Orchestration of adhesion signalling by the mechanosensors talin and vinculin.

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Cells continuously sense and produce their surrounding environment, which consists of fibrillar material the cells can attach to and is called extracellular matrix (ECM). Cell-ECM communication is particularly important during development or regeneration processes that require specific cellular responses to changing environments. Cellular responses comprise changes in motile behaviour (e.g. closing of wounds), contractility (e.g. functioning of the cardiovascular system) but also active remodelling of their ECM for the purpose of formation of new functional tissue. Many studies have focused on how cells sense their environment, but we are still far from understanding the mechanisms how cells perceive environmental signals and how they are translated into signals within cells that promote specific cellular responses.The environment of cells alters enormously during development, normal ageing, injury and certain diseases. For example, the mechanical properties of the ECM is thought to influence tumour progression and increased breast matrix stiffness is associated with poor survival. Stiffening of ECM also causes cardiovascular malfunctioning. Intriguingly cells contribute to the production of specific matrix on one hand but also respond to this produced environment on the other hand. Therefore, understanding how cells sense and produce their ECM environment is critically important if we want to get a step closer to treating the roots of diseases and promote regeneration.Cells can feel or sense their environment by exerting forces on it and probing its deformation. To transmit forces, they 'grab' neighbouring structures using surface proteins, which are called integrins. These integrins not only bind to the environment of the cells but also connect to a skeleton inside the cells. This link is not direct but is regulated by components that couple or uncouple the two. We published a number of manuscripts showing that two of these coupling proteins, called talin and vinculin, are central to sensing of environmental changes. They are particularly important to measure the stiffness of their environment, they control cell migration, as well as cell growth and differentiation. In this proposal we also present important pilot data demonstrating that vinculin is critical for ECM remodelling. However how they do this is still unclear. In order to investigate how these proteins regulate the response to their environment, and to what extent they are involved in telling cells how to behave, the two laboratories in the prestigious Cell-Matrix Centre at the University of Manchester will team up and combine their long-standing expertise with the field of integrins signalling and cell-matrix interactions. The proposed research aims to to (i) understand the role of mechanical signals in the activation of talin and vinculin, (ii) how this activation helps vinculin and talin to associate with a large number other proteins that serve to exert specific signals (e.g. cell migration or cell growth) (iii) how vinculin with the newly found association of another protein called tensin is contributing to the formation and remodelling of ECM environment. To reach our goals, we will not only use cutting edge microscopy, biochemisty and molecular biology techniques but also a newly generated intracellular system whereby we can target proteins to specific compartments (mitochondria) in the cells which enable us to visualise and probe molecular interactions and behaviour under defined conditions. Our results will be combined into a model that outlines and potentially predicts how cells interpret and remodel their environment. Ultimately, the knowledge gained may lead to important changes in how we currently envisage environmental changes and their contribution to diseases. This may also lead to changes in treatment of patients, and it might thus, for example, contribute to improvements in disease prevention and in regeneration processes.