UNIVERSITY OF CALIFORNIA, SANTA CRUZ
Relevance Cells show extraordinary diversity in size and shape. Generation of diverse sizes and shapes requires regulation of the amount and location of growth, as well as coordination of growth with the cell cycle. The mechanisms by which cells regulate and coordinate growth in the context of the cell cycle are poorly understood. The focus of our work is to use budding yeast as a model system to understand how cell growth is coordinated with the cell cycle. It is likely that the mechanisms used by budding yeast to coordinate growth with the cell cycle are relevant to all eukaryotic cells. In addition, these mechanisms are potential targets for new drugs aimed at blocking the proliferation of cancer cells. Summary In budding yeast, growth of a new daughter cell is initiated in G1 by the activity of cyclin-dependent kinase 1 (Cdk1). It is thought that Cdk1 initiates growth of a new cell by activating a highly conserved signaling module that includes the Cdc42 GTPase. The molecular mechanisms by which Cdk1 activates the Cdc42 signaling module have remained elusive. In our preliminary studies, we have shown that key components of the Cdc42 signaling module are direct targets of Cdk1. A major goal of this proposal is to test the hypothesis that phosphorylation of these proteins represents a direct link between Cdk1 activity and the initiation of new cell growth. A second cyclin-dependent kinase called Pho85 also plays a role in initiation of cell growth in G1; however the downstream targets of Pho85 that control cell growth are poorly understood. Our preliminary studies suggest that the Shs1 septin is an important and direct target of Pho85. Moreover, we have identified a Pho85-dependent signaling network that is required for regulation of cell growth. The second major goal of this proposal is to test the hypothesis that phosphorylation of Shs1 by Pho85 is a critical step in the Pho85-dependent signaling network. We will also characterize the roles of additional proteins that function in the network.