Molecular Genetics Professor Receives Four-Year, $1.2 Million NIH Grant
Molecular Genetics Professor Hay-Oak Park’s four-year, $1.2 million grant from the National Institutes of Health/National Institute of General Medical Sciences funds her project, "Spatial and temporal regulation of polarity establishment in budding yeast."
“Placement of the cell division plane and polarity establishment are crucial for cell proliferation and cell movement, as seen in developing embryos, wound healing, and bud formation during yeast growth,” Park said. “And, this four-year grant capitalizes on the tractable yeast system to investigate spatial and temporal regulation of cell polarization.”
Research in Park’s lab employs a combination of methodologies including live-cell imaging, biochemistry and genetics, as well as mathematical modeling to delve into the mechanisms underlying cell polarity development.
Graduate and undergraduate students and PhD scientists in her group look at two main questions in cell biology: How do cells achieve polarized organization of the cytoskeleton in response to spatial cues? And, how do cells respond to oxidative stress caused by cellular metabolism and other environmental stresses?
This grant supports her on-going project focusing on the GTPase signaling networks involved in the development of cell polarity and cell asymmetry.
“One of the fundamental questions in cell biology is how asymmetry and polarity within a cell are established, resulting in oriented cell divisions or a functionally specialized cell fate,” Park said.
Budding yeast is particularly attractive as a model for this study, owing to both its experimental tractability and the high conservation of core biological processes in eukaryotes.
Park said, “We are using budding yeast as a model to understand spatial and temporal control of polarity development. Selection of a growth site in budding yeast determines the axis of cell polarity and the cell division plane. Proper choice of the cell division plane is critical for proliferation of many cell types including epithelial tissues and for the prevention of cancer.
“Our goal is to elucidate the molecular mechanisms underlying spatial cue-directed cell polarization and ultimately to understand general principles underlying cell polarization in all eukaryotes and what is unique to yeast.”
A recent paper from her lab, which was highlighted in the Journal of Cell Biology, revealed that two different proteins sequentially activate Cdc42, a small GTP-binding protein conserved from yeast to humans, to ensure yeast form a bud at the right place and at the right time.
“One of the significant findings,” Park said, “is that it appears that this stepwise activation of Cdc42 allows spatial cue–directed cell polarization to occur in timely fashion.”
Another new paper about to appear in the Journal of Cell Science builds on this previous study. In this newest work, Park and her colleagues used live-cell imaging and mathematical modeling to show how polarization of Cdc42 is established in response to spatial cues during growth of haploid yeast cells.
In this work, they showed that the active Cdc42 becomes polarized in distinct dynamics depending on the length of the G1 phase in the cell cycle and that its polarization is regulated by another GTPase module including Rsr1 and Bud2 and its own regulators such as Rga1, a Cdc42 GTPase activating protein.
Importantly, graduate student Mid Eum Lee refined the spatiotemporal distribution of the Cdc42 GAP Rga1 and showed that this transient localization pattern is critical for selection of a proper growth site.
Based on their experimental data, Park’s collaborator Wing-Cheong Lo, a former MBI postdoc, developed a mathematical model that best fits the scenario in which the polarization axis is established via a biphasic mechanism that includes sequential positive and transient negative feedback loops.
Park believes that the budding yeast continues to provide a robust experimental platform to study cell polarity and cell cycle and a guide for studying more complicated systems. Her grant will allow further investigation of the mechanisms underlying cell polarization and detailed assembly and disassembly of the molecular complexes that set up cellular asymmetry.
"Furthermore," Park said, “I hope that outcomes of this study will provide a deeper understanding of why such a genetic program of cell polarization has been selected throughout evolution.”