, gsk3b, kdeg_c4, kdeg_c4gsk3b, (kdeg_c4+kdeg_c4gsk3b*gsk3b)*S10/cell)
 
 Function for reaction_20 lambda(S13, cell, gsk3b, kdeg_c2, kdeg_c2gsk3b, (kdeg_c2+kdeg_c2gsk3b*gsk3b)*S13/cell)
 
 Function for reaction_21 lambda(S13, cell, kp_c2cak, kp_c2cak*S13/cell)
 
 Function for reaction_22 lambda(S10, S12, cell, kb_p21c4, kb_p21c4*S10*S12/cell)
 
 Function for reaction_23 lambda(S12, S4, cell, kb_p21c2, kb_p21c2*S4*S12/cell)
 
 Function for reaction_24 lambda(S11, S13, cell, kb_p21c2, kb_p21c2*S11*S13/cell)
 
 Function for reaction_25 lambda(S12, Vratio, cell, kimport, kimport/Vratio*S12/cell)
 
 Function for reaction_26 lambda(S12, Vratio, cell, kimport, kimport*(1-1/Vratio)*S12/cell)
 
 Function for reaction_27 lambda(S11, cell, erk, gsk3b, kdeg_p21erk, kdeg_p21gsk3b, (kdeg_p21gsk3b*gsk3b+kdeg_p21erk*erk)*S11/cell)
 
 Function for reaction_28 lambda(S12, cell, erk, gsk3b, kdeg_p21erk, kdeg_p21gsk3b, (kdeg_p21gsk3b*gsk3b+kdeg_p21erk*erk)*S12/cell)
 
 Function for reaction_29 lambda(S15, cell, kdeg_rbfree, kdeg_rbfree*S15/cell)
 
 Function for reaction_30 lambda(S16, cell, kdeg_rbbound, kdeg_rbbound*S16/cell)
 
 Function for reaction_31 lambda(S11, S15, cell, kdeg_rbp21, kdeg_rbp21*S11*S15/cell)
 
 Function for reaction_32 lambda(S11, S16, cell, kdeg_rbp21, kdeg_rbp21*S11*S16/cell)
 
 Function for reaction_33 lambda(S14, cell, kdeg_e2ffree, kdeg_e2ffree*S14/cell)
 
 Function for reaction_34 lambda(S16, cell, kdeg_e2fbound, kdeg_e2fbound*S16/cell)
 
 Function for reaction_35 lambda(S1, S14, cell, kb_rbe2f, kb_rbe2f*S1*S14/cell)
 
 Function for reaction_36 lambda(S14, S15, cell, kb_rbpe2f, kb_rbpe2f*S14*S15/cell)
 
 Function for reaction_37 lambda(S16, cell, kd_rbpe2f, kd_rbpe2f*S16/cell)
 
 Function for reaction_38 lambda(Km_prb, S15, S18, cell, kcatp_rbc2, nrb, kcatp_rbc2*S18*S15^nrb/(Km_prb^nrb+S15^nrb)/cell)
 
 Function for reaction_39 lambda(Km_prb, S16, S18, cell, kcatp_rbc2, nrb, kcatp_rbc2*S18*S16^nrb/(Km_prb^nrb+S16^nrb)/cell)
 
 Function for reaction_40 lambda(Km_dprb, S15, S18, cell, kcatdp_rbc4, kinh_pp1, nrb, kcatdp_rbc4*S15^nrb/(Km_dprb^nrb+S15^nrb)*1/(1+kinh_pp1*S18)/cell)
 
 Function for reaction_41 lambda(Km_dprb, S16, S18, cell, kcatdp_rbc4, kinh_pp1, nrb, kcatdp_rbc4*S16^nrb/(Km_dprb^nrb+S16^nrb)*1/(1+kinh_pp1*S18)/cell)
 
 Function for reaction_42 lambda(S17, cell, k_delay, k_delay*S17/cell)
 
 Function for reaction_43 lambda(S19, cell, gsk3b, kdeg_c4, kdeg_c4gsk3b, (kdeg_c4+kdeg_c4gsk3b*gsk3b)*S19/cell)
 
 Function for reaction_44 lambda(S18, cell, gsk3b, kdeg_c2, kdeg_c2gsk3b, (kdeg_c2+kdeg_c2gsk3b*gsk3b)*S18/cell)
 
 Function for reaction_45 lambda(S20, cell, gsk3b, kdeg_c2, kdeg_c2gsk3b, (kdeg_c2+kdeg_c2gsk3b*gsk3b)*S20/cell)
 
 Function for reaction_46 lambda(S18, cell, gsk3b, kdeg_c2c2gsk3b, kdeg_c2c2gsk3b*gsk3b*S18/cell)
 
 Function for reaction_47 lambda(S18, cell, kdp_c2cak, kdp_c2cak*S18/cell)
 
 Function for reaction_48 lambda(S19, cell, kd_p21c4, kd_p21c4*S19/cell)
 
 Function for reaction_49 lambda(S11, S18, cell, kb_p21c2, kb_p21c2*S11*S18/cell)
 
 Function for reaction_50 lambda(S20, cell, kd_p21c2, kd_p21c2*S20/cell)
 
 Function for reaction_51 lambda(S19, Vratio, cell, kimport, kimport/Vratio*S19/cell)
 
 Function for reaction_52 lambda(S20, Vratio, cell, kimport, kimport/Vratio*S20/cell)
 
 Function for reaction_53 lambda(S19, Vratio, cell, kimport, kimport*(1-1/Vratio)*S19/cell)
 
 Function for reaction_54 lambda(S20, Vratio, cell, kimport, kimport*(1-1/Vratio)*S20/cell)
 
 Function for reaction_55 lambda(S21, cell, kdeg_rbfree, kdeg_rbfree*S21/cell)
 
 Function for reaction_56 lambda(S11, S21, cell, kdeg_rbp21, kdeg_rbp21*S11*S21/cell)
 
 Function for reaction_57 lambda(Km_dprb, S18, S21, cell, kcatdp_rbc2, kinh_pp1, nrb, kcatdp_rbc2*S21^nrb/(Km_dprb^nrb+S21^nrb)*1/(1+kinh_pp1*S18)/cell)
 
 Function for reaction_60 lambda(S23, cell, gsk3b, kdeg_c2, kdeg_c2gsk3b, (kdeg_c2+kdeg_c2gsk3b*gsk3b)*S23/cell)
 
 Function for reaction_61 lambda(S24, cell, kd_p21c4, kd_p21c4*S24/cell)
 
 Function for reaction_62 lambda(S23, cell, kd_p21c2, kd_p21c2*S23/cell)
 
 Function for reaction_63 lambda(S14, S18, S23, cell, erk, kdeg_p21c2skp2, kdeg_p21erkskp2, kdeg_p21skp2, (kdeg_p21erkskp2*erk+kdeg_p21c2skp2*S18+kdeg_p21skp2)*S14*S23/cell)
 
 Function for reaction_64 lambda(S14, S18, S24, cell, erk, kdeg_p21c2skp2, kdeg_p21erkskp2, kdeg_p21skp2, (kdeg_p21erkskp2*erk+kdeg_p21c2skp2*S18+kdeg_p21skp2)*S14*S24/cell)
 
 Function for reaction_65 lambda(S25, cell, k_delay, k_delay*S25/cell)
 
 Function for reaction_66 lambda(S26, cell, gsk3b, kdeg_c4, kdeg_c4gsk3b, (kdeg_c4+kdeg_c4gsk3b*gsk3b)*S26/cell)
 
 Function for reaction_67 lambda(S11, S26, cell, kb_p21c4, kb_p21c4*S11*S26/cell)
 
 Function for reaction_68 lambda(S27, cell, k_delay, k_delay*S27/cell)
 
 Function for reaction_69 lambda(S28, cell, k_delay, k_delay*S28/cell)
 
 Cytoplasm Spatial dimensions: 3.0  Compartment size: 1.0
 
 @cyto::C2E(T160~U,b)
Compartment: Cytoplasm
Initial concentration: 0.415
 
 @cyto::C4D1(b)
Compartment: Cytoplasm
Initial concentration: 0.0
 
 @cyto::p21(b)
Compartment: Cytoplasm
Initial concentration: 0.0
 
 @cyto::C4D1(b!1).p21(b!1)
Compartment: Cytoplasm
Initial concentration: 0.0
 
 @cyto::C2E(T160~U,b!1).p21(b!1)
Compartment: Cytoplasm
Initial concentration: 0.0
 
  HGF
Compartment: Cytoplasm
Initial concentration: 0.0
 
  inhp53
Compartment: Cytoplasm
Initial concentration: 0.0
 
  inhERK
Compartment: Cytoplasm
Initial concentration: 0.0
 
  inhAKT
Compartment: Cytoplasm
Initial concentration: 0.0
 
  inhc4d1
Compartment: Cytoplasm
Initial concentration: 0.0
 
 Nucleus Spatial dimensions: 3.0  Compartment size: 1.0
 
  TotCycECDK2
Compartment: Nucleus
Initial concentration: 0.099620260255418
 
  TotCDK2T160
Compartment: Nucleus
Initial concentration: 0.0
 
  TotCycDCDK4
Compartment: Nucleus
Initial concentration: 0.0
 
  TotP21
Compartment: Nucleus
Initial concentration: 0.020805213622291
 
  CDK2P21
Compartment: Nucleus
Initial concentration: 0.0409109861876772
 
  TotE2F
Compartment: Nucleus
Initial concentration: 0.0337275199303406
 
  TotRb
Compartment: Nucleus
Initial concentration: 0.129299840363777
 
  PhosRbS788
Compartment: Nucleus
Initial concentration: 0.0
 
  PhosRbS800
Compartment: Nucleus
Initial concentration: 0.0
 
  DNAContent
Compartment: Nucleus
Initial concentration: 1.0
 
 @nuc::C2E(T160~P,b!1).p21(b!1)
Compartment: Nucleus
Initial concentration: 0.0
 
 @nuc::C2E(T160~P,b)
Compartment: Nucleus
Initial concentration: 0.0
 
 @nuc::C2E(T160~U,b!1).p21(b!1)
Compartment: Nucleus
Initial concentration: 6.2223
 
 @nuc::C2E(T160~U,b)
Compartment: Nucleus
Initial concentration: 0.0
 
 @nuc::C4D1(b!1).p21(b!1)
Compartment: Nucleus
Initial concentration: 0.0
 
 @nuc::C4D1(b)
Compartment: Nucleus
Initial concentration: 0.0
 
 @nuc::dnapre()
Compartment: Nucleus
Initial concentration: 1.0
 
 @nuc::dnapre1()
Compartment: Nucleus
Initial concentration: 0.0
 
 @nuc::dnapre2()
Compartment: Nucleus
Initial concentration: 0.0
 
 @nuc::dnapre3()
Compartment: Nucleus
Initial concentration: 0.0
 
 @nuc::dnapre4()
Compartment: Nucleus
Initial concentration: 0.0
 
 @nuc::e2f(b!1).rb(S788~P,S800~U,b!1)
Compartment: Nucleus
Initial concentration: 0.0
 
 @nuc::e2f(b!1).rb(S788~U,S800~U,b!1)
Compartment: Nucleus
Initial concentration: 0.0601
 
 @nuc::e2f(b)
Compartment: Nucleus
Initial concentration: 0.0
 
 @nuc::p21(b)
Compartment: Nucleus
Initial concentration: 0.0
 
 @nuc::rb(S788~P,S800~P,b)
Compartment: Nucleus
Initial concentration: 0.0
 
 @nuc::rb(S788~P,S800~U,b)
Compartment: Nucleus
Initial concentration: 0.0
 
 @nuc::rb(S788~U,S800~U,b)
Compartment: Nucleus
Initial concentration: 25.5914
 
 @nuc::dnapre5()
Compartment: Nucleus
Initial concentration: 0.0
 
Global Parameters (79)
 
   Vnuc
Value: 0.25
Constant
 
   Vcyto
Value: 12.67
Constant
 
   perk
Value: 0.00857314138104046
Constant
 
   nerk
Value: 1.14663416967514
Constant
 
   pakt
Value: 0.0348
Constant
 
   nakt
Value: 1.0957
Constant
 
   aerk
Value: 0.16
Constant
 
   aakt
Value: 0.53
Constant
 
   atf
Value: 0.601288203846636
Constant
 
   ks_c4
Value: 14298.6715905912
Constant
 
   kdeg_c4
Value: 1.01433121526038
Constant
 
   kdeg_c4gsk3b
Value: 0.107637073030656
Constant
 
   ks_c2myc
Value: 0.157511710670132
Constant
 
   ks_c2e2f
Value: 2.19944932286058
Constant
 
   kdeg_c2c2gsk3b
Value: 5.58835572681068
Constant
 
   kdeg_c2gsk3b
Value: 1.55090179808215E-5
Constant
 
   kdeg_c2
Value: 0.225746618767114
Constant
 
   kdp_c2cak
Value: 101.282119534273
Constant
 
   kc2cak
Value: 0.316993285134466
Constant
 
   ks_p21p53
Value: 3.84136205729286E-6
Constant
 
   ks_p21e2f
Value: 0.811617200647839
Constant
 
   kdeg_p21erkskp2
Value: 2.82976267377082E-4
Constant
 
   kdeg_p21c2skp2
Value: 0.040108041739907
Constant
 
   kdeg_p21skp2
Value: 0.750574831653576
Constant
 
   kdeg_p21gsk3b
Value: 0.00464010657330714
Constant
 
   kdeg_p21erk
Value: 0.736488746268804
Constant
 
   Kd_p21c4
Value: 99.9965429570432
Constant
 
   kb_p21c4
Value: 14.3083360067931
Constant
 
   Kd_p21c2
Value: 0.0100024233821379
Constant
 
   kb_p21c2
Value: 997.938141166465
Constant
 
   ki
Value: 0.0918326575000322
Constant
 
   kinh_p21akt
Value: 0.439662894183616
Constant
 
   ks_e2fe2f
Value: 0.459601740303536
Constant
 
   ks_e2fmyc
Value: 2.49174531457788E-6
Constant
 
   kdege2fplus
Value: 4.18153340918872E-5
Constant
 
   kdeg_e2fbound
Value: 0.0999954023364359
Constant
 
   ks_rb
Value: 72.5245257602228
Constant
 
   ks_rbe2f
Value: 20.0129834334888
Constant
 
   kdeg_rbp21
Value: 0.863570809432207
Constant
 
   kdeg_rbbound
Value: 0.0889964132806627
Constant
 
   kdegrbplus
Value: 0.257763482477731
Constant
 
   kb_rbe2f
Value: 229.976400323907
Constant
 
   Kd_rb_e2f
Value: 50.002528361226
Constant
 
   kb_rbpe2f
Value: 182.218452288549
Constant
 
   Kd_rbp_e2f
Value: 481.484530572552
Constant
 
   kcatprbc4
Value: 2797.82326282727
Constant
 
   kcatp_rbc2
Value: 7142308.07232621
Constant
 
   kcatdp_rbc2
Value: 0.00313841707547858
Constant
 
   kcatdp_rbc4
Value: 2892.0219338341
Constant
 
   kinh_pp1
Value: 16634.9400020267
Constant
 
   Km_dprb
Value: 0.118988383643671
Constant
 
   Km_prb
Value: 2.03458881189349
Constant
 
   nrb
Value: 3.0
Constant
 
   k_dna
Value: 0.00949790539669408
Constant
 
   k_delay
Value: 23.6658781343201
Constant
 
   Vratio
Value: 0.0197316495659037
 
   erk
Value: 0.16
 
   akt
Value: 0.53
 
   gsk3b
Value: 0.47
 
   tf
Value: 0.635098964160441
 
   tfp21
Value: 0.635098964160441
 
   kp_c2cak
Value: 101.599112819407
 
   kd_p21c4
Value: 1430.78413614709
 
   kd_p21c2
Value: 9.98179979713068
 
   kimport
Value: 0.0744777523096695
 
   kdeg_e2ffree
Value: 0.100037217670528
 
   kdeg_rbfree
Value: 0.346759895758394
 
   kd_rbe2f
Value: 11499.4014796088
 
   kd_rbpe2f
Value: 87735.365961809
 
   kcatp_rbc4
Value: 2797.82326282727
 
   scale_TotcycDCDK4
Value: 0.5651
Constant
 
   scale_TotcycECDK2
Value: 0.1889
Constant
 
   scale_Totp21CDK2
Value: 0.339790715037712
Constant
 
   scale_TotCDK2T160
Value: 2.728395741944
Constant
 
   scale_TotRb
Value: 0.2605
Constant
 
   scale_PhosRbS788
Value: 0.673907327042472
Constant
 
   scale_PhosRbS800
Value: 0.82377467648995
Constant
 
   scale_Totp21
Value: 0.1728
Constant
 
   scale_TotE2F
Value: 28.7418
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000568

Curator's comment: (updated: 11 May 2015 16:24:10 GMT)

Figure 4 of the reference publication has been reproduced here. The model describes the dynamics of cell cycle proteins in HGF-stimulated primary mouse hepatocytes. The curves correspond to blue lines (Model 40 ng/ml HGF) from A to J.
"DNA Content (f.c)" label in Y-axis is used uniquely in panel J while "Signal Intensity (a.u.)" is used for the rest of panels (A-I).

The simulation was done using Copasi v4.14 (Build 89) and the plots were generated using Gnuplot. The Copasi file of the model with simulation settings can be downloaded from the below link:

Additional file(s)
  • Mueller2015 - Hepatocyte proliferation, T160 phosphorylation of CDK2:
    PottersWheel file of the model, matlab format
  • Mueller2015 - Hepatocyte proliferation, T160 phosphorylation of CDK2:
    Copasi file of the model
spacer
spacer