Living cells are often polarized with a distinct front and back or top and bottom. Cell asymmetry and polarity are critical for cell proliferation and development. Indeed, the loss of cell polarity and asymmetry has been implicated in many diseases including cancer and cellular aging. Our current research has two main focuses: 1) spatial and temporal regulation of cell polarization; and 2) regulation of cellular lifespan. Some of our recent work is highlighted below.
Spatial and Temporal Control of Cell Polarity
In yeast and animal cells, signaling pathways involving small guanosine triphosphatases (GTPases) regulate cell polarization. In budding yeast, selection of a bud site directs polarity establishment and subsequently determines the plane of cell division. Budding yeast is a particularly attractive model system because it displays pronounced cell polarity in response to intracellular and extracellular cues. Our goal is to delve deeper into the molecular mechanisms underlying polarity development during yeast budding, and ultimately to understand general principles underlying cell polarization in all eukaryotes. We discovered how two different proteins Bud3 and Cdc24 sequentially activate the Cdc42 GTPase to ensure yeast form a bud at the right place. Bud3 stimulated nucleotide release from Cdc42 in vitro and activated Cdc42 in Cdc24-deficient cells. Live imaging of wild-type cells revealed that Cdc42 normally undergoes two waves of activation: a Bud3-dependent wave in late mitosis/early G1 followed by a Cdc24-dependent activation phase in late G1 (Kang et al., J Cell Biol 2014). Such biphasic activation of Cdc42 is necessary for spatial cue–directed polarity establishment in haploid budding yeast in the correct time in the cell cycle. While the positive signaling of polarity establishment is important, we found that negative GTPase signaling involving Rga1, a Cdc42 GTPase activating protein, is also critical for establishing a proper axis of cell polarization (Miller et al., Mol Biol Cell 2017). Rga1 inhibits Cdc42 at all previously used cell division sites so that Cdc42 polarization and thus bud growth is directed to a new unused site. Live cell imaging and mathematical modeling suggests that strict spatial control of Rga1 in coordination with G1 progression is critical for establishing a proper axis of cell polarization.
Biphasic activation of the Cdc42 GTPase in G1 (Kang et al., J Cell Biol 2014; see also– “In This Issue” of the J Cell Biol. July 7, 2014)
Negative signaling of Cdc42 polarization at the current and old cell division sites (Miller et al. Mol Biol Cell 2017)
Cellular Aging and Stress Response
Most eukaryotic cells are constantly exposed to reactive oxygen species (ROS), which are produced as byproducts of metabolism and upon exposure to diverse environmental stresses. The increased production of ROS also leads to the induction of defense mechanisms to avoid molecular damage, but the redox balance is disturbed under excessive stress. We discovered that the Rho5 GTPase is necessary for apoptotic cell death induced by oxidants (Singh et al., PNAS 2008). We investigate how asymmetric cell division and cell polarity are involved in maintaining cellular damage in mother cells and what limits cellular lifespan.
PARK LAB MEMBERS:
Pil Jung Kang (PhD), Kristi E. Miller, Kendra Lian, Jack Fioretti, Grant Leever, Sarah Johnson
We welcome highly motivated students to join our group. Our research projects provide interdisciplinary training including genetics, biochemistry, quantitative microscopy, and mathematical modeling. For any questions, please contact Hay-Oak Park (firstname.lastname@example.org).
SELECTED PUBLICATIONS since 2007 (*Corresponding Author):
Carmona-Gutiérrez, D.* et al., …… H.-O. Park, ….…, F. Madeo* (2018) “Guidelines and recommendations on yeast cell death nomenclature” Microb Cell. 2018 Jan 1; 5(1): 4–31.
Mol Biol Cell. 2017 Dec 15;28(26):3773-3788. Epub 2017 Oct 26.
Okada, S., M. E. Lee, E. Bi E, H.-O. Park* (2017) Probing Cdc42 Polarization Dynamics in Budding Yeast Using a Biosensor. Methods Enzymol. 2017;589:171-190. Epub 2017 Feb 20.
Lee, M. E.@, W.-C Lo@, K. E. Miller, C.-S. Chou, and H.-O. Park* (2015) Regulation of Cdc42 polarization by the Rsr1 GTPase and Rga1, a Cdc42 GTPase activating protein, in budding yeast. J Cell Sci 128: 2106-2117 (@ equal contribution)
Highlighted in “In This Issue” of the J Cell Sci 2015 128:e1103:
Miller, K. E., Y. Kim, W.-K. Huh, and H.-O. Park* (2015) Bimolecular Fluorescence Complementation (BiFC Analysis): advances and recent applications for genome-wide interaction studies J Mol Biol [2015 Mar 12; Epub ahead of print] — invited review
Lam, M. H. Y., J. Snider1, M. Rehal, V. Wong, F. Aboualizadeh, L. Drecun, O. Wong, B. Jubran, M. Li, M. Ali, M. Jessulat; V. Dieneko, R. Miller, M. E. Lee, H.-O. Park, A. Davidson, M. Babu, and I. Stagljar* (2015) A comprehensive membrane interactome mapping of Sho1p reveals Fps1p as a novel key player in the regulation of the HOG Pathway in S. cerevisiae. J Mol Biol [2015 Jan 30; Epub ahead of print]
Kang, P.J., M.E. Lee, and H.-O. Park* (2014) Bud3 activates Cdc42 to establish a proper growth site in budding yeast. J Cell Biol 206: 19 - 28. Highlighted in “In This Issue” of the J Cell Biol.
Lo, W.-C.*, H.-O. Park, and C.-S. Chou (2014) Mathematical Analysis of Spontaneous Emergence of Cell Polarity Bull. Math. Biol. 76(8): 1835-65.
Snider, J., A. Hanif, M. E. Lee, K. Jin, A. R Yu, C. Graham, M. Chuk, D. Damjanovic, M. Wierzbicka, P. Tang, D. Balderes, V. Wong, M. Jessulat, K. D. Darowski, B.-J. San Luis, I. Shevelev, S. L. Sturley, C. Boone, J. F. Greenblatt, Z. Zhang, C. M. Paumi, M. Babu, H.-O. Park, S. Michaelis, and I. Stagljar* (2013) Mapping the functional yeast ABC transporter interactome. Nature Chem Biol. 9(9):565-72 [Epub 2013 Jul 7].
Lo, W.-C. #,M. Lee#,M. Narayan,C.-S. Chou,and H.-O. Park* (2013) Polarization of diploid daughter cells directed by spatial cues and GTP hydrolysis of Cdc42 in budding yeast. PLoS ONE 8(2):e56665. [Epub 2013 Feb 20]; #equal contribution to the work.
Kang, P. J., J. K. Hood-DeGrenier, and H.-O. Park* (2013) Coupling of septins to the axial landmark by Bud4 in budding yeast. J Cell Sci. 126:1218-26 [Epub 2013 Jan 23].
Lee ME, Singh K, Snider J, Shenoy A, Paumi CM, Stagljar I, Park HO* (2011) The Rho1 GTPase Acts Together With a Vacuolar Glutathione S-conjugate Transporter to Protect Yeast Cells from Oxidative Stress. Genetics. 188(4):859-70.
Kang, P. J., L. Beven, S. Hariharan and H.-O. Park* (2010) The Rsr1/Bud1 GTPase interacts with itself and the Cdc42 GTPase during bud-site selection and polarity establishment in budding yeast. Mol. Biol. Cell 21: 3007-3016.
Kozminski, K. G. and Park, H.-O.* (2009) Yeast small G protein function: Molecular basis of cell polarity in yeast, in Handbook of Cell Signaling, Second Ed., eds. R. A. Bradshaw & E. A. Dennis, Vol. 2, pp. 1813-1817, Academic Press, Elsevier Inc.
Singh, K., P. J. Kang, and H.-O. Park* (2008) The Rho5 GTPase is necessary for oxidant-induced cell death in budding yeast. Proc. Natl. Acad. Sci. USA 105: 1522-1527
Park, H.-O.* and E. Bi (2007) Central roles of small GTPases in the development of cell polarity in yeast and beyond. Microbiology & Molecular Biology Reviews, 71: 48-96