Spatial and temporal dynamics of signalling pathways

A problem presented at the UK MMSG Reading 2011.

Presented by:
Prof Rob Krams (Department of Bioengineering, Imperial College London)
MJ Baines, BS Bhattacharya, Yh Davit, L Dyson, MP Edgington, R Krams, S Modhara, CP Please, JH Siggers, AF Smith, J Tindall

Problem Description

Cardiovascular disease (CVD) carries a high mortality with 4.3 million deaths in Europe and over 2.0 million deaths in the European Union (EU). Atherosclerosis, which underlies the CVD related mortality, has been associated with a number of risk factors (eg. hypercholesteraemia, hypertension, diabetes and others) that are associated with progression of the disease. These risk factors predict a random or a homogeneous distribution of plaques over the arterial system, but this differs from clinical observations that indicate plaques are confined to curved vessels, bifurcations and side branches. It has been postulated that disturbances of the blood flow pattern at these sites could induce atherosclerosis there, either through a direct effect on the endothelial cells or by remote transport effects.

Endothelial cells sense the local blood flow by detecting the shear stress, although the mechanism by which they do this is not fully understood. Approximately 7 intracellular signalling pathways are modified by mechanical stimulation, and these regulate 8 acknowledged transcription factors, which leads to a total of around 2000 genes responsible for the response to shear stress. It is currently unknown which signalling pathway is dominant under flow conditions and what controls this activity. It has been suggested that specificity of signalling pathways resides in their spatial organisation and indeed for the mitogen activated protein kinase (MAPK) pathways, one of the most fundamental for mechanotransduction, signalling specificity is by scaffolding proteins.

The Study Group participants are asked to develop a model of an endothelial cell exposed to flow, which includes the activation of the MAPK pathway through RAS signalling. In the first instance, activation of the MAPK pathway will be simulated without spatial control, and then spatial control will be incorporated through scaffolds to be included in the model. Finally, if time permits, the polarisation of endothelial cells (RAS activation upstream and RAC activation downstream) will be considered.

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Study Group Report

Signal transduction pathways such as the MAPK cascade are complex. In addition to the reactions involved in activating the KSR-Ras-Raf complex to initiate the cascade, there are the phosphorylation steps involved in releasing activated MAPK molecules which can influence transcription. These reactions are further complicated by the necessity of KSR and MAPK to diffuse within the crowded medium of the cytoplasm in order to reach the cellular locations where they may have an effect. By considering reactions between relevant molecules and receptors at the cell membrane, and diffusion of these molecules towards the membrane, we have created a preliminary model to describe the processes involved in the MAPK pathway.

The ultimate aim of this work is to extend existing models by including the spatial dependence of the concentration of KSR and MAPK within the cytoplasm. We have presented a simple but insightful model which, to our knowledge, is the first to include the effect of diffusion in the study of mechano-transduction dynamics and thus represents a significant new approach to this problem, laying the foundations for further work. The potential for extending this project is vast.

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Follow-Up Activities

The following follow-up meetings have occured to continue work on aspects of this problem:

2012 Signalling Pathways Follow-up Meeting
Tuesday 24th January 2012, Imperial College