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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:
The mitotic checkpoint is the major cell cycle control mechanismfor maintaining chromosome content in multicellular organisms.Prevention of premature onset of anaphase requires activationat unattached kinetochores of the BubR1 kinase, which acts withother components to generate a diffusible "stop anaphase" inhibitor.Not only does direct binding of BubR1 to the centromere-associatedkinesin family member CENP-E activate its essential kinase,binding of a motorless fragment of CENP-E is shown here to constitutivelyactivate BubR1 bound at kinetochores, producing checkpoint signalingthat is not silenced either by spindle microtubule capture orthe tension developed at those kinetochores by other components.Using purified BubR1, microtubules, and CENP-E, microtubulecapture by the CENP-E motor domain is shown to silence BubR1kinase activity in a ternary complex of BubR1–CENP-E–microtubule.Together, this reveals that CENP-E is the signal transducinglinker responsible for silencing BubR1-dependent mitotic checkpointsignaling through its capture at kinetochores of spindle microtubules.
Y. Mao's present address is Department of Pathology, ColumbiaUniversity College of Physicians and Surgeons, New York, NY10032.
Abbreviations used in this paper: APC/C, anaphase-promotingcomplex/cyclosome; CSF, cytostatic factor.
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