Role of TPD52-like proteins in cell migration and disease

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Cells have lots of proteins on their surface. They use these proteins to sense the environment and also to stick themselves to surfaces and move around. One way a cell can change how it senses or how it moves is to alter how many of these proteins are on the cell surface. A cell does this by taking these proteins into the cell and then putting them back onto the surface. Speeding up or slowing down the uptake or return legs of the pathway can tweak this "recycling" process. These tweaks work because they change the number of proteins on the surface and thereby alter how the cell senses or moves. Scientists know a lot about the uptake leg (endocytosis) but they know much less about the return leg. My lab has found that two proteins (TPD52 and TPD54) might be involved in the return leg. They are found together with three other proteins (Rab4, Rab11a and Rab25), which are known to be involved with the return leg, and changing how cells move. We are proposing to pin down exactly how TPD52 and TPD54 are involved in the uptake and return legs of the recycling pathway. Next, we want to find out which other Rabs the TPD proteins move around with and which ones they stick to (humans have ~70 Rabs!) and if sticking changes the activity of Rabs. We'll look at how these proteins affect cell movement. Finally, we will look at the sticky proteins on the surface of cells called integrins, and see if TPD proteins are needed for recycling integrins. Finding out all of these things is important because recycling is at the heart of many different things that cells do, not just sensing the environment and moving, but also how cells respond to drugs, how they control cell division, and much more. Also, we're interested in cell movement because cells need to move while an animal is developing and when it responds to injury. Finally, in diseases such as cancer, cell movement makes the disease very difficult to treat due to cancer cells moving away and starting new tumours somewhere else. This is known as "the cancer spreading in the body". In fact, TPD52 and TPD54 were first identified in breast cancer patients with fast growing and moving tumour cells. Understanding what TPD proteins do in cells to recycle proteins like integrins is important to understanding cell movements in disease and may provide new targets for future therapies.