BIOPHYSICAL THEORY AND MODELING |
Competing Docking Interactions Can Bring About Bistability in the MAPK Cascade
Stefan Legewie 1*, Birgit Schoeberl 2, Nils Bluthgen 3 and Hanspeter Herzel 4
1 Humboldt University
2 Merrimack Pharmaceuticals, Cambridge, USA
3 Manchester Integrative Biocenter, University of Manchester, UK
4 Institute for Theoretical Biology, Humboldt University, Berlin, Germany
* To whom correspondence should be addressed. E-mail: s.legewie{at}biologie.hu-berlin.de.
Submitted on March 19, 2007
Revised on May 17, 2007
Accepted on 18 May 2007
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Abstract |
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MAP kinases are crucial regulators of various cell fate decisions including proliferation, differentiation and apoptosis. Depending on the cellular context, the Raf-Mek-Erk MAPK cascade responds to extracellular stimuli in an all-or-none manner, most likely due to bistable behaviour. Here, we describe a previously unrecognized positive feedback mechanism that emerges from experimentally observed sequestration effects in the core Raf-Mek-Erk cascade. Un-/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 that were experimentally measured 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 paper 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 behaviour of signaling pathways.
Key Words:
Feedback, Kinase, Signaling, Stoichiometric Inhibition, Switch, Ultrasensitivity
