E-cadherin subcomplexes: function and regulation by microtubules

E-钙粘蛋白亚复合物：微管的功能和调节

• 批准号: BB/K00056X/1
• 负责人: Nicholas Brown
• 金额: $ 72.31万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK00056X%2F1
• 关键词: cadherin; subcomplexes; function; regulation; microtubules

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.

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。在细胞中，E-cadherin粘附形成一个薄带，称为粘附小带，它勾勒出细胞的外围并将其连接到多个邻居。E-cadherin对于身体从早期阶段的正常发育至关重要。此外，E-cadherin的粘附缺陷通过增加肿瘤的生长和转移而促进肿瘤的进展。为了使细胞与细胞之间正确粘附，将粘附小带定位在离细胞表面特定距离处是至关重要的。更令人意想不到的是，细胞还仔细控制E-钙粘蛋白如何分布在细胞周围的粘附小带内。虽然大多数细胞具有均匀分布，但已经发现越来越多的情况下E-钙粘蛋白不对称分布。这种不对称分布在发育中的动物中的作用还有待检验。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。我们最近的研究结果表明，在果蝇胚胎上皮细胞中存在两个不同的E-cadherin群体。一个种群均匀地分布在细胞周围。另一个种群分布不对称。E-cadherin的第二个群体与称为Bazooka/Par-3的蛋白质特异性相关，其不对称性需要细胞骨架的亚型：称为微管的长管状结构。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，那么就有可能干扰一个而不影响其他人，这可能有助于控制异常的E-钙粘蛋白功能。第二，我们能否识别出与不同的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。我们预期，仅存在于一个或其他群体中的蛋白质可用于调节特定E-cad群体的水平、分布或作用，从而成为药物发现的靶点，此外还可证明可标记出异常细胞用于诊断目的。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的E-钙粘蛋白不对称性，并专门控制这一群体。我们预计，我们将发现所有动物之间共享的基本机制。在未来，我们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，如果我们发现只有一种E-cadherin群体可以防止癌症过度生长，并且我们确定了特异性结合这种E-cadherin群体的分子，那么就有可能寻找攻击这种E-cadherin群体以减少癌症生长的药物，而不会破坏E-cadherin在周围非肿瘤细胞中的粘附。

项目成果

Supplementary figure and table from Diverse integrin adhesion stoichiometries caused by varied actomyosin activity

不同肌动球蛋白活性引起的不同整合素粘附化学计量的补充图和表

• DOI: 10.6084/m9.figshare.4833995
• 发表时间: 2017
• 作者: Bulgakova N

Diverse integrin adhesion stoichiometries caused by varied actomyosin activity

不同的肌动球蛋白活性引起不同的整合素粘附化学计量

• DOI: 10.17863/cam.10175
• 发表时间: 2017
• 作者: Bulgakova N

Microtubule organization is determined by the shape of epithelial cells.

• DOI: 10.1038/ncomms13172
• 发表时间: 2016-10-25
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Gomez JM;Chumakova L;Bulgakova NA;Brown NH
• 通讯作者: Brown NH

The BAF chromatin remodelling complex is an epigenetic regulator of lineage specification in the early mouse embryo.

• DOI: 10.1242/dev.131961
• 发表时间: 2016-04-15
• 期刊: Development (Cambridge, England)
• 作者: Panamarova M;Cox A;Wicher KB;Butler R;Bulgakova N;Jeon S;Rosen B;Seong RH;Skarnes W;Crabtree G;Zernicka-Goetz M
• 通讯作者: Zernicka-Goetz M

Cell adhesion in Drosophila: versatility of cadherin and integrin complexes during development.

• DOI: 10.1016/j.ceb.2012.07.006
• 发表时间: 2012-10
• 期刊: CURRENT OPINION IN CELL BIOLOGY
• 影响因子: 7.5
• 作者: Bulgakova, Natalia A.;Klapholz, Benjamin;Brown, Nicholas H.
• 通讯作者: Brown, Nicholas H.