Substrate-Induced Modulation of Signal Transduction Networks

The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. ABSTRACT Biological signal transduction networks are commonly viewed as circuits that pass-along information-in the process amplifying, enhancing sensitivity, or performing other signal-processing tasks-to transcriptional and other components. Here, we report on a " reverse-causality " phenomenon, which we call substrate-induced modulation. Employing a combination of analytical and experimental tools, we discovered that signal communication is modulated, in a surprising way, by substrate components. Specifically, we found non-intuitive timescale changes: for a first-order covalent modification cycle, the presence of substrates speeds-up signaling; by contrast, for a zeroth-order cycle, substrates slowdown signaling. The bandwidth, the range of frequency where the system can process information, decreases in the presence of substrates. This way, substrates participate in establishing trade-offs between noise-filtering capabilities and a circuit's ability to process high-frequency stimulation. We conclude that the view of signaling networks as independent relay devices, whose operating characteristics are not affected by their substrates, is fundamentally flawed. Our study highlights a fundamental and hereto unrecognized property of intracellular communication, bringing up issues that are generally relevant to biological signal transmission.