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Originally published as MBC in Press, 10.1091/mbc.E08-05-0460 on August 20, 2008

Vol. 19, Issue 11, 4852-4862, November 2008

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Phosphatase Inhibitor-2 Balances Protein Phosphatase 1 and Aurora B Kinase for Chromosome Segregation and Cytokinesis in Human Retinal Epithelial Cells

Weiping Wang*,{dagger}, P. Todd Stukenberg{ddagger}, and David L. Brautigan*,{dagger}

*Center for Cell Signaling, Departments of {dagger}Microbiology and {ddagger}Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908

Submitted May 6, 2008; Accepted August 8, 2008
Monitoring Editor: Yixian Zheng

Mitosis in Saccharomyces cerevisiae depends on IPL1 kinase, which genetically interacts with GLC8. The metazoan homologue of GLC8 is inhibitor-2 (I-2), but its function is not understood. We found endogenous and ectopic I-2 localized to the spindle, midzone, and midbody of mitotic human epithelial ARPE-19 cells. Knockdown of I-2 by RNA interference produced multinucleated cells, with supernumerary centrosomes, multipolar spindles and lagging chromosomes during anaphase. These defects did not involve changes in levels of protein phosphatase-1 (PP1), and the multinuclear phenotype was rescued by overexpression of I-2. Appearance of multiple nuclei and supernumerary centrosomes required progression through the cell cycle and I-2 knockdown cells failed cytokinesis, as observed by time-lapse microscopy. Inhibition of Aurora B by hesperadin produced multinucleated cells and reduced H3S10 phosphorylation. I-2 knockdown enhanced this latter effect. Partial knockdown of PP1C{alpha} prevented multiple nuclei caused by either knockdown of I-2 or treatment with hesperadin. Expression of enhanced green fluorescent protein-I-2 or hemagglutinin-I-2 made cells resistant to hesperadin. We propose that I-2 acts to enhance Aurora B by inhibiting specific PP1 holoenzymes that dephosphorylate Aurora B substrates necessary for chromosome segregation and cytokinesis. Conserved together throughout eukaryotic evolution, I-2, PP1 and Aurora B function interdependently during mitosis.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E08-05-0460) on August 20, 2008.

Address correspondence to: David L. Brautigan (db8g{at}virginia.edu)

Abbreviations used: PP1, protein phosphatase 1; I-2, phosphatase inhibitor-2.






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