The long-term objective of this project is to understand the signal-transduction mechanisms that control cellular morphogenesis during the eukaryotic cell cycle. Normal morphogenesis is essential for the fidelity of cellular differentiation and reproduction. The goal of this project is to decipher the signal-transduction mechanisms that control the cell polarity process in the yeast Saccharomyces cerevisiae. Polarized growth in response to different signals during the yeast cell cycle can result in the generation of several different morphological structures, such as buds, mating projections, and pseudohyphae. The principal investigator has previously characterized two protein components of the cell polarity apparatus in yeast; the Ras-related GTPase Cdc42p and its guanine-nucleotide exchange factor (GEF) Cdc24p. These components are integral parts of a signal-transduction pathway that leads to the generation of cell polarity during the cell cycle. These components have conserved counterparts in other eukaryotes, suggesting that common signal-transduction mechanisms controlling cell polarity may exist. The goal of this project is directed at understanding the regulation of the Cdc42p GTPase and how it interfaces with different cell-cycle regulatory processes. The hypothesis that will be tested with these proposed experiments is: The Cdc42p GTPase regulates multiple cell-cycle events through interactions with different downstream effectors. Analysis of Cdc42p effector domain mutations has indicated that Cdc42p is involved in multiple processes during the mitotic cell cycle, including bud emergence, a early post-bud emergence checkpoint, the apical-isotropic switch, the G 2 /M morphogenetic checkpoint, and cytokinesis. However, the molecular mechanisms by which Cdc42p interacts with multiple downstream effectors to regulate these processes is still unclear. The function of Cdc42p in these multiple cell-cycle events will be examined, concentrating on the early post-bud emergence checkpoint, through the characterization of the D38E mutant allele and new Cdc42 effector-domain mutants. In addition, the mechanism by which Cdc42p is targeted to sites of polarized growth will be determined, through the mutational analysis of a functional GFP-Cdc42 fusion protein. The answers to these questions will not only be relevant to the basic understanding of signal-transduction mechanisms in cell biology, but also to the understanding of the cellular morphogenesis process in yeast and other eukaryotes.

National Science Foundation (NSF)
Division of Molecular and Cellular Biosciences (MCB)
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Gerald A. Berkowitz
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University of Vermont & State Agricultural College
United States
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