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Checkpoint signaling and error correction require regulation of the MPS1 T-loop by PP2A-B56

During mitosis, the formation of microtubule–kinetochore attachments is monitored by the serine/threonine kinase monopolar spindle 1 (MPS1). MPS1 is recruited to unattached kinetochores where it phosphorylates KNL1, BUB1, and MAD1 to initiate the spindle assembly checkpoint. This arrests the cell cy...

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Autores principales: Hayward, Daniel, Bancroft, James, Mangat, Davinderpreet, Alfonso-Pérez, Tatiana, Dugdale, Sholto, McCarthy, Julia, Barr, Francis A., Gruneberg, Ulrike
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781431/
https://www.ncbi.nlm.nih.gov/pubmed/31511308
http://dx.doi.org/10.1083/jcb.201905026
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author Hayward, Daniel
Bancroft, James
Mangat, Davinderpreet
Alfonso-Pérez, Tatiana
Dugdale, Sholto
McCarthy, Julia
Barr, Francis A.
Gruneberg, Ulrike
author_facet Hayward, Daniel
Bancroft, James
Mangat, Davinderpreet
Alfonso-Pérez, Tatiana
Dugdale, Sholto
McCarthy, Julia
Barr, Francis A.
Gruneberg, Ulrike
author_sort Hayward, Daniel
collection PubMed
description During mitosis, the formation of microtubule–kinetochore attachments is monitored by the serine/threonine kinase monopolar spindle 1 (MPS1). MPS1 is recruited to unattached kinetochores where it phosphorylates KNL1, BUB1, and MAD1 to initiate the spindle assembly checkpoint. This arrests the cell cycle until all kinetochores have been stably captured by microtubules. MPS1 also contributes to the error correction process rectifying incorrect kinetochore attachments. MPS1 activity at kinetochores requires autophosphorylation at multiple sites including threonine 676 in the activation segment or “T-loop.” We now demonstrate that the BUBR1-bound pool of PP2A-B56 regulates MPS1 T-loop autophosphorylation and hence activation status in mammalian cells. Overriding this regulation using phosphomimetic mutations in the MPS1 T-loop to generate a constitutively active kinase results in a prolonged mitotic arrest with continuous turnover of microtubule–kinetochore attachments. Dynamic regulation of MPS1 catalytic activity by kinetochore-localized PP2A-B56 is thus critical for controlled MPS1 activity and timely cell cycle progression.
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spelling pubmed-67814312020-04-07 Checkpoint signaling and error correction require regulation of the MPS1 T-loop by PP2A-B56 Hayward, Daniel Bancroft, James Mangat, Davinderpreet Alfonso-Pérez, Tatiana Dugdale, Sholto McCarthy, Julia Barr, Francis A. Gruneberg, Ulrike J Cell Biol Research Articles During mitosis, the formation of microtubule–kinetochore attachments is monitored by the serine/threonine kinase monopolar spindle 1 (MPS1). MPS1 is recruited to unattached kinetochores where it phosphorylates KNL1, BUB1, and MAD1 to initiate the spindle assembly checkpoint. This arrests the cell cycle until all kinetochores have been stably captured by microtubules. MPS1 also contributes to the error correction process rectifying incorrect kinetochore attachments. MPS1 activity at kinetochores requires autophosphorylation at multiple sites including threonine 676 in the activation segment or “T-loop.” We now demonstrate that the BUBR1-bound pool of PP2A-B56 regulates MPS1 T-loop autophosphorylation and hence activation status in mammalian cells. Overriding this regulation using phosphomimetic mutations in the MPS1 T-loop to generate a constitutively active kinase results in a prolonged mitotic arrest with continuous turnover of microtubule–kinetochore attachments. Dynamic regulation of MPS1 catalytic activity by kinetochore-localized PP2A-B56 is thus critical for controlled MPS1 activity and timely cell cycle progression. Rockefeller University Press 2019-10-07 2019-09-11 /pmc/articles/PMC6781431/ /pubmed/31511308 http://dx.doi.org/10.1083/jcb.201905026 Text en © 2019 Hayward et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/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 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Hayward, Daniel
Bancroft, James
Mangat, Davinderpreet
Alfonso-Pérez, Tatiana
Dugdale, Sholto
McCarthy, Julia
Barr, Francis A.
Gruneberg, Ulrike
Checkpoint signaling and error correction require regulation of the MPS1 T-loop by PP2A-B56
title Checkpoint signaling and error correction require regulation of the MPS1 T-loop by PP2A-B56
title_full Checkpoint signaling and error correction require regulation of the MPS1 T-loop by PP2A-B56
title_fullStr Checkpoint signaling and error correction require regulation of the MPS1 T-loop by PP2A-B56
title_full_unstemmed Checkpoint signaling and error correction require regulation of the MPS1 T-loop by PP2A-B56
title_short Checkpoint signaling and error correction require regulation of the MPS1 T-loop by PP2A-B56
title_sort checkpoint signaling and error correction require regulation of the mps1 t-loop by pp2a-b56
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781431/
https://www.ncbi.nlm.nih.gov/pubmed/31511308
http://dx.doi.org/10.1083/jcb.201905026
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