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eLifeVolume 6, 2 May 2017, Article number e25366

Protein phosphatase 1 inactivates Mps1 to ensure efficient spindle assembly checkpoint silencing(Article)(Open Access)

  • ai3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
  • bInstituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
  • cDepartamento de Biomedicina, Unidade de Biologia Experimental, FMUP - Faculdade de Medicina da Universidade do Porto, Porto, Portugal
  • dDepartamento de Biologia Molecular, ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Porto, Portugal

Abstract

Faithfull genome partitioning during cell division relies on the Spindle Assembly Checkpoint (SAC), a conserved signaling pathway that delays anaphase onset until all chromosomes are attached to spindle microtubules. Mps1 kinase is an upstream SAC regulator that promotes the assembly of an anaphase inhibitor through a sequential multi-target phosphorylation cascade. Thus, the SAC is highly responsive to Mps1, whose activity peaks in early mitosis as a result of its T-loop autophosphorylation. However, the mechanism controlling Mps1 inactivation once kinetochores attach to microtubules and the SAC is satisfied remains unknown. Here we show in vitro and in Drosophila that Protein Phosphatase 1 (PP1) inactivates Mps1 by dephosphorylating its T-loop. PP1-mediated dephosphorylation of Mps1 occurs at kinetochores and in the cytosol, and inactivation of both pools of Mps1 during metaphase is essential to ensure prompt and efficient SAC silencing. Overall, our findings uncover a mechanism of SAC inactivation required for timely mitotic exit. © Moura et al.

Indexed keywords

EMTREE drug terms:aurora B kinasecyclin Bcyclin dependent kinase 1mitotic kinase monopolar spindle 1peptides and proteinsphosphoprotein phosphatase 1unclassified drugald protein, Drosophilacell cycle proteinDrosophila proteinphosphoprotein phosphatase 1protein serine threonine kinase
EMTREE medical terms:Articleautophosphorylationcontrolled studyenzyme activityfluorescence recovery after photobleachinggene expressiongene mutationgene silencingimmunofluorescenceimmunoprecipitationkinetochoremetaphasemitosis spindlemutagenesisnonhumanpolymerase chain reactionprotein depletionWestern blottinganimalcell divisionchromosome segregationDrosophilaM phase cell cycle checkpointmetabolismphysiology
MeSH:AnimalsCell Cycle ProteinsCell DivisionChromosome SegregationDrosophilaDrosophila ProteinsM Phase Cell Cycle CheckpointsProtein Phosphatase 1Protein-Serine-Threonine Kinases

Chemicals and CAS Registry Numbers:

protein serine threonine kinase;

ald protein, Drosophila; Cell Cycle Proteins; Drosophila Proteins; Protein Phosphatase 1; Protein-Serine-Threonine Kinases

Funding details

Funding sponsor Funding number Acronym
University of Massachusetts Amherst
Fundação Portugal Telecom
Norte-01-0145-FEDER-000029
Universitair Medisch Centrum UtrechtUMC
IF/01755/2014,SFRH/BD/87871/2012
European Research Council
i3S
European Regional Development FundPD/BD/105746/2014
NORTE 2020

  • 1

    We thank Geert Kops (UMC, Utrecht, The Netherlands), Thomas Maresca (University of Massachusetts Amherst, USA) and Christian Lehner (University of Zurich, Switzerland) for antibodies, constructs and fly stocks. We thank Carla Sofia Lopes (i3S, IBMC, University of Porto) and all the members of the Sunkel laboratory for critical and helpful discussions. This article is a result of the project Norte-01-0145-FEDER-000029 - Advancing Cancer Research: From basic knowledge to application, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). MO is supported by a fellowship from the GABBA PhD program from the University of Porto, PD/BD/105746/2014. JB is supported by an FCT PhD grant SFRH/BD/87871/2012. CC is supported by an FCT investigator position and funding (IF/01755/2014). HM is funded by PRECISE and CODECHECK grants from the European Research Council, FLAD Life Science 2020, and the Louis-Jeantet Young Investigator Career Award.

  • ISSN: 2050084X
  • Source Type: Journal
  • Original language: English
  • DOI: 10.7554/eLife.25366
  • PubMed ID: 28463114
  • Document Type: Article
  • Publisher: eLife Sciences Publications Ltd

  Sunkel, C.E.; i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal;
© Copyright 2017 Elsevier B.V., All rights reserved.

Cited by 13 documents

Koch, L.B. , Opoku, K.N. , Deng, Y.
Autophosphorylation is sufficient to release Mps1 kinase from native kinetochores
(2019) Proceedings of the National Academy of Sciences of the United States of America
Brás, R. , Sunkel, C.E. , Resende, L.P.
Tissue stem cells: the new actors in the aneuploidy field
(2019) Cell Cycle
Wang, S. , Zhang, M. , Liang, D.
Molecular design and anticancer activities of small-molecule monopolar spindle 1 inhibitors: A Medicinal chemistry perspective
(2019) European Journal of Medicinal Chemistry
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