Cellular signalling transduction has been studied using experimental, computational and theoretical approaches. The regulation of signal transduction in organisms is a key systems aspect which determines the pathway behaviour and function.
However, due to the lack of systematic engineering-based understanding of cellular signalling behaviour and pathways, the underlying design principles and potential controlling methods of cellular signal transductions and correlated pathological states in a large number of cellular signalling pathways still remain uncharted. This thesis focusses on two studies involving regulation of signal transduction.
The first study focusses on feedback regulation, specifically multiple feedback regulation. In order to gain an insight into regulatory effects mechanisms of multiple feedback pathways in regulating cellular signal transduction, generic models of enzymatic modification and substrate modification signalling cascades were built and studied with different types and different architectures of the feedback regulatory pathways. Hereby, an understanding and synthesis of how the system output responded to different structures of single and double feedback regulations in both classes of signalling pathways was characterised. Building on this, multiple feedback regulation in open systems, as well as feedback regulation in bacterial two component systems were also studied.
The other study focussed on membrane level regulation of signalling in ovarian cancer. Cancer has been recognised as a serious disease for centuries, it is primarily triggered by misfunctions of cellular signal transduction. We focus here on AXL signalling in ovarian cancer to understand this pathological state in cells, the receptor tyrosine kinase AXL and its relating membrane and cytosol signalling pathways, during the metastasis of tumorous cells, were studied and analysed computationally, building on and collaborating with experimental work. A key ingredient here is the membrane-level compartmentalization of phosphatases involved in the regulation. We built a systems framework to analyse the interplay of key factors affecting AXL signalling. This also reveals underlying design principles for the regulation of AXL signalling which are more broadly applicable. Finally, some basic analysis of feedback regulation building on this was also studied.