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，并附着在物体表面并四处移动。细胞改变感知或移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内，然后将它们放回细胞表面来完成这一过程。加快或减慢摄取或返回路径可以调整这个“循环”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，从而改变了细胞感知或移动的方式。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。我的实验室发现两种蛋白质（TPD52和TPD54）可能与回程有关。它们与其他三种蛋白质（Rab4， Rab11a和Rab25）一起被发现，这三种蛋白质已知与返回腿有关，并改变细胞的运动方式。我们建议确定TPD52和TPD54是如何参与回收途径的吸收和返回腿的。接下来，我们想要找出TPD蛋白与哪些其他Rabs一起移动，它们粘附在哪些Rabs上（人类有大约70个Rabs!），以及粘附是否会改变Rabs的活性。我们会看看这些蛋白质是如何影响细胞运动的。最后，我们将看看细胞表面的粘性蛋白质，称为整合素，看看是否需要TPD蛋白来回收整合素。发现所有这些都很重要，因为循环利用是细胞许多不同活动的核心，不仅仅是感知环境和移动，还包括细胞对药物的反应，细胞如何控制细胞分裂等等。此外，我们对细胞运动也很感兴趣，因为动物在发育过程中以及对损伤做出反应时，细胞需要运动。最后，在癌症等疾病中，由于癌细胞转移并在其他地方形成新的肿瘤，细胞运动使疾病很难治疗。这就是所谓的“癌症在体内扩散”。事实上，TPD52和TPD54最初是在肿瘤细胞快速生长和移动的乳腺癌患者中发现的。了解TPD蛋白在细胞中如何回收整合素等蛋白质，对于理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.