E-cadherin subcomplexes: function and regulation by microtubules

将我们体内相邻的单位或细胞相互连接的机制被称为细胞-细胞粘附。最近的研究表明，细胞间的粘附对于邻近细胞之间的交流也很重要，从而决定何时分裂、迁移或死亡。特异性细胞粘附蛋白确保细胞间的粘附：一个细胞表面的蛋白质直接与相邻细胞表面的类似蛋白质结合。一种主要的细胞粘附蛋白叫做e -钙粘蛋白。e -钙粘蛋白在上皮细胞之间提供细胞间的粘附，上皮细胞是勾勒出身体所有腔和表面结构的细胞。在细胞内，e -钙粘蛋白的粘附形成了一条细带，称为小带粘附，它勾勒出细胞的外围，并将其与多个相邻细胞连接起来。e -钙粘蛋白对身体的早期发育至关重要。此外，错误的e -钙粘蛋白粘附通过增加生长和转移来促进癌症的进展。为了使细胞与细胞之间有适当的黏附，将小带黏附物置于离腔面细胞表面一定距离的位置至关重要。更令人意想不到的是，细胞还小心翼翼地控制着e -钙粘蛋白在细胞周围和小带粘附体内的分布。虽然大多数细胞具有均匀分布，但已经发现越来越多的e -钙粘蛋白分布不对称的情况。这种不对称分布在发育中的动物身上的作用还有待检验。我们选择了一种简单的动物来研究这个问题，果蝇。果蝇使用e -钙粘蛋白的方式和我们一样。例如，如果果蝇胚胎缺乏e -钙粘蛋白，它们就会在发育早期死亡，因为上皮细胞不能保持彼此的接触，组织就会分裂。我们最近的研究结果表明，在果蝇胚胎上皮细胞中存在两种不同的e -钙粘蛋白群体。一个种群均匀分布在细胞周围。另一个种群是不对称分布的。第二种e -钙粘蛋白与一种叫做Bazooka/Par-3的蛋白质特别相关，它的不对称性需要细胞骨架的一种亚型：一种叫做微管的长管状结构。这些发现提出了几个问题，这些问题是本提案的重点。首先，不同的e -钙粘蛋白群体是否具有不同的功能？如果他们这样做，那么就有可能在不影响其他的情况下干扰其中一个，这可能有助于控制异常的e -钙粘蛋白功能。其次，我们能否识别出与不同e -钙粘蛋白群体一起工作的其他蛋白质，以帮助我们了解它们的作用。我们预计，仅存在于一种或其他群体中的蛋白质可能用于调节特定E-cad群体的水平、分布或作用，从而成为药物发现的靶标，此外还可能被证明是用于诊断目的的异常细胞。第三，我们希望发现微管如何控制e -钙粘蛋白不对称。了解这一机制将使我们能够在细胞中操纵e -钙粘蛋白的不对称性，并特异性地控制这一群体。我们期望能发现所有动物共有的基本机制。未来，我们将能够将这些知识应用于治疗由e -钙粘蛋白功能缺陷引起的疾病，如上皮源性肿瘤。例如，如果我们发现只有一种e -钙粘蛋白群可以阻止癌症的过度生长，并且我们确定了特异性结合e -钙粘蛋白群的分子，那么就有可能寻找攻击e -钙粘蛋白群的药物来减少癌症的生长，而不会破坏e -钙粘蛋白在周围非肿瘤细胞中的粘附。

The mechanism that attaches neighbouring units, or cells, in our body to each other is known as cell-cell adhesion. Recent work has demonstrated that cell-cell adhesion is also important for communication between the neighbouring cells to decide when to divide, migrate or die. Specific cell adhesion proteins ensure cell-cell adhesion: the proteins on the surface of one cell bind directly to similar proteins on the surface of adjacent cell. One of the major cell adhesion proteins is called E-cadherin. E-cadherin provides cell-cell adhesion between the epithelial cells: the cells that outline all cavities and surface structures of the body. In the cell, E-cadherin adhesion forms a thin belt, called zonula adherens that outlines the periphery of the cell and connects it to multiple neighbours. E-cadherin is vital for proper development of the body from very early stages. Furthermore, faulty E-cadherin adhesion contributes to cancer progression by increasing growth and metastasis.For proper cell-cell adhesion it is vital to position the zonula adherens at a particular distance from the surface of the cell that faces the cavity. More unexpectedly, the cell also carefully controls how E-cadherin is distributed around the circumference of the cell, within the zonula adherens. While most cells have an even distribution, an increasing number of cases have been discovered where E-cadherin is distributed asymmetrically. The function of such asymmetric distribution in the developing animal has yet to be tested. We have chosen a simple animal to study this problem, the fruit fly Drosophila. Fruit flies use E-cadherin in the same way as we do. For example, if fruit fly embryos lack E-cadherin they die early in development because epithelial cells cannot maintain contacts to each other and tissues fall apart. Our recent findings demonstrate that there are two different populations of E-cadherin in epithelial cells in Drosophila embryo. One population is distributed uniformly around cell periphery. Another population is distributed asymmetrically. This second population of E-cadherin is specifically associated with protein called Bazooka/Par-3, and its asymmetry requires a subtype of cytoskeleton: long tubular structures called microtubules. These findings raise several questions that are the focus of this proposal. First, do different E-cadherin populations have different functions? If they do then it may be possible to interfere with one without affecting the others, which could help control aberrant E-cadherin functions. Second, can we identify other proteins that work with the different E-cadherin populations to help us to understand what they do. We anticipate that proteins that are present in just one or other population may be used to regulate the levels, distribution or action of a particular E-cad population, and thus be targets for drug discovery, and in addition may prove to be mark out aberrant cells for diagnostic purposes. Third, we wish to discover how microtubules control E-cadherin asymmetry. Knowing this mechanism will allow us to manipulate E-cadherin asymmetry in the cells and specifically control this population.We anticipate that we will discover basic mechanisms that are shared between all animals. In future, we will be able to apply this knowledge to treatment of medical conditions arising from defects in E-cadherin function such as epithelia-derived tumours. For example, if we find that only one population of E-cadherin prevents excessive cancer growth, and we identify the molecules that specifically bind this population of E-cadherin, it will be possible to search for drugs that attack this population of E-cadherin to reduce cancer growth, without disrupting E-cadherin adhesion in the surrounding non-tumour cells.