Paxillin regulation of the integrin-cytoskeletal link

将组成我们身体的单个单位或细胞连接在一起的机制被称为细胞粘附。因此，细胞粘附形成了将细胞粘合在一起的“胶水”，它有两种类型。在第一种类型中，一个细胞表面的细胞粘附蛋白直接与相邻细胞表面的类似蛋白结合。在第二种类型中，也是本研究的重点，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结合，即细胞外基质。细胞外基质蛋白由周围细胞制造，向外运输，并组装成一个稳定的网络。在许多情况下，这种基质在两层细胞之间形成，并用于将两层细胞连接在一起，因为每层中的整合素都与相同的细胞外基质结合。这方面的一个例子是我们皮肤的两层，表皮和真皮层之间的联系。如果粘附机制出现故障，那么两层就会分离，从而产生水泡。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，并与细胞内的蛋白质连接。细胞内的整合素部分为复杂连接结构的组装提供了一个锚点，该结构由许多蛋白质组成，将整合素与细胞内的纤维（细胞骨架）连接起来，细胞骨架决定了细胞的形状，就像水泥中的加强棒一样。最近的发现表明，连接结构中的一些蛋白质通过再次将结构拆开来起作用。其中一种蛋白质被称为paxillin，它协调参与整合素和细胞骨架之间连接的分解的蛋白质的活动。帕罗西林就像一个支架，把许多蛋白质固定在一起，就像一串葡萄的茎。对于在细胞外基质上爬行的细胞来说，能够关闭整合素的粘附是很重要的，因为细胞表面前部的部分细胞粘附在基质上，这样细胞骨架就可以在这些附着点上移动细胞，然后附着点必须在细胞后部被分解，这样细胞才能继续移动。这项研究的目标是发现更多关于帕西林和分解蛋白的工作原理，以及它们如何以不同的方式在从一个单细胞受精卵发育成一个有机体的过程中发挥作用。这些不同的方式包括指导发育中的胚胎周围的细胞运动，允许细胞具有特殊能力，以及在细胞层之间形成强粘附的稳定点。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它们。果蝇使用整合素的方式和我们一样，苍蝇体内有缺陷的整合素也会引起水泡。我们的目标是发现所有动物共有的帕罗西林作用的基本机制。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血液凝固，以及整合素活性使疾病恶化的疾病，例如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.