Cdc42 plays a key role in the polarization of cells towards a variety of signals (e.g., T cell polarization towards antigen-presenting cells, fibroblas polarization towards wound sites, or yeast bud formation). Human CDC42 can functionally substitute for its yeast counterpart, suggesting that key functions of Cdc42 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 Cdc42 action in cell polarization. The goal of the proposed research is to understand how Cdc42 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 Cdc42), which are likely to be important for numerous aspects of malignant transformation. Deregulation of Cdc42 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, Cdc42 deregulation affects the proliferation as well as the metastatic potential of cancer cells. Understanding the normal regulation and function of Cdc42 is an important first step towards addressing how their misregulation might promote cancer.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM062300-14
Application #
8703121
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Nie, Zhongzhen
Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Durham
State
NC
Country
United States
Zip Code
27705
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Wu, Chi-Fang; Chiou, Jian-Geng; Minakova, Maria et al. (2015) Role of competition between polarity sites in establishing a unique front. Elife 4:
Woods, Benjamin; Kuo, Chun-Chen; Wu, Chi-Fang et al. (2015) Polarity establishment requires localized activation of Cdc42. J Cell Biol 211:19-26
Ramirez, Samuel A; Raghavachari, Sridhar; Lew, Daniel J (2015) Dendritic spine geometry can localize GTPase signaling in neurons. Mol Biol Cell 26:4171-81
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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
Wu, Chi-Fang; Lew, Daniel J (2013) Beyond symmetry-breaking: competition and negative feedback in GTPase regulation. Trends Cell Biol 23:476-83
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
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

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