Journal
BIOSYSTEMS
Volume 83, Issue 2-3, Pages 152-166Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biosystems.2005.03.006
Keywords
scaffold; tyrosine kinase receptor; adapter protein; complex signaling networks; time series; model reduction
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Funding
- NIAAA NIH HHS [AA08714, R01 AA008714] Funding Source: Medline
- NIGMS NIH HHS [R01 GM059570, R01 GM059570-06, GM59570] Funding Source: Medline
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Membrane receptors and proteins involved in signal transduction display numerous binding domains and operate as molecular scaffolds generating a variety of parallel reactions and protein complexes. The resulting combinatorial explosion of the number of feasible chemical species and, hence, different states of a network greatly impedes mechanistic modeling of signaling systems. Here we present novel general principles and identify kinetic requirements that allow us to replace a mechanistic picture of all possible micro-states and transitions by a macro-description of states of separate binding sites of network proteins. This domain-oriented approach dramatically reduces computational models of cellular signaling networks by dissecting mechanistic trajectories into the dynamics of macro- and meso-variables. We specify the conditions when the temporal dynamics of micro-states can be exactly or approximately expressed in terms of the product of the relative concentrations of separate domains. We prove that our macro-modeling approach equally applies to signaling systems with low population levels, analyzed by stochastic rather than deterministic equations. Thus, our results greatly facilitate quantitative analysis and computational modeling of multi-protein signaling networks. (C) 2005 Elsevier Ireland Ltd. All rights reserved.
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