Abstract
Aurora-C, a member of the Aurora kinase family that can complement Aurora-B function in mitosis is either moderately expressed or repressed in most adult somatic tissues but is active in early embryonic development and expressed at elevated levels in multiple human cancers. Aurora-C overexpression reportedly plays a role in tumorigenic transformation. We performed detailed characterization of Aurora-C interactions with members of the Chromosome Passenger Complex (CPC), Survivin and Inner Centromere Protein (INCENP) in reference to known Aurora-B interactions to understand the functional significance of Aurora-C overexpression in human cancer cells. The results revealed that silencing of Aurora-C or -B individually does not affect localization of the other kinase and the two kinases exist predominantly in independent complexes in vivo. Presence of Aurora-C and -B in molecular complexes of varying as well as overlapping sizes and co-existence in INCENP overexpressing cells indicated oligomerization of ternary complexes under different physiological conditions in vivo. Furthermore, Aurora-C and -B stabilized INCENP through interaction with and phosphorylation of the IN box domain while Aurora-C was activated following Survivin phosphorylation on Serine 20. Phosphorylation of Survivin residue Serine 20 by Aurora-C and –B appears important for proper chromosome segregation. Taken together, our study suggests that Aurora-C, expressed at low levels in somatic cells, functions as a catalytic component of the CPC together with Aurora-B through mitosis. Elevated expression of Aurora-C in cancer cells alters the structural and functional characteristics of the Aurora-B-CPC leading to chromosomal instability.
Highlights
Aurora kinase family proteins have been conserved through evolution as critical regulators of cell division
Aurora-B kinase activity, required for proper chromosome alignment, segregation, and cytokinesis is regulated through interactions with three non-enzymatic proteins, Inner centromere protein (INCENP), Borealin/Dasra B, and Survivin, which are involved in targeting the kinase to its subcellular localizations [3]
The findings that Aurora-C expression is elevated in multiple human cancers indicates a functional role for the kinase in adult somatic tissues and makes it imperative that the molecular details of Aurora-C interactions with the chromosomal passenger complex (CPC) components and the functional consequences of Aurora-C over expression in cancer cells be well elucidated
Summary
Aurora kinase family proteins have been conserved through evolution as critical regulators of cell division. While the genomes of fission and budding yeast encode a single Aurora kinase, Ipl and Ark respectively, larger metazoan genomes express up to three members of the kinase family. Aurora-B kinase activity, required for proper chromosome alignment, segregation, and cytokinesis is regulated through interactions with three non-enzymatic proteins, Inner centromere protein (INCENP), Borealin/Dasra B, and Survivin, which are involved in targeting the kinase to its subcellular localizations [3]. Aurora-B, INCENP, Borealin, and Survivin, exist in a conserved complex, referred to as chromosomal passenger complex (CPC), which displays a dynamic localization pattern during mitosis, appearing first along the chromosome arms followed by localization at the inner centromeres from prophase through metaphase, and relocalization at the spindle midzone and midbody during anaphase through cytokinesis. Inactivation of Aurora-B and loss of CPC subunits impair error correction of kinetochore-microtubule attachments and cytokinesis [5, 6]
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