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BIOMD0000000027 - Markevich2004_MAPK_orderedMM

 

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Reference Publication
Publication ID: 14744999
Markevich NI, Hoek JB, Kholodenko BN.
Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades.
J. Cell Biol. 2004 Feb; 164(3): 353-359
Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, 1020 Locust St., Philadelphia, PA 19107, USA.  [more]
Model
Original Model: BIOMD0000000027.xml.origin
Submitter: Nicolas Le Novère
Submission ID: MODEL6618496308
Submission Date: 13 Sep 2005 13:35:17 UTC
Last Modification Date: 15 May 2012 21:42:12 UTC
Creation Date: 23 May 2005 13:41:40 UTC
Encoders:  Nicolas Le Novère
set #1
bqbiol:occursIn Taxonomy Xenopus laevis
bqbiol:isVersionOf Gene Ontology MAPK cascade
Notes

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 in the main 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.

Model
Publication ID: 14744999 Submission Date: 13 Sep 2005 13:35:17 UTC Last Modification Date: 15 May 2012 21:42:12 UTC Creation Date: 23 May 2005 13:41:40 UTC
Mathematical expressions
Reactions
phosphorylation of MAPK phosphorylation of P-MAPK dephosphorylation of PP-MAPK dephosphorylation of P-MAPK
Physical entities
Compartments Species
uVol M Mp Mpp
MAPKK MKP3  
Global parameters
k1cat Km1 k2cat Km2
k3cat Km3 k4cat Km4
Km5      
Reactions (4)
 
 phosphorylation of MAPK [M] → [Mp];   {MAPKK}
 
 phosphorylation of P-MAPK [Mp] → [Mpp];   {MAPKK} , {M}
 
 dephosphorylation of PP-MAPK [Mpp] → [Mp];   {MKP3} , {M}
 
 dephosphorylation of P-MAPK [Mp] → [M];   {MKP3} , {Mpp}
 
   Spatial dimensions: 3.0  Compartment size: 1.0
 
 M
Compartment: uVol
Initial amount: 500.0
 
 Mp
Compartment: uVol
Initial amount: 0.0
 
 Mpp
Compartment: uVol
Initial amount: 0.0
 
 MAPKK
Compartment: uVol
Initial amount: 50.0
Constant
 
 MKP3
Compartment: uVol
Initial amount: 100.0
Constant
 
Global Parameters (9)
 
   k1cat
Value: 0.01
Constant
 
   Km1
Value: 50.0
Constant
 
   k2cat
Value: 15.0
Constant
 
   Km2
Value: 500.0
Constant
 
   k3cat
Value: 0.084
Constant
 
   Km3
Value: 22.0
Constant
 
   k4cat
Value: 0.06
Constant
 
   Km4
Value: 18.0
Constant
 
   Km5
Value: 78.0
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000027

Curator's comment: (updated: 25 Nov 2010 22:51:51 GMT)

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.

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