This Article Full Text Full Text (PDF) Supplement All Versions of this Article: biophysj.107.109132v1 93/7/2279    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Legewie, S. Articles by Herzel, H. Search for Related Content PubMed PubMed Citation Articles by Legewie, S. Articles by Herzel, H.

Competing Docking Interactions can Bring About Bistability in the MAPK Cascade

Stefan Legewie ^*, Birgit Schoeberl , Nils Blüthgen ^* and Hanspeter Herzel ^*

^* Institute for Theoretical Biology, Humboldt University, Berlin, Germany; and Merrimack Pharmaceuticals, Cambridge, Massachusetts

Correspondence: Address reprint requests to Stefan Legewie, Institute for Theoretical Biology, Humboldt University, Invalidenstrasse 43 D, 10115 Berlin, Germany. Tel.: 0049-30-2093-8496; Fax: 0049-30-2093-8801; E-mail: s.legewie{at}biologie.hu-berlin.de.

Mitogen-activated protein kinases are crucial regulators of various cell fate decisions including proliferation, differentiation, and apoptosis. Depending on the cellular context, the Raf-Mek-Erk mitogen-activated protein kinase cascade responds to extracellular stimuli in an all-or-none manner, most likely due to bistable behavior. Here, we describe a previously unrecognized positive-feedback mechanism that emerges from experimentally observed sequestration effects in the core Raf-Mek-Erk cascade. Unphosphorylated/monophosphorylated Erk sequesters Mek into Raf-inaccessible complexes upon weak stimulation, and thereby inhibits cascade activation. Mek, once phosphorylated by Raf, triggers Erk phosphorylation, which in turn induces dissociation of Raf-inaccessible Mek-Erk heterodimers, and thus further amplifies Mek phosphorylation. We show that this positive circuit can bring about bistability for parameter values measured experimentally in living cells. Previous studies revealed that bistability can also arise from enzyme depletion effects in the Erk double (de)phosphorylation cycle. We demonstrate that the feedback mechanism proposed in this article synergizes with such enzyme depletion effects to bring about a much larger bistable range than either mechanism alone. Our results show that stable docking interactions and competition effects, which are common in protein kinase cascades, can result in sequestration-based feedback, and thus can have profound effects on the qualitative behavior of signaling pathways.

This article has been cited by other articles:

				S. Legewie, D. Dienst, A. Wilde, H. Herzel, and I. M. Axmann Small RNAs Establish Delays and Temporal Thresholds in Gene Expression Biophys. J., October 1, 2008; 95(7): 3232 - 3238. [Abstract] [Full Text] [PDF]

				P. Smolen, D. A. Baxter, and J. H. Byrne Bistable MAP kinase activity: a plausible mechanism contributing to maintenance of late long-term potentiation Am J Physiol Cell Physiol, February 1, 2008; 294(2): C503 - C515. [Abstract] [Full Text] [PDF]