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Sustained Mps1 activity is required in mitosis to recruit O-Mad2 to the Mad1–C-Mad2 core complex

Mps1 is an essential component of the spindle assembly checkpoint. In this study, we describe a novel Mps1 inhibitor, AZ3146, and use it to probe the role of Mps1’s catalytic activity during mitosis. When Mps1 is inhibited before mitotic entry, subsequent recruitment of Mad1 and Mad2 to kinetochores...

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Detalles Bibliográficos
Autores principales: Hewitt, Laura, Tighe, Anthony, Santaguida, Stefano, White, Anne M., Jones, Clifford D., Musacchio, Andrea, Green, Stephen, Taylor, Stephen S.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911659/
https://www.ncbi.nlm.nih.gov/pubmed/20624899
http://dx.doi.org/10.1083/jcb.201002133
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author Hewitt, Laura
Tighe, Anthony
Santaguida, Stefano
White, Anne M.
Jones, Clifford D.
Musacchio, Andrea
Green, Stephen
Taylor, Stephen S.
author_facet Hewitt, Laura
Tighe, Anthony
Santaguida, Stefano
White, Anne M.
Jones, Clifford D.
Musacchio, Andrea
Green, Stephen
Taylor, Stephen S.
author_sort Hewitt, Laura
collection PubMed
description Mps1 is an essential component of the spindle assembly checkpoint. In this study, we describe a novel Mps1 inhibitor, AZ3146, and use it to probe the role of Mps1’s catalytic activity during mitosis. When Mps1 is inhibited before mitotic entry, subsequent recruitment of Mad1 and Mad2 to kinetochores is abolished. However, if Mps1 is inhibited after mitotic entry, the Mad1–C-Mad2 core complex remains kinetochore bound, but O-Mad2 is not recruited to the core. Although inhibiting Mps1 also interferes with chromosome alignment, we see no obvious effect on aurora B activity. In contrast, kinetochore recruitment of centromere protein E (CENP-E), a kinesin-related motor protein, is severely impaired. Strikingly, inhibition of Mps1 significantly increases its own abundance at kinetochores. Furthermore, we show that Mps1 can dimerize and transphosphorylate in cells. We propose a model whereby Mps1 transphosphorylation results in its release from kinetochores, thus facilitating recruitment of O-Mad2 and CENP-E and thereby simultaneously promoting checkpoint signaling and chromosome congression.
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spelling pubmed-29116592011-01-12 Sustained Mps1 activity is required in mitosis to recruit O-Mad2 to the Mad1–C-Mad2 core complex Hewitt, Laura Tighe, Anthony Santaguida, Stefano White, Anne M. Jones, Clifford D. Musacchio, Andrea Green, Stephen Taylor, Stephen S. J Cell Biol Research Articles Mps1 is an essential component of the spindle assembly checkpoint. In this study, we describe a novel Mps1 inhibitor, AZ3146, and use it to probe the role of Mps1’s catalytic activity during mitosis. When Mps1 is inhibited before mitotic entry, subsequent recruitment of Mad1 and Mad2 to kinetochores is abolished. However, if Mps1 is inhibited after mitotic entry, the Mad1–C-Mad2 core complex remains kinetochore bound, but O-Mad2 is not recruited to the core. Although inhibiting Mps1 also interferes with chromosome alignment, we see no obvious effect on aurora B activity. In contrast, kinetochore recruitment of centromere protein E (CENP-E), a kinesin-related motor protein, is severely impaired. Strikingly, inhibition of Mps1 significantly increases its own abundance at kinetochores. Furthermore, we show that Mps1 can dimerize and transphosphorylate in cells. We propose a model whereby Mps1 transphosphorylation results in its release from kinetochores, thus facilitating recruitment of O-Mad2 and CENP-E and thereby simultaneously promoting checkpoint signaling and chromosome congression. The Rockefeller University Press 2010-07-12 /pmc/articles/PMC2911659/ /pubmed/20624899 http://dx.doi.org/10.1083/jcb.201002133 Text en © 2010 Hewitt 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.rupress.org/terms). 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/).
spellingShingle Research Articles
Hewitt, Laura
Tighe, Anthony
Santaguida, Stefano
White, Anne M.
Jones, Clifford D.
Musacchio, Andrea
Green, Stephen
Taylor, Stephen S.
Sustained Mps1 activity is required in mitosis to recruit O-Mad2 to the Mad1–C-Mad2 core complex
title Sustained Mps1 activity is required in mitosis to recruit O-Mad2 to the Mad1–C-Mad2 core complex
title_full Sustained Mps1 activity is required in mitosis to recruit O-Mad2 to the Mad1–C-Mad2 core complex
title_fullStr Sustained Mps1 activity is required in mitosis to recruit O-Mad2 to the Mad1–C-Mad2 core complex
title_full_unstemmed Sustained Mps1 activity is required in mitosis to recruit O-Mad2 to the Mad1–C-Mad2 core complex
title_short Sustained Mps1 activity is required in mitosis to recruit O-Mad2 to the Mad1–C-Mad2 core complex
title_sort sustained mps1 activity is required in mitosis to recruit o-mad2 to the mad1–c-mad2 core complex
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911659/
https://www.ncbi.nlm.nih.gov/pubmed/20624899
http://dx.doi.org/10.1083/jcb.201002133
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