Markevich2004_MAPK_phosphoRandomElementary

  public model
Model Identifier
BIOMD0000000028
Short description

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.

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 MODEL6618552953
BioModels Database BIOMD0000000028
isDescribedBy
PubMed 14744999
hasTaxon
Taxonomy Xenopus laevis
isVersionOf
Gene Ontology GO:0000165

Curation status
Curated

Tags
Name Description Size Actions

Model files

BIOMD0000000028_url.xml SBML L2V4 representation of Markevich2004_MAPK_phosphoRandomElementary 43.53 KB Preview | Download

Additional files

BIOMD0000000028.xpp Auto-generated XPP file 6.60 KB Preview | Download
BIOMD0000000028.sci Auto-generated Scilab file 5.89 KB Preview | Download
BIOMD0000000028-biopax2.owl Auto-generated BioPAX (Level 2) 36.78 KB Preview | Download
BIOMD0000000028.png Auto-generated Reaction graph (PNG) 148.71 KB Preview | Download
BIOMD0000000028.svg Auto-generated Reaction graph (SVG) 48.61 KB Preview | Download
BIOMD0000000028.vcml Auto-generated VCML file 67.01 KB Preview | Download
BIOMD0000000028.m Auto-generated Octave file 9.66 KB Preview | Download
BIOMD0000000028-biopax3.owl Auto-generated BioPAX (Level 3) 59.22 KB Preview | Download
BIOMD0000000028.pdf Auto-generated PDF file 216.73 KB Preview | Download
BIOMD0000000028_urn.xml Auto-generated SBML file with URNs 46.67 KB Preview | Download

  • Model originally submitted by : Nicolas Le Novère
  • Submitted: 13-Sep-2005 14:36:04
  • Last Modified: 15-May-2012 22:42:30
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 15-May-2012 22:42:30
    • Submitted by: Nicolas Le Novère
    • With comment: Current version of Markevich2004_MAPK_phosphoRandomElementary
  • Version: 1 public model Download this version
    • Submitted on: 13-Sep-2005 14:36:04
    • Submitted by: Nicolas Le Novère
    • With comment: Original import of Markevich2004_MAPK_phosphoRandomElementary
Legends
: Variable used inside SBML models


Species
Reactions
Reactions Rate Parameters
(ERK-PY + MEK) => (ERK-PY_MEK)

([Mitogen-activated protein kinase 1] + [Dual specificity mitogen-activated protein kinase kinase 1]) => ([Dual specificity mitogen-activated protein kinase kinase 1; Mitogen-activated protein kinase 1])
cell*(k3*MpY*MEK-k_3*MpY_MEK)

cell*(k3*[Mitogen-activated protein kinase 1]*[Dual specificity mitogen-activated protein kinase kinase 1]-k_3*[Dual specificity mitogen-activated protein kinase kinase 1; Mitogen-activated protein kinase 1])
k3 = 0.025; k_3 = 1.0
(ERK-PY_MEK) => (ERK-PP + MEK)

([Dual specificity mitogen-activated protein kinase kinase 1; Mitogen-activated protein kinase 1]) => ([Mitogen-activated protein kinase 1] + [Dual specificity mitogen-activated protein kinase kinase 1])
cell*k4*MpY_MEK

cell*k4*[Dual specificity mitogen-activated protein kinase kinase 1; Mitogen-activated protein kinase 1]
k4 = 0.007
(ERK-PT + MEK) => (ERK-PT_MEK)

([Mitogen-activated protein kinase 1] + [Dual specificity mitogen-activated protein kinase kinase 1]) => ([Mitogen-activated protein kinase 1; Dual specificity mitogen-activated protein kinase kinase 1])
cell*(k7*MpT*MEK-k_7*MpT_MEK)

cell*(k7*[Mitogen-activated protein kinase 1]*[Dual specificity mitogen-activated protein kinase kinase 1]-k_7*[Mitogen-activated protein kinase 1; Dual specificity mitogen-activated protein kinase kinase 1])
k_7 = 1.0; k7 = 0.005
(ERK_MEK_T) => (ERK-PT + MEK)

([Mitogen-activated protein kinase 1; Dual specificity mitogen-activated protein kinase kinase 1]) => ([Mitogen-activated protein kinase 1] + [Dual specificity mitogen-activated protein kinase kinase 1])
cell*k6*M_MEK_T

cell*k6*[Mitogen-activated protein kinase 1; Dual specificity mitogen-activated protein kinase kinase 1]
k6 = 0.008
(ERK-PT + MKP3) => (ERK-PT_MKP3_T)

([Mitogen-activated protein kinase 1] + [Dual specificity protein phosphatase 1-B]) => ([Mitogen-activated protein kinase 1; Dual specificity protein phosphatase 1-B])
cell*(h4*MpT*MKP3-h_4*MpT_MKP3_T)

cell*(h4*[Mitogen-activated protein kinase 1]*[Dual specificity protein phosphatase 1-B]-h_4*[Mitogen-activated protein kinase 1; Dual specificity protein phosphatase 1-B])
h4 = 0.01; h_4 = 1.0
(ERK_MKP3_Y) => (ERK + MKP3)

([Dual specificity protein phosphatase 1-B; Mitogen-activated protein kinase 1]) => ([Mitogen-activated protein kinase 1] + [Dual specificity protein phosphatase 1-B])
cell*(h9*M_MKP3_Y-h_9*M*MKP3)

cell*(h9*[Dual specificity protein phosphatase 1-B; Mitogen-activated protein kinase 1]-h_9*[Mitogen-activated protein kinase 1]*[Dual specificity protein phosphatase 1-B])
h9 = 0.14; h_9 = 0.0018
(ERK-PP_MKP3) => (ERK-PT_MKP3_Y)

([Mitogen-activated protein kinase 1; Dual specificity protein phosphatase 1-B]) => ([Mitogen-activated protein kinase 1; Dual specificity protein phosphatase 1-B])
cell*h2*Mpp_MKP3

cell*h2*[Mitogen-activated protein kinase 1; Dual specificity protein phosphatase 1-B]
h2 = 0.092
(ERK_MKP3_T) => (ERK + MKP3)

([Mitogen-activated protein kinase 1; Dual specificity protein phosphatase 1-B]) => ([Mitogen-activated protein kinase 1] + [Dual specificity protein phosphatase 1-B])
cell*(h6*M_MKP3_T-h_6*M*MKP3)

cell*(h6*[Mitogen-activated protein kinase 1; Dual specificity protein phosphatase 1-B]-h_6*[Mitogen-activated protein kinase 1]*[Dual specificity protein phosphatase 1-B])
h6 = 0.086; h_6 = 0.0011
Curator's comment:
(added: 25 Nov 2010, 23:39:56, updated: 25 Nov 2010, 23:39:56)
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).