Mathematical modelling of the Jak-Stat1 signal transduction pathway

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The Jak/Stat1 signalling pathway exemplifies a direct signal transduction system that conveys external signals from the cellular membrane receptor to nuclear target genes. This work aims to develop a thorough theoretical understanding of the quantitative and qualitative aspects of Jak/Stat1 signal transduction through various theoretical approaches and experimental measurements. The thesis is divided into three parts. Part I introduces the biological system and presents a detailed model of Jak/Stat1 signalling, including parameter estimation and verification against independent experimental data. Numerical simulations explore the dynamics of Stat1 signalling and the control properties of system processes. Part II offers a general treatment of Jak/Stat signal transduction with analytical methods, simplifying the detailed model into a linear core model. This core model establishes a relationship between the lifetimes of subcellular Stat fractions and their steady-state concentrations. Additionally, it models general signal transduction systems as networks of linear state transitions, deriving a rule that links control distribution among network processes to steady-state occupancy. Part III tests the theoretical predictions regarding the control properties of Stat1 transport processes using experimental data from various Stat1 transport mutants, comparing their altered phenotypes to model simulations. The high regulatory potentia