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Shape changes are common to most cell types and are essential for the normal development of multicellular organisms. For example, they are necessary for cells to migrate to their final destinations during embryogenesis, for the outgrowth of axons and dendrites from neurons, and for the fusion of muscle precursor cells into multinucleated muscle fibers. Extracellular cues initiate shape changes by activating cellular signaling pathways that regulate dynamic rearrangements of the cytoskeleton.
My laboratory uses a combination of cell biological, molecular biological and biochemical techniques to study the signaling mechanisms that regulate cell shape changes in mammalian cells. Our primary focus has been to understand how changes in the lipid composition of the plasma membrane affect remodeling of the actin cytoskeleton. We study an enzyme called diacylglycerol kinase z (DGKz), which catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). Both DAG and PA are lipid second messengers with roles in actin organization. Actin rearrangements are governed by regulatory proteins called Rho GTPases (Rho, Rac and Cdc42 are the best studied of these) that function like switches. They are "off" when GDP bound and "on" when GTP-bound. Rho GTPases are normally held in the off position by Rho GDP dissociation inhibitor (RhoGDI).
Our recent findings demonstrate that DGKz is part of a signaling complex that functions as a Rac1-selective RhoGDI dissociation factor and define a direct link between lipid second messengers and regulation of the actin cytoskeleton. Together, these results establish a mechanism whereby changes in lipid second messengers modulate the amount of active Rac and thus contribute to the regulation of the actin cytoskeleton.
- Mechanisms Regulating Neurite Outgrowth
Nervous system function depends upon highly specific connections that form between neurons during development. Before these connections can be established however, neurons must first elaborate cellular processes called "neurites", which eventually mature into a single axon and multiple dendrites. Dynamic remodeling of the actin-based cytoskeleton is fundamental to neurite outgrowth and retraction, axon guidance, and dendritic branching. Understand how lipid signaling contributes to the regulation of these processes.
- Cancer Metastasis
Tumor cells have the ability to invade, colonize and destroy distant organs, a phenomenon termed metastasis. It is this process, rather than the primary tumor, that is responsible for most cancer-related deaths. To prevent these deaths, improved ways to treat metastatic disease are needed. Metastasis is a complex process that begins with the invasion of cancer cells into the surrounding tissues. Understanding the cell migration pathways that contribute to invasion can provide new approaches and targets for anticancer therapy. Our recent studies demonstrate that DGKz affects cell migration in normal fibroblasts. We are investigating DGKz's role in cancer cell migration using three independent strategies to alter its expression and/or function. These strategies will be combined with cell-based assays of (A) two-dimensional migration, (B) invasion, and (C) lamellipodium production. We expect our findings will show DGKz is a target for the design of anti-cancer therapeutics.
diacylglycerol kinases, Rho GTPases, cellular signaling actin cytoskeleton, lipid kinases, syntrophins