Signal Processing by the Control Cycle of the IKK Kinase in the NFκB Signaling Axis

Abstract

The inflammatory response transcription factor NFkB, a key component of the immune system, shows intricate stimulus-specific temporal dynamics. It has been proposed that those dynamics play a role controlling the genetic outcome of inflammatory signals and hence the specificity of the cellular response to cytokines and other stimuli. As malfunctions in NFkB signaling are linked to many immune diseases as well as the onset and development of cancers, it is of considerable clinical interest to understand the mechanisms that control NFkB dynamics. Here we focus on IKK, a hub kinase that targets the main negative regulators of NFκB activity and onto which diverse receptor associated signals converge. Biochemical evidence suggests that IKK is regulated via a multi-state regulatory cycle and therefore we hypothesize that it can operate as a modulator, actively reshaping the signals generated at the receptor proximal level. Here we demonstrate that the IKK control cycle can function in at least three dynamical regimes some of them producing signals comprising multiple temporal phases with distinct coding capabilities. In particular, we show that the simplest three-state regulatory cycle generates biphasic signals with an early phase well suited for relaying information about stimuli amplitude and a late phase more apt for encoding stimulus duration. This study demonstrates that an actively regulated hub kinase can play a crucial role functioning as a signal “categorizer” classifying complex incoming signals into a limited set of output activities. Expanding the general analysis to a more detailed model of IKK regulation revealed how specific features of IKK and NFkB activities are controlled by the different enzymatic mechanisms within the kinase cycle.