Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pgen.1006310
Title: Loss of the Greatwall Kinase Weakens the Spindle Assembly Checkpoint
Authors: Diril M.K.
Bisteau X.
Kitagawa M. 
Caldez M.J.
Wee S.
Gunaratne J. 
Lee S.H. 
Kaldis P. 
Keywords: cell enzyme
cyclin dependent kinase 1
MPS1 protein
okadaic acid
phosphoprotein phosphatase 2A
phosphotransferase
protein Mad1
unclassified drug
cyclin dependent kinase 1
greatwall protein, mouse
microtubule associated protein
phosphoprotein phosphatase 2
Ppp2r2a protein, mouse
protein serine threonine kinase
Ttk protein, mouse
adult
animal cell
animal experiment
animal tissue
Article
cell proliferation
cellular distribution
centromere
chromosome segregation
controlled study
cytokinesis
embryo
embryo development
enzyme activity
enzyme localization
enzyme phosphorylation
essential gene
fibroblast
gene function
gene inactivation
gene loss
in vitro study
knockout gene
knockout mouse
M phase cell cycle checkpoint
Mastl gene
microtubule
mitosis inhibition
mouse
nonhuman
protein dephosphorylation
protein determination
protein localization
protein phosphorylation
animal
genetics
kinetochore
M phase cell cycle checkpoint
metabolism
mitosis
phosphorylation
spindle apparatus
Animals
CDC2 Protein Kinase
Chromosome Segregation
Cytokinesis
Kinetochores
M Phase Cell Cycle Checkpoints
Mice
Mice, Knockout
Microtubule-Associated Proteins
Microtubules
Mitosis
Phosphorylation
Protein Phosphatase 2
Protein-Serine-Threonine Kinases
Spindle Apparatus
Issue Date: 2016
Publisher: Public Library of Science
Citation: Diril M.K., Bisteau X., Kitagawa M., Caldez M.J., Wee S., Gunaratne J., Lee S.H., Kaldis P. (2016). Loss of the Greatwall Kinase Weakens the Spindle Assembly Checkpoint. PLoS Genetics 12 (9) : e1006310. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pgen.1006310
Abstract: The Greatwall kinase/Mastl is an essential gene that indirectly inhibits the phosphatase activity toward mitotic Cdk1 substrates. Here we show that although Mastl knockout (MastlNULL) MEFs enter mitosis, they progress through mitosis without completing cytokinesis despite the presence of misaligned chromosomes, which causes chromosome segregation defects. Furthermore, we uncover the requirement of Mastl for robust spindle assembly checkpoint (SAC) maintenance since the duration of mitotic arrest caused by microtubule poisons in MastlNULL MEFs is shortened, which correlates with premature disappearance of the essential SAC protein Mad1 at the kinetochores. Notably, MastlNULL MEFs display reduced phosphorylation of a number of proteins in mitosis, which include the essential SAC kinase MPS1. We further demonstrate that Mastl is required for multi-site phosphorylation of MPS1 as well as robust MPS1 kinase activity in mitosis. In contrast, treatment of MastlNULL cells with the phosphatase inhibitor okadaic acid (OKA) rescues the defects in MPS1 kinase activity, mislocalization of phospho-MPS1 as well as Mad1 at the kinetochore, and premature SAC silencing. Moreover, using in vitro dephosphorylation assays, we demonstrate that Mastl promotes persistent MPS1 phosphorylation by inhibiting PP2A/B55-mediated MPS1 dephosphorylation rather than affecting Cdk1 kinase activity. Our findings establish a key regulatory function of the Greatwall kinase/Mastl->PP2A/B55 pathway in preventing premature SAC silencing. © 2016 Diril et al.
Source Title: PLoS Genetics
URI: https://scholarbank.nus.edu.sg/handle/10635/165381
ISSN: 15537390
DOI: 10.1371/journal.pgen.1006310
Appears in Collections:Staff Publications
Elements

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
10_1371_journal_pgen_1006310.pdf3.61 MBAdobe PDF

OPEN

NoneView/Download

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.