Elucidating the spatial organization and control of information processing in cell signalling networks: from network and enzymatic building blocks to concrete systems

摘要

Cells function and survive by making decisions in response to dynamic environments. The core controllers of decision-making are highly complex intracellular networks of proteins and genes, which harbour sophisticated information processing capabilities. The effect of spatial organization and control of signaling networks is typically ignored. However, the role of space in signalling networks is being increasingly recognized. While there are some experimental and modelling efforts that incorporate spatial aspects in specific cellular contexts, the role of spatial regulation of signalling across different cell networks remains largely unexplored.udIn this thesis, we utilize a combination of mathematical modeling, systems engineering and in silico synthetic approaches to understand the spatial organization and control of signaling networks at multiple levels. We examine spatial effects in representative networks and enzymatic building blocks, including typical network modules, covalent modification cycles and enzymatic modification cascades and pathways. We complement these studies by dissecting the role of spatial regulation in the concrete context of the Caulobacter cell cycle, which involves specific combinations of these building blocks. In another investigation, we examine the organization of spatially regulated signaling networks underlying chemotaxis.udWe explicitly examine the effects of diffusion and its interplay with spatially varying signals and localization/compartmentalization of signalling entities and gain key insights into the interplay of these factors. At the network level, examining typical network modules reveals how introduction of diffusion/global entities may significantly distort temporal characteristics and introduce new types of signal transduction characteristics. At the enzymatic level, dissecting spatial regulation in enzymatic modules highlights the subtle effect and new facets that arise due to the interweaving of cycle kinetics and diffusion. The var- ious ways in which spatial compartmentalization affects pathway behaviour is revealed in the study of various types of signaling pathways. The study of spatial regulation of these enzymatic/network building blocks provides a systematic basis for understanding how spatial control can affect the spatiotemporal interactions driving Caulobacter cell cycle and we use an in-silico synthetic approach to create a platform for further understanding the functioning of the networks controlling this process. In a different study, we use a design approach to shed light on different signalling configurations of chemotactic networks that allow cells to exhibit both attractive and repulsive behaviour, in light of known signalling characteristics seen in cells.udOur results uncover the various capabilities, constraints and trade-offs associated withudthe spatial control of information processing in signalling networks, which come to the surface only if spatial factors are explicitly considered. Overall, using a focused multipronged approach reveals different facets of spatial regulation of signalling at multiple levels and in different contexts. Combining mathematical modelling, systems engineering and synthetic design approaches creates a powerful framework, which may be used to elucidate spatial control of information processing in multiple contexts and design synthetic systems that could fruitfully exploit spatial organization and regulation.