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BIOMD0000000010 - Kholodenko2000 - Ultrasensitivity and negative feedback bring oscillations in MAPK cascade

 

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Reference Publication
Publication ID: 10712587
Kholodenko BN.
Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades.
Eur. J. Biochem. 2000 Mar; 267(6): 1583-1588
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA. Boris.Kholodenko@mail.tju.edu  [more]
Model
Original Model: BIOMD0000000010.xml.origin
Submitter: Nicolas Le Novère
Submission ID: MODEL6615119181
Submission Date: 13 Sep 2005 20:39:02 UTC
Last Modification Date: 16 Jul 2013 18:04:39 UTC
Creation Date: 12 Feb 2005 08:18:12 UTC
Encoders:  Herbert Sauro
set #1
bqbiol:isVersionOf Gene Ontology MAPK cascade
bqbiol:isHomologTo Reactome REACT_634
bqbiol:occursIn Taxonomy Xenopus laevis
Notes
Kholodenko2000 - Ultrasensitivity and negative feedback bring oscillations in MAPK cascade

The combination of ultrasensitivity and negative feedback bring sustained oscillations in the mitogen-activated protein kinase cascades.

This model is described in the article:

Kholodenko BN
Eur. J. Biochem. 2000; 267(6):1583-8

Abstract:

Functional organization of signal transduction into protein phosphorylation cascades, such as the mitogen-activated protein kinase (MAPK) cascades, greatly enhances the sensitivity of cellular targets to external stimuli. The sensitivity increases multiplicatively with the number of cascade levels, so that a tiny change in a stimulus results in a large change in the response, the phenomenon referred to as ultrasensitivity. In a variety of cell types, the MAPK cascades are imbedded in long feedback loops, positive or negative, depending on whether the terminal kinase stimulates or inhibits the activation of the initial level. Here we demonstrate that a negative feedback loop combined with intrinsic ultrasensitivity of the MAPK cascade can bring about sustained oscillations in MAPK phosphorylation. Based on recent kinetic data on the MAPK cascades, we predict that the period of oscillations can range from minutes to hours. The phosphorylation level can vary between the base level and almost 100% of the total protein. The oscillations of the phosphorylation cascades and slow protein diffusion in the cytoplasm can lead to intracellular waves of phospho-proteins.

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.

Model
Publication ID: 10712587 Submission Date: 13 Sep 2005 20:39:02 UTC Last Modification Date: 16 Jul 2013 18:04:39 UTC Creation Date: 12 Feb 2005 08:18:12 UTC
Mathematical expressions
Reactions
MAPKKK activation MAPKKK inactivation phosphorylation of MAPKK phosphorylation of MAPKK-P
dephosphorylation of MAPKK-PP dephosphorylation of MAPKK-P phosphorylation of MAPK phosphorylation of MAPK-P
dephosphorylation of MAPK-PP dephosphorylation of MAPK-P    
Physical entities
Compartments Species
uVol Mos Mos-P Mek1
Mek1-P Mek1-PP Erk2
Erk2-P Erk2-PP  
Reactions (10)
 
 MAPKKK activation [Mos] → [Mos-P];   {Erk2-PP}
 
 MAPKKK inactivation [Mos-P] → [Mos];  
 
 phosphorylation of MAPKK [Mek1] → [Mek1-P];   {Mos-P}
 
 phosphorylation of MAPKK-P [Mek1-P] → [Mek1-PP];   {Mos-P}
 
 dephosphorylation of MAPKK-PP [Mek1-PP] → [Mek1-P];  
 
 dephosphorylation of MAPKK-P [Mek1-P] → [Mek1];  
 
 phosphorylation of MAPK [Erk2] → [Erk2-P];   {Mek1-PP}
 
 phosphorylation of MAPK-P [Erk2-P] → [Erk2-PP];   {Mek1-PP}
 
 dephosphorylation of MAPK-PP [Erk2-PP] → [Erk2-P];  
 
 dephosphorylation of MAPK-P [Erk2-P] → [Erk2];  
 
   Spatial dimensions: 3.0  Compartment size: 1.0
 
 Mos
Compartment: uVol
Initial concentration: 90.0
 
 Mos-P
Compartment: uVol
Initial concentration: 10.0
 
 Mek1
Compartment: uVol
Initial concentration: 280.0
 
 Mek1-P
Compartment: uVol
Initial concentration: 10.0
 
 Mek1-PP
Compartment: uVol
Initial concentration: 10.0
 
 Erk2
Compartment: uVol
Initial concentration: 280.0
 
 Erk2-P
Compartment: uVol
Initial concentration: 10.0
 
 Erk2-PP
Compartment: uVol
Initial concentration: 10.0
 
MAPKKK activation (4)
 
   V1
Value: 2.5
Constant
 
   Ki
Value: 9.0
Constant
 
   n
Value: 1.0
Constant
 
   K1
Value: 10.0
Constant
 
MAPKKK inactivation (2)
 
   V2
Value: 0.25
Constant
 
   KK2
Value: 8.0
Constant
 
phosphorylation of MAPKK (2)
 
   k3
Value: 0.025
Constant
 
   KK3
Value: 15.0
Constant
 
phosphorylation of MAPKK-P (2)
 
   k4
Value: 0.025
Constant
 
   KK4
Value: 15.0
Constant
 
dephosphorylation of MAPKK-PP (2)
 
   V5
Value: 0.75
Constant
 
   KK5
Value: 15.0
Constant
 
dephosphorylation of MAPKK-P (2)
 
   V6
Value: 0.75
Constant
 
   KK6
Value: 15.0
Constant
 
phosphorylation of MAPK (2)
 
   k7
Value: 0.025
Constant
 
   KK7
Value: 15.0
Constant
 
phosphorylation of MAPK-P (2)
 
   k8
Value: 0.025
Constant
 
   KK8
Value: 15.0
Constant
 
dephosphorylation of MAPK-PP (2)
 
   V9
Value: 0.5
Constant
 
   KK9
Value: 15.0
Constant
 
dephosphorylation of MAPK-P (2)
 
   V10
Value: 0.5
Constant
 
   KK10
Value: 15.0
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000010

Curator's comment: (updated: 15 Jul 2013 13:30:51 PDT)

Figure 2A of the reference publication has been reproduced using Copasi 4.10 (Build 55). The oscillations of active MAPK (PP-Erk2) and inactive MAPK (Erk2) is shown here.

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