Signaling through receptors and scaffolds: independent interactions reduce combinatorial complexity

¹ Thomas Jefferson University

^* To whom correspondence should be addressed. E-mail: boris.kholodenko{at}jefferson.edu.

Submitted on February 1, 2005
Revised on April 19, 2005
Accepted on 23 May 2005

	Abstract

Following activation, many receptors and their adapter proteins act as scaffolds displaying numerous docking sites and engaging multiple targets. The consequent assemblage of a variety of protein complexes results in a combinatorial increase in the number of feasible molecular species presenting different states of a receptor-scaffold signaling module. Tens of thousands of such "micro-states" emerge even for the initial signal propagation events, greatly impeding a quantitative analysis of networks. Here, we demonstrate that the assumption of independence of molecular events occurring at distinct sites enables us to approximate a mechanistic picture of all possible micro-states by a macro-description of states of separate domains, i.e., macro-states that correspond to experimentally verifiable variables. This analysis dissects a highly branched network into interacting pathways originated by protein complexes assembled on different sites of receptors and scaffolds. We specify when the temporal dynamics of any given micro-state can be expressed using the product of the relative concentrations of individual sites. The methods presented here are equally applicable to deterministic and stochastic calculations of the temporal dynamics. Our domain-oriented approach drastically reduces the number of states, processes and kinetic parameters to be considered for quantification of complex signaling networks that propagate distinct physiological responses.

Key Words: adapter protein, complex signaling networks, model reduction, quantitative analysis, time series, tyrosine kinase receptor

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