University of Virginia Health System

Centromeric Aurora-B activation requires TD-60, microtubules, and substrate priming phosphorylation. Science. 2008 Jan 25;319(5862):469-72.

The progression of mitosis is driven by several key kinases: Cdc2, Polo, Aurora A, and Aurora B. These kinases coordinate the many complicated events leading up to the faithful segregation of genetic material into two individual cells. Errors in the regulation of these kinases can have deleterious effects such as birth defects and cancers. Aurora kinases are commonly overexpressed in human tumors. We are interested in understanding the regulation of these kinases during mitosis. Aurora B kinase localizes to the inner centromere region on a pair of sister chromatids during the early stages of mitosis, where it plays an integral role in spindle checkpoint signaling, and promoting both metaphase alignment of chromosomes, and microtubule attachments to the kinetochore.

My main research interest is in understanding the regulation of Aurora B kinase activity as chromosomes move towards the metaphase plate. We have found that TD-60, a protein with homology to RCC1, (the guanine nucleotide exchange factor for Ran), is intricately involved in the regulation of Aurora B activity during mitosis. TD-60, together with microtubules, acts as a co-factor for Aurora B activation in the presence of specific substrates. Aurora B activation is also dependent on phosphorylation events by other mitotic kinases on these substrates. We believe that TD-60 activates Aurora B on chromosomes that have not yet traveled to the metaphase plate. Understanding the substrate specificity and regulation of a mitotic kinase is important when considering the development of cancer therapeutics, as this knowledge will help create specific targets and hopefully minimize side effects.