Koo2013 - Shear stress induced AKT and eNOS phosphorylation - Model 2

  public model
Model Identifier
BIOMD0000000465
Short description
Format
SBML (L2V4)
Related Publication
  • In silico modeling of shear-stress-induced nitric oxide production in endothelial cells through systems biology.
  • Koo A, Nordsletten D, Umeton R, Yankama B, Ayyadurai S, García-Cardeña G, Dewey CF Jr
  • Biophysical journal , 5/ 2013 , Volume 104 , pages: 2295-2306 , PubMed ID: 23708369
  • Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Nitric oxide (NO) produced by vascular endothelial cells is a potent vasodilator and an antiinflammatory mediator. Regulating production of endothelial-derived NO is a complex undertaking, involving multiple signaling and genetic pathways that are activated by diverse humoral and biomechanical stimuli. To gain a thorough understanding of the rich diversity of responses observed experimentally, it is necessary to account for an ensemble of these pathways acting simultaneously. In this article, we have assembled four quantitative molecular pathways previously proposed for shear-stress-induced NO production. In these pathways, endothelial NO synthase is activated 1), via calcium release, 2), via phosphorylation reactions, and 3), via enhanced protein expression. To these activation pathways, we have added a fourth, a pathway describing actual NO production from endothelial NO synthase and its various protein partners. These pathways were combined and simulated using CytoSolve, a computational environment for combining independent pathway calculations. The integrated model is able to describe the experimentally observed change in NO production with time after the application of fluid shear stress. This model can also be used to predict the specific effects on the system after interventional pharmacological or genetic changes. Importantly, this model reflects the up-to-date understanding of the NO system, providing a platform upon which information can be aggregated in an additive way.
Contributors
Andrew Koo

Metadata information

is
BioModels Database MODEL1302180004
BioModels Database BIOMD0000000465
isDescribedBy
PubMed 23708369
hasTaxon
Taxonomy Homo sapiens

Curation status
Curated

Original model(s)
Koh, G., H. F. C. Teong, M.-V. Clément, D. Hsu, and P. S. Thiagarajan. 2006. A decompositional approach to parameter estimation in pathway modeling: a case study of the Akt and MAPK pathways and their crosstalk. Bioinformatics 22:e271-280.

Tags
Name Description Size Actions

Model files

BIOMD0000000465_url.xml SBML L2V4 representation of Koo2013 - Shear stress induced AKT and eNOS phosphorylation - Model 2 94.81 KB Preview | Download

Additional files

BIOMD0000000465.xpp Auto-generated XPP file 4.50 KB Preview | Download
BIOMD0000000465.sci Auto-generated Scilab file 205.00 bytes Preview | Download
BIOMD0000000465.pdf Auto-generated PDF file 202.43 KB Preview | Download
BIOMD0000000465-biopax3.owl Auto-generated BioPAX (Level 3) 33.73 KB Preview | Download
BIOMD0000000465.svg Auto-generated Reaction graph (SVG) 42.31 KB Preview | Download
BIOMD0000000465.png Auto-generated Reaction graph (PNG) 170.77 KB Preview | Download
BIOMD0000000465.m Auto-generated Octave file 7.07 KB Preview | Download
BIOMD0000000465_urn.xml Auto-generated SBML file with URNs 94.28 KB Preview | Download
BIOMD0000000465.vcml Auto-generated VCML file 43.16 KB Preview | Download
BIOMD0000000465-biopax2.owl Auto-generated BioPAX (Level 2) 22.57 KB Preview | Download

  • Model originally submitted by : Andrew Koo
  • Submitted: Feb 18, 2013 8:26:10 PM
  • Last Modified: Apr 7, 2014 3:59:25 AM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Apr 7, 2014 3:59:25 AM
    • Submitted by: Andrew Koo
    • With comment: Current version of Koo2013 - Shear stress induced AKT and eNOS phosphorylation - Model 2
  • Version: 1 public model Download this version
    • Submitted on: Feb 18, 2013 8:26:10 PM
    • Submitted by: Andrew Koo
    • With comment: Original import of BIOMD0000000465.xml.origin
Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
AKT:PI3P

RAC-alpha serine/threonine-protein kinase ; 53480352
29.203 1E-9*mol
PDK1

3-phosphoinositide-dependent protein kinase 1
0.246 1E-9*mol
PI3P

53480352
0.345 1E-9*mol
PIP2

1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
6967.271 1E-9*mol
p-AKT:PI3P

RAC-alpha serine/threonine-protein kinase ; 53480352; phosphorylated residue
1.457 1E-9*mol
pp-AKT:PI3P

RAC-alpha serine/threonine-protein kinase ; 53480352; phosphorylated residue
1.723 1E-9*mol
s3 0.0 1E-9*mol
Time 0.0 1E-9*mol
PDK1 cyto

3-phosphoinositide-dependent protein kinase 1 ; intracellular
999.754 1E-9*mol
Reactions
Reactions Rate Parameters
(PI3P + AKT) => (AKT:PI3P)

([53480352] + [RAC-alpha serine/threonine-protein kinase]) => ([RAC-alpha serine/threonine-protein kinase; 53480352])
k4*s17*s16-kr4*s28

k4*[53480352]*[RAC-alpha serine/threonine-protein kinase]-kr4*[RAC-alpha serine/threonine-protein kinase; 53480352]
k4=0.045 inv_sec_sub; kr4=0.089 inv_sec
(AKT:PI3P) => (p-AKT:PI3P)

([RAC-alpha serine/threonine-protein kinase; 53480352]) => ([RAC-alpha serine/threonine-protein kinase; 53480352; phosphorylated residue])
k8*s28*s14/(Km8+s28)

k8*[RAC-alpha serine/threonine-protein kinase; 53480352]*[3-phosphoinositide-dependent protein kinase 1]/(Km8+[RAC-alpha serine/threonine-protein kinase; 53480352])
k8=20.0 inv_sec; Km8=80000.0 substance
(p-AKT:PI3P) => (AKT:PI3P)

([RAC-alpha serine/threonine-protein kinase; 53480352; phosphorylated residue]) => ([RAC-alpha serine/threonine-protein kinase; 53480352])
k7*s26*s15/(Km7+s26)

k7*[RAC-alpha serine/threonine-protein kinase; 53480352; phosphorylated residue]*[protein phosphatase type 2A complex]/(Km7+[RAC-alpha serine/threonine-protein kinase; 53480352; phosphorylated residue])
Km7=8800.0 substance; k7=0.037 inv_sec
(PDK1) => (PDK1_cyto)

([3-phosphoinositide-dependent protein kinase 1]) => ([3-phosphoinositide-dependent protein kinase 1; intracellular])
k6*s14

k6*[3-phosphoinositide-dependent protein kinase 1]
k6=0.98 inv_sec
(PIP2) => (PI3P)

([1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate]) => ([53480352])
k2*s19*s20/(Km2+s19)

k2*[1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate]*[phosphorylated residue]/(Km2+[1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate])
k2=0.2 inv_sec; Km2=6170.0 substance
(PI3P) => (PIP2)

([53480352]) => ([1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate])
k3*s17*s18/(Km3+s17)

k3*[53480352]*[Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN]/(Km3+[53480352])
Km3=80.9 substance; k3=7.5 inv_sec
(p-AKT:PI3P) => (pp-AKT:PI3P)

([RAC-alpha serine/threonine-protein kinase; 53480352; phosphorylated residue]) => ([RAC-alpha serine/threonine-protein kinase; 53480352; phosphorylated residue])
k10*s26*s24/(Km10+s26)

k10*[RAC-alpha serine/threonine-protein kinase; 53480352; phosphorylated residue]*[[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial]/(Km10+[RAC-alpha serine/threonine-protein kinase; 53480352; phosphorylated residue])
k10=20.0 inv_sec; Km10=80000.0 substance
(pp-AKT:PI3P) => (PI3P + AKT)

([RAC-alpha serine/threonine-protein kinase; 53480352; phosphorylated residue]) => ([53480352] + [RAC-alpha serine/threonine-protein kinase])
k11*s27*s15/(Km11+s27)

k11*[RAC-alpha serine/threonine-protein kinase; 53480352; phosphorylated residue]*[protein phosphatase type 2A complex]/(Km11+[RAC-alpha serine/threonine-protein kinase; 53480352; phosphorylated residue])
k11=0.163 inv_sec; Km11=48000.0 substance
(s3) => (Time)

([s3]) => ([Time])
unitime

unitime
unitime=1.0 sub_sec
(PDK1_cyto) => (PDK1)

([3-phosphoinositide-dependent protein kinase 1; intracellular]) => ([3-phosphoinositide-dependent protein kinase 1])
k5*s17*s25

k5*[53480352]*[3-phosphoinositide-dependent protein kinase 1; intracellular]
k5=7.0E-4 inv_sec_sub
Curator's comment:
(added: 19 Aug 2013, 13:58:36, updated: 19 Aug 2013, 13:58:36)
The paper describes four sub-models and an integrated version of the four sub-models. This model corresponds to Model 2 - Shear stress induced AKT and eNOS phosphorylation. Figure 3B of the paper is reproduced here using Copasi 4.10 (Build 55).