Endosomal regulation of Notch by Nedd4 proteins

为了使细胞正常工作并在正确的位置发育成正确类型的细胞，信号必须在它们之间传递。这些信号最常被细胞表面的受体检测到，这些受体通过改变它们的结构来响应信号。这种构象变化引发了细胞内的一系列事件，最终改变了基因表达的数量和水平。当这些信号出错时，可能会产生严重的后果，导致癌症等疾病。很明显，我们对这些信号了解得越多，我们就越能够更好地利用操纵它们的潜力来为我们服务。该提案的目的是研究由称为Notch的受体介导的这样一种信号的调节。调节信号的一种方式是改变受体在细胞不同位置的转运。我们已经发现，如果Notch受体被运输到特定的细胞区室，那么它就会被激活。我们已经发现了细胞内的调节蛋白，它们与Notch结合，以某种方式修饰Notch，将其发送到或转移到该细胞位置。这控制了Notch一旦被内化到细胞中是否被激活。Notch也被认为通过与相邻细胞上的配体结合而在细胞表面被激活。我们还不知道这两种激活模式是如何联系在一起的。它们是激活受体的两种不同机制，还是同一分子途径中的两个不同步骤？该项目的工作旨在在生物化学水平上了解Notch调节其细胞内定位和激活的不同类型的修饰。我们还将确定内体激活途径如何与配体依赖性Notch信号传导的正常机制相关。这项工作将在曼彻斯特大学生命科学学院内进行。我们的实验生物是果蝇，这是一种常用的生物，因为许多控制其发育的信号也在人类身上发现。果蝇有明显的优势，因为它很容易进行实验，而且因为它繁殖快，很容易识别影响我们希望研究的信号的突变。通过观察事情出错时发生的情况，我们可以发现它们是如何正常工作的。该赠款旨在为已经在该领域开展重要工作的博士后研究科学家提供支持。

For cells to function properly and develop into the right type of cell in the correct location, then signals have to pass between them. These signals are most often detected by receptors at the cell surface, which respond to the signal by altering their structure. This conformational change initiates a series of events inside the cell, ultimately changing the number and level of genes expressed. When such signals go wrong there can be serious consequences resulting in diseases like cancer for example. It will be evident that the more we understand these signals, the better we will be able to exploit the potential to manipulate them to our advantage. The aim of this proposal is to investigate the regulation of one such signal that mediated by a receptor called Notch. One way in which a signal can be regulated is to alter the transport of receptor within different locations in the cell. We have found that if the Notch receptor is trafficked to a particular cellular compartment then it is activated. We have found intracellular regulatory proteins that bind to Notch, modify it in a way as to send Notch to or divert it from this cellular location. This controls whether Notch is activated or not once it has been internalised into the cell. Notch is also thought to be activated at the cell surface by binding to ligands on an adjacent cell. We do not understand yet how these two modes of activation are related. Are they two different mechanisms of activating the receptor, or are they two different steps in the same molecular pathway? The work for this project aims to understand, at the biochemical level, the different types of modification of Notch that regulate its intracellular location and activation. We will also determine how the endosomal activation route is related to the normal mechanism of ligand-dependant Notch signalling. This work will be carried out within the Faculty of Life Sciences at the University of Manchester. Our experimental organism is the fruit fly, which is a commonly used organism because many of the signals controlling its development are also found in humans. The fly has obvious advantages in that it is easy to experiment with and because it breeds fast it is easy to identify mutations that affect the signals that we wish to study. It is by looking at what happens when things go wrong that we can find out how they work normally. This grants seeks support for a post-doctoral research scientist who has already performed important work in this area.