Ortega2006 - bistability from double phosphorylation in signal transduction

View the 2010-12 Model of the Month entry for this model
  public model
Model Identifier
BIOMD0000000258
Short description
Ortega2006 - bistability from double phosphorylation in signal transduction

This model is described in the article:

Ortega F, Garcés JL, Mas F, Kholodenko BN, Cascante M.
FEBS J. 2006 Sep; 273(17): 3915-3926

Abstract:

Previous studies have suggested that positive feedback loops and ultrasensitivity are prerequisites for bistability in covalent modification cascades. However, it was recently shown that bistability and hysteresis can also arise solely from multisite phosphorylation. Here we analytically demonstrate that double phosphorylation of a protein (or other covalent modification) generates bistability only if: (a) the two phosphorylation (or the two dephosphorylation) reactions are catalyzed by the same enzyme; (b) the kinetics operate at least partly in the zero-order region; and (c) the ratio of the catalytic constants of the phosphorylation and dephosphorylation steps in the first modification cycle is less than this ratio in the second cycle. We also show that multisite phosphorylation enlarges the region of kinetic parameter values in which bistability appears, but does not generate multistability. In addition, we conclude that a cascade of phosphorylation/dephosphorylation cycles generates multiple steady states in the absence of feedback or feedforward loops. Our results show that bistable behavior in covalent modification cascades relies not only on the structure and regulatory pattern of feedback/feedforward loops, but also on the kinetic characteristics of their component proteins.

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.

Format
SBML (L2V4)
Related Publication
  • Bistability from double phosphorylation in signal transduction. Kinetic and structural requirements.
  • Ortega F, Garcés JL, Mas F, Kholodenko BN, Cascante M
  • The FEBS journal , 9/ 2006 , Volume 273 , pages: 3915-3926 , PubMed ID: 16934033
  • Centre for Research in Theoretical Chemistry, Scientific Park of Barcelona, Spain.
  • Previous studies have suggested that positive feedback loops and ultrasensitivity are prerequisites for bistability in covalent modification cascades. However, it was recently shown that bistability and hysteresis can also arise solely from multisite phosphorylation. Here we analytically demonstrate that double phosphorylation of a protein (or other covalent modification) generates bistability only if: (a) the two phosphorylation (or the two dephosphorylation) reactions are catalyzed by the same enzyme; (b) the kinetics operate at least partly in the zero-order region; and (c) the ratio of the catalytic constants of the phosphorylation and dephosphorylation steps in the first modification cycle is less than this ratio in the second cycle. We also show that multisite phosphorylation enlarges the region of kinetic parameter values in which bistability appears, but does not generate multistability. In addition, we conclude that a cascade of phosphorylation/dephosphorylation cycles generates multiple steady states in the absence of feedback or feedforward loops. Our results show that bistable behavior in covalent modification cascades relies not only on the structure and regulatory pattern of feedback/feedforward loops, but also on the kinetic characteristics of their component proteins.
Contributors
Vijayalakshmi Chelliah

Metadata information

is
BioModels Database MODEL1008100000
BioModels Database BIOMD0000000258
isDescribedBy
PubMed 16934033
hasTaxon
isVersionOf
Gene Ontology protein phosphorylation

Curation status
Curated

Tags
Name Description Size Actions

Model files

BIOMD0000000258_url.xml SBML L2V4 representation of Ortega2006 - bistability from double phosphorylation in signal transduction 13.47 KB Preview | Download

Additional files

BIOMD0000000258.png Auto-generated Reaction graph (PNG) 18.09 KB Preview | Download
BIOMD0000000258.pdf Auto-generated PDF file 148.72 KB Preview | Download
BIOMD0000000258.xpp Auto-generated XPP file 1.88 KB Preview | Download
BIOMD0000000258.m Auto-generated Octave file 3.70 KB Preview | Download
BIOMD0000000258.svg Auto-generated Reaction graph (SVG) 8.43 KB Preview | Download
BIOMD0000000258.vcml Auto-generated VCML file 20.13 KB Preview | Download
BIOMD0000000258-biopax3.owl Auto-generated BioPAX (Level 3) 11.34 KB Preview | Download
BIOMD0000000258_urn.xml Auto-generated SBML file with URNs 12.80 KB Preview | Download
BIOMD0000000258-biopax2.owl Auto-generated BioPAX (Level 2) 8.08 KB Preview | Download
BIOMD0000000258.sci Auto-generated Scilab file 1.72 KB Preview | Download

  • Model originally submitted by : Vijayalakshmi Chelliah
  • Submitted: 10-Aug-2010 13:59:29
  • Last Modified: 22-May-2015 14:16:21
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 22-May-2015 14:16:21
    • Submitted by: Vijayalakshmi Chelliah
    • With comment: Current version of Ortega2006 - bistability from double phosphorylation in signal transduction
  • Version: 1 public model Download this version
    • Submitted on: 10-Aug-2010 13:59:29
    • Submitted by: Vijayalakshmi Chelliah
    • With comment: Original import of Ortega2006_bistability_doublePhosphorylation
Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
alpha

Protein ; protein polypeptide chain
0.462 mol
beta

Phosphoprotein
0.2 mol
gamma

Phosphoprotein
0.338 mol
Reactions
Reactions Rate Parameters
(alpha) => (beta)

([Protein; protein polypeptide chain]) => ([Phosphoprotein])
Vm1*alpha/Ks1/(1+alpha/Ks1+beta/Ks3)

Vm1*[Protein; protein polypeptide chain]/Ks1/(1+[Protein; protein polypeptide chain]/Ks1+[Phosphoprotein]/Ks3)
Ks3 = 0.01; Ks1 = 0.01; Vm1 = 1.0
(beta) => (alpha)

([Phosphoprotein]) => ([Protein; protein polypeptide chain])
r24*Vm1/Chi14*beta/Ks2/(1+gamma/Ks4+beta/Ks2)

r24*Vm1/Chi14*[Phosphoprotein]/Ks2/(1+[Phosphoprotein]/Ks4+[Phosphoprotein]/Ks2)
Ks4 = 0.01; r24 = 1.0; Chi14 = 1.1; Ks2 = 0.01; Vm1 = 1.0
(gamma) => (beta)

([Phosphoprotein]) => ([Phosphoprotein])
Vm1/Chi14*gamma/Ks4/(1+gamma/Ks4+beta/Ks2)

Vm1/Chi14*[Phosphoprotein]/Ks4/(1+[Phosphoprotein]/Ks4+[Phosphoprotein]/Ks2)
Ks4 = 0.01; Chi14 = 1.1; Ks2 = 0.01; Vm1 = 1.0
Curator's comment:
(added: 10 Aug 2010, 14:03:52, updated: 10 Aug 2010, 14:03:52)
The figures 5A, 5B and 5C of the reference publication is reproduced. The model was integrated and simulated using Copasi v4.5.31.