The role of G alpha signaling in gradient tracking

University Of Maine Orono, Orono ME

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Abstract

Abstract The ability to detect and respond to a gradient of external signal is a process conserved from prokaryotes to humans. In humans, gradient tracking underlies such processes as the immune response to invading bacteria, wound healing, tissue development, and cancer metastasis. In single celled organisms, gradient tracking allows bacteria to find nutrients and yeast to find mating partners. The yeast, Saccharomyces cerevisiae, detects shallow gradients of mating pheromone using signaling pathways homologous to those used by human cells. The extracellular signal is detected by a receptor that activates a G-protein inside the cell. This cellular on/off switch splits into two subunits, the G? subunit and the G?? subunit, each of which is capable of initiating a cellular response. Previous studies have focused on the role of the G?? side of the pathway that results in a MAP kinase cascade and activates the small G-protein Cdc42. These pathways polarize the cytoskeleton and drive gradient tracking by recruiting an actin polymerizing protein called a formin. Signaling through the G? branch of the pathway is less well understood. It is known that G? recruits active MAPK to the plasma membrane to phosphorylate formins, a family of actin polymerizing proteins. The proposed research will test the overarching hypothesis that the G? branch of the signaling pathway contributes to the accuracy of gradient tracking through spatial regulation of formins, a family of actin polymerizing proteins. The proposed research is as follows: Aim 1) Determine whether G? activation of formin enhances accuracy of gradient tracking. Aim 2) Determine whether G? activation of formin enhances accuracy of gradient tracking. Aim 3) Develop a mathematical model of yeast polarity that incorporates G? regulation of formins to test the feasibility of G? control of polarity of the cell, and to facilitate the development and testing of new hypotheses. The questions proposed will be answered using live cell microscopy in microfluidic devices, coupled with computational image analysis and mathematical modeling. These studies will uncover new modes of signaling by G-protein coupled receptor signaling pathways, the targets of 30% of all drugs. Better understanding of the basic signaling processes used by gradient tracking pathways will inform studies on human GPCR signaling and facilitate the development of new potential drug targets.