Cell function and behavior depends on the ability to respond to signals in the extracellular environment and make appropriate decisions about whether or not to proliferate. In eukaryotic cells, responses to external signals are commonly initiated at the plasma membrane and then disseminated throughout the cell by signal transduction pathways, which control both cytoplasmic and nuclear events including gene expression. In addition, the potential responses to a given signal must also be integrated with other information about the physiological status of the cell such as the position in the cell division cycle. The process of cell division involves a sequential series of carefully orchestrated events that involve profound alterations in the functions of numerous proteins. These events must be carefully orchestrated to ensure that they occur with high fidelity, and they must coordinate with signaling pathways so that the cell division machinery can respond to relevant signals and counteract interfering signals. This proposal uses the mating reaction of the yeast Saccharomyces cerevisiae as a model system for understanding both eukaryotic signal transduction and cell division, using a molecular genetics and cell biological approach. The response to yeast mating pheromones involves a dynamic assembly of plasma membrane-localized signaling complexes, which include proteins found ubiquitously from yeast to humans, such as a heterotrimeric G protein and a MAP kinase cascade. The long-term objective of this project is to gain a molecular understanding of how protein kinase activities in cells are regulated and harnessed to control cell division and responses to stimuli. The specific projects emphasize the role of subcellular localization in the activation of signaling kinases, and the role of cyclin proteins in the activation of cell cycle kinases. One goal will be to determine how the plasma membrane localization of the MAP kinase cascade scaffold protein, Ste5, is regulated by dynamic phosphorylation that may be controlled by more than one protein kinase. Another project will probe how the affinity of the membrane-binding domain in Ste5 is controlled by interaction is modulated by phosphorylation at multiple flanking positions. Also under investigation will be how specific cyclin proteins recognize substrate proteins of the cyclin dependent kinase (CDK), and how these specific interactions contribute to control of cell morphology. Overall, these studies will contribute to our general understanding of signaling mechanisms and cell division, with relevance to the mechanisms by which both normal and diseased cells make decisions regarding differentiation or proliferation.
This proposal seeks to shed light on the fundamental mechanisms by which cells respond to external signals and control their division. We use yeast as a model system to probe the functions of signal transduction pathways and protein modifying enzymes that are common throughout eukaryotic biology, from yeast to humans. The discoveries learned about the basic functions of signaling proteins and cell division machinery under study here will further our understanding of similar signaling events relevant to human health, such as those in vision, hormone responses, and neoplastic growth.
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