Published online 26 January 2004. doi:10.1083/jcb.200308060
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 164, Number 3, 353-359
Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades
Nick I. Markevich,
Jan B. Hoek, and
Boris N. Kholodenko
Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107
Address correspondence to Boris N. Kholodenko, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, 1020 Locust St., Philadelphia, PA 19107. Tel.: (215) 503-1614. Fax: (215) 923-2218. email: Boris.Kholodenko{at}jefferson.edu
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 signalregulated 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.
Key Words: covalent protein modification; multisite phosphorylation; mitogen-activated protein kinase cascades; bistable biological switch
The online version of this article includes supplemental material.
Abbreviations used in this paper: ERK, extracellular signalregulated kinase; MAPKK, MAPK kinase; MEK, ERK kinase; MKP, MAP kinase phosphatase.

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