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

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. In 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. We 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. Our results uncover the various capabilities, constraints and trade-offs associated with the 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.Open Acces

An investigation of spatial signal transduction in cellular networks

<p>Abstract</p> <p>Background</p> <p>Spatial signal transduction plays a vital role in many intracellular processes such as eukaryotic chemotaxis, polarity generation and cell division. Furthermore it is being increasingly realized that the spatial dimension to signalling may play an important role in other apparently purely temporal signal transduction processes. It is increasingly being recognized that a conceptual basis for studying spatial signal transduction in signalling networks is necessary.</p> <p>Results</p> <p>In this work we examine spatial signal transduction in a series of standard motifs/networks. These networks include coherent and incoherent feedforward, positive and negative feedback, cyclic motifs, monostable switches, bistable switches and negative feedback oscillators. In all these cases, the driving signal has spatial variation. For each network we consider two cases, one where all elements are essentially non-diffusible, and the other where one of the network elements may be highly diffusible. A careful analysis of steady state signal transduction provides many insights into the behaviour of all these modules. While in the non-diffusible case for the most part, spatial signalling reflects the temporal signalling behaviour, in the diffusible cases, we see significant differences between spatial and temporal signalling characteristics. Our results demonstrate that the presence of diffusible elements in the networks provides important constraints and capabilities for signalling.</p> <p>Conclusions</p> <p>Our results provide a systematic basis for understanding spatial signalling in networks and the role of diffusible elements therein. This provides many insights into the signal transduction capabilities and constraints in such networks and suggests ways in which cellular signalling and information processing is organized to conform to or bypass those constraints. It also provides a framework for starting to understand the organization and regulation of spatial signal transduction in individual processes.</p