? Phosphoserine/threonine-binding domains play critical roles in controlling multiple aspects of cell proliferation, including cell cycle progression and the cellular response to DNA damage. The current list of pSer/pThr-binding domains includes 14-3-3 proteins, FHA domains, WW domains, WD40 repeats of F-box proteins, tandem BRCT domains and the Polo-box domains of Polo-like kinases. The long-term goal of our laboratory is to identify and characterize these domains with a focus on identifying their physiological ligands, determining the structural basis for their pSer/Thr-motif recognition, and elucidating the molecular basis for their functions in cell cycle control within complex protein kinase signaling networks. Polo-like kinases are essential during multiple stages of the eukaryotic cell cycle, including many of the events that occur during M-phase, as well as in the DNA damage response. Despite their importance, details about how Polo-like kinase activity is regulated, and the identity of their substrates are poorly understood. In this proposal we use a combination of biochemical, structural and cell biological techniques to determine the function of the invariant pSer/pThr-binding Polo-box domain in regulating the activation of, and the substrate selection and phosphorylation by Polo-like kinases. In the process, we will identify many new Polo-like kinase ligands and substrates that may be responsible for the pleiotropic role these kinases play in the cell. Since Polo-like kinases are upregulated in many types of human cancer, and since their experimental down-regulation results in decreased cell proliferation and tumor regression, the results of our experiments should determine whether the Polo-box domain is a good target for novel anti-cancer drug design. ? ?
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