Kholodenko2000 - Ultrasensitivity and negative feedback bring oscillations in MAPK cascade

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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.

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Format
SBML (L2V4)
Related Publication
  • Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades.
  • Kholodenko BN
  • European journal of biochemistry , 3/ 2000 , Volume 267 , pages: 1583-1588
  • Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA. Boris.Kholodenko@mail.tju.edu
  • 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.
Contributors
Nicolas Le Novère

Metadata information

is
BioModels Database MODEL6615119181
BioModels Database BIOMD0000000010
isDescribedBy
PubMed 10712587
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 1:39:02 PM
  • Last Modified: Jun 2, 2015 1:04:33 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Jun 2, 2015 1:04:33 PM
    • Submitted by: Nicolas Le Novère
    • With comment: Current version of Kholodenko2000 - Ultrasensitivity and negative feedback bring oscillations in MAPK cascade
  • Version: 1 public model Download this version
    • Submitted on: Sep 13, 2005 1:39:02 PM
    • Submitted by: Nicolas Le Novère
    • With comment: Original import of BIOMD0000000010.xml.origin
Curator's comment:
(added: 15 Jul 2013, 13:30:51, updated: 15 Jul 2013, 13:30:51)
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.