Regulation of Signal Duration and the Statistical Dynamics of Kinase Activation by Scaffold Proteins

Scaffolding proteins that direct the assembly of multiple kinases into a spatially localized signaling complex are often essential for the maintenance of an appropriate biological response. Although scaffolds are widely believed to have dramatic effects on the dynamics of signal propagation, the mechanisms that underlie these consequences are not well understood. Here, Monte Carlo simulations of a model kinase cascade are used to investigate how the temporal characteristics of signaling cascades can be influenced by the presence of scaffold proteins. Specifically, we examine the effects of spatially localizing kinase components on a scaffold on signaling dynamics. The simulations indicate that a major effect that scaffolds exert on the dynamics of cell signaling is to control how the activation of protein kinases is distributed over time. Scaffolds can influence the timing of kinase activation by allowing for kinases to become activated over a broad range of times, thus allowing for signaling at both early and late times. Scaffold concentrations that result in optimal signal amplitude also result in the broadest distributions of times over which kinases are activated. These calculations provide insights into one mechanism that describes how the duration of a signal can potentially be regulated in a scaffold mediated protein kinase cascade. Our results illustrate another complexity in the broad array of control properties that emerge from the physical effects of spatially localizing components of kinase cascades on scaffold proteins.Author Summary: Signal transduction is the science of cellular communication. Cells detect signals from their environment and use them to make decisions such as whether or when to proliferate. Tight regulation of signal transduction is required for all healthy cells, and aberrant signaling leads to countless diseases such as cancer and diabetes. For example, in higher organisms such as mammals, signal transduction that leads to cell proliferation is often guided by a scaffold protein. Scaffolding proteins direct the assembly of multiple proteins involved in cell signaling by providing a platform for these proteins to carry out efficient signal transmission. Although scaffolds are widely believed to have dramatic effects on how signal transduction is carried out, the mechanisms that underlie these consequences are not well understood. Therefore, we used a computational approach that simulates the behavior of a model signal transduction module comprising a set of proteins in the presence of a scaffold. The simulations reveal mechanisms for how scaffolds can dynamically regulate the timing of cell signaling. Scaffolds allow for controlled levels of signal that are delivered inside the cell at appropriate times. Our findings support the possibility that these signaling dynamics regulated by scaffolds affect cell decision-making in many medically important intracellular processes.