Paxillin regulation of the integrin-cytoskeletal link

保持组成我们身体的各个单位或细胞附着在一起的机制被称为细胞粘附。因此，细胞粘附形成将细胞保持在一起的“胶水”，并且有两种类型。在第一种类型中，一个细胞表面上的细胞粘附蛋白直接与相邻细胞表面上的类似蛋白结合。在第二种类型中，这是本研究的重点，细胞表面的细胞粘附蛋白，称为整合素，与细胞外的蛋白质网络，细胞外基质结合。细胞外基质蛋白由周围的细胞制造，运输到外部，并组装成稳定的网络。在许多情况下，这种基质形成于两层细胞之间，并用于将两者连接在一起，因为每层中的整合素结合到相同的居间细胞外基质。这方面的一个例子是我们皮肤中两层之间的联系，表皮和真皮。如果粘合机制有缺陷，那么两层就会分离，导致起泡。整合素不仅需要与细胞外基质紧密结合，而且还需要穿过形成细胞外表面的膜，并连接到细胞内的蛋白质。细胞内的整联蛋白部分为组装复杂的连接结构提供了一个锚，该连接结构由许多蛋白质构建块组成，将整联蛋白连接到细胞内的纤维，细胞骨架，决定细胞形状，就像水泥中的钢筋。最近的研究结果表明，连接结构中的一些蛋白质通过再次拆开结构来发挥作用。这些蛋白质之一被称为桩蛋白，其协调参与整合素和细胞骨架之间的连接的分解的蛋白质的活性。桩蛋白作为一种支架将许多蛋白质结合在一起，就像一串葡萄的茎。能够关闭整合素粘附对于在细胞外基质上爬行的细胞是重要的，因为细胞前部的细胞表面部分粘附在基质上，使得细胞骨架可以将细胞移动到这些附着点上，然后附着必须在细胞后部被破坏，使得细胞可以继续移动。这项研究的目的是发现更多关于桩蛋白和拆卸蛋白如何工作，以及它们如何以不同的方式用于从单细胞受精卵发育成生物体。这些不同的方式包括引导细胞在发育中的胚胎周围运动，允许细胞具有特殊的能力，并在细胞层之间形成稳定的强粘附点。由于这些都是复杂的问题，我们选择了一种简单的动物来研究，果蝇，这样我们就有最好的机会解决这些问题。果蝇使用整合素的方式和我们一样，例如，果蝇中有缺陷的整合素也会引起水泡。我们的目标是发现桩蛋白功能的基本机制，所有动物之间共享。在未来，我们将能够将这些知识应用于治疗由整合素功能缺陷引起的疾病，包括皮肤起泡疾病和异常凝血，以及整合素活性使疾病恶化的疾病，例如通过帮助癌细胞在体内移动。

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.