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BIOMD0000000223 - Borisov2009_EGF_Insulin_Crosstalk

 

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Reference Publication
Publication ID: 19357636
Borisov N, Aksamitiene E, Kiyatkin A, Legewie S, Berkhout J, Maiwald T, Kaimachnikov NP, Timmer J, Hoek JB, Kholodenko BN.
Systems-level interactions between insulin-EGF networks amplify mitogenic signaling.
Mol. Syst. Biol. 2009; 5: 256
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.  [more]
Model
Original Model: BIOMD0000000223.origin
Submitter: Nicolas Le Novère
Submission ID: MODEL6194251662
Submission Date: 28 Jun 2009 14:04:15 UTC
Last Modification Date: 28 May 2014 00:41:56 UTC
Creation Date: 09 Jul 2009 11:00:31 UTC
Encoders:  Lukas Endler
   Nikolay Borisov
set #1
bqmodel:isDerivedFrom BioModels Database Markevich2004_MAPK_orderedMM2kinases
BioModels Database Markevich2004_MAPK_AllRandomElementary
BioModels Database Markevich2004_MAPK_phosphoRandomMM
BioModels Database Markevich2004_MAPK_phosphoRandomElementary
BioModels Database Markevich2004_MAPK_orderedMM
BioModels Database Markevich2004_MAPK_orderedElementary
BioModels Database Hatakeyama2003_MAPK
BioModels Database Kholodenko1999 - EGFR signaling
PubMed 17052120
set #2
bqbiol:isVersionOf Gene Ontology positive regulation of mitotic nuclear division
set #3
bqbiol:hasVersion KEGG Pathway Insulin signaling pathway - Homo sapiens (human)
KEGG Pathway ErbB signaling pathway - Homo sapiens (human)
bqbiol:hasTaxon Taxonomy Homo sapiens
set #4
bqbiol:hasVersion Reactome REACT_498
Reactome REACT_9417
Notes

described in: Systems-level interactions between insulin-EGF networks amplify mitogenic signaling.
Borisov N, Aksamitiene E, Kiyatkin A, Legewie S, Berkhout J, Maiwald T, Kaimachnikov NP, Timmer J, Hoek JB, Kholodenko BN.;Mol Syst Biol. 2009;5:256. Epub 2009 Apr 7. PMID:19357636; doi:10.1038/msb.2009.19
Abstract:
Crosstalk mechanisms have not been studied as thoroughly as individual signaling pathways. We exploit experimental and computational approaches to reveal how a concordant interplay between the insulin and epidermal growth factor (EGF) signaling networks can potentiate mitogenic signaling. In HEK293 cells, insulin is a poor activator of the Ras/ERK (extracellular signal-regulated kinase) cascade, yet it enhances ERK activation by low EGF doses. We find that major crosstalk mechanisms that amplify ERK signaling are localized upstream of Ras and at the Ras/Raf level. Computational modeling unveils how critical network nodes, the adaptor proteins GAB1 and insulin receptor substrate (IRS), Src kinase, and phosphatase SHP2, convert insulin-induced increase in the phosphatidylinositol-3,4,5-triphosphate (PIP(3)) concentration into enhanced Ras/ERK activity. The model predicts and experiments confirm that insulin-induced amplification of mitogenic signaling is abolished by disrupting PIP(3)-mediated positive feedback via GAB1 and IRS. We demonstrate that GAB1 behaves as a non-linear amplifier of mitogenic responses and insulin endows EGF signaling with robustness to GAB1 suppression. Our results show the feasibility of using computational models to identify key target combinations and predict complex cellular responses to a mixture of external cues.

An extracellular compartment with 34 times the volume of the cell was added and the association rate as well as the dissociation constants for Insulin and EGF binding were altered (kon'=34*kon, KD'=KD/34). This was done to allow using the concentrations for those species given in the article and retaining the same dynamics and Ligand depletion as in the matlab file the SBML file was exported from.

SBML model exported from PottersWheel on 2008-10-14 16:26:44.

This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
For more information see the terms of use.
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Model
Publication ID: 19357636 Submission Date: 28 Jun 2009 14:04:15 UTC Last Modification Date: 28 May 2014 00:41:56 UTC Creation Date: 09 Jul 2009 11:00:31 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_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_34 reaction_35 reaction_36 reaction_37
reaction_38 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 reaction_70
reaction_71 reaction_72 reaction_73 reaction_74
reaction_75 reaction_76 reaction_77 reaction_78
reaction_79 reaction_80 reaction_81 reaction_82
reaction_83 reaction_84 reaction_85 reaction_88
reaction_89 reaction_90 reaction_91 reaction_92
reaction_93 reaction_94 reaction_95 reaction_96
reaction_97 reaction_98 reaction_99 reaction_100
reaction_101 reaction_102 reaction_103 reaction_104
reaction_105 reaction_106 reaction_107 reaction_108
reaction_109 reaction_110 reaction_111 reaction_112
reaction_113 reaction_114 reaction_115 reaction_117
reaction_118      
Rules
Assignment Rule (variable: phosphorylated_Akt) Assignment Rule (variable: EGF_tot) Assignment Rule (variable: k_1) Assignment Rule (variable: k_2)
Assignment Rule (variable: k_4) Assignment Rule (variable: k_5) Assignment Rule (variable: k_7) Assignment Rule (variable: k_9)
Assignment Rule (variable: k_10) Assignment Rule (variable: k_11) Assignment Rule (variable: k11) Assignment Rule (variable: k_12)
Assignment Rule (variable: k_13) Assignment Rule (variable: k_24) Assignment Rule (variable: k_26) Assignment Rule (variable: k_27)
Assignment Rule (variable: k_28) Assignment Rule (variable: k_30) Assignment Rule (variable: k_42) Assignment Rule (variable: k_45)
Assignment Rule (variable: k_46) Assignment Rule (variable: k_47) Assignment Rule (variable: k_49) Assignment Rule (variable: k_52)
Assignment Rule (variable: k_53) Assignment Rule (variable: k_54) Assignment Rule (variable: k_55) Assignment Rule (variable: k_59)
Assignment Rule (variable: k_74)      
Physical entities
Compartments Species
cell RE Rd Rp
GS Rp_GS Shc
Rp_Shc Rp_pShc pShc
Rp_pShc_GS PI3K Rp_PI3K
RasGAP Rp_RasGAP IRL
IRp IRp_PI3K IRp_RasGAP
IRS IRp_IRS IRp_IRSp
IRSp iSrc mIRS
mIRSp mIRSp_GS mIRSp_PI3K
SHP2 mIRSp_SHP2 GAB
mGAB mGABp mGABp_GS
mGABp_PI3K mGABp_SHP2 mGABp_pSHP2
PIP3 dRas Raf
aRaf Mek Erk
pErk PDK1 Akt
pAkt mTOR Null
aaRaf PKA pShc_GS
ppMek mGABp_pSHP2_GS R
ppErk IR mPDK1
tRas tRas_PI3K ppAkt
mGABp_RasGAP amTOR iGS
imGAB imIRS aSrc
Ri IRi iPX
aPX aPX_GS IRSp_PI3K
IRSp_GS IRSp_SHP2 GABp
GABp_PI3K GABp_GS GABp_RasGAP
GABp_SHP2 GABp_pSHP2 GABp_pSHP2_GS
imGABp bRasGAP phosphorylated_Akt
extracellular space EGF I  
Global parameters
EGF_tot k1 Kd1 k2
Kd2 k3 k4 Kd4
Kd5 k5 k6 k7
Kd7 V8 Km8 Kd9
k9 Kd10 k10 k11
k12 Kd12 k13 Kd13
k17 k24 Kd24 k25
k26 Kd26 k27 Kd27
k28 Kd28 k29 k30
Kd30 V31 Km31 kcat40
Km40 alpha40 V41 Km41
k42 Kd42 kcat43 Km43
alpha43 Kd45 k45 k46
Kd46 k47 Kd47 k48
k49 Kd49 kcat50 alpha50
Km50 V51 Km51 k52
Kd52 k53 Kd53 k54
Kd54 k55 Kd55 k56
kcat57 Km57 V58 Km58
k59 Kd59 k60 k61
kcat62 Km62 kcat63 Km63
k64 k_64 kcat65 Km65
kcat66 Km66 kcat67 Km67
alpha67 beta67 kcat68 Km68
V69 Km69 kcat70 Km70
kcat71 Km71 V72 Km72
V73 Km73 k74 Kd74
kcat75 Km75 V76 Km76
kcat77 alpha77 Km77 k_77
kcat78 Km78 k_78 kcat79
Km79 k_79 kcat80 Km80
k_80 kcat81 Km81 k_81
V_82 Km82 k83 V_84
Km84 k85 k111 k118
k_1 k_2 k_4 k_5
k_7 k_9 k_10 k_11
k_12 k_13 k_24 k_26
k_27 k_28 k_30 k_42
k_45 k_46 k_47 k_49
k_52 k_53 k_54 k_55
k_59 k_74    
Reactions (109)
 
 reaction_1 [R] + [EGF] ↔ [RE];  
 
 reaction_2 2.0 × [RE] ↔ [Rd];  
 
 reaction_3 [Rd] → [Rp];  
 
 reaction_4 [Rp] + [GS] ↔ [Rp_GS];  
 
 reaction_5 [Rp] + [Shc] ↔ [Rp_Shc];  
 
 reaction_6 [Rp_Shc] → [Rp_pShc];  
 
 reaction_7 [Rp_pShc] ↔ [Rp] + [pShc];  
 
 reaction_8 [pShc] → [Shc];  
 
 reaction_9 [GS] + [Rp_pShc] ↔ [Rp_pShc_GS];  
 
 reaction_10 [Rp_pShc_GS] ↔ [Rp] + [pShc_GS];  
 
 reaction_11 [pShc_GS] ↔ [GS] + [pShc];  
 
 reaction_12 [Rp] + [PI3K] ↔ [Rp_PI3K];  
 
 reaction_13 [Rp] + [RasGAP] ↔ [Rp_RasGAP];  
 
 reaction_17 [Rp] → [Null];  
 
 reaction_18 [Rp_GS] → [GS];  
 
 reaction_19 [Rp_Shc] → [Shc];  
 
 reaction_20 [Rp_pShc] → [pShc];  
 
 reaction_21 [Rp_pShc_GS] → [pShc_GS];  
 
 reaction_22 [Rp_PI3K] → [PI3K];  
 
 reaction_23 [Rp_RasGAP] → [RasGAP];  
 
 reaction_24 [I] + [IR] ↔ [IRL];  
 
 reaction_25 [IRL] → [IRp];  
 
 reaction_26 [PI3K] + [IRp] ↔ [IRp_PI3K];  
 
 reaction_27 [RasGAP] + [IRp] ↔ [IRp_RasGAP];  
 
 reaction_28 [IRp] + [IRS] ↔ [IRp_IRS];  
 
 reaction_29 [IRp_IRS] → [IRp_IRSp];  
 
 reaction_30 [IRp_IRSp] ↔ [IRp] + [IRSp];  
 
 reaction_31 [IRSp] → [IRS];  
 
 reaction_34 [IRp] → [Null];  
 
 reaction_35 [IRp_PI3K] → [PI3K];  
 
 reaction_36 [IRp_RasGAP] → [RasGAP];  
 
 reaction_37 [IRp_IRS] → [IRS];  
 
 reaction_38 [IRp_IRSp] → [IRSp];  
 
 reaction_40 [iSrc] → [aSrc];   {Rp} , {IRp}
 
 reaction_41 [aSrc] → [iSrc];  
 
 reaction_42 [IRS] + [PIP3] ↔ [mIRS];  
 
 reaction_43 [mIRS] → [mIRSp];   {Rp} , {IRp}
 
 reaction_44 [mIRSp] → [mIRS];  
 
 reaction_45 [GS] + [mIRSp] ↔ [mIRSp_GS];  
 
 reaction_46 [PI3K] + [mIRSp] ↔ [mIRSp_PI3K];  
 
 reaction_47 [mIRSp] + [SHP2] ↔ [mIRSp_SHP2];  
 
 reaction_48 [mIRSp_SHP2] → [mIRS] + [SHP2];  
 
 reaction_49 [GAB] + [PIP3] ↔ [mGAB];  
 
 reaction_50 [mGAB] → [mGABp];   {Rp} , {aSrc}
 
 reaction_51 [mGABp] → [mGAB];  
 
 reaction_52 [GS] + [mGABp] ↔ [mGABp_GS];  
 
 reaction_53 [PI3K] + [mGABp] ↔ [mGABp_PI3K];  
 
 reaction_54 [RasGAP] + [mGABp] ↔ [mGABp_RasGAP];  
 
 reaction_55 [SHP2] + [mGABp] ↔ [mGABp_SHP2];  
 
 reaction_56 [mGABp_SHP2] → [SHP2] + [mGAB];  
 
 reaction_57 [mGABp_SHP2] → [mGABp_pSHP2];   {Rp} , {aSrc}
 
 reaction_58 [mGABp_pSHP2] → [mGABp_SHP2];  
 
 reaction_59 [GS] + [mGABp_pSHP2] ↔ [mGABp_pSHP2_GS];  
 
 reaction_60  → [PIP3];   {Rp_PI3K} , {IRp_PI3K} , {mIRSp_PI3K} , {mGABp_PI3K} , {tRas_PI3K}
 
 reaction_61 [PIP3] → [Null];  
 
 reaction_62 [dRas] → [tRas];   {Rp_GS} , {Rp_pShc_GS} , {mIRSp_GS} , {mGABp_GS} , {mGABp_pSHP2_GS}
 
 reaction_63 [tRas] → [dRas];   {Rp_RasGAP} , {IRp_RasGAP} , {mGABp_RasGAP} , {bRasGAP}
 
 reaction_64 [PI3K] + [tRas] → [tRas_PI3K];  
 
 reaction_65 [Raf] → [aRaf];   {tRas}
 
 reaction_66 [aRaf] → [aaRaf];   {aSrc}
 
 reaction_67 [aaRaf] → [Raf];   {pAkt} , {PKA} , {ppAkt}
 
 reaction_68 [Mek] → [ppMek];   {aaRaf}
 
 reaction_69 [ppMek] → [Mek];  
 
 reaction_70 [Erk] → [pErk];   {ppMek}
 
 reaction_71 [pErk] → [ppErk];   {Erk} , {ppMek}
 
 reaction_72 [ppErk] → [pErk];  
 
 reaction_73 [pErk] → [Erk];   {ppErk}
 
 reaction_74 [PIP3] + [PDK1] ↔ [mPDK1];  
 
 reaction_75 [Akt] → [pAkt];   {mPDK1}
 
 reaction_76 [pAkt] → [Akt];  
 
 reaction_77 [mTOR] ↔ [amTOR];   {pAkt} , {ppAkt}
 
 reaction_78 [pAkt] ↔ [ppAkt];   {amTOR}
 
 reaction_79 [GS] ↔ [iGS];   {ppErk}
 
 reaction_80 [mGAB] ↔ [imGAB];   {ppErk}
 
 reaction_81 [mIRS] ↔ [imIRS];   {amTOR}
 
 reaction_82 [Rp] → [Ri];  
 
 reaction_83 [Ri] → [Rd];  
 
 reaction_84 [IRp] → [IRi];  
 
 reaction_85 [IRi] → [IRL];  
 
 reaction_88 [mIRSp] ↔ [IRSp] + [PIP3];  
 
 reaction_89 [mIRSp_PI3K] ↔ [PIP3] + [IRSp_PI3K];  
 
 reaction_90 [mIRSp_GS] ↔ [PIP3] + [IRSp_GS];  
 
 reaction_91 [mIRSp_SHP2] ↔ [PIP3] + [IRSp_SHP2];  
 
 reaction_92 [mGABp] ↔ [PIP3] + [GABp];  
 
 reaction_93 [mGABp_PI3K] ↔ [PIP3] + [GABp_PI3K];  
 
 reaction_94 [mGABp_GS] ↔ [PIP3] + [GABp_GS];  
 
 reaction_95 [mGABp_RasGAP] ↔ [PIP3] + [GABp_RasGAP];  
 
 reaction_96 [mGABp_SHP2] ↔ [PIP3] + [GABp_SHP2];  
 
 reaction_97 [mGABp_pSHP2] ↔ [PIP3] + [GABp_pSHP2];  
 
 reaction_98 [mGABp_pSHP2_GS] ↔ [PIP3] + [GABp_pSHP2_GS];  
 
 reaction_99 [IRSp_PI3K] → [PI3K] + [IRS];  
 
 reaction_100 [IRSp_GS] → [GS] + [IRS];  
 
 reaction_101 [IRSp_SHP2] → [IRS] + [SHP2];  
 
 reaction_102 [mGABp_pSHP2] → [SHP2] + [mGAB];  
 
 reaction_103 [mGABp_pSHP2_GS] → [GS] + [SHP2] + [mGAB];  
 
 reaction_104 [GABp] → [GAB];  
 
 reaction_105 [GABp_PI3K] → [PI3K] + [GAB];  
 
 reaction_106 [GABp_GS] → [GS] + [GAB];  
 
 reaction_107 [GABp_RasGAP] → [RasGAP] + [GAB];  
 
 reaction_108 [GABp_SHP2] → [SHP2] + [GAB];  
 
 reaction_109 [GABp_pSHP2] → [SHP2] + [GAB];  
 
 reaction_110 [GABp_pSHP2_GS] → [GS] + [SHP2] + [GAB];  
 
 reaction_111 [mGABp_RasGAP] → [RasGAP] + [mGAB];   {mIRSp_SHP2} , {mGABp_SHP2} , {mGABp_pSHP2} , {mGABp_pSHP2_GS}
 
 reaction_112 [Rp_RasGAP] → [Rp] + [RasGAP];   {mGABp_SHP2} , {mGABp_pSHP2} , {mGABp_pSHP2_GS}
 
 reaction_113 [IRp_RasGAP] → [RasGAP] + [IRp];   {mGABp_SHP2} , {mGABp_pSHP2} , {mGABp_pSHP2_GS}
 
 reaction_114 [Rp_RasGAP] → [Rp] + [RasGAP];   {mIRSp_SHP2}
 
 reaction_115 [IRp_RasGAP] → [RasGAP] + [IRp];   {mIRSp_SHP2}
 
 reaction_117 [mGABp] ↔ [imGABp];   {ppErk}
 
 reaction_118 [imGABp] → [imGAB];  
 
Rules (29)
 
 Assignment Rule (name: phosphorylated_Akt) phosphorylated_Akt = pAkt+ppAkt
 
 Assignment Rule (name: EGF_tot) EGF_tot = EGF+(RE+2*(Rd+Rp+Ri+Rp_GS+Rp_Shc+Rp_pShc+Rp_pShc_GS+Rp_PI3K+Rp_RasGAP))*cell/extra
 
 Assignment Rule (name: k_1) k_1 = Kd1*k1
 
 Assignment Rule (name: k_2) k_2 = Kd2*k2
 
 Assignment Rule (name: k_4) k_4 = Kd4*k4
 
 Assignment Rule (name: k_5) k_5 = Kd5*k5
 
 Assignment Rule (name: k_7) k_7 = Kd7*k7
 
 Assignment Rule (name: k_9) k_9 = Kd9*k9
 
 Assignment Rule (name: k_10) k_10 = Kd10*k10
 
 Assignment Rule (name: k_11) k_11 = k_9
 
 Assignment Rule (name: k11) k11 = k9
 
 Assignment Rule (name: k_12) k_12 = Kd12*k12
 
 Assignment Rule (name: k_13) k_13 = Kd13*k13
 
 Assignment Rule (name: k_24) k_24 = Kd24*k24
 
 Assignment Rule (name: k_26) k_26 = Kd26*k26
 
 Assignment Rule (name: k_27) k_27 = Kd27*k27
 
 Assignment Rule (name: k_28) k_28 = Kd28*k28
 
 Assignment Rule (name: k_30) k_30 = Kd30*k30
 
 Assignment Rule (name: k_42) k_42 = Kd42*k42
 
 Assignment Rule (name: k_45) k_45 = k45*Kd45
 
 Assignment Rule (name: k_46) k_46 = Kd46*k46
 
 Assignment Rule (name: k_47) k_47 = Kd47*k47
 
 Assignment Rule (name: k_49) k_49 = Kd49*k49
 
 Assignment Rule (name: k_52) k_52 = k52*Kd52
 
 Assignment Rule (name: k_53) k_53 = Kd53*k53
 
 Assignment Rule (name: k_54) k_54 = Kd54*k54
 
 Assignment Rule (name: k_55) k_55 = Kd55*k55
 
 Assignment Rule (name: k_59) k_59 = Kd59*k59
 
 Assignment Rule (name: k_74) k_74 = k74*Kd74
 
 cell Spatial dimensions: 3.0  Compartment size: 1.0
 
 RE
Compartment: cell
Initial concentration: 0.0
 
 Rd
Compartment: cell
Initial concentration: 0.0
 
 Rp
Compartment: cell
Initial concentration: 0.0
 
   GS
Compartment: cell
Initial concentration: 200.0
 
 Rp_GS
Compartment: cell
Initial concentration: 0.0
 
   Shc
Compartment: cell
Initial concentration: 270.0
 
 Rp_Shc
Compartment: cell
Initial concentration: 0.0
 
   Rp_pShc
Compartment: cell
Initial concentration: 0.0
 
   pShc
Compartment: cell
Initial concentration: 0.0
 
   Rp_pShc_GS
Compartment: cell
Initial concentration: 0.0
 
   PI3K
Compartment: cell
Initial concentration: 200.0
 
   Rp_PI3K
Compartment: cell
Initial concentration: 0.0
 
   RasGAP
Compartment: cell
Initial concentration: 50.0
 
   Rp_RasGAP
Compartment: cell
Initial concentration: 0.0
 
   IRL
Compartment: cell
Initial concentration: 0.0
 
   IRp
Compartment: cell
Initial concentration: 0.0
 
   IRp_PI3K
Compartment: cell
Initial concentration: 0.0
 
   IRp_RasGAP
Compartment: cell
Initial concentration: 0.0
 
   IRS
Compartment: cell
Initial concentration: 300.0
 
   IRp_IRS
Compartment: cell
Initial concentration: 0.0
 
   IRp_IRSp
Compartment: cell
Initial concentration: 0.0
 
   IRSp
Compartment: cell
Initial concentration: 0.0
 
   iSrc
Compartment: cell
Initial concentration: 518.0
 
   mIRS
Compartment: cell
Initial concentration: 0.0
 
   mIRSp
Compartment: cell
Initial concentration: 0.0
 
   mIRSp_GS
Compartment: cell
Initial concentration: 0.0
 
   mIRSp_PI3K
Compartment: cell
Initial concentration: 0.0
 
   SHP2
Compartment: cell
Initial concentration: 300.0
 
   mIRSp_SHP2
Compartment: cell
Initial concentration: 0.0
 
   GAB
Compartment: cell
Initial concentration: 225.0
 
   mGAB
Compartment: cell
Initial concentration: 0.0
 
   mGABp
Compartment: cell
Initial concentration: 0.0
 
   mGABp_GS
Compartment: cell
Initial concentration: 0.0
 
   mGABp_PI3K
Compartment: cell
Initial concentration: 0.0
 
   mGABp_SHP2
Compartment: cell
Initial concentration: 0.0
 
   mGABp_pSHP2
Compartment: cell
Initial concentration: 0.0
 
   PIP3
Compartment: cell
Initial concentration: 0.0
 
   dRas
Compartment: cell
Initial concentration: 150.0
 
   Raf
Compartment: cell
Initial concentration: 100.0
 
   aRaf
Compartment: cell
Initial concentration: 0.0
 
   Mek
Compartment: cell
Initial concentration: 200.0
 
   Erk
Compartment: cell
Initial concentration: 400.0
 
   pErk
Compartment: cell
Initial concentration: 0.0
 
   PDK1
Compartment: cell
Initial concentration: 100.0
 
   Akt
Compartment: cell
Initial concentration: 100.0
 
   pAkt
Compartment: cell
Initial concentration: 0.0
 
   mTOR
Compartment: cell
Initial concentration: 100.0
 
   Null
Compartment: cell
Initial concentration: 0.0
 
   aaRaf
Compartment: cell
Initial concentration: 0.0
 
   PKA
Compartment: cell
Initial concentration: 100.0
 
   pShc_GS
Compartment: cell
Initial concentration: 0.0
 
   ppMek
Compartment: cell
Initial concentration: 0.0
 
   mGABp_pSHP2_GS
Compartment: cell
Initial concentration: 0.0
 
   R
Compartment: cell
Initial concentration: 100.0
 
   ppErk
Compartment: cell
Initial concentration: 0.0
 
   IR
Compartment: cell
Initial concentration: 150.0
 
   mPDK1
Compartment: cell
Initial concentration: 0.0
 
   tRas
Compartment: cell
Initial concentration: 0.0
 
   tRas_PI3K
Compartment: cell
Initial concentration: 0.0
 
   ppAkt
Compartment: cell
Initial concentration: 0.0
 
   mGABp_RasGAP
Compartment: cell
Initial concentration: 0.0
 
   amTOR
Compartment: cell
Initial concentration: 0.0
 
   iGS
Compartment: cell
Initial concentration: 0.0
 
   imGAB
Compartment: cell
Initial concentration: 0.0
 
   imIRS
Compartment: cell
Initial concentration: 0.0
 
   aSrc
Compartment: cell
Initial concentration: 0.0
 
   Ri
Compartment: cell
Initial concentration: 0.0
 
   IRi
Compartment: cell
Initial concentration: 0.0
 
   iPX
Compartment: cell
Initial concentration: 200.0
 
   aPX
Compartment: cell
Initial concentration: 0.0
 
   aPX_GS
Compartment: cell
Initial concentration: 0.0
 
   IRSp_PI3K
Compartment: cell
Initial concentration: 0.0
 
   IRSp_GS
Compartment: cell
Initial concentration: 0.0
 
   IRSp_SHP2
Compartment: cell
Initial concentration: 0.0
 
   GABp
Compartment: cell
Initial concentration: 0.0
 
   GABp_PI3K
Compartment: cell
Initial concentration: 0.0
 
   GABp_GS
Compartment: cell
Initial concentration: 0.0
 
   GABp_RasGAP
Compartment: cell
Initial concentration: 0.0
 
   GABp_SHP2
Compartment: cell
Initial concentration: 0.0
 
   GABp_pSHP2
Compartment: cell
Initial concentration: 0.0
 
   GABp_pSHP2_GS
Compartment: cell
Initial concentration: 0.0
 
   imGABp
Compartment: cell
Initial concentration: 0.0
 
   bRasGAP
Compartment: cell
Initial concentration: 1.0E-5
 
   phosphorylated_Akt
Compartment: cell
 
   extracellular space Spatial dimensions: 3.0  Compartment size: 34.0
 
 EGF
Compartment: extracellular space
Initial concentration: 1.0
 
 I
Compartment: extracellular space
Initial concentration: 0.0
 
Global Parameters (162)
 
   EGF_tot
Value: 3.4   (Units: nM)
 
   k1
Value: 0.068   (Units: per nM per s)
Constant
 
   Kd1
Value: 0.58824   (Units: nM)
Constant
 
   k2
Value: 0.033   (Units: per nM per s)
Constant
 
   Kd2
Value: 15.0   (Units: nM)
Constant
 
   k3
Value: 0.4   (Units: per second)
Constant
 
   k4
Value: 6.66E-4   (Units: per nM per s)
Constant
 
   Kd4
Value: 10.0   (Units: nM)
Constant
 
   Kd5
Value: 10.0   (Units: nM)
Constant
 
   k5
Value: 0.0133   (Units: per nM per s)
Constant
 
   k6
Value: 0.333   (Units: per second)
Constant
 
   k7
Value: 6.66E-4   (Units: per nM per s)
Constant
 
   Kd7
Value: 400.0   (Units: nM)
Constant
 
   V8
Value: 200.0   (Units: nM per sec)
Constant
 
   Km8
Value: 100.0   (Units: nM)
Constant
 
   Kd9
Value: 10.0   (Units: nM)
Constant
 
   k9
Value: 0.00666   (Units: per nM per s)
Constant
 
   Kd10
Value: 400.0   (Units: nM)
Constant
 
   k10
Value: 4.0E-4   (Units: per nM per s)
Constant
 
   k11  
 
   k12
Value: 0.00933   (Units: per nM per s)
Constant
 
   Kd12
Value: 12.45   (Units: nM)
Constant
 
   k13
Value: 6.66E-6   (Units: per nM per s)
Constant
 
   Kd13
Value: 200.0   (Units: nM)
Constant
 
   k17
Value: 1.85E-4   (Units: per second)
Constant
 
   k24
Value: 0.011322   (Units: per nM per s)
Constant
 
   Kd24
Value: 0.029412   (Units: nM)
Constant
 
   k25
Value: 1.66   (Units: per second)
Constant
 
   k26
Value: 0.00933   (Units: per nM per s)
Constant
 
   Kd26
Value: 124.5   (Units: nM)
Constant
 
   k27
Value: 6.66E-8   (Units: per nM per s)
Constant
 
   Kd27
Value: 2000000.0   (Units: nM)
Constant
 
   k28
Value: 0.1066   (Units: per nM per s)
Constant
 
   Kd28
Value: 3.75   (Units: nM)
Constant
 
   k29
Value: 0.66   (Units: per second)
Constant
 
   k30
Value: 0.0066   (Units: per nM per s)
Constant
 
   Kd30
Value: 10.0   (Units: nM)
Constant
 
   V31
Value: 333.0   (Units: nM per sec)
Constant
 
   Km31
Value: 143.3   (Units: nM)
Constant
 
   kcat40
Value: 6.6   (Units: per second)
Constant
 
   Km40
Value: 110.0   (Units: nM)
Constant
 
   alpha40
Value: 2.5E-4   (Units: dimensionless)
Constant
 
   V41
Value: 6.66   (Units: nM per sec)
Constant
 
   Km41
Value: 50.0   (Units: nM)
Constant
 
   k42
Value: 0.00666   (Units: per nM per s)
Constant
 
   Kd42
Value: 10.0   (Units: nM)
Constant
 
   kcat43
Value: 33.3   (Units: per second)
Constant
 
   Km43
Value: 150.0   (Units: nM)
Constant
 
   alpha43
Value: 0.05   (Units: dimensionless)
Constant
 
   Kd45
Value: 100000.0   (Units: nM)
Constant
 
   k45
Value: 6.66E-4   (Units: per nM per s)
Constant
 
   k46
Value: 0.00666   (Units: per nM per s)
Constant
 
   Kd46
Value: 1.0   (Units: nM)
Constant
 
   k47
Value: 6.66E-4   (Units: per nM per s)
Constant
 
   Kd47
Value: 1000.0   (Units: nM)
Constant
 
   k48
Value: 0.666   (Units: per second)
Constant
 
   k49
Value: 6.66E-4   (Units: per nM per s)
Constant
 
   Kd49
Value: 1.0   (Units: nM)
Constant
 
   kcat50
Value: 3333.0   (Units: per second)
Constant
 
   alpha50
Value: 1.0E-4   (Units: dimensionless)
Constant
 
   Km50
Value: 150.0   (Units: nM)
Constant
 
   V51
Value: 333.0   (Units: nM per sec)
Constant
 
   Km51
Value: 130.0   (Units: nM)
Constant
 
   k52
Value: 0.002   (Units: per nM per s)
Constant
 
   Kd52
Value: 1.0   (Units: nM)
Constant
 
   k53
Value: 0.0133   (Units: per nM per s)
Constant
 
   Kd53
Value: 2.5   (Units: nM)
Constant
 
   k54
Value: 1.0E-5   (Units: per nM per s)
Constant
 
   Kd54
Value: 66666.0   (Units: nM)
Constant
 
   k55
Value: 6.66E-4   (Units: per nM per s)
Constant
 
   Kd55
Value: 100.0   (Units: nM)
Constant
 
   k56
Value: 0.666   (Units: per second)
Constant
 
   kcat57
Value: 0.133   (Units: per second)
Constant
 
   Km57
Value: 150.0   (Units: nM)
Constant
 
   V58
Value: 2.0   (Units: nM per sec)
Constant
 
   Km58
Value: 130.0   (Units: nM)
Constant
 
   k59
Value: 0.01   (Units: per nM per s)
Constant
 
   Kd59
Value: 20.0   (Units: nM)
Constant
 
   k60
Value: 4.66   (Units: per second)
Constant
 
   k61
Value: 3.33   (Units: per second)
Constant
 
   kcat62
Value: 5.33   (Units: per second)
Constant
 
   Km62
Value: 50.0   (Units: nM)
Constant
 
   kcat63
Value: 20000.0   (Units: per second)
Constant
 
   Km63
Value: 50.0   (Units: nM)
Constant
 
   k64
Constant
 
   k_64
Value: 2.5   (Units: per second)
Constant
 
   kcat65
Value: 0.1   (Units: per second)
Constant
 
   Km65
Value: 400.0   (Units: nM)
Constant
 
   kcat66
Value: 3.33   (Units: per second)
Constant
 
   Km66
Value: 10.0   (Units: nM)
Constant
 
   kcat67
Value: 0.666   (Units: per second)
Constant
 
   Km67
Value: 10000.0   (Units: nM)
Constant
 
   alpha67
Value: 1.0E-6   (Units: per nM per s)
Constant
 
   beta67
Value: 2.0   (Units: dimensionless)
Constant
 
   kcat68
Value: 0.133   (Units: per second)
Constant
 
   Km68
Value: 50.0   (Units: nM)
Constant
 
   V69
Value: 16.6   (Units: nM per sec)
Constant
 
   Km69
Value: 675.299   (Units: nM)
Constant
 
   kcat70
Value: 0.333   (Units: per second)
Constant
 
   Km70
Value: 500.0   (Units: nM)
Constant
 
   kcat71
Value: 0.666   (Units: per second)
Constant
 
   Km71
Value: 500.0   (Units: nM)
Constant
 
   V72
Value: 33.3   (Units: nM per sec)
Constant
 
   Km72
Value: 500.0   (Units: nM)
Constant
 
   V73
Value: 23.33   (Units: nM per sec)
Constant
 
   Km73
Value: 500.0   (Units: nM)
Constant
 
   k74
Value: 0.00666   (Units: per nM per s)
Constant
 
   Kd74
Value: 100.0   (Units: nM)
Constant
 
   kcat75
Value: 4.66   (Units: per second)
Constant
 
   Km75
Value: 500.0   (Units: nM)
Constant
 
   V76
Value: 16.66   (Units: nM per sec)
Constant
 
   Km76
Value: 1.0   (Units: nM)
Constant
 
   kcat77
Value: 0.666   (Units: per second)
Constant
 
   alpha77
Value: 0.5   (Units: dimensionless)
Constant
 
   Km77
Value: 100.0   (Units: nM)
Constant
 
   k_77
Value: 0.666   (Units: per second)
Constant
 
   kcat78
Value: 0.666   (Units: per second)
Constant
 
   Km78
Value: 100.0   (Units: nM)
Constant
 
   k_78
Value: 0.666   (Units: per second)
Constant
 
   kcat79
Value: 0.0466   (Units: per second)
Constant
 
   Km79
Value: 5000.0   (Units: nM)
Constant
 
   k_79
Value: 6.66E-5   (Units: per second)
Constant
 
   kcat80
Value: 0.04   (Units: per second)
Constant
 
   Km80
Value: 700.0   (Units: nM)
Constant
 
   k_80
Value: 6.66E-5   (Units: per second)
Constant
 
   kcat81
Value: 0.166   (Units: per second)
Constant
 
   Km81
Value: 300.0   (Units: nM)
Constant
 
   k_81
Value: 6.66E-5   (Units: per second)
Constant
 
   V_82
Value: 133.0   (Units: nM per sec)
Constant
 
   Km82
Value: 50.0   (Units: nM)
Constant
 
   k83
Value: 0.0166   (Units: per second)
Constant
 
   V_84
Value: 333.0   (Units: nM per sec)
Constant
 
   Km84
Value: 266.0   (Units: nM)
Constant
 
   k85
Value: 0.0166   (Units: per second)
Constant
 
   k111
Value: 0.0133   (Units: per nM per s)
Constant
 
   k118
Value: 0.001   (Units: per second)
Constant
 
   k_1
Value: NaN   (Units: per second)
 
   k_2
Value: NaN   (Units: per second)
 
   k_4
Value: NaN   (Units: per second)
 
   k_5
Value: NaN   (Units: per second)
 
   k_7
Value: NaN   (Units: per second)
 
   k_9
Value: NaN   (Units: per second)
 
   k_10
Value: NaN   (Units: per second)
 
   k_11
Value: NaN   (Units: per second)
 
   k_12
Value: NaN   (Units: per second)
 
   k_13
Value: NaN   (Units: per second)
 
   k_24
Value: NaN   (Units: per second)
 
   k_26
Value: NaN   (Units: per second)
 
   k_27
Value: NaN   (Units: per second)
 
   k_28
Value: NaN   (Units: per second)
 
   k_30
Value: NaN   (Units: per second)
 
   k_42
Value: NaN   (Units: per second)
 
   k_45
Value: NaN   (Units: per second)
 
   k_46
Value: NaN   (Units: per second)
 
   k_47
Value: NaN   (Units: per second)
 
   k_49
Value: NaN   (Units: per second)
 
   k_52
Value: NaN   (Units: per second)
 
   k_53
Value: NaN   (Units: per second)
 
   k_54
Value: NaN   (Units: per second)
 
   k_55
Value: NaN   (Units: per second)
 
   k_59
Value: NaN   (Units: per second)
 
   k_74
Value: NaN   (Units: per second)
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000223

Curator's comment: (updated: 13 Jul 2009 14:32:32 BST)

Reproduction of some time courses from figure 3A of the original article.

Simulations were performed using SBML ODESolver, the graphs created using R.

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