Biography
Reserach Interests:
Small GTPases of the Ras superfamily are key regulators of a wide variety of cellular processes in all eukaryotic cells. Ras itself regulates a signal transduction pathway linking plasma membrane receptors to the ERK MAP kinase cascade, an essential and rate limiting signal for growth and differentiation. Rho, Rac and Cdc42, three other small GTPases, control signal transduction pathways linking membrane receptors to the assembly and disassembly of the actin cytoskeleton. Rho regulates stress fiber and focal adhesion assembly, Rac regulates the formation of lamellipodia and membrane ruffles and Cdc42 triggers filopodial extensions at the cell periphery. These observations have led to the suggestion that wherever filamentous actin is used to drive a cellular process, eg cell movement, axon guidance, phagocytosis and cytokinesis, the Rho GTPases may play an important regulatory role. More recently, Rho, Rac and Cdc42 have been reported to control other cellular activities, including regulation of the JNK and p38 MAP kinase cascades. All three GTPases have been implicated in growth control and although mutations at these loci have not been found in human cancers, experiments suggest that Rac in particular might play an important role in invasion and metastasis.
We are directly assessing the role of Rho and Ras family members in the control of cell movement using an in vitro wound healing assay, in which inhibitors and activators of the GTPases are microinjected into moving cells and the cellular responses analyzed by immunofluorescence and time lapse video microscopy. Although not cell movement, the growth cone of an extending axon has many structural similarities (eg filopodia and lamellipodia) to the leading edge of a migrating cell. We are using microinjection techniques to analyze the role of GTPases in the process of axon guidance in cultured neurons. Another actin-driven process of great interest is phagocytosis. Using microinjection and transfection approaches we are analyzing the role of Rho, Rac and Cdc42 in both Fcg- and CR3- mediated phagoctyosis in macrophages.
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