My laboratory is interested in the role of Rho and Ras family GTPases in regulating animal cell biology. Rho, Rac and Cdc42, three members of the Rho family, each control a signal transduction pathway linking plasma membrane receptors to the assembly of the actin cytoskeleton and associated integrin adhesion complexes. Rho regulates contractile actin:myosin filament and focal adhesion assembly, Rac regulates the formation of membrane protrusions (lamellipodia and membrane ruffles), while Cdc42 triggers filopodial extensions at the cell periphery. In addition, Rho GTPases promote a diverse set of other cellular activities, including activation of the JNK and p38 MAP kinase cascades, the establishment of cell polarity, cell cycle progression, the organization and dynamics of the microtubule cytoskeleton and activation of a variety of enzymes including PI 3-kinase and NADPH oxidases. The actin and microtubule cytoskeletons play a central role in driving many of the dynamic aspects of cell behavior such as migration, morphogenesis, axon guidance, phagocytosis and cell division. It is no surprise, therefore, to find that Rho family members play an important part in regulating these cell biological processes.
The ability to establish cell asymmetry with respect to the external environment is a fundamental feature of all eukaryotic cells and is the basis for such diverse processes as asymmetric cell division, polarized migration and neuronal and epithelial morphogenesis. Recent work in mammalian cells, flies and worms has suggested that the initiation of cell asymmetry is mediated by a common set of biochemical pathways and that this is then reinforced through subsequent changes in the organization of the actin and microtubule cytoskeletons and the polarized transport of membranes and proteins. My lab is exploring the molecular details of the pathways that promote cell and tissue morphogenesis and cell migration using a variety of assays and cell types, including primary fibroblasts, primary neurons and epithelial cell lines. The loss of tissue integrity and the appearance of inappropriate migratory activity are characteristics associated with cancer progression and our long-term goal is to identify the mechanisms that drive these changes.
Some of the current issues being addressed include:
- Identification of Cdc42-dependent signal transduction pathways that control cell polarity.
- The role of non-canonical Wnt signaling in polarity.
- Identification of steps in cell cycle progression of normal and cancer cells controlled by Rho GTPases.
- Rho GTPase pathways that promote cell migration in normal and cancer cells.
- Signal transduction pathways leading to neuronal and epithelial cell morphogenesis.
- The mechanism by which the PTEN and LKB1 tumor suppressor proteins contribute to polarized cell migration.