Cellular function of Ras and Rho GTPases

Lead Research Organisation: MRC Cell Biology Unit

Abstract

The formation of human cancers requires an accumulation of distinct genetic alterations that block the normal control mechanisms regulating cell behaviour. In addition to being able to grow inappropriately, a key feature of malignant cancers is their ability to invade neighbouring tissues and to migrate to distant sites. A major aim of my research team is to understand how normal cells move and to use this information to identify how this is subverted in malignant cancer cells.

Technical Summary

The aim of this project is to understand how a family of highly conserved proteins found in all eukaryotic cells, the small GTPases, regulates cell behaviour in response to extracellular cues. We are focussed primarily on three proteins, Rho, Rac and Cdc42, whose function is to co-ordinately regulate the organization of the actin and microtubule cytoskeletons. Since changes in the cytoskeleton drive such fundamental processes as cell movement and alterations in cell shape, these proteins are likely to play an important role in many aspects of normal biology as well as in disease. In particular, we are interested in their potential contribution to metastatic cancers and to neurodegeneration. Rho, Rac and Cdc42 act as molecular switches. Their activity is tightly controlled, but when activated they have the potential to interact with over 50 cellular target proteins. This complexity was somewhat unexpected, but the bottom line is that these GTPases are able to regulate many distinct signal trans vduction pathways and thereby contribute to many aspects of cell biology. One of their major roles is to control actin filament assembly and organization. Rho regulates the assembly of contractile actin:myosin filaments and is, therefore key to understanding how a cell changes shape, such as during morphogenesis in the embryo and in smooth muscle contraction in the adult. Rac and Cdc42, on the other hand, generate new actin filaments at the cell periphery causing membrane protrusion and this provides the driving force for cell migration, phagocytosis and the invasion of mammalian cells by pathogenic bacteria. Using primary rat embryo astrocytes in an in vitro assay for cell migration, we have recently described another role for Cdc42 that is conserved in all multicellular organisms, namely the control of cell polarity. We have identified a Cdc42-dependent signal transduction pathway in migrating cells, which controls the direction of migration. The pathway involves a novel mechanism of activation of the enzyme GSK3 and of the protein APC (the product of the adenomatous polyposis coli tumour suppressor gene). This new function for APC may be functionally significant in the many cancers where the gene is mutated. More recently we have been analyzing the contribution of another tumour suppressor protein, PTEN, to cell migration. Using assays with invasive human glioma cell lines, we have identified a new mechanism by which it inhibits cell movement and we are currently characterising this novel pathway.

Publications

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