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BIOMD0000000288 - Wang2009 - PI3K Ras Crosstalk

 

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Reference Publication
Publication ID: 19225459
Wang CC, Cirit M, Haugh JM.
PI3K-dependent cross-talk interactions converge with Ras as quantifiable inputs integrated by Erk.
Mol. Syst. Biol. 2009; 5: 246
Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695-7905, USA.  [more]
Model
Original Model: http://www.nature.com/msb/...
Submitter: Lukas Endler
Submission ID: MODEL0910130003
Submission Date: 08 Nov 2009 20:02:55 UTC
Last Modification Date: 14 Feb 2014 11:33:07 UTC
Creation Date: 21 Jan 2010 13:25:37 UTC
Encoders:  Vijayalakshmi Chelliah
   Jason M Haugh
set #1
bqbiol:isPartOf KEGG Pathway ko04012
KEGG Pathway ko04010
bqbiol:isVersionOf Gene Ontology platelet-derived growth factor receptor signaling pathway
Gene Ontology ERK1 and ERK2 cascade
Gene Ontology phosphatidylinositol 3-kinase signaling
bqbiol:occursIn Taxonomy Homo sapiens
set #2
bqmodel:isDerivedFrom PubMed 12871957
PubMed 16314431
Notes

This model is from the article:
PI3K-dependent cross-talk interactions converge with Ras as quantifiable inputs integrated by Erk.
Wang CC, Cirit M, Haugh JM Mol. Syst. Biol. 2009;5:246. 19225459 ,
Abstract:
Although it is appreciated that canonical signal-transduction pathways represent dominant modes of regulation embedded in larger interaction networks, relatively little has been done to quantify pathway cross-talk in such networks. Through quantitative measurements that systematically canvas an array of stimulation and molecular perturbation conditions, together with computational modeling and analysis, we have elucidated cross-talk mechanisms in the platelet-derived growth factor (PDGF) receptor signaling network, in which phosphoinositide 3-kinase (PI3K) and Ras/extracellular signal-regulated kinase (Erk) pathways are prominently activated. We show that, while PI3K signaling is insulated from cross-talk, PI3K enhances Erk activation at points both upstream and downstream of Ras. The magnitudes of these effects depend strongly on the stimulation conditions, subject to saturation effects in the respective pathways and negative feedback loops. Motivated by those dynamics, a kinetic model of the network was formulated and used to precisely quantify the relative contributions of PI3K-dependent and -independent modes of Ras/Erk activation.


This model is parameterized with the median of the estimated parameters given in the supplementary material of the original publication's (doi: 10.1038/msb.2009.4 ) supplement on pages 8 and 9.

This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2010 The BioModels.net Team.
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.

In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..

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: 19225459 Submission Date: 08 Nov 2009 20:02:55 UTC Last Modification Date: 14 Feb 2014 11:33:07 UTC Creation Date: 21 Jan 2010 13:25:37 UTC
Mathematical expressions
Reactions
sumrc1ODE c2ODE m3PIODE mRasODE
x1ODE x2ODE yODE yppODE
zODE zppODE fGEFODE wODE
ephODE      
Rules
Assignment Rule (variable: r) Assignment Rule (variable: c1) Assignment Rule (variable: ePI3K) Assignment Rule (variable: eGEF)
Assignment Rule (variable: yp) Assignment Rule (variable: zp)    
Physical entities
Compartments Species
cell sumrc1 r c1
c2 ePI3K m3PI
eGEF mRas x1
x2 y yp
ypp z zp
zpp fGEF w
eph    
Global parameters
L KDL kxR0 kminusx
ke kt alphaPI3K kappaPI3K
k3PI KGR KGP kRas
Gamma kdx1 kdx2 Kx2
VmaxOVERKMx11 KMx11 VmaxOVERKMx21 KMx21
VmaxOVERKMyph1 KMyph1 VmaxOVERKMx12 KMx12
VmaxOVERKMx22 KMx22 VmaxOVERKMyph2 KMyph2
VmaxOVERKMy1 KMy1 VmaxOVERKMzph1 KMzph1
VmaxOVERKMy2 KMy2 VmaxOVERKMzph2 KMzph2
kFBf Zf n Kf
kdw kFBph Wph p
Kph      
Reactions (13)
 
 sumrc1ODE  ↔ [sumrc1];   {c2} , {c1}
 
 c2ODE  ↔ [c2];   {c1}
 
 m3PIODE  ↔ [m3PI];   {ePI3K}
 
 mRasODE  ↔ [mRas];   {eGEF}
 
 x1ODE  ↔ [x1];   {mRas} , {y} , {yp}
 
 x2ODE  ↔ [x2];   {m3PI} , {y} , {yp}
 
 yODE  ↔ [y];   {yp} , {ypp} , {x1} , {x2}
 
 yppODE  ↔ [ypp];   {x1} , {yp} , {y} , {x2} , {z} , {zp}
 
 zODE  ↔ [z];   {eph} , {zp} , {zpp} , {ypp}
 
 zppODE  ↔ [zpp];   {ypp} , {zp} , {z} , {eph}
 
 fGEFODE  ↔ [fGEF];   {zpp}
 
 wODE  ↔ [w];   {zpp}
 
 ephODE  ↔ [eph];   {w}
 
Rules (6)
 
 Assignment Rule (name: r) r = KDL*sumrc1/(KDL+L)
 
 Assignment Rule (name: c1) c1 = L*sumrc1/(KDL+L)
 
 Assignment Rule (name: ePI3K) ePI3K = (1+kappaPI3K+2*alphaPI3K*c2-((1+kappaPI3K+2*alphaPI3K*c2)^2-8*alphaPI3K*c2)^0.5)/2
 
 Assignment Rule (name: eGEF) eGEF = (KGR*c2+KGP*m3PI)/(1+KGR*c2+KGP*m3PI)*fGEF
 
 Assignment Rule (name: yp) yp = 1-y-ypp
 
 Assignment Rule (name: zp) zp = 1-z-zpp
 
  Spatial dimensions: 3.0  Compartment size: 1.0
 
 sumrc1
Compartment: cell
Initial concentration: 1.0
 
  r
Compartment: cell
 
  c1
Compartment: cell
 
 c2
Compartment: cell
Initial concentration: 0.0
 
  ePI3K
Compartment: cell
 
 m3PI
Compartment: cell
Initial concentration: 0.0
 
  eGEF
Compartment: cell
 
 mRas
Compartment: cell
Initial concentration: 0.0
 
 x1
Compartment: cell
Initial concentration: 0.0
 
 x2
Compartment: cell
Initial concentration: 0.0
 
 y
Compartment: cell
Initial concentration: 1.0
 
  yp
Compartment: cell
Initial concentration: 0.0
 
 ypp
Compartment: cell
Initial concentration: 0.0
 
 z
Compartment: cell
Initial concentration: 1.0
 
  zp
Compartment: cell
Initial concentration: 0.0
 
 zpp
Compartment: cell
Initial concentration: 0.0
 
 fGEF
Compartment: cell
Initial concentration: 1.0
 
 w
Compartment: cell
Initial concentration: 0.0
 
 eph
Compartment: cell
Initial concentration: 1.0
 
Global Parameters (45)
 
 L
Value: 1.0
Constant
 
 KDL
Value: 1.5
Constant
 
 kxR0
Value: 0.3
Constant
 
 kminusx
Value: 0.0070
Constant
 
 ke
Value: 0.2
Constant
 
 kt
Value: 0.0050
Constant
 
 alphaPI3K
Value: 80.0
Constant
 
 kappaPI3K
Value: 0.3
Constant
 
 k3PI
Value: 1.0
Constant
 
 KGR
Value: 495.0
Constant
 
 KGP
Value: 5.09
Constant
 
 kRas
Value: 1.0
Constant
 
 Gamma
Value: 0.1
Constant
 
 kdx1
Value: 0.745
Constant
 
 kdx2
Value: 2.85
Constant
 
 Kx2
Value: 6.77
Constant
 
 VmaxOVERKMx11
Value: 1.18
Constant
 
 KMx11
Value: 30.3
Constant
 
 VmaxOVERKMx21
Value: 0.405
Constant
 
 KMx21
Value: 13.7
Constant
 
 VmaxOVERKMyph1
Value: 1.65
Constant
 
 KMyph1
Value: 23.0
Constant
 
 VmaxOVERKMx12
Value: 3.45
Constant
 
 KMx12
Value: 18.6
Constant
 
 VmaxOVERKMx22
Value: 1.09
Constant
 
 KMx22
Value: 9.59
Constant
 
 VmaxOVERKMyph2
Value: 4.2
Constant
 
 KMyph2
Value: 7.99
Constant
 
 VmaxOVERKMy1
Value: 6.57
Constant
 
 KMy1
Value: 9.91
Constant
 
 VmaxOVERKMzph1
Value: 0.167
Constant
 
 KMzph1
Value: 8.27
Constant
 
 VmaxOVERKMy2
Value: 31.9
Constant
 
 KMy2
Value: 8.81
Constant
 
 VmaxOVERKMzph2
Value: 0.228
Constant
 
 KMzph2
Value: 31.5
Constant
 
 kFBf
Value: 0.976
Constant
 
 Zf
Value: 0.272
Constant
 
 n
Value: 1.03
Constant
 
 Kf
Value: 3.76
Constant
 
 kdw
Value: 0.0333
Constant
 
 kFBph
Value: 2.34
Constant
 
 Wph
Value: 0.385
Constant
 
 p
Value: 1.98
Constant
 
 Kph
Value: 4.64
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000288

Curator's comment: (updated: 14 Dec 2010 13:11:55 GMT)

This model is parameterized with the median of the estimated parameters given in the supplementary material (page 8-9) of the original publication. The model reproduces figure 7 of the original publication. The curation figure is obtained by a single deterministic simulation run using Copasi v4.6 (Build 32), whereas figure 7 in the paper, plots the means and means+sd from 10000 runs. The concentration of ERK_PP (zpp), Ras-GTP (mRas) and MKP (eph) at different concentration of ligand PDGF (L) are ploted here. PDGF (L) concentrations are: red, 1 nM; green, 300 pM; blue, 100 pM; gray, 50 pM; black, 30 pM.

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