Cell function and behavior depends on the ability to respond to signals in the extracellular environment. In eukaryotic cells, response to external signals is commonly initiated at the plasma membrane and subsequently disseminated throughout the cell by signal transduction pathways, which control cytoplasmic and nuclear events including gene expression. Because of this transfer of information between different compartments, the subcellular localization of signaling proteins is an important aspect of their function. In addition, cellular decisions about whether it is appropriate to respond to a given signal must also be integrated with other information about the physiological status of the cell. This proposal uses the mating reaction of the yeast Saccharomyces cerevisiae as a model system for understanding eukaryotic signal transduction, using a molecular genetics and cell biological approach. Response to mating pheromones in yeast involves the dynamic assembly of plasma membrane-localized signaling complexes, which include proteins found ubiquitously in a variety of signaling systems from yeast to humans, such as a PAK-family kinase, a heterotrimeric G protein, a MAP kinase cascade, and a scaffold protein. The long-term objective of this project is to gain a molecular understanding of how signaling through this pathway is initiated and propagated, with an emphasis on the function of scaffold proteins, the role of subcellular localization, and the interface between signaling and the cell cycle. One goal will be to determine how distinct domains in the MAP kinase cascade scaffold protein, Ste5, regulate the transmission of signal between different pathway kinases, and how different domains interact and coordinate with each other in order to control localization and function. Another project will probe how signaling proteins become restricted to discrete regions at the plasma membrane, and how this impacts the efficiency and dynamics of signal transmission. Also under investigation will be the mechanism by which proteins in this signaling pathway are recognized by specific forms of the cyclin-Cdk kinase during entry into the cell cycle. Overall, these studies will contribute to our general understanding of signal transduction, with relevance to the mechanisms by which both normal and diseased cells make decisions regarding differentiation or proliferation.

Public Health Relevance

This proposal seeks to shed light on the fundamental mechanisms by which cells respond to external signals. We use a yeast signaling pathway as a model system, but the molecules involved are common to signaling throughout eukaryotic biology, from yeast to humans. The discoveries learned about the basic functions of signaling proteins and pathways 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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cellular Signaling and Regulatory Systems Study Section (CSRS)
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Gindhart, Joseph G
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University of Massachusetts Medical School Worcester
Schools of Medicine
United States
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Bhaduri, Samyabrata; Valk, Ervin; Winters, Matthew J et al. (2015) A docking interface in the cyclin Cln2 promotes multi-site phosphorylation of substrates and timely cell-cycle entry. Curr Biol 25:316-25
Pope, Patricia A; Bhaduri, Samyabrata; Pryciak, Peter M (2014) Regulation of cyclin-substrate docking by a G1 arrest signaling pathway and the Cdk inhibitor Far1. Curr Biol 24:1390-1396
Pope, Patricia A; Pryciak, Peter M (2013) Functional overlap among distinct G1/S inhibitory pathways allows robust G1 arrest by yeast mating pheromones. Mol Biol Cell 24:3675-88
Bhaduri, Samyabrata; Pryciak, Peter M (2011) Cyclin-specific docking motifs promote phosphorylation of yeast signaling proteins by G1/S Cdk complexes. Curr Biol 21:1615-23
Pryciak, Peter M (2009) Designing new cellular signaling pathways. Chem Biol 16:249-54
Takahashi, Satoe; Pryciak, Peter M (2008) Membrane localization of scaffold proteins promotes graded signaling in the yeast MAP kinase cascade. Curr Biol 18:1184-91
Strickfaden, Shelly C; Pryciak, Peter M (2008) Distinct roles for two Galpha-Gbeta interfaces in cell polarity control by a yeast heterotrimeric G protein. Mol Biol Cell 19:181-97
Strickfaden, Shelly C; Winters, Matthew J; Ben-Ari, Giora et al. (2007) A mechanism for cell-cycle regulation of MAP kinase signaling in a yeast differentiation pathway. Cell 128:519-31
Takahashi, Satoe; Pryciak, Peter M (2007) Identification of novel membrane-binding domains in multiple yeast Cdc42 effectors. Mol Biol Cell 18:4945-56
Moskow, J J; Gladfelter, A S; Lamson, R E et al. (2000) Role of Cdc42p in pheromone-stimulated signal transduction in Saccharomyces cerevisiae. Mol Cell Biol 20:7559-71

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