The Aurora kinases are critical regulators of cell division in organisms from yeast to humans. My lab uses C. elegans as a model system for studying the role of these kinases in chromosome and microtubule dynamics. Recently, specific Aurora substrates have been shown to be activators of the Aurora kinases. In 2002, my lab found that phosphorylation of the C. elegans chromosomal passenger protein ICP-1 enhances the activity of the AIR-2 Aurora B kinase. Others have since shown that this property is conserved in human INCENP and Aurora B. We have recently discovered that the C. elegans Tousled kinase TLK-1 is a second substrate activator of AIR-2. Tousled kinases are highly expressed in S-phase and phosphorylate Asf1 chromatin assembly factors. Our findings suggest that Tousled kinases may have mitotic functions and that AIR-2 may act independently of the chromosomal passenger complex. We hypothesize that distinct substrate activators of Aurora B impart specificity for different substrates and cellular functions. To determine the role of Aurora B substrate activators in the C. elegans cell cycle we will: 1) Determine the functional relationship between TLK-1, ASF-1, ICP-1, and AIR-2 in chromosome behavior, 2) Define the molecular differences between the TLK-1/ICP-1/AIR-2 complex and the chromosomal passenger complex, 3) Perform a molecular screen to identify substrates of the ICP-1/AIR-2 and TLK-1/ICP-1/AIR-2 kinase complexes, 4) Perform a yeast genetic screen to isolate additional substrate activators of the AIR-2/Aurora B kinase. Relevance: Aurora kinases are potent oncogenes and are overexpressed in a number of human tumors. Since Aurora substrate activators have the potential to impart spatial, temporal, and substrate specificity to the Aurora kinases, they are sure to be valuable targets for cancer therapy.
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