Elucidation of signalling enzymes regulating the small GTPase RhoA

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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.