Markevich2004 - MAPK double phosphorylation, ordered Michaelis-Menton

  public model
Model Identifier
BIOMD0000000027
Short description
Markevich2004 - MAPK double phosphorylation, ordered Michaelis-Menton
The model corresponds to the schemas 1 and 2 of Markevich et al 2004, as described in the figure 1 and modelled using Michaelis-Menten like kinetics. Phosphorylations and dephosphorylations follow distributive ordered kinetics. It reproduces figure 3 of the main article.

This model is described in the article:

Markevich NI, Hoek JB, Kholodenko BN.
J. Cell Biol. 2004 Feb; 164(3): 353-359

Abstract:

Mitogen-activated protein kinase (MAPK) cascades can operate as bistable switches residing in either of two different stable states. MAPK cascades are often embedded in positive feedback loops, which are considered to be a prerequisite for bistable behavior. Here we demonstrate that in the absence of any imposed feedback regulation, bistability and hysteresis can arise solely from a distributive kinetic mechanism of the two-site MAPK phosphorylation and dephosphorylation. Importantly, the reported kinetic properties of the kinase (MEK) and phosphatase (MKP3) of extracellular signal-regulated kinase (ERK) fulfill the essential requirements for generating a bistable switch at a single MAPK cascade level. Likewise, a cycle where multisite phosphorylations are performed by different kinases, but dephosphorylation reactions are catalyzed by the same phosphatase, can also exhibit bistability and hysteresis. Hence, bistability induced by multisite covalent modification may be a widespread mechanism of the control of protein activity.

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
  • Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades.
  • Markevich NI, Hoek JB, Kholodenko BN
  • The Journal of cell biology , 2/ 2004 , Volume 164 , pages: 353-359 , PubMed ID: 14744999
  • Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, 1020 Locust St., Philadelphia, PA 19107, USA.
  • Mitogen-activated protein kinase (MAPK) cascades can operate as bistable switches residing in either of two different stable states. MAPK cascades are often embedded in positive feedback loops, which are considered to be a prerequisite for bistable behavior. Here we demonstrate that in the absence of any imposed feedback regulation, bistability and hysteresis can arise solely from a distributive kinetic mechanism of the two-site MAPK phosphorylation and dephosphorylation. Importantly, the reported kinetic properties of the kinase (MEK) and phosphatase (MKP3) of extracellular signal-regulated kinase (ERK) fulfill the essential requirements for generating a bistable switch at a single MAPK cascade level. Likewise, a cycle where multisite phosphorylations are performed by different kinases, but dephosphorylation reactions are catalyzed by the same phosphatase, can also exhibit bistability and hysteresis. Hence, bistability induced by multisite covalent modification may be a widespread mechanism of the control of protein activity.
Contributors
Nicolas Le Novère

Metadata information

is
BioModels Database MODEL6618496308
BioModels Database BIOMD0000000027
isDescribedBy
PubMed 14744999
hasTaxon
Taxonomy Xenopus laevis
isVersionOf
Gene Ontology MAPK cascade

Curation status
Curated

Tags
Name Description Size Actions

Model files

BIOMD0000000027_url.xml SBML L2V4 representation of Markevich2004 - MAPK double phosphorylation, ordered Michaelis-Menton 17.79 KB Preview | Download

Additional files

BIOMD0000000027.m Auto-generated Octave file 4.07 KB Preview | Download
BIOMD0000000027.png Auto-generated Reaction graph (PNG) 39.13 KB Preview | Download
BIOMD0000000027.xpp Auto-generated XPP file 2.10 KB Preview | Download
BIOMD0000000027-biopax3.owl Auto-generated BioPAX (Level 3) 15.28 KB Preview | Download
BIOMD0000000027.sci Auto-generated Scilab file 2.00 KB Preview | Download
BIOMD0000000027.svg Auto-generated Reaction graph (SVG) 13.83 KB Preview | Download
BIOMD0000000027_urn.xml Auto-generated SBML file with URNs 16.89 KB Preview | Download
BIOMD0000000027.vcml Auto-generated VCML file 26.46 KB Preview | Download
BIOMD0000000027.pdf Auto-generated PDF file 149.90 KB Preview | Download
BIOMD0000000027-biopax2.owl Auto-generated BioPAX (Level 2) 11.83 KB Preview | Download

  • Model originally submitted by : Nicolas Le Novère
  • Submitted: 13-Sep-2005 14:35:17
  • Last Modified: 01-Jun-2015 14:12:49
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 01-Jun-2015 14:12:49
    • Submitted by: Nicolas Le Novère
    • With comment: Current version of Markevich2004 - MAPK double phosphorylation, ordered Michaelis-Menton
  • Version: 1 public model Download this version
    • Submitted on: 13-Sep-2005 14:35:17
    • Submitted by: Nicolas Le Novère
    • With comment: Original import of Markevich2004_MAPK_orderedMM
Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
M

Mitogen-activated protein kinase 1
500.0 nmol
Mp

Mitogen-activated protein kinase 1
0.0 nmol
Mpp

Mitogen-activated protein kinase 1
0.0 nmol
Reactions
Reactions Rate Parameters
(M) => (Mp)

([Mitogen-activated protein kinase 1]) => ([Mitogen-activated protein kinase 1])
uVol*k1cat*MAPKK*M/Km1/(1+M/Km1+Mp/Km2)

uVol*k1cat*[Dual specificity mitogen-activated protein kinase kinase 1]*[Mitogen-activated protein kinase 1]/Km1/(1+[Mitogen-activated protein kinase 1]/Km1+[Mitogen-activated protein kinase 1]/Km2)
Km2 = 500.0; k1cat = 0.01; Km1 = 50.0
Curator's comment:
(added: 25 Nov 2010, 22:51:51, updated: 25 Nov 2010, 22:51:51)
Reproduction of figure 3 from the original publication using Copasi 4.6. To calculate all steady states a parameter scan was performed over the initial concentrations of MAPKK and M, with the sum of the initial concentrations of Mpp and M being held constant at 500 nM. For MAPKK the scanned range was from 0 to 100 with 100 intervals, for M from 450 to 100 with 5 intervals.