Aberrant cellular proliferation is the basis of several human disease processes. A complete understanding of how cells regulate their progression through the cell cycle at the molecular level is crucial to our understanding of the molecular basis of human cancer. In addition, this information is essential for identifying new targets for future drug development. The goal of this research proposal is to ascertain the function of serine 216 phosphorylation in Cdc25C by an associating protein kinase, TAK1. Entry of cells into mitosis requires the dephosphorylation and activation of p34cdc2. Dephosphorylation of p34cdc2 is catalyzed by Cdc25C, a dual specificity protein phosphatase. Thus, Cdc25C activity affects cell cycle progression. Therefore, we are interested in mechanisms which regulate Cdc25C on serine 216, the major Cdc25C phosphorylation site in vivo in asynchronously growing HeLa cells. We have named this protein kinase TAK1, for twenty-five associating kinase. Using molecular biological and biochemical approaches, we intend to determine the function of serine 216 phosphorylation in Cdc25C. In addition, we hope to understand the regulation of TAK1 itself and identify signal transduction pathways upstream of the protein kinase which will ultimately result in a better understanding of mechanisms which control entry of cells into mitosis and cell cycle progression.
