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Role of Par-3 in E-cadherin recycling and signalling

Par-3 在 E-钙粘蛋白回收和信号转导中的作用

基本信息

批准号：
BB/P007503/1
负责人：
Natalia Bulgakova
金额：
$ 45.17万
依托单位：
University of Sheffield
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FP007503%2F1
关键词：
Role Par cadherin recycling signalling

项目摘要

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 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 epithelial cells: the cells that outline all cavities and surface structures of the body. E-cadherin is vital for proper development of the body from very early stages, whereas faulty E-cadherin adhesion contributes to cancer progression by increasing growth and metastasis. Two reasons make it important for a cell to be able to control amounts of E-cadherin at its surface. First, more E-cadherin results in stronger adhesion between neighbouring cells, and reverse. Increasing strength of adhesion is required in response to mechanical forces to prevent rapture of epithelia, whereas reducing strength of adhesion is needed when cells decide to exchange neighbours. Both mechanical stretching and neighbour exchange participate in normal development of an organism and its maintenance during adult life, and occur in disease. The second reason is that the amount of E-cadherin at the cell surface determines the number of E-cadherin molecules available to interact with other proteins that are involved in communication between cells. To be able to rapidly adjust the amount of E-cadherin at the cell surface according to the current needs of a cell, a portion of E-cadherin constantly circulates between cell surface and cell's interior, a process called recycling. To date, little is known about how E-cadherin recycling is regulated, for example why after E-cadherin moves inside the cell, it is then returned back to the cell surface instead of being destroyed inside the cell. I 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. I have recently discovered that recycled E-cadherin is specifically associated with the protein called Bazooka/Par-3 in Drosophila embryos. Bazooka/Par-3 is a large protein that has many parts, which bind other proteins. During my past research I obtained a list of all proteins that interact with Bazooka/Par-3, and found that it includes several proteins that are known to either participate in transport of proteins between cell's surface and interior, or in communication between cells. Therefore, Bazooka/Par-3 is a good candidate to link E-cadherin to recycling and cell-cell communication machineries, and it is the focus of this proposal to discover how Bazooka/Par-3 does this. The knowledge of how Bazooka/Par-3 regulates E-cadherin recycling and links it to communication between cells may be used to regulate the levels, distribution or action of E-cadherin. I anticipate to discover basic mechanisms that are shared between all animals. In future, I 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 I find that Bazooka/Par-3 binds a particular protein that allows E-cadherin to be re-delivered to the cell surface instead of being destroyed inside cells, absence of this protein might be used to mark cells that are likely to break down cell-cell adhesion and start invading other tissues, or this protein might be used as a drug target to prevent cells from re-building adhesion and forming secondary tumours in other tissues.

将我们身体中的相邻单位或细胞彼此连接的机制称为细胞-细胞粘附。最近的研究表明，细胞间粘附对于相邻细胞之间的通信也很重要，以决定何时分裂，迁移或死亡。特定的细胞粘附蛋白确保细胞间的粘附：一个细胞表面上的蛋白质直接与相邻细胞表面上的类似蛋白质结合。其中一种主要的细胞粘附蛋白被称为E-钙粘蛋白。E-钙粘蛋白提供上皮细胞之间的细胞粘附：这些细胞勾勒出身体的所有腔和表面结构。E-cadherin对于身体从非常早期阶段的适当发育至关重要，而错误的E-cadherin粘附通过增加生长和转移而有助于癌症进展。有两个原因使得细胞能够控制其表面的E-钙粘蛋白的量很重要。首先，更多的E-cadherin导致相邻细胞之间更强的粘附，反之亦然。增加粘附强度是响应于机械力以防止上皮破裂所需的，而当细胞决定交换邻居时则需要降低粘附强度。机械拉伸和邻居交换都参与生物体的正常发育及其在成年期的维持，并发生在疾病中。第二个原因是细胞表面E-钙粘蛋白的量决定了可与参与细胞间通讯的其他蛋白质相互作用的E-钙粘蛋白分子的数量。为了能够根据细胞的当前需要快速调节细胞表面的E-钙粘蛋白的量，一部分E-钙粘蛋白不断地在细胞表面和细胞内部之间循环，这一过程称为再循环。到目前为止，人们对E-钙粘蛋白的循环是如何调节的知之甚少，例如为什么E-钙粘蛋白在细胞内移动后，会返回细胞表面，而不是在细胞内被破坏。我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，它们在发育早期就会死亡，因为上皮细胞不能保持相互接触，组织就会分裂。我最近发现，回收的E-cadherin与果蝇胚胎中称为Bazooka/Par-3的蛋白质特别相关。Bazooka/Par-3是一种大蛋白质，它有许多部分，可以结合其他蛋白质。在我过去的研究中，我获得了与Bazooka/Par-3相互作用的所有蛋白质的列表，并发现它包括已知参与细胞表面和内部之间蛋白质运输或细胞之间通信的几种蛋白质。因此，Bazooka/Par-3是将E-cadherin与回收和细胞间通讯机制联系起来的良好候选者，并且发现Bazooka/Par-3如何做到这一点是本提案的重点。了解Bazooka/Par-3如何调节E-钙粘蛋白再循环并将其与细胞之间的通信联系起来，可用于调节E-钙粘蛋白的水平、分布或作用。我期望发现所有动物共有的基本机制。在未来，我将能够将这些知识应用于治疗E-钙粘蛋白功能缺陷引起的疾病，如上皮源性肿瘤。例如，如果我发现Bazooka/Par-3结合了一种特殊的蛋白质，使E-钙粘蛋白重新传递到细胞表面，而不是在细胞内被破坏，这种蛋白质的缺失可能被用来标记可能破坏细胞间粘附并开始入侵其他组织的细胞，或者这种蛋白质可以用作药物靶点，以防止细胞重新建立粘附并在其他组织中形成继发性肿瘤。