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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057769-15
Application #
8322014
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Gindhart, Joseph G
Project Start
1997-09-30
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
15
Fiscal Year
2012
Total Cost
$362,711
Indirect Cost
$142,218
Name
University of Massachusetts Medical School Worcester
Department
Genetics
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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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
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Takahashi, Satoe; Pryciak, Peter M (2007) Identification of novel membrane-binding domains in multiple yeast Cdc42 effectors. Mol Biol Cell 18:4945-56
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Butty, A C; Pryciak, P M; Huang, L S et al. (1998) The role of Far1p in linking the heterotrimeric G protein to polarity establishment proteins during yeast mating. Science 282:1511-6
Pryciak, P M; Huntress, F A (1998) Membrane recruitment of the kinase cascade scaffold protein Ste5 by the Gbetagamma complex underlies activation of the yeast pheromone response pathway. Genes Dev 12:2684-97