Role of TPD52-like proteins in cell migration and disease

细胞表面有很多蛋白质。它们利用这些蛋白质来感知环境，并将自己粘在表面上四处移动。细胞改变其感知或运动方式的一种方法是改变细胞表面这些蛋白质的数量。细胞通过将这些蛋白质带入细胞，然后将它们放回表面来做到这一点。加快或减慢吸收或返回路径的腿可以调整这个“回收”过程。这些调整之所以有效，是因为它们改变了表面蛋白质的数量，从而改变了细胞的感觉或运动方式。科学家们对摄取腿（内吞作用）了解很多，但对返回腿却知之甚少。我的实验室已经发现两种蛋白质（TPD 52和TPD 54）可能参与了返回腿。它们与其他三种蛋白质（Rab 4，Rab 11 a和Rab 25）一起被发现，已知这些蛋白质与返回腿有关，并改变细胞的运动方式。我们建议确切地确定TPD 52和TPD 54是如何参与回收途径的吸收和返回腿的。接下来，我们想找出TPD蛋白与哪些其他Rabs一起移动，以及它们粘在哪些Rabs上（人类有大约70个Rabs！）以及粘附是否会改变Rabs的活性。我们将研究这些蛋白质如何影响细胞运动。最后，我们将研究细胞表面称为整合素的粘性蛋白质，看看是否需要TPD蛋白质来回收整合素。发现所有这些事情都很重要，因为回收是细胞所做的许多不同事情的核心，不仅仅是感知环境和移动，还包括细胞如何对药物做出反应，它们如何控制细胞分裂等等。此外，我们对细胞运动感兴趣，因为细胞在动物发育过程中以及对损伤做出反应时需要运动。最后，在癌症等疾病中，细胞运动使疾病非常难以治疗，因为癌细胞会离开并在其他地方产生新的肿瘤。这被称为“癌症在体内扩散”。事实上，TPD 52和TPD 54首先在具有快速生长和移动的肿瘤细胞的乳腺癌患者中被发现。了解TPD蛋白在细胞中对整合素等蛋白质的回收作用对于了解疾病中的细胞运动非常重要，并可能为未来的治疗提供新的靶点。

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.