Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

J. Cell Biol. 170 (6): 873-880

Copyright © 2005 by the Rockefeller University Press.

Report

Microtubule capture by CENP-E silences BubR1-dependent mitotic checkpoint signaling

Yinghui Mao1, Arshad Desai1,2, , and Don W. Cleveland1,2

1 Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093
2 Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093

Correspondence to Don W. Cleveland: dcleveland{at}ucsd.edu

Abstract Back to Top

Abstract: The mitotic checkpoint is the major cell cycle control mechanism for maintaining chromosome content in multicellular organisms. Prevention of premature onset of anaphase requires activation at unattached kinetochores of the BubR1 kinase, which acts with other components to generate a diffusible "stop anaphase" inhibitor. Not only does direct binding of BubR1 to the centromere-associated kinesin family member CENP-E activate its essential kinase, binding of a motorless fragment of CENP-E is shown here to constitutively activate BubR1 bound at kinetochores, producing checkpoint signaling that is not silenced either by spindle microtubule capture or the tension developed at those kinetochores by other components. Using purified BubR1, microtubules, and CENP-E, microtubule capture by the CENP-E motor domain is shown to silence BubR1 kinase activity in a ternary complex of BubR1–CENP-E–microtubule. Together, this reveals that CENP-E is the signal transducing linker responsible for silencing BubR1-dependent mitotic checkpoint signaling through its capture at kinetochores of spindle microtubules.

Y. Mao's present address is Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY 10032.

Abbreviations used in this paper: APC/C, anaphase-promoting complex/cyclosome; CSF, cytostatic factor.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Cancer-Specific Requirement for BUB1B/BUBR1 in Human Brain Tumor Isolates and Genetically Transformed Cells.
Y. Ding, C. G. Hubert, J. Herman, P. Corrin, C. M. Toledo, K. Skutt-Kakaria, J. Vazquez, R. Basom, B. Zhang, J. K. Risler, et al. (2013)
Cancer Discovery 3, 198-211
   Abstract »    Full Text »    PDF »
Force generation by kinesin and myosin cytoskeletal motor proteins.
F. J. Kull and S. A. Endow (2013)
J. Cell Sci. 126, 9-19
   Abstract »    Full Text »    PDF »
CENP-E-dependent BubR1 autophosphorylation enhances chromosome alignment and the mitotic checkpoint.
Y. Guo, C. Kim, S. Ahmad, J. Zhang, and Y. Mao (2012)
J. Cell Biol. 198, 205-217
   Abstract »    Full Text »    PDF »
Gene expression profiles in promoted-growth rice seedlings that germinated from the seeds implanted by low-energy N+ beam.
H. Ya, Q. Chen, W. Wang, W. Chen, G. Qin, and Z. Jiao (2012)
J Radiat Res 53, 558-569
   Abstract »    Full Text »    PDF »
CENP-E Kinesin Interacts with SKAP Protein to Orchestrate Accurate Chromosome Segregation in Mitosis.
Y. Huang, W. Wang, P. Yao, X. Wang, X. Liu, X. Zhuang, F. Yan, J. Zhou, J. Du, T. Ward, et al. (2012)
J. Biol. Chem. 287, 1500-1509
   Abstract »    Full Text »    PDF »
Bub1 and BubR1: at the Interface between Chromosome Attachment and the Spindle Checkpoint.
S. Elowe (2011)
Mol. Cell. Biol. 31, 3085-3093
   Abstract »    Full Text »    PDF »
Defining the Molecular Basis of BubR1 Kinetochore Interactions and APC/C-CDC20 Inhibition.
S. D'Arcy, O. R. Davies, T. L. Blundell, and V. M. Bolanos-Garcia (2010)
J. Biol. Chem. 285, 14764-14776
   Abstract »    Full Text »    PDF »
Antitumor activity of an allosteric inhibitor of centromere-associated protein-E.
K. W. Wood, L. Lad, L. Luo, X. Qian, S. D. Knight, N. Nevins, K. Brejc, D. Sutton, A. G. Gilmartin, P. R. Chua, et al. (2010)
PNAS 107, 5839-5844
   Abstract »    Full Text »    PDF »
Targeting a kinetochore-associated motor protein to kill cancer cells.
S. A. Wacker and T. M. Kapoor (2010)
PNAS 107, 5699-5700
   Full Text »    PDF »
Overcoming inhibition in the spindle checkpoint.
V. Vanoosthuyse and K. G. Hardwick (2009)
Genes & Dev. 23, 2799-2805
   Abstract »    Full Text »    PDF »
Identification of FANCA as a protein interacting with centromere-associated protein E.
J. Du, L. Chen, and J. Shen (2009)
Acta Biochim Biophys Sin 41, 816-821
   Abstract »    Full Text »    PDF »
PinX1 Is a Novel Microtubule-binding Protein Essential for Accurate Chromosome Segregation.
K. Yuan, N. Li, K. Jiang, T. Zhu, Y. Huo, C. Wang, J. Lu, A. Shaw, K. Thomas, J. Zhang, et al. (2009)
J. Biol. Chem. 284, 23072-23082
   Abstract »    Full Text »    PDF »
G2 histone methylation is required for the proper segregation of chromosomes.
R. Heit, J. B. Rattner, G. K. T. Chan, and M. J. Hendzel (2009)
J. Cell Sci. 122, 2957-2968
   Abstract »    Full Text »    PDF »
Kinase Signaling in the Spindle Checkpoint.
J. Kang and H. Yu (2009)
J. Biol. Chem. 284, 15359-15363
   Abstract »    Full Text »    PDF »
Systematic Analysis in Caenorhabditis elegans Reveals that the Spindle Checkpoint Is Composed of Two Largely Independent Branches.
A. Essex, A. Dammermann, L. Lewellyn, K. Oegema, and A. Desai (2009)
Mol. Biol. Cell 20, 1252-1267
   Abstract »    Full Text »    PDF »
UA62784, a novel inhibitor of centromere protein E kinesin-like protein.
M. C. Henderson, Y.-J. Y. Shaw, H. Wang, H. Han, L. H. Hurley, G. Flynn, R. T. Dorr, and D. D. Von Hoff (2009)
Mol. Cancer Ther. 8, 36-44
   Abstract »    Full Text »    PDF »
Centromere-Associated Protein E: A Motor That Puts the Brakes on the Mitotic Checkpoint.
K. W. Wood, P. Chua, D. Sutton, and J. R. Jackson (2008)
Clin. Cancer Res. 14, 7588-7592
   Abstract »    Full Text »    PDF »
Phosphorylation sites in BubR1 that regulate kinetochore attachment, tension, and mitotic exit.
H. Huang, J. Hittle, F. Zappacosta, R. S. Annan, A. Hershko, and T. J. Yen (2008)
J. Cell Biol. 183, 667-680
   Abstract »    Full Text »    PDF »
Septin 7 Interacts with Centromere-associated Protein E and Is Required for Its Kinetochore Localization.
M. Zhu, F. Wang, F. Yan, P. Y. Yao, J. Du, X. Gao, X. Wang, Q. Wu, T. Ward, J. Li, et al. (2008)
J. Biol. Chem. 283, 18916-18925
   Abstract »    Full Text »    PDF »
The mitotic kinesin CENP-E is a processive transport motor.
H. Yardimci, M. van Duffelen, Y. Mao, S. S. Rosenfeld, and P. R. Selvin (2008)
PNAS 105, 6016-6021
   Abstract »    Full Text »    PDF »
Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis.
K. Jeganathan, L. Malureanu, D. J. Baker, S. C. Abraham, and J. M. van Deursen (2007)
J. Cell Biol. 179, 255-267
   Abstract »    Full Text »    PDF »
BubR1 and APC/EB1 cooperate to maintain metaphase chromosome alignment.
J. Zhang, S. Ahmad, and Y. Mao (2007)
J. Cell Biol. 178, 773-784
   Abstract »    Full Text »    PDF »
Spindly, a novel protein essential for silencing the spindle assembly checkpoint, recruits dynein to the kinetochore.
E. R. Griffis, N. Stuurman, and R. D. Vale (2007)
J. Cell Biol. 177, 1005-1015
   Abstract »    Full Text »    PDF »
Human NUF2 Interacts with Centromere-associated Protein E and Is Essential for a Stable Spindle Microtubule-Kinetochore Attachment.
D. Liu, X. Ding, J. Du, X. Cai, Y. Huang, T. Ward, A. Shaw, Y. Yang, R. Hu, C. Jin, et al. (2007)
J. Biol. Chem. 282, 21415-21424
   Abstract »    Full Text »    PDF »
Mitotic Chromosome Biorientation in Fission Yeast Is Enhanced by Dynein and a Minus-end-directed, Kinesin-like Protein.
E. L. Grishchuk, I. S. Spiridonov, and J. R. McIntosh (2007)
Mol. Biol. Cell 18, 2216-2225
   Abstract »    Full Text »    PDF »
Farnesyl transferase inhibitors impair chromosomal maintenance in cell lines and human tumors by compromising CENP-E and CENP-F function.
K. Schafer-Hales, J. Iaconelli, J. P. Snyder, A. Prussia, J. H. Nettles, A. El-Naggar, F. R. Khuri, P. Giannakakou, and A. I. Marcus (2007)
Mol. Cancer Ther. 6, 1317-1328
   Abstract »    Full Text »    PDF »
Loading of the 3F3/2 Antigen onto Kinetochores Is Dependent on the Ordered Assembly of the Spindle Checkpoint Proteins.
O. K. Wong and G. Fang (2006)
Mol. Biol. Cell 17, 4390-4399
   Abstract »    Full Text »    PDF »
CELL BIOLOGY: Serving Up a Plate of Chromosomes.
R. Heald (2006)
Science 311, 343-344
   Abstract »    Full Text »    PDF »
Chromosomes Can Congress to the Metaphase Plate Before Biorientation.
T. M. Kapoor, M. A. Lampson, P. Hergert, L. Cameron, D. Cimini, E. D. Salmon, B. F. McEwen, and A. Khodjakov (2006)
Science 311, 388-391
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882