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

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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 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.