E-cadherin subcomplexes: function and regulation by microtubules

我们身体中相邻的单位或细胞相互连接的机制被称为细胞-细胞黏附。最近的研究表明，细胞间的黏附对于相邻细胞之间的沟通也很重要，以决定何时分裂、迁移或死亡。特定的细胞黏附蛋白确保细胞与细胞之间的黏附：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。一种主要的细胞黏附蛋白被称为E-钙粘蛋白。E-钙粘附素提供了上皮细胞之间的细胞间黏附：这些细胞勾勒出身体所有的空洞和表面结构。在细胞中，E-钙粘附素黏附形成一条被称为带状黏附的细带，它勾勒出细胞的外围，并将其连接到多个相邻细胞。E-钙粘附素在早期阶段对身体的正常发育至关重要。此外，错误的E-钙粘附素黏附通过增加生长和转移而促进癌症的进展。为了正确的细胞-细胞黏附，至关重要的是将小带黏附放置在距离面对空洞的细胞表面特定的距离处。更出乎意料的是，细胞还小心地控制E-钙粘附素在细胞周围的分布，即在小带内的分布。虽然大多数细胞的分布是均匀的，但也发现了越来越多的E-钙粘蛋白分布不对称的病例。这种不对称分布在发育中的动物中的作用还有待测试。我们选择了一种简单的动物--果蝇来研究这个问题。果蝇使用E-钙粘素的方式和我们一样。例如，如果果蝇胚胎缺乏E-钙粘附素，它们在发育早期就会死亡，因为上皮细胞不能保持彼此的联系，组织会分裂。我们最近的发现表明，在果蝇胚胎的上皮细胞中存在两种不同的E-钙粘蛋白。一个种群均匀地分布在细胞周围。另一个种群分布不对称。这第二类E-钙粘蛋白与名为Bazooka/PAR-3的蛋白质特别相关，其不对称性需要细胞骨架的一个亚型：称为微管的长管结构。这些发现提出了几个问题，这些问题是这项提案的重点。首先，不同的E-钙粘附素群体是否具有不同的功能？如果他们这样做了，那么就有可能在不影响其他人的情况下干扰一个人，这可能有助于控制E-钙粘附素的异常功能。其次，我们能否识别出与不同的E-钙粘附素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，仅存在于一个或另一个群体中的蛋白质可能被用来调节特定E-cad群体的水平、分布或作用，从而成为药物发现的靶点，此外，还可能被证明标记出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-钙粘蛋白的不对称性。了解这一机制将使我们能够操纵细胞中E-钙粘附素的不对称性，并特别控制这种群体。我们预计我们将发现所有动物共享的基本机制。未来，我们将能够将这一知识应用于E-钙粘附素功能缺陷引起的医疗疾病的治疗，如上皮源性肿瘤。例如，如果我们发现只有一组E-钙粘附素可以防止癌症过度生长，并且我们确定了专门结合这一组E-钙粘附素的分子，那么就有可能寻找攻击这一组E-钙粘附素的药物来减少癌症生长，而不会破坏周围非肿瘤细胞中的E-钙粘附素黏附。

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.