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BIOMD0000000028 - Markevich2004_MAPK_phosphoRandomElementary

 

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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: BIOMD0000000028.origin
Submitter: Nicolas Le Novère
Submission ID: MODEL6618552953
Submission Date: 13 Sep 2005 14:36:04 UTC
Last Modification Date: 15 May 2012 22:42:30 UTC
Creation Date: 23 May 2005 17:11:24 UTC
Encoders:  Nicolas Le Novère
set #1
bqbiol:hasTaxon Taxonomy Xenopus laevis
bqbiol:isVersionOf Gene Ontology MAPK cascade
Notes

The model corresponds to the schema 3 of Markevich et al 2004, as described in the figure 2 and the supplementary table S2. Phosphorylations follow distributive random kinetics, while dephosphorylations follow an ordered mechanism. The phosphorylations are modeled with three elementary reactions:
E+S<=>ES->E+P
The dephosphorylations are modeled with five elementary reactions:
E+S<=>ES->EP<=>E+P
The model reproduces figure 5 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 14:36:04 UTC Last Modification Date: 15 May 2012 22:42:30 UTC Creation Date: 23 May 2005 17:11:24 UTC
Mathematical expressions
Reactions
binding ERK and MEK tyr phosphorylation of ERK binding ERK-PY and MEK thr phosphorylation of ERK
binding ERK and MEK thr phosphorylation of ERK binding ERK-PT and MEK tyr phosphorylation of ERK
binding ERK-PP and MKP3 dephosphorylation of tyr on ERK-PP dissociation ERK-PT and MKP3 dephosphorylation of ERK-PT
binding ERK-PT and MKP3 dephosphorylation of ERK-PY dissociation ERK and MKP3 binding ERK-PY and MKP3
Dissociation ERK and MKP3      
Physical entities
Compartments Species
cell ERK ERK-PY ERK-PT
ERK-PP MEK MKP3
ERK-PY_MEK ERK-PT_MEK ERK_MEK_Y
ERK_MEK_T ERK-PP_MKP3 ERK-PY_MKP3
ERK-PT_MKP3_Y ERK-PT_MKP3_T ERK_MKP3_T
ERK_MKP3_Y    
Global parameters
k1 k_1 k2 k3
k_3 k4 k5 k_5
k6 k7 k_7 k8
h1 h_1 h2 h3
h_3 h4 h_4 h5
h6 h_6 h7 h_7
h8 h9 h_9  
Reactions (17)
 
 binding ERK and MEK [ERK] + [MEK] ↔ [ERK_MEK_Y];  
 
 tyr phosphorylation of ERK [ERK_MEK_Y] → [ERK-PY] + [MEK];  
 
 binding ERK-PY and MEK [ERK-PY] + [MEK] ↔ [ERK-PY_MEK];  
 
 thr phosphorylation of ERK [ERK-PY_MEK] → [ERK-PP] + [MEK];  
 
 binding ERK and MEK [ERK] + [MEK] ↔ [ERK_MEK_T];  
 
 thr phosphorylation of ERK [ERK_MEK_T] → [ERK-PT] + [MEK];  
 
 binding ERK-PT and MEK [ERK-PT] + [MEK] ↔ [ERK-PT_MEK];  
 
 tyr phosphorylation of ERK [ERK-PT_MEK] → [ERK-PP] + [MEK];  
 
 binding ERK-PP and MKP3 [ERK-PP] + [MKP3] ↔ [ERK-PP_MKP3];  
 
 dephosphorylation of tyr on ERK-PP [ERK-PP_MKP3] → [ERK-PT_MKP3_Y];  
 
 dissociation ERK-PT and MKP3 [ERK-PT_MKP3_Y] ↔ [ERK-PT] + [MKP3];  
 
 dephosphorylation of ERK-PT [ERK-PT_MKP3_T] → [ERK_MKP3_T];  
 
 binding ERK-PT and MKP3 [ERK-PT] + [MKP3] ↔ [ERK-PT_MKP3_T];  
 
 dephosphorylation of ERK-PY [ERK-PY_MKP3] → [ERK_MKP3_Y];  
 
 dissociation ERK and MKP3 [ERK_MKP3_T] ↔ [ERK] + [MKP3];  
 
 binding ERK-PY and MKP3 [ERK-PY] + [MKP3] ↔ [ERK-PY_MKP3];  
 
 Dissociation ERK and MKP3 [ERK_MKP3_Y] ↔ [ERK] + [MKP3];  
 
 cell Spatial dimensions: 3.0  Compartment size: 1.0
 
 ERK
Compartment: cell
Initial concentration: 800.0
 
 ERK-PY
Compartment: cell
Initial concentration: 0.0
 
 ERK-PT
Compartment: cell
Initial concentration: 0.0
 
 ERK-PP
Compartment: cell
Initial concentration: 0.0
 
 MEK
Compartment: cell
Initial concentration: 180.0
 
 MKP3
Compartment: cell
Initial concentration: 100.0
 
 ERK-PY_MEK
Compartment: cell
Initial concentration: 0.0
 
 ERK-PT_MEK
Compartment: cell
Initial concentration: 0.0
 
 ERK_MEK_Y
Compartment: cell
Initial concentration: 0.0
 
 ERK_MEK_T
Compartment: cell
Initial concentration: 0.0
 
 ERK-PP_MKP3
Compartment: cell
Initial concentration: 0.0
 
 ERK-PY_MKP3
Compartment: cell
Initial concentration: 0.0
 
 ERK-PT_MKP3_Y
Compartment: cell
Initial concentration: 0.0
 
 ERK-PT_MKP3_T
Compartment: cell
Initial concentration: 0.0
 
 ERK_MKP3_T
Compartment: cell
Initial concentration: 0.0
 
 ERK_MKP3_Y
Compartment: cell
Initial concentration: 0.0
 
Global Parameters (27)
 
   k1
Value: 0.005
Constant
 
   k_1
Value: 1.0
Constant
 
   k2
Value: 1.08
Constant
 
   k3
Value: 0.025
Constant
 
   k_3
Value: 1.0
Constant
 
   k4
Value: 0.007
Constant
 
   k5
Value: 0.05
Constant
 
   k_5
Value: 1.0
Constant
 
   k6
Value: 0.008
Constant
 
   k7
Value: 0.005
Constant
 
   k_7
Value: 1.0
Constant
 
   k8
Value: 0.45
Constant
 
   h1
Value: 0.045
Constant
 
   h_1
Value: 1.0
Constant
 
   h2
Value: 0.092
Constant
 
   h3
Value: 1.0
Constant
 
   h_3
Value: 0.01
Constant
 
   h4
Value: 0.01
Constant
 
   h_4
Value: 1.0
Constant
 
   h5
Value: 0.5
Constant
 
   h6
Value: 0.086
Constant
 
   h_6
Value: 0.0011
Constant
 
   h7
Value: 0.01
Constant
 
   h_7
Value: 1.0
Constant
 
   h8
Value: 0.47
Constant
 
   h9
Value: 0.14
Constant
 
   h_9
Value: 0.0018
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000028

Curator's comment: (updated: 25 Nov 2010 23:39:56 GMT)

Reproduction of figure 5 from the original publication using Copasi 4.6. The total concentration of ERK was 1000 nM, the one of MKP 180 nM. To obtain all steady states, two parameter scan were performed. One over the initial concentration of MEK from 300 to 400 nM with 100 intervals, and one over the initial concentration of ERK from 100 to 600 nM with 10 intervals. To assure the total concentration of ERK was 1000, ERKpp was set by the initial condition: 1000 - ERK(t=0).

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