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A Signal Transduction Pathway Model Prototype I: From Agonist to Cellular Endpoint

Department of Molecular Pharmacology and Drug Discovery Program, Northwestern University, Chicago, Illinois

Correspondence: Address reprint requests to Prof. Thomas J. Lukas, Dept. of Molecular Pharmacology and Biological Chemistry, Northwestern University, Ward 8-200, 303 E. Chicago Ave., Mail Code S-215, Chicago, IL 60611. Tel.: 312-503-0847; E-mail: t-lukas{at}northwestern.edu.

The postgenomic era is providing a wealth of information about the genes involved in many cellular processes. However, the ability to apply this information to understanding cellular signal transduction is limited by the lack of tools that quantitatively describe cellular signaling processes. The objective of the current studies is to provide a framework for modeling cellular signaling processes beginning at a plasma membrane receptor and ending with a measurable endpoint in the signaling process. Agonist-induced Ca²⁺ mobilization coupled to down stream phosphorylation events was modeled using knowledge of in vitro and in vivo process parameters. The simulation process includes several modules that describe cellular processes involving receptor activation phosphoinositide metabolism, Ca²⁺-release, and activation of a calmodulin-dependent protein kinase. A Virtual Cell-based simulation was formulated using available literature data and compared to new and existing experimental results. The model provides a new approach to facilitate hypothesis-driven investigation and experimental design based upon simulation results. These investigations may be directed at the timing of multiple phosphorylation/dephosphorylation events affecting key enzymatic activities in the signaling pathway.

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