regulation of signal duration and the statistical dynamics of kinase activation by scaffold proteins调节信号的持续时间和统计动态脚手架蛋白激酶激活.pdfVIP

Regulation of Signal Duration and the Statistical Dynamics of Kinase Activation by Scaffold Proteins 1 1,2,3 Jason W. Locasale , Arup K. Chakraborty * 1 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, 2 Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, 3 Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America Abstract 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 calcu