E-cadherin subcomplexes: function and regulation by microtubules

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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.