YEAST HETEROTRIMERIC G PROTEIN AND CELL POLARITY

Univ Of Massachusetts Med Sch Worcester, Worcester MA

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Abstract

DESCRIPTION (provided by applicant): A fundamental property of virtually all cells is the ability to respond to cues from the surrounding environment. Information about the presence of extracellular stimuli is converted into intracellular behaviors by the use of signal transduction pathways. In addition, many cells show directional responses such as growth or movement toward a localized stimulus, which implies communication between the signal transduction molecules that detect the stimulus and those that govern cell shape, polarity, and motility. This work uses the mating reaction of the yeast Saccharomyces cerevisiae as a model system to study the control of signaling and cell polarity by external stimuli, using a molecular genetic and cell biological approach. In this system, intracellular signaling occurs via modules of proteins that are conserved from yeast to humans, such as heterotrimeric G proteins, MAP kinase cascades, PAK-family kinases, and Rho-family GTPases. The long-term objective of this project is to provide a molecular description of signal transduction and polarization events initiated by the yeast heterotrimeric G protein beta-gamma dimer (Gbeta-gamma). One goal will be to understand how the ability of Gbeta-gamma to induce cell polarization is spatially regulated by its associated receptor and Galpha subunit, with emphasis on recent observations that suggest qualitatively different roles for different Galpha-Gbeta interfaces in this spatial control. Also under investigation will be mechanisms by which Gbeta-gamma cooperates with additional proteins to control the recruitment of a MAP kinase cascade "scaffold" protein to the cell periphery. Another goal will be to examine the effects of scaffold proteins on signal transmission, in terms of how scaffolds help shape the dose-response behavior of a MAP kinase pathway. The means by which Gbeta-gamma triggers the yeast PAK Ste20 to activate the mating MAP kinase cascade will be pursued by exploring the role of the SH3 domain protein Bem1 in Ste20 signaling and localization and by investigating determinants within Ste20 that confer the ability to act in the mating pathway. These studies will impact our understanding of signal transduction and cytoskeletal organization in response to growth factors, hormones, neurotransmitters, and chemoattractants, with relevance to cellular decisions about proliferation and cellular identity in both normal and diseased cells.