title: Multi-Compartmentalisation in the MAPK Signalling Pathway Contributes to the Emergence of Oscillatory Behaviour and to Ultrasensitivity.
abstract: Signal transduction through the Mitogen Activated Protein Kinase (MAPK) pathways is evolutionarily highly conserved. Many cells use these pathways to interpret changes to their environment and respond accordingly. The pathways are central to triggering diverse cellular responses such as survival, apoptosis, differentiation and proliferation. Though the interactions between the different MAPK pathways are complex, nevertheless, they maintain a high level of fidelity and specificity to the original signal. There are numerous theories explaining how fidelity and specificity arise within this complex context; spatio-temporal regulation of the pathways and feedback loops are thought to be very important. This paper presents an agent based computational model addressing multi-compartmentalisation and how this influences the dynamics of MAPK cascade activation. The model suggests that multi-compartmentalisation coupled with periodic MAPK kinase (MAPKK) activation may be critical factors for the emergence of oscillation and ultrasensitivity in the system. Finally, the model also establishes a link between the spatial arrangements of the cascade components and temporal activation mechanisms, and how both contribute to fidelity and specificity of MAPK mediated signalling.
authors.affiliation: Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom.|Department of Computer Science, University of Sheffield, Sheffield, United Kingdom.|INSIGNEO Institute for in silico Medicine, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Aban
authors.initials: A
authors.lastname: Shuaib
authors.affiliation: Department of Automatic Control and Systems Engineering, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Adam
authors.initials: A
authors.lastname: Hartwell
authors.affiliation: Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Endre
authors.initials: E
authors.lastname: Kiss-Toth
authors.affiliation: Department of Computer Science, University of Sheffield, Sheffield, United Kingdom.|Advanced Computing Research Centre, The Sheffield Bioincubator, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Mike
authors.initials: M
authors.lastname: Holcombe
mesh_terms: D000818:Animals; D019295:Computational Biology; D003198:Computer Simulation; D004789:Enzyme Activation / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation
chemical_list: D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases