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Mps1 regulates kinetochore-microtubule attachment stability via the ska complex to ensure error-free chromosome segregation
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Maciejowski, John, Drechsler, Hauke, Grundner-Culemann, Kathrin, Ballister, Edward R., Rodriguez-Rodriguez, Jose-Antonio, Rodriguez-Bravo, Veronica, Jones, Mathew J. K., Foley, Emily, Lampson, Michael A., Daub, Henrik, McAinsh, Andrew D. and Jallepalli, Prasad V. (2017) Mps1 regulates kinetochore-microtubule attachment stability via the ska complex to ensure error-free chromosome segregation. Developmental Cell, 41 (2). 143-156.e6. doi:10.1016/j.devcel.2017.03.025
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WRAP-Mps1-regulates-kinetochore-microtubule-attachment-stability-via-Ska-complex-McAinsh-2017.pdf - Accepted Version - Requires a PDF viewer. Available under License Creative Commons Attribution Non-commercial No Derivatives 4.0. Download (2627Kb) | Preview |
Official URL: http://dx.doi.org/10.1016/j.devcel.2017.03.025
Abstract
The spindle assembly checkpoint kinase Mps1 not only inhibits anaphase but also corrects erroneous attachments that could lead to missegregation and aneuploidy. However, Mps1’s error correction-relevant substrates are unknown. Using a chemically tuned kinetochore-targeting assay, we show that Mps1 destabilizes microtubule attachments (K fibers) epistatically to Aurora B, the other major error-correcting kinase. Through quantitative proteomics, we identify multiple sites of Mps1-regulated phosphorylation at the outer kinetochore. Substrate modification was microtubule sensitive and opposed by PP2A-B56 phosphatases that stabilize chromosome-spindle attachment. Consistently, Mps1 inhibition rescued K-fiber stability after depleting PP2A-B56. We also identify the Ska complex as a key effector of Mps1 at the kinetochore-microtubule interface, as mutations that mimic constitutive phosphorylation destabilized K fibers in vivo and reduced the efficiency of the Ska complex’s conversion from lattice diffusion to end-coupled microtubule binding in vitro. Our results reveal how Mps1 dynamically modifies kinetochores to correct improper attachments and ensure faithful chromosome segregation.
| Item Type: | Journal Article | ||||||
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| Divisions: | Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology Faculty of Medicine > Warwick Medical School > Biomedical Sciences Faculty of Medicine > Warwick Medical School |
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| Journal or Publication Title: | Developmental Cell | ||||||
| Publisher: | Cell Press | ||||||
| ISSN: | 1534-5807 | ||||||
| Official Date: | 24 April 2017 | ||||||
| Dates: |
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| Volume: | 41 | ||||||
| Number: | 2 | ||||||
| Page Range: | 143-156.e6 | ||||||
| DOI: | 10.1016/j.devcel.2017.03.025 | ||||||
| Status: | Peer Reviewed | ||||||
| Publication Status: | Published | ||||||
| Access rights to Published version: | Restricted or Subscription Access | ||||||
| Open Access Version: |
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