The role of plasma membrane microdomains in regulating Ras-dependent Raf activation

在人类癌症中，从细胞表面的生长因子受体到细胞分裂起始的细胞核的一个或多个信号传导途径被破坏。例如，一种名为Ras的蛋白质，调节一系列主要的信号通路，在25%的人类肿瘤中发生突变。这使得Ras和信号通路永久地打开，导致不受控制的细胞增殖。我们以前的工作已经证明Ras必须附着在细胞膜的内表面才能正常发挥功能。该项目现在试图确切了解Ras如何附着在质膜上并与质膜中的特定位点相互作用。越来越清楚的是，Ras的不同亚型，称为H-、N-和K-ras，在细胞中具有不同的功能，这可能反过来又是由于它们与细胞膜的不同附着位点。这一点很重要，因为通过了解不同Ras蛋白运作的精确微环境以及它们如何激活其信号网络中的后续蛋白，我们将能够很好地设计出选择性地损害每种特定Ras亚型功能的药物。一个高度相关的例子是K-ras，它在90%的胰腺癌和50%的结肠癌中发生突变。显然，一种可以选择性地中和这些肿瘤中K-Ras功能的药物的临床影响可能是巨大的。

In human cancers one or more of the signaling pathways leading from growth factor receptors at the cell surface to the nucleus where cell division is initiated are subverted. For example, a protein called Ras, that regulates a series of major signaling pathways, is mutated in 25% of all human tumours. This leaves Ras and the signaling pathways permanently switched on causing uncontrolled cell proliferation. Our previous work has demonstrated that Ras must be attached to the inner surface of the cell membrane in order to function properly. This project now seeks to understand exactly how Ras attaches to and interacts with specific sites in the plasma membrane. Its is becoming clear that different isoforms of Ras, called H-, N- and K-ras have different functions in the cell which may in turn result from their different sites of attachment to the cell membrane. This is important because by understanding the precise micro-environment in which the different Ras proteins operate and how they activate subsequent proteins in their signaling networks we will be in a good position to design drugs that selectively compromise the function of each specific Ras isoform. A highly relevant example is provided by K-ras which is mutated in 90% of all pancreatic cancers and 50% of all colon cancers. Clearly the clinical impact of a drug that could selectively neutralise K-Ras function in these tumours is potentially enormous.