Cellular behavior is commonly controlled by signals in the extracellular environment. The effects can be dramatic, such as the decision to proliferate or to differentiate, and so the responses must be highly regulated and carefully orchestrated. While many signaling pathways and their molecular components have been identified, some well-studied systems offer a unique opportunity to test how multiple components achieve a unified cellular response that integrates information from different subcellular regions as well as information about the physiological status of the cell. The signal transduction pathway that is activated by extracellular mating pheromones in the yeast Saccharomycescerevisiae presents an ideal model system in which to probe the intricacies that are built into a cellular response. Signaling in this system involves the dynamic assembly of plasma membrane-localized signaling complexes, which include proteins found ubiquitously in a variety of signaling pathwaysfrom yeast to humans, such as a PAK-family kinase, a heterotrimeric G protein, a MAP kinase cascade, and a scaffold protein. Here we make use of a rich foundation of information and genetic reagents to test several intriguing models about the mechanisms that propagate intracellular signaling and their interface with cell biological structures, with particular emphasis on the role of subcellular localization. One goal will be to determine how membrane recruitment of the MAP kinase cascade scaffold protein Ste5 amplifies signaling through the kinase cascade, and whether this signaling occurs predominantly between or within individual scaffold molecules. Another goal will be to dissect the multiple routes by which the mating MAP kinase cascade can inhibit the mitotic cell cycle, and to determine why it is important for this signaling pathway to be inactivated as cells commit to division. Also under investigation will be the role of a small membrane-binding domain in the PAK-family kinase Ste20, and the prevalence of similar domains in other polarized proteins. Overall, we expect these studies to contribute to a sophisticated understanding of signal transduction by revealing mechanisms that are built into signaling systems to allow dynamic and integrative responses within a cell.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Cellular Signaling and Dynamics Study Section (CSD)
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Gindhart, Joseph G
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University of Massachusetts Medical School Worcester
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Winters, Matthew J; Pryciak, Peter M (2018) Analysis of the thresholds for transcriptional activation by the yeast MAP kinases Fus3 and Kss1. Mol Biol Cell 29:669-682
Repetto, MarĂ­a Victoria; Winters, Matthew J; Bush, Alan et al. (2018) CDK and MAPK Synergistically Regulate Signaling Dynamics via a Shared Multi-site Phosphorylation Region on the Scaffold Protein Ste5. Mol Cell 69:938-952.e6
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 25:316-325
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

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