Paxillin regulation of the integrin-cytoskeletal link

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The mechanism that keeps the individual units that make up our body, or cells, attached together is known as cell adhesion. Thus, cell adhesion forms the 'glue' that holds cells together, and is of two types. In the first type, cell adhesion proteins on the surface of one cell bind directly to similar proteins on the surface of the adjacent cell. In the second type, which is the focus of this research, cell adhesion proteins on the surface of the cell, called integrins, bind to a network of proteins outside the cell, the extracellular matrix. Extracellular matrix proteins are made by the surrounding cells, transported outside, and assembled into a stable network. In many cases this matrix forms between two layers of cells and is used to link the two together, as the integrins in each layer bind to the same intervening extracellular matrix. An example of this is the link between two layers in our skin, the epidermis and the dermis. If the adhesion mechanism is faulty, then the two layers separate, resulting in a blister. Not only do integrins need to bind tightly to the extracellular matrix, but they also cross the membrane that forms the outer surface of the cell, and connect to proteins inside the cell. The portion of the integrin inside the cell provides an anchor for the assembly of a complicated linking structure, composed of many proteins building blocks, that connects integrins to the fibres within the cell, the cytoskeleton, that dictate cell shape, like reinforcing rods within cement. Recent findings have shown that some of the proteins within the linking structure act by taking the structure apart again. One of these proteins is called paxillin, which coordinates the activities of the proteins involved in the disassembly of the link between integrins and the cytoskeleton. Paxillin works as a scaffold that holds many proteins together, like the stem of a bunch of grapes. Being able to turn integrin adhesion off is important for cells that crawl over the extracellular matrix, as portions of the cell surface at the front of the cell stick to the matrix, so that the cytoskeleton can move the cell over these attachment points, and then the attachment must be broken down at the rear of the cell so that the cell can continue to move. The goal of this research is to discover more about how paxillin and the disassembly proteins work and how they are used in different ways in the development of an organism from a single cell, the fertilised egg. These different ways include directing cell movements around the developing embryo, permitting cells to take on special abilities, and forming stable points of strong adhesion between cell layers. As these are complex problems, we have chosen a simple animal to study, the fruit fly Drosophila, so that we have the best chance of solving them. Fruit flies use integrins in the same way as we do, as exemplified by the fact that faulty integrins in the fly also cause blisters. We aim to discover the basic mechanisms of paxillin function that are shared between all animals. In future, we will be able to apply this knowledge to the treatment of medical conditions arising from defects in integrin function, which include skin blistering diseases and aberrant blood clotting, as well as diseases where integrin activity makes the illness worse, for example by helping cancerous cells move around the body.