Employing systems biology to quantify receptor tyrosine kinase signaling in time and space

Abstract

Environmental cues received by plasma membrane receptors are processed and encoded into complex spatiotemporal response patterns of protein phosphorylation networks, which generate signaling specificity. The emerging synergistic, experimental computational approach is presented, which provides insights into the intricate relationships between stimuli and cellular responses. Computational models reveal how positive and negative feedback circuits and other kinetic mechanisms enable signaling networks to amplify signals, reduce noise, and generate complex nonlinear responses, including oscillations, ultrasensitive switches, and discontinuous bistable dynamics; and many of these predictions have been verified experimentally. The analysis of the spatial signaling dynamics highlights an important distinction between electronic and living circuitry and shows how intriguing signaling phenomena are brought about by the heterogeneous cellular architecture and diffusion. Spatial gradients of signaling activities emerge as hallmarks of living cells. These gradients guide pivotal physiological processes, such as cell motility and mitosis, but also impose a need for facilitated signal propagation, which involves trafficking of endosomes and signaling complexes along microtubules and traveling waves of phosphorylated kinases. © 2007 Humana Press Inc.