Cdc42p plays a key role in the polarization of cells towards a variety of signals (e.g., T cell polarization towards antigen-presenting cells, fibroblast polarization towards wound sites, or yeast bud formation). Human CDC42 can functionally substitute for its yeast counterpart, suggesting that key functions of Cdc42p have been highly conserved, and the ability to apply genetic, biochemical, and cell biological approaches makes yeast a very powerful system for delineating the mechanism of Cdc42p action in cell polarization. In this system, a cell-cycle signal provided by a cyclin-dependent kinase triggers the polarization of Cdc42p, which in turn promotes the polarization of the actin cytoskeleton, the assembly of a ring of septin filaments, and the targeting of secretion towards the designated patch. The goal of the proposed research is to understand how Cdc42p polarization is regulated, and how the process is restricted so that cells only form one polarization "front". Cancer cells display alterations of cell shape, cell-cell adhesion, and cell motility (all actin-dependent processes regulated by Cdc42p), which are likely to be important for numerous aspects of malignant transformation. Deregulation of Cdc42p in mammalian cells promotes anchorage-independent growth, and is necessary for the morphological changes (as well as anchorage independence) that occur in Ras- transformed cells. Thus, Cdc42p deregulation affects the proliferation as well as the metastatic potential of cancer cells. Understanding the normal regulation and function of Cdc42p is an important first step towards addressing how their misregulation might promote cancer.

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The research concerns the basic mechanisms responsible for cell polarity in eukaryotic cells. Cell polarity enables cell migration, a key aspect of metastatic malignancy. Therefore, understanding how polarity is established and regulated may reveal weak links that can be attacked by cancer therapies.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cell Structure and Function (CSF)
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Gindhart, Joseph G
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Duke University
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Kuo, Chun-Chen; Savage, Natasha S; Chen, Hsin et al. (2014) Inhibitory GEF phosphorylation provides negative feedback in the yeast polarity circuit. Curr Biol 24:753-9
Atkins, Benjamin D; Yoshida, Satoshi; Saito, Koji et al. (2013) Inhibition of Cdc42 during mitotic exit is required for cytokinesis. J Cell Biol 202:231-40
Dyer, Jayme M; Savage, Natasha S; Jin, Meng et al. (2013) Tracking shallow chemical gradients by actin-driven wandering of the polarization site. Curr Biol 23:32-41
Wu, Chi-Fang; Lew, Daniel J (2013) Beyond symmetry-breaking: competition and negative feedback in GTPase regulation. Trends Cell Biol 23:476-83
Wu, Chi-Fang; Savage, Natasha S; Lew, Daniel J (2013) Interaction between bud-site selection and polarity-establishment machineries in budding yeast. Philos Trans R Soc Lond B Biol Sci 368:20130006
Howell, Audrey S; Lew, Daniel J (2012) Morphogenesis and the cell cycle. Genetics 190:51-77
Howell, Audrey S; Jin, Meng; Wu, Chi-Fang et al. (2012) Negative feedback enhances robustness in the yeast polarity establishment circuit. Cell 149:322-33
Savage, Natasha S; Layton, Anita T; Lew, Daniel J (2012) Mechanistic mathematical model of polarity in yeast. Mol Biol Cell 23:1998-2013
Layton, Anita T; Savage, Natasha S; Howell, Audrey S et al. (2011) Modeling vesicle traffic reveals unexpected consequences for Cdc42p-mediated polarity establishment. Curr Biol 21:184-94
Lew, Daniel J; Rout, Michael P (2009) Cell structure and dynamics. Curr Opin Cell Biol 21:1-3

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