Dynamic localization of Mps1 kinase to kinetochores is essential for accurate spindle microtubule attachment

Dou, Zhen; Liu, Xing; Wang, Wenwen; Zhu, Tongge; Wang, Xinghui; Xu, Leilei; Abrieu, Ariane; Fu, Chuanhai; Hill, Donald L.; Yao, Xuebiao

doi:10.1073/pnas.1508791112

Cited by 60 publications

(70 citation statements)

References 68 publications

(119 reference statements)

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“…We purified recombinant GST-tagged Aurora B, which is active and autophosphorylated at Thr 232 (42,43). Aurora B was incubated with purified PP1 either alone or with increasing concentrations of Sds22, as described previously (32).…”

Section: Dmentioning

confidence: 99%

Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation

Duan

Wang²,

Wang

et al. 2016

Journal of Biological Chemistry

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During cell division, accurate chromosome segregation is tightly regulated by Polo-like kinase 1 (PLK1) and opposing activities of Aurora B kinase and protein phosphatase 1 (PP1). However, the regulatory mechanisms underlying the aforementioned hierarchical signaling cascade during mitotic chromosome segregation have remained elusive. Sds22 is a conserved regulator of PP1 activity, but how it regulates PP1 activity in space and time during mitosis remains elusive. Here we show that Sds22 is a novel and cognate substrate of PLK1 in mitosis, and the phosphorylation of Sds22 by PLK1 elicited an inhibition of PP1-mediated dephosphorylation of Aurora B at threonine 232 (Thr 232 ) in a dose-dependent manner. Overexpression of a phosphomimetic mutant of Sds22 causes a dramatic increase in mitotic delay, whereas overexpression of a non-phosphorylatable mutant of Sds22 results in mitotic arrest. Mechanistically, the phosphorylation of Sds22 by PLK1 strengthens the binding of Sds22 to PP1 and inhibits the dephosphorylation of Thr 232 of Aurora B to ensure a robust, error-free metaphase-anaphase transition. These findings delineate a conserved signaling hierarchy that orchestrates dynamic protein phosphorylation and dephosphorylation of critical mitotic regulators during chromosome segregation to guard chromosome stability.

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Section: Dmentioning

confidence: 99%

Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation

Duan

Wang²,

Wang

et al. 2016

Journal of Biological Chemistry

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“…Here, we showed that the Mps1 inhibitor TC Mps1 12 induced the formation of multicentrosomes as well as misaligned Several studies show that depletion of Mps1 affects mitosis. A lack of Mps1 perturbs centrosome duplication (Fisk et al, 2003) (Continued) BJP M Choi et al Santaguida et al, 2010;Dou et al, 2015), a failure to correct erroneous microtubule attachment (Jelluma et al, 2008), cytokinesis failure (Fisk et al, 2003) and apoptosis (Jemaa et al, 2016), shortens mitosis (Dou et al, 2015;Jemaa et al, 2016), and prevents the recruitment of SAC-related proteins, including Mad1, Mad2, Bub1, BubR1 and RodZw10-Zwilch (Martin-Lluesma et al, 2002;Santaguida et al, 2010;Jemaa et al, 2016). In addition, depletion of (Hewitt et al, 2010) Chromosome misalignment (Dou et al, 2015) Failure in recruitment of Mad1, Mad2, Bub1 and CENP-E (Hewitt et al, 2010) Short mitotic duration (Hewitt et al, 2010;Gurden et al, 2015) Apoptosis (Jemaa et al, 2016) BAY 1161909 0.34 nM (Wengner et al, 2016) Breast, lung and ovarian cancer (Wengner et al, 2016) Phase I ClinicalTrials.gov ID: NCT02138812 BAY 1217389 0.63 nM (Wengner et al, 2016) Phase I ClinicalTrials.gov ID: NCT02366949 CFI-402257 1.7 nM (Liu et al, 2016) MPI-0479605 1.8 nM (Tardif et al, 2011) Chromosome missegregation Colon cancer (Tardif et al, 2011) Hyperploidy Apoptosis Up-regulation of p53, p21 and γ-H2AX (Tardif et al, 2011) continues Effect of Mps1 inhibitor on hepatocellular carcinoma cells BJP Mps1 inhibits proliferation of HCC cells (Liang et al, 2014;Liu et al, 2015;Miao et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Mps1 phosphorylates borealin to control aurora kinase B activity (Jelluma et al, 2008), Knl1 to recruit MCC components (Yamagishi et al, 2012), Mad2 to maintain SAC-induced arrest (Zich et al, 2012), Mad3/BubR1 to correct kinetochore attachment (Huang et al, 2008), Dam1 to couple kinetochores to microtubules (Shimogawa et al, 2006) and Hec1/Ndc80 to activate the SAC (Kemmler et al, 2009). Chemical or RNAi-based inhibition of Mps1 have confirmed its role in mitosis (Dou et al, 2015;Jemaa et al, 2016). Therefore, suppression of Mps1 could be an anti-mitotic target.…”

Section: Introductionmentioning

confidence: 99%

TC Mps1 12, a novel Mps1 inhibitor, suppresses the growth of hepatocellular carcinoma cells via the accumulation of chromosomal instability

Choi

Min

Pyo

et al. 2017

British J Pharmacology

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contributed equally to the work. BACKGROUND AND PURPOSEChromosomal instability is not only a hallmark of cancer but also an attractive therapeutic target. A diverse set of mitotic kinases maintains chromosomal stability. One of these is monopolar spindle 1 (Mps1, also known as TTK), which is essential for chromosome alignment and for the spindle assembly checkpoint (SAC). Pharmacological inhibition of Mps1 has been suggested as a cancer therapeutic; however, despite the existence of a novel Mps1 inhibitor, TC Mps1 12, no such studies have been performed. EXPERIMENTAL APPROACHThe effects of TC Mps1 12 on cell viability, chromosome alignment, centrosome number, mitotic duration, apoptosis and SAC were determined in hepatocellular carcinoma (HCC) cells. In addition, the association of Mps1 expression with the overall survival of HCC patients was analysed. KEY RESULTSTreatment of human HCC cells with TC Mps1 12 led to chromosome misalignment and missegregation, and disorganization of centrosomes. Even in the presence of these errors, TC Mps1 12-treated cells overrode the SAC, resulting in a shortened mitotic duration and mitotic slippage. This mitotic catastrophe triggered apoptosis and, finally, inhibited the growth of HCC cells. In addition, the expression of the Mps1-encoding TTK gene was associated with poor overall survival of HCC patients. CONCLUSION AND IMPLICATIONSTC Mps1 12 results in the accumulation of chromosomal instabilities and mitotic catastrophe in HCC cells. Overall, these data demonstrate that the inhibition of Mps1 kinase using TC Mps1 12 is a promising therapeutic approach for liver cancer.Abbreviations HCC, hepatocellular carcinoma; MCC, mitotic checkpoint complex; Mps1 (TTK), monopolar spindle 1; SAC, spindle assembly checkpoint

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“…S6E), but because it failed to support mitotic arrest, we conclude it could not support SAC function to the threshold required for mitotic arrest. BubR1 recruitment is critical for chromosome alignment in metaphase (30), and indeed, Mps1 depletion led to major chromosome alignment defects; these defects were rescued by GFP-sirMps1 and GFP-siRMps1…”

Section: Noncentrosomal Mps1 Can Still Localize and Function At Kinetmentioning

confidence: 99%

Modular elements of the TPR domain in the Mps1 N terminus differentially target Mps1 to the centrosome and kinetochore

Marquardt

Perkins

Beuoy

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Faithful segregation of chromosomes to two daughter cells is regulated by the formation of a bipolar mitotic spindle and the spindle assembly checkpoint, ensuring proper spindle function. Here we show that the proper localization of the kinase Mps1 (monopolar spindle 1) is critical to both these processes. Separate elements in the Mps1 N-terminal extension (NTE) and tetratricopeptide repeat (TPR) domains govern localization to either the kinetochore or the centrosome. The third TPR (TPR3) and the TPR-capping helix (C-helix) are each sufficient to target Mps1 to the centrosome. TPR3 binds to voltage-dependent anion channel 3, but although this is sufficient for centrosome targeting of Mps1, it is not necessary because of the presence of the C-helix. A version of Mps1 lacking both elements cannot localize to or function at the centrosome, but maintains kinetochore localization and spindle assembly checkpoint function, indicating that TPR3 and the C-helix define a bipartite localization determinant that is both necessary and sufficient to target Mps1 to the centrosome but dispensable for kinetochore targeting. In contrast, elements required for kinetochore targeting (the NTE and first two TPRs) are dispensable for centrosomal localization and function. These data are consistent with a separation of Mps1 function based on localization determinants within the N terminus.Mps1/TTK | centrosome | centriole | kinetochore | TPR

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Dynamic localization of Mps1 kinase to kinetochores is essential for accurate spindle microtubule attachment

Cited by 60 publications

References 68 publications

Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation

Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation

TC Mps1 12, a novel Mps1 inhibitor, suppresses the growth of hepatocellular carcinoma cells via the accumulation of chromosomal instability

Modular elements of the TPR domain in the Mps1 N terminus differentially target Mps1 to the centrosome and kinetochore

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