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Nat Cell Biol. 2014 Dec;16(12):1257-64. doi: 10.1038/ncb3065. Epub 2014 Nov 17.

Negative feedback at kinetochores underlies a responsive spindle checkpoint signal.

Author information

1
1] Department of Medical Oncology, UMC Utrecht, Universiteitsweg 100, 3584CG Utrecht, The Netherlands [2] Molecular Cancer Research, UMC Utrecht, Universiteitsweg 100, 3584CG Utrecht, The Netherlands [3] Center for Molecular Medicine, UMC Utrecht, Universiteitsweg 100, 3584CG Utrecht, The Netherlands.
2
Division of Cancer Research, Medical Research Institute, Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.
3
1] Department of Medical Oncology, UMC Utrecht, Universiteitsweg 100, 3584CG Utrecht, The Netherlands [2] Molecular Cancer Research, UMC Utrecht, Universiteitsweg 100, 3584CG Utrecht, The Netherlands [3] Center for Molecular Medicine, UMC Utrecht, Universiteitsweg 100, 3584CG Utrecht, The Netherlands [4] Cancer Genomics Netherlands, UMC Utrecht, Universiteitsweg 100, 3584CG Utrecht, The Netherlands.

Abstract

Kinetochores are specialized multi-protein complexes that play a crucial role in maintaining genome stability. They bridge attachments between chromosomes and microtubules during mitosis and they activate the spindle assembly checkpoint (SAC) to arrest division until all chromosomes are attached. Kinetochores are able to efficiently integrate these two processes because they can rapidly respond to changes in microtubule occupancy by switching localized SAC signalling ON or OFF. We show that this responsiveness arises because the SAC primes kinetochore phosphatases to induce negative feedback and silence its own signal. Active SAC signalling recruits PP2A-B56 to kinetochores where it antagonizes Aurora B to promote PP1 recruitment. PP1 in turn silences the SAC and delocalizes PP2A-B56. Preventing or bypassing key regulatory steps demonstrates that this spatiotemporal control of phosphatase feedback underlies rapid signal switching at the kinetochore by: allowing the SAC to quickly transition to the ON state in the absence of antagonizing phosphatase activity; and ensuring phosphatases are then primed to rapidly switch the SAC signal OFF when kinetochore kinase activities are diminished by force-producing microtubule attachments.

PMID:
25402682
PMCID:
PMC6485516
DOI:
10.1038/ncb3065
[Indexed for MEDLINE]
Free PMC Article

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