Elucidation of signalling enzymes regulating the small GTPase RhoA

人体的许多正常和病理过程依赖于细胞附着在生物表面(粘连)、扩散或移动到另一个位置(迁移)的能力。需要这些事件的生物过程的例子包括发育中的胚胎中细胞的分裂和排列，或者癌细胞扩散(转移)的能力。细胞附着或移动背后的驱动力是它们重新排列称为细胞骨架的支架的能力。细胞骨架类似于人体的骨骼，它的作用是维持细胞的形状和硬度。然而，它也被积极地重组以参与许多细胞过程，包括细胞附着和运动。通过进一步了解细胞骨架是如何重新排列的，这不仅将为细胞行为的基本知识提供重要的见解，而且还将对许多人类疾病状态产生重要影响。这项提议旨在研究调节细胞骨架重组的机制。众所周知，在许多不同类型的细胞中，这种支架的重排是由一个被称为Rho小GTP酶家族的蛋白质家族控制的。该家族的成员之一，RhoA，在控制细胞附着方面具有特殊的作用，有趣的是，它与人类肿瘤细胞的侵袭和转移特性有关。我们最近发现了一种负责控制RhoA激活的蛋白质。这项建议旨在加深我们对该蛋白如何调节RhoA，从而调节细胞附着和运动的理解。鉴于细胞附着和运动是导致肿瘤扩散的重要事件，这项研究可能为控制细胞运动和最终恶性进展的替代方法提供重要的见解。

Many normal and pathological processes in the human body depend on the ability of cells to attach to a biological surface (adhesion), spread out, or move to another site (migration). Examples of biological processes that require such events include the division and arrangement of cells in a developing embryo, or the ability of cancer cells to spread (metastasise). A driving force behind the attachment or movement of cells is their ability to rearrange a scaffolding called the cytoskeleton. The cytoskeleton is similar to the skeleton of the human body, in that it acts to maintain cell shape and rigidity. However, it is also actively reorganised to participate in many cellular processes, including cell attachment and movement. By furthering our understanding of how the cytoskeleton is rearranged, this will provide important insights not only into the basics of cell behaviour, but will also have important implications for a number of human disease states. This proposal aims to investigate mechanisms that regulate the reorganisation of the cytoskeleton. It is well established that the rearrangement of this scaffolding, in many different types of cells, is controlled by a family of proteins called the Rho family of small GTPases. One of the members of this family, RhoA, has a specific role in controlling cell attachment, and interestingly, has been implicated in the invasive and metastatic properties of human tumour cells. We have recently identified a protein that is responsible for controlling the activation of RhoA. This proposal aims to further our understanding of how this protein regulates RhoA, and therefore cell attachment and movement. Given that cell attachment and movement are important events contributing to the spread of tumours, this study may provide important insight into alternative approaches of controlling cell movement, and ultimately malignant progression.