Kindlin and EGFR control convergent pathways to regulate epithelial cell function

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This research relates to two proteins that we know are not correctly controlled in patients with skin blistering disease. These proteins are called Kindlin-1 and Epidermal Growth Factor Receptor (or EGFR). We already know that lack of Kindlin-1 in the skin leads to Kindler Syndrome - a rare genetic disorder that results in skin blistering and sometimes leads to skin cancer. We have also recently identified a new group of patients that have defective EGFR protein and this similarly results in fragile skin. Our recent research on these two proteins strongly suggests that the observed clinical defects in the patients are partly caused by similar processes going wrong. This defect is mainly in the ability of cells to stick, or 'adhere' to the proteins that surround them in the skin. Normal functioning of the adhesion process is critical to health, and if it goes wrong, the sort of diseases that might occur include skin fragility, psoriasis, cancer, reduced immunity and inflammation. The research we would like to do now involves analysing Kindlin-1 and EGFR function in more detail. We firstly want to know precisely how these proteins work together to contribute to normal skin function. We plan to use a number of biochemical and microscopy techniques to answer questions such as: do these two proteins bind together in cells; how does loss of one or the other upset the ability of cells to adhere to proteins around them, and how do the common 'targets' of this protein complex also control this process? In our research we would also like to create more complex models to allow us to study Kindlin-1 and EGFR function in an intact organism. The reason we want to do this is because we would like to find out how these proteins behave in a more 'real' setting where there are other cells and tissues that might alter how these proteins behave. We will use a very well characterized model of epidermal blistering in the Fruitfly for this purpose. These animals are much easier, cheaper and faster to work with than mice and have versions of all of the genes/proteins we are planning to study, so are ideal for our experiments. By combining the information we get from experiments in cells, human tissues and the Fruitfly model, we can also start to plan potential corrective treatments with genes, proteins and drugs, work that could lead to improvements for patients in the future. Such work could lead to less skin blistering and improved quality of life in this and other families that have defects in Kindlin-1 or EGFR. The work is expected to expand our knowledge of the fundamentally important basic science topic of cell adhesion to surrounding tissues as well as the physiological maintenance of healthy skin.