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J. Cell Biol. 183 (4): 667-680

Copyright © 2008 by the Rockefeller University Press.

Article

Phosphorylation sites in BubR1 that regulate kinetochore attachment, tension, and mitotic exit

Haomin Huang1, James Hittle1, Francesca Zappacosta2, Roland S. Annan2, Avram Hershko3, , and Timothy J. Yen1

1 Fox Chase Cancer Center, Philadelphia, PA 19111
2 GlaxoSmithKline, King of Prussia, PA 19406
3 Unit of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel

Correspondence to T. Yen: tj_yen{at}fccc.edu

Abstract: BubR1 kinase is essential for the mitotic checkpoint and also for kinetochores to establish microtubule attachments. In this study, we report that BubR1 is phosphorylated in mitosis on four residues that differ from sites recently reported to be phosphorylated by Plk1 (Elowe, S., S. Hummer, A. Uldschmid, X. Li, and E.A. Nigg. 2007. Genes Dev. 21:2205–2219; Matsumura, S., F. Toyoshima, and E. Nishida. 2007. J. Biol. Chem. 282:15217–15227). S670, the most conserved residue, is phosphorylated at kinetochores at the onset of mitosis and dephosphorylated before anaphase onset. Unlike the Plk1-dependent S676 phosphorylation, S670 phosphorylation is sensitive to microtubule attachments but not to kinetochore tension. Functionally, phosphorylation of S670 is essential for error correction and for kinetochores with end-on attachments to establish tension. Furthermore, in vitro data suggest that the phosphorylation status of BubR1 is important for checkpoint inhibition of the anaphase-promoting complex/cyclosome. Finally, RNA interference experiments show that Mps1 is a major but not the exclusive kinase that specifies BubR1 phosphorylation in vivo. The combined data suggest that BubR1 may be an effector of multiple kinases that are involved in discrete aspects of kinetochore attachments and checkpoint regulation.

Abbreviations used in this paper: ACA, anticentromere antibody; APC/C, anaphase-promoting complex/cyclosome; CENP, centromere protein; KD, kinase dead; MCC, mitotic checkpoint complex; NEB, nuclear envelope breakdown.

© 2008 Huang et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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