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.
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.
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