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My research focuses on understanding G protein signaling. The heterotrimeric G proteins, composed of subunits, function as molecular switches. They detect agonist-activated G protein-coupled receptors (GPCRs) and then regulate specific intracellular signal pathways. To function properly, intracellular signaling pathways depend upon appropriate and unique subcellular locations of their constituent proteins.
Mechanisms of reversible membrane targeting of G protein and subunits. Although G proteins must reside at the cytoplasmic surface of the plasma membrane (PM) to interact with GPCRs, they are not statically localized there. We are interested in the basic questions of what are the specific pathways and mechanisms that G proteins use to arrive at the PM, how and where in the cell are the G protein subunits assembled, and what are the mechanisms of GPCR-activated G protein translocation and recycling back to the PM. Importantly, we also wish to understand how trafficking affects signaling, and thus we are addressing non-canonical signaling roles for G proteins at intracellular organelle locations.
Mechanisms of localization and signaling by RhoGEFs. The Rho small GTPases are critical signaling proteins that play central roles in numerous biological responses. A major function is to regulate rapid and reversible changes in the actin cytoskeleton, such as those that occur in migrating cells and extension and retraction of neurites. A sub-family of three Rho guanine-nucleotide exchange factors (RhoGEFs) are directly activated by heterotrimeric G proteins, thus providing a direct link between the "big" G proteins and the "small" GTPases. We are defining how these RhoGEFs regulate G protein activation of Rho signaling and defining a novel role for one RhoGEF in mitosis and cytokinesis.
We anticipate that a detailed under-standing of localization and trafficking mechanisms will reveal new therapeutic targets for inhibiting unwanted signaling pathways
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