Inhibitor‐3 ensures bipolar mitotic spindle attachment by limiting association of <scp>SDS</scp>22 with kinetochore‐bound protein phosphatase‐1

Eiteneuer, Annika; Seiler, Jonas; Weith, Matthias; Beullens, Monique; Lesage, Bart; Krenn, Veronica; Musacchio, Andrea; Meyer, Hemmo

doi:10.15252/embj.201489054

Cited by 36 publications

(60 citation statements)

References 38 publications

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“…Right panel, the same gel was dried and subsequently exposed with x-ray film. Note that there was dramatic incorporation of 32 P into wild type Sds22 but little into the mutant Sds22 or MBP.…”

Section: Plk1 Interacts With and Phosphorylatesmentioning

confidence: 99%

“…G, Sds22 is a substrate of PLK1 in vitro. Bacterial expression of recombinant MBP-Sds22 fusion proteins were phosphorylated in vitro using [␥- 32 P]ATP and active PLK1 as described under "Materials and Methods." The samples were separated by SDS-PAGE.…”

Section: Plk1 Interacts With and Phosphorylatesmentioning

confidence: 99%

“…During anaphase, Sds22 is required to stabilize kinetochorespindle attachment (30,31). However, whether Sds22 localizes to kinetochores remains elusive (7,32).…”

mentioning

confidence: 99%

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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: Plk1 Interacts With and Phosphorylatesmentioning

confidence: 99%

Section: Plk1 Interacts With and Phosphorylatesmentioning

confidence: 99%

See 1 more Smart Citation

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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“…Inhibitor-1 and CPI-17) are phosphorylation-dependent or only inhibit a subset of PP1 holoenzymes (Endo et al, 1996;Eto, 2009). Inhibitor-2, Inhibitor-3 and Sds22 have been biochemically identified as inhibitors of PP1, but genetic data from yeast indicate that they are actually positive regulators, possibly involved in the biogenesis of PP1 (Cheng and Chen, 2015;Eiteneuer et al, 2014;Heroes et al, 2015). In contrast, substantial biochemical and cell biological evidence indicates that full-length NIPP1 is a very specific and extremely potent inhibitor of PP1 (Beullens et al, 1992 tested protein substrates of PP1, except for phosphoproteins that are recruited through the FHA domain and probably represent the natural substrates of the PP1-NIPP1 holoenzyme.…”

Section: Discussionmentioning

confidence: 99%

“…It is not clear whether the deletion or inhibition of PP1 also causes a similarly strong mitoticarrest phenotype in vertebrate cells. Various PIPs mediate the interaction of PP1 with the centrosomes, spindle and mitotic chromosomes in vertebrates, including CENP-E (Kim et al, 2010), Kif18A (Häfner et al, 2014), KNL1 (Espert et al, 2014;Liu et al, 2010;Nijenhuis et al, 2014), RepoMan (also known as CDCA2) (Qian et al, 2013b;Vagnarelli et al, 2011;Wurzenberger et al, 2012) and Sds22 (Eiteneuer et al, 2014;Wurzenberger et al, 2012). These mitotic pools of PP1 holoenzymes have functions throughout the M-phase.…”

Section: Introductionmentioning

confidence: 99%

The selective inhibition of protein phosphatase-1 results in mitotic catastrophe and impaired tumor growth

Winkler

Munter

Dessel

et al. 2015

Journal of Cell Science

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The serine/threonine protein phosphatase-1 (PP1) complex is a key regulator of the cell cycle. However, the redundancy of PP1 isoforms and the lack of specific inhibitors have hampered studies on the global role of PP1 in cell cycle progression in vertebrates. Here, we show that the overexpression of nuclear inhibitor of PP1 (NIPP1; also known as PPP1R8) in HeLa cells culminated in a prometaphase arrest, associated with severe spindle-formation and chromosome-congression defects. In addition, the spindle assembly checkpoint was activated and checkpoint silencing was hampered. Eventually, most cells either died by apoptosis or formed binucleated cells. The NIPP1-induced mitotic arrest could be explained by the inhibition of PP1 that was titrated away from other mitotic PP1 interactors. Consistent with this notion, the mitoticarrest phenotype could be rescued by the overexpression of PP1 or the inhibition of the Aurora B kinase, which acts antagonistically to PP1. Finally, we demonstrate that the overexpression of NIPP1 also hampered colony formation and tumor growth in xenograft assays in a PP1-dependent manner. Our data show that the selective inhibition of PP1 can be used to induce cancer cell death through mitotic catastrophe.

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Phosphatase inhibitor PPP1R11 modulates resistance of human T cells toward Treg-mediated suppression of cytokine expression

Joshi

Fernandes

Shang

et al. 2019

Journal of Leukocyte Biology

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Regulatory T cells (Tregs) act as indispensable unit for maintaining peripheral immune tolerance mainly by regulating effector T cells. T cells resistant to suppression by Tregs pose therapeutic challenges in the treatment of autoimmune diseases, while augmenting susceptibility to suppression may be desirable for cancer therapy. To understand the cell intrinsic signals in T cells during suppression by Tregs, we have previously performed a global phosphoproteomic characterization. We revealed altered phosphorylation of protein phosphatase 1 regulatory subunit 11 (PPP1R11; Inhibitor‐3) in conventional T cells upon suppression by Tregs. Here, we show that silencing of PPP1R11 renders T cells resistant toward Treg‐mediated suppression of TCR‐induced cytokine expression. Furthermore, whole‐transcriptome sequencing revealed that PPP1R11 differentially regulates not only the expression of specific T cell stimulation‐induced cytokines but also other molecules and pathways in T cells. We further confirmed the target of PPP1R11, PP1, to augment TCR‐induced cytokine expression. In conclusion, we present PPP1R11 as a novel negative regulator of T cell activation‐induced cytokine expression. Targeting PPP1R11 may have therapeutic potential to regulate the T cell activation status including modulating the susceptibility of T cells toward Treg‐mediated suppression, specifically altering the stimulation‐induced T cell cytokine milieu.

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Inhibitor‐3 ensures bipolar mitotic spindle attachment by limiting association of SDS22 with kinetochore‐bound protein phosphatase‐1

Cited by 36 publications

References 38 publications

Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation

Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation

The selective inhibition of protein phosphatase-1 results in mitotic catastrophe and impaired tumor growth

Phosphatase inhibitor PPP1R11 modulates resistance of human T cells toward Treg-mediated suppression of cytokine expression

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