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  • 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
  • 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.
Nicolas Le Novère

Metadata information

BioModels Database MODEL6618676537
BioModels Database BIOMD0000000030
PubMed 14744999
Taxonomy Xenopus laevis
Gene Ontology GO:0000165
Curation status
  • Model originally submitted by : Nicolas Le Novère
  • Submitted: Sep 13, 2005 2:38:08 PM
  • Last Modified: May 15, 2012 10:43:15 PM
  • Version: 2 public model Download this version
    • Submitted on: May 15, 2012 10:43:15 PM
    • Submitted by: Nicolas Le Novère
    • With comment: Current version of Markevich2004_MAPK_AllRandomElementary
  • Version: 1 public model Download this version
    • Submitted on: Sep 13, 2005 2:38:08 PM
    • Submitted by: Nicolas Le Novère
    • With comment: Original import of Markevich2005_MAPK_AllRandomElementary