Mitotic kinase cascades orchestrating timely disjunction and movement of centrosomes maintain chromosomal stability and prevent cancer

Ree, Janine H. van; Nam, Hyun Ja; Deursen, Jan M. van

doi:10.1007/s10577-015-9501-9

Cited by 16 publications

(11 citation statements)

References 80 publications

(113 reference statements)

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“…Centrosome separation may proceed with different timing and protein requirements through the prophase of the prometaphase pathways. The first is completed before nuclear envelope breakdown (NEBD) involving the interaction between MTs and the nuclear envelope, whereas the second pathway taking place in prometaphase requires myosin activity at the cell cortex [ 9 , 12 ]. Improper timing of centrosome disjunction and separation through these pathways may result in monopolar or bipolar mitotic spindles with geometry defects in metaphase [ 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Mdm2-Mediated Downmodulation of GRK2 Restricts Centrosome Separation for Proper Chromosome Congression

Reglero

Castillo

Rivas

et al. 2021

Cells

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The timing of centrosome separation and the distance moved apart influence the formation of the bipolar spindle, affecting chromosome stability. Epidermal growth factor receptor (EGFR) signaling induces early centrosome separation through downstream G protein-coupled receptor kinase GRK2, which phosphorylates the Hippo pathway component MST2 (Mammalian STE20-like protein kinase 2), in turn allowing NIMA kinase Nek2A activation for centrosomal linker disassembly. However, the mechanisms that counterbalance centrosome disjunction and separation remain poorly understood. We unveil that timely degradation of GRK2 by the E3 ligase Mdm2 limits centrosome separation in the G2. Both knockout expression and catalytic inhibition of Mdm2 result in GRK2 accumulation and enhanced centrosome separation before mitosis onset. Phosphorylation of GRK2 on residue S670 enables a complex pattern of non-K48-linked polyubiquitin chains assembled by Mdm2, which correlate with kinase protein degradation. Remarkably, GRK2-S670A protein fails to phosphorylate MST2 despite overcoming Mdm2-dependent degradation, which results in defective centrosome separation, shorter spindles, and abnormal chromosome congression. Conversely, extra levels of wild-type kinase in the G2 cause increased inter-centrosome distances with longer spindles, also converging in congression issues. Our findings show that the signals enabling activity of the GRK2/MST2/Nek2A axis for separation also switches on Mdm2 degradation of GRK2 to ensure accurate centrosome dynamics and proper mitotic spindle functionality.

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Section: Introductionmentioning

confidence: 99%

Mdm2-Mediated Downmodulation of GRK2 Restricts Centrosome Separation for Proper Chromosome Congression

Reglero

Castillo

Rivas

et al. 2021

Cells

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“…Centrosomes duplicate in concomitant with DNA replication, after which the sister centrosomes are glued together by two proteinaceous linkers, c-Nap1 and rootletin (3,4), as well as other components such as Cep68, Cep215 and LRRC45 (5). C-Nap1, a large coiled-coiled protein, links rootletin to the centrioles so that the centrosome pair is joined by fibrous polymers (3).…”

Section: Introductionmentioning

confidence: 99%

O-GlcNAcylation of myosin phosphatase targeting subunit 1 (MYPT1) dictates timely disjunction of centrosomes

Liu

Shi

et al. 2020

Journal of Biological Chemistry

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The role of O-linked N-acetylglucosamine (O-GlcNAc) modification in the cell cycle has been enigmatic. Previously, both O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) disruptions have been shown to derail the mitotic centrosome numbers, suggesting that mitotic O-GlcNAc oscillation needs to be in concert with mitotic progression to account for centrosome integrity. Here, using both chemical approaches and biological assays with HeLa cells, we attempted to address the underlying molecular mechanism and observed that incubation of the cells with the OGA inhibitor Thiamet-G strikingly elevates centrosomal distances, suggestive of premature centrosome disjunction. These aberrations could be overcome by inhibiting Polo-like kinase 1 (PLK1), a mitotic master kinase. PLK1 inactivation is modulated by the myosin phosphatase targeting subunit 1 (MYPT1)–protein phosphatase 1cβ (PP1cβ) complex. Interestingly, MYPT1 has been shown to be abundantly O-GlcNAcylated, and the modified residues have been detected in a recent O-GlcNAc–profiling screen utilizing chemoenzymatic labeling and bioorthogonal conjugation. We demonstrate here that MYPT1 is O-GlcNAcylated at Thr-577, Ser-585, Ser-589, and Ser-601, which antagonizes CDK1-dependent phosphorylation at Ser-473 and attenuates the association between MYPT1 and PLK1, thereby promoting PLK1 activity. We conclude that under high O-GlcNAc levels, PLK1 is untimely activated, conducive to inopportune centrosome separation and disruption of the cell cycle. We propose that too much O-GlcNAc is equally deleterious as too little O-GlcNAc, and a fine balance between the OGT/OGA duo is indispensable for successful mitotic divisions.

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“…At the onset of mitosis, NIMA (never in mitosis A)-related kinase Nek2A is the primary kinase responsible for initiating centrosome separation (also called centrosome disjunction) (Mardin and Schiebel, 2012, van Ree et al., 2016, Wang et al., 2014). It phosphorylates C-Nap1, rootletin, and LRRC45, thereby disassembling the linker to disconnect the centrosomes (Bahe et al., 2005, Faragher and Fry, 2003, Fry et al., 1998a, Hardy et al., 2014, He et al., 2013).…”

Section: Introductionmentioning

confidence: 99%

“…In G2, besides Nek2A, three other mitotic kinases including Cdk1, Plk1, and Aurora A (AurA) are also implicated in centrosome disjunction (Mardin et al., 2011, Mardin and Schiebel, 2012, van Ree et al., 2016, Wang et al., 2014). Among them, AurA is mainly responsible for the activation of Plk1 by phosphorylating Thr210 residue in the activation loop of Plk1 (Macurek et al., 2008, Seki et al., 2008).…”

Section: Introductionmentioning

confidence: 99%

Cep85 Relays Plk1 Activity to Phosphorylated Nek2A for Its Timely Activation in Centrosome Disjunction

Chen

Zhang

et al. 2019

iScience

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SummaryTimely centrosome separation is critical for accurate chromosome separation. It is initiated by Nek2A at the onset of mitosis, but the mechanism for the strict requirement of phosphorylated Nek2A for its own activation remains unclear. In this study, we have found that Plk1 interacts with Cep85 and forms a ternary complex with Cep85-Nek2A. Nek2A binding, but not its kinase activity, is pre-required for Cep85 to be phosphorylated by Plk1. Nek2A-dependent Cep85 phosphorylation, in turn, leads to the dissociation of phosphorylated Cep85 exclusively from phospho-Nek2A, thereby increasing the freed phospho-Nek2A activity. Both kinases are also required for phosphorylating endogenous Cep85 in cells, and timely phosphorylation of Cep85 and Nek2A is crucial for initiating centrosome disjunction at G2/M. Overall, our study has uncovered a previously unrecognized role of Plk1 and Nek2A and identified Cep85 as a missing piece directly relaying Plk1 activity to Nek2A for its activation in centrosome disjunction.

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Mitotic kinase cascades orchestrating timely disjunction and movement of centrosomes maintain chromosomal stability and prevent cancer

Cited by 16 publications

References 80 publications

Mdm2-Mediated Downmodulation of GRK2 Restricts Centrosome Separation for Proper Chromosome Congression

Mdm2-Mediated Downmodulation of GRK2 Restricts Centrosome Separation for Proper Chromosome Congression

O-GlcNAcylation of myosin phosphatase targeting subunit 1 (MYPT1) dictates timely disjunction of centrosomes

Cep85 Relays Plk1 Activity to Phosphorylated Nek2A for Its Timely Activation in Centrosome Disjunction

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