Huang1996 - Ultrasensitivity in MAPK cascade

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Short description
Huang1996 - Ultrasensitivity in MAPK cascade

The temporal sequence of kinase activation, from MAPKKK (activated RAF) to the final effector MAPK (activated ERK), is described here. It is observed from the model that there is an increase in sensitivity along the levels of the cascade, where the activity of MAPK reaches its maximal before MAPKKK.

This model is described in the article:

Huang CY, Ferrell JE Jr
Proc. Natl. Acad. Sci. U.S.A. 1996:93(19):10078-83

Abstract:

The mitogen-activated protein kinase (MAPK) cascade is a highly conserved series of three protein kinases implicated in diverse biological processes. Here we demonstrate that the cascade arrangement has unexpected consequences for the dynamics of MAPK signaling. We solved the rate equations for the cascade numerically and found that MAPK is predicted to behave like a highly cooperative enzyme, even though it was not assumed that any of the enzymes in the cascade were regulated cooperatively. Measurements of MAPK activation in Xenopus oocyte extracts confirmed this prediction. The stimulus/response curve of the MAPK was found to be as steep as that of a cooperative enzyme with a Hill coefficient of 4-5, well in excess of that of the classical allosteric protein hemoglobin. The shape of the MAPK stimulus/ response curve may make the cascade particularly appropriate for mediating processes like mitogenesis, cell fate induction, and oocyte maturation, where a cell switches from one discrete state to another.

The species K_PP_norm, KKK_P_norm and KK_PP_norm are the relative concentrations of the active MAPK, MAPKK and MAPKKK, that is the double, or single resp. phophorylated forms divided by the total concentrations of each kinase. For MAPK additionally the also active MAPK divided by the maximal concentration of active MAPK is given by rel_K_PP_max. The parameter K_PP_norm_max, the maximal ratio of active MapK, has to be calculated for each change of parameters.

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.

Format
SBML (L2V4)
Related Publication
  • Ultrasensitivity in the mitogen-activated protein kinase cascade.
  • Huang CY, Ferrell JE Jr
  • Proceedings of the National Academy of Sciences of the United States of America , 9/ 1996 , Volume 93 , pages: 10078-10083
  • Department of Molecular Pharmacology, Stanford University School of Medicine, CA 94305-5332, USA.
  • The mitogen-activated protein kinase (MAPK) cascade is a highly conserved series of three protein kinases implicated in diverse biological processes. Here we demonstrate that the cascade arrangement has unexpected consequences for the dynamics of MAPK signaling. We solved the rate equations for the cascade numerically and found that MAPK is predicted to behave like a highly cooperative enzyme, even though it was not assumed that any of the enzymes in the cascade were regulated cooperatively. Measurements of MAPK activation in Xenopus oocyte extracts confirmed this prediction. The stimulus/response curve of the MAPK was found to be as steep as that of a cooperative enzyme with a Hill coefficient of 4-5, well in excess of that of the classical allosteric protein hemoglobin. The shape of the MAPK stimulus/ response curve may make the cascade particularly appropriate for mediating processes like mitogenesis, cell fate induction, and oocyte maturation, where a cell switches from one discrete state to another.
Contributors
Nicolas Le Novère

Metadata information

is
BioModels Database MODEL6615048798
BioModels Database BIOMD0000000009
isDescribedBy
PubMed 8816754
hasTaxon
Taxonomy Xenopus laevis
isVersionOf
Gene Ontology MAPK cascade
isHomologTo
Reactome REACT_634
Curation status
Curated
  • Model originally submitted by : Nicolas Le Novère
  • Submitted: Sep 13, 2005 1:37:52 PM
  • Last Modified: Jun 2, 2015 1:02:44 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Jun 2, 2015 1:02:44 PM
    • Submitted by: Nicolas Le Novère
    • With comment: Current version of Huang1996 - Ultrasensitivity in MAPK cascade
  • Version: 1 public model Download this version
    • Submitted on: Sep 13, 2005 1:37:52 PM
    • Submitted by: Nicolas Le Novère
    • With comment: Original import of BIOMD0000000009.xml.origin
Curator's comment:
(added: 09 Dec 2014, 14:50:07, updated: 09 Dec 2014, 14:50:07)
Figure 2B of the reference publication has been reproduced. The simulation was done using Copasi v4.14 (Build 89) and plot was generated using Gnuplot.