Markevich2004_MAPK_orderedMM2kinases

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Short description

The model describes the double phosphorylation of MAP kinase by an ordered mechanism using the Michaelis-Menten formalism. Two different enzymes, MAPKK1 and MAPKK2, successively phosphorylate the MAP kinase, but one and the same phosphatase dephosphorylates both sites.
The model reproduces figure S9 in the supplemental material of the article.

The model is further described in:
Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades. Markevich NI, Hoek JB, Kholodenko BN. J Cell Biol. 2004 Feb 2;164(3):353-9.
PMID: 14744999 ; DOI: 10.1083/jcb.200308060
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.

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.
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.

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
  • 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 MODEL6618738800
BioModels Database BIOMD0000000031
isDescribedBy
PubMed 14744999
hasTaxon
Taxonomy Xenopus laevis
isVersionOf
Gene Ontology GO:0000165
Curation status
Curated
  • Model originally submitted by : Nicolas Le Novère
  • Submitted: Sep 13, 2005 2:39:09 PM
  • Last Modified: May 15, 2012 10:43:41 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: May 15, 2012 10:43:41 PM
    • Submitted by: Nicolas Le Novère
    • With comment: Current version of Markevich2004_MAPK_orderedMM2kinases
  • Version: 1 public model Download this version
    • Submitted on: Sep 13, 2005 2:39:09 PM
    • Submitted by: Nicolas Le Novère
    • With comment: Original import of Markevich2004_MAPK_orderedMM2kinases
Curator's comment:
(added: 25 Nov 2010, 03:56:26, updated: 25 Nov 2010, 03:56:26)
Steady state behavior of the model for varying concentrations of MAPKK2 and MAPKK1, as in supplementary figure 9 of the article. Each curve is calculated for a different initial concentration of MAPKK1. A parameter scan to determine the steady states at different parameter values was performed using Copasi 4.6.