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.
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2 February 2004
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January 26 2004
Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades
Nick I. Markevich,
Nick I. Markevich
Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107
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Jan B. Hoek,
Jan B. Hoek
Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107
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Boris N. Kholodenko
Boris N. Kholodenko
Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107
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Nick I. Markevich
Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107
Jan B. Hoek
Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107
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: [email protected]
The online version of this article includes supplemental material.
Abbreviations used in this paper: ERK, extracellular signal–regulated kinase; MAPKK, MAPK kinase; MEK, ERK kinase; MKP, MAP kinase phosphatase.
Received:
August 11 2003
Accepted:
December 19 2003
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2004
J Cell Biol (2004) 164 (3): 353–359.
Article history
Received:
August 11 2003
Accepted:
December 19 2003
Citation
Nick I. Markevich, Jan B. Hoek, Boris N. Kholodenko; Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades . J Cell Biol 2 February 2004; 164 (3): 353–359. doi: https://doi.org/10.1083/jcb.200308060
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