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Peter Pryciak, Ph.D.Academic Role: Associate Professor
Faculty Appointment(s) In:
Other Affiliation(s):
Signal Transduction and Cell Polarity
To investigate these issues, we use the simple eukaryotic cells of bakers yeast,Saccharomyces cerevisiae. The yeast mating reaction provides examples of signal transduction and cell shape control in a model system that is highly amenable to experimentation using genetics, biochemistry, and cell biology. Here, secreted pheromones stimulate fusion of partner cells in a process involving cell cycle arrest, transcriptional regulation, and cell polarization. These responses are mediated by two signaling modules found in all eukaryotes from yeast to humans: heterotrimeric G proteins and mitogen activated protein (MAP) kinase cascades. We also study two other ubiquitous proteins, the GTPase Cdc42 and a PAK-family kinase (Ste20), which control signaling and cytoskeletal rearrangements. Subcellular localization can play a crucial role in signal transduction. Activation of the mating pathway involves plasma membrane recruitment of the MAP kinase cascade “scaffold” protein, Ste5 (Pryciak and Huntress, 1998). (see Figure 1 and Figure 2) This recruitment requires synergistic protein-protein and protein-membrane interactions (Winters et al, 2005). Furthermore, Ste5 localization is regulated during the cell cycle by cyclin-dependent kinases (CDKs), which phosphorylate Ste5 near its membrane-binding domain and thus inhibit membrane recruitment and signaling (Strickfaden et al, 2007). This allows cells that are beginning a new division cycle to ignore the antiproliferative and differentiation effects of pheromone, which otherwise would cause a catastrophic division arrest. The factor awaiting the MAP kinase cascade at the membrane is the PAK-family kinase Ste20, whose activity and localization are regulated by multiple factors including Cdc42 (Lamson et al, 2002), the SH3 domain protein Bem1 (Winters and Pryciak, 2005), and direct membrane interactions (Takahashi and Pryciak, 2007). (see Figure 3) Another project is focused on how cells polarize toward localized signals. (see Figure 4) This behavior, exhibited by many cell types, implies communication between proteins that sense the signal and those that govern cell polarity. Indeed, in addition to its role in activating the MAP kinase cascade, the yeast heterotrimeric G protein has a separate function in orienting cell polarity along gradients of pheromone chemoattractants. This involves the formation of multiprotein complexes between Gbg and polarity-control proteins (Butty et al, 1998). Our recent work suggests that Gbg must be regulated in a spatially-asymmetric manner by the receptor and Ga subunit in order for it to properly guide cell polarization (Strickfaden and Pryciak, in press). We are also interested in the fidelity of signaling pathways. In yeast, as in human cells, independent pathways generate different responses to different stimuli. But some proteins can function in multiple pathways, raising the question of how the pathways avoid “crosstalk”. (see Figure 4) Earlier, we showed that pathway-specific binding interactions can route signaling toward specific pathways. We developed a method to force shared signaling proteins to associate with a subset of their possible partners, creating custom signaling molecules that are “steered” toward chosen pathways (Harris et al, 2001). More recently, we found that membrane recruitment has an enhancing, or "amplifying" effect on signal transmission, which helps ensure signaling fidelity because it acts only on factors that are included in the recruited signaling complex (Lamson et al, 2006).
Office: Bio IV Rm# 330
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Research in my laboratory is aimed at understanding how cellular behavior is dictated by external signals. Our studies stress three general topics: What is the role of subcellular compartmentalization in signal transduction? How do cells judge the location of extracellular cues and mount a directional response? How is signaling specificity ensured?
55 Lake Avenue North Worcester, MA 01655