In silico identification of potential therapeutic targets in the TGF-β signal transduction pathway

Abstract

The transforming growth factor-β (TGF-β) superfamily of cytokines controls fundamental cellular processes, such as proliferation, motility, differentiation, and apoptosis. This fundamental role is emphasized by the widespread presence of mutations of the core components of the TGF-β signal transduction pathway in a number of human diseases. Therefore, there is an increasing interest in the development of therapies to specifically target this pathway. Here we develop a computational approach to identify potential intervention points that are capable of restoring the normal signaling dynamics to the mutated system while maintaining the behavior of normal cells substantially unperturbed. We apply this approach explicitly to the TGF-β pathway to study the signaling dynamics of mutated and normal cells treated with inhibitory drugs and identify the processes in the pathway that are most susceptible to therapeutic intervention.