Characterization of Spindle Checkpoint Kinase Mps1 Reveals Domain with Functional and Structural Similarities to Tetratricopeptide Repeat Motifs of Bub1 and BubR1 Checkpoint Kinases

Lee, Semin; Thebault, Philippe; Freschi, Luca; Beaufils, Sylvie; Blundell, Tom L.; Landry, Christian R.; Bolaños-García, Víctor M.; Elowe, Sabine

doi:10.1074/jbc.m111.307355

Cited by 36 publications

(34 citation statements)

References 66 publications

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“…Increased p53 levels, however, has correlated with decreased cyclin E, cdk1, cdk2, and cdk6, and their upstream kinase ERK1/2 activation suggested severed cell cycle machinery, especially the mitosis. Although endoreduplication is an alternate to enforced replication in the functional compromise of classical cell division [34], which lead to polyploidy [35,36], we did not observe increased nuclear content or polyploidy in our study. Activation of caspase-3 is another indication that these cells are subsequently are subjected to apoptosis.…”

Section: Discussioncontrasting

confidence: 34%

Geldanamycin Combination with Colcemid Induces Mitotic Arrest through Stabilization of bubR1 Mitotic Kinase in Human Tumor Cells

Vinay¹,

Reddy²,

Kumar³

et al. 2013

JCT

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Mitosis-targeted anti-cancer therapies gained much attention in recent years. However, lack of tumor selectivity poses limitations to the current anti-mitotic drugs to be used as broad-spectrum anti-cancer agents. In this study, we show that combination treatment of colcemid, an inhibitor of microtubule polymerization with geldanamycin, an inhibitor of cancer chaperone, Hsp90 irreversibly targets mitosis through mitotic kinase bubR1 stabilization. When the individual and combination drugs treatments were tested against tumor cells (IMR-32 and HeLa) and non-tumor cells (SRA01), the combination treatment showed significant increase in cytotoxicity only in tumor cells followed by G2/M cell cycle block. The IMR-32 cells showed enhanced cytotoxicity in response to combination treatments, compared to HeLa cells. Further studies revealed that the G2/M arrest in IMR-32 correlates with both increased bubR1 nuclear localization and metaphase arrest. The siRNA knockdown of bubR1 has decreased tumor cell response to geldanamycin suggesting Hsp90-dependent regulation of bubR1. The combination treatment also showed inactivation of non-canonical β-catenin signaling suggesting inhibition of cancer growth. In addition, the combination treatment has significantly affected the distribution and functions of bubR1 downstream mitotic kinases such as aurks and plk1 indicating the combinatorial attack of combination treatment. In conclusion, we demonstrate that colcemid and GA combination treatment compromises the division potential of tumor cells interfering with the mitosis through bubR1 kinase.

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Section: Discussioncontrasting

confidence: 34%

Geldanamycin Combination with Colcemid Induces Mitotic Arrest through Stabilization of bubR1 Mitotic Kinase in Human Tumor Cells

Vinay¹,

Reddy²,

Kumar³

et al. 2013

JCT

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“…The kinetochore recruitment of Mps1 depends on an N-terminal region containing the tetratricopeptide repeat (TPR), which also exists in Bub1 and BubR1 (Lee, et al 2012; Maciejowski, et al 2010). This domain is required for kinetochore localization of Bub1 and long-lasting SAC maintenance, but not for SAC activation in human tissue culture cells (Maciejowski, et al 2010).…”

Section: Phosphorylations That Support the Sacmentioning

confidence: 99%

Making an effective switch at the kinetochore by phosphorylation and dephosphorylation

2013

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The kinetochore, the proteinaceous structure on the mitotic centromere, functions as a mechanical latch that hooks onto microtubules to support directional movement of chromosomes. The structure also brings in a number of signaling molecules, such as kinases and phosphatases, which regulate microtubule dynamics and cell cycle progression. Erroneous microtubule attachment is destabilized by Aurora B-mediated phosphorylation of multiple microtubule-binding protein complexes at the kinetochore, such as the KMN network proteins and the Ska/Dam1 complex, while Plk-dependent phosphorylation of BubR1 stabilizes kinetochore-microtubule attachment by recruiting PP2A-B56. Spindle assembly checkpoint (SAC) signaling, which is activated by unattached kinetochores and inhibits the metaphase-to-anaphase transition, depends on kinetochore recruitment of the kinase Bub1 through Mps1-mediated phosphorylation of the kinetochore protein KNL1 (also known as Blinkin in mammals, Spc105 in budding yeast, and Spc7 in fission yeast). Recruitment of protein phosphatase 1 (PP1) to KNL1 is necessary to silence the SAC upon bioriented microtubule attachment. One of the key unsolved questions in the mitosis field is how a mechanical change at the kinetochore upon microtubule attachment is converted to these and other chemical signals that control microtubule attachment and the SAC. Rapid progress in the field is revealing the existence of an intricate signaling network created right on the kinetochore. Here we review the current understanding of phosphorylation-mediated regulation of kinetochore functions and discuss how this signaling network generates an accurate switch that turns on and off the signaling output in response to kinetochore-microtubule attachment.

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“…The catalytic domain of Mps1 is in the C-terminal region, and the N-terminal region includes TPR repeats that promote homodimer formation, which is important for proper Mps1 function [54]. Mps1 becomes phosphorylated on multiple sites during mitosis, which is at least partly due to autophosphorylation, and phospho-Mps1 is localized to both kinetochores and centrosomes [55].…”

Section: Families Of Mitotic Kinasesmentioning

confidence: 99%

On the molecular mechanisms of mitotic kinase activation

et al. 2012

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During mitosis, human cells exhibit a peak of protein phosphorylation that alters the behaviour of a significant proportion of proteins, driving a dramatic transformation in the cell's shape, intracellular structures and biochemistry. These mitotic phosphorylation events are catalysed by several families of protein kinases, including Auroras, Cdks, Plks, Neks, Bubs, Haspin and Mps1/TTK. The catalytic activities of these kinases are activated by phosphorylation and through protein–protein interactions. In this review, we summarize the current state of knowledge of the structural basis of mitotic kinase activation mechanisms. This review aims to provide a clear and comprehensive primer on these mechanisms to a broad community of researchers, bringing together the common themes, and highlighting specific differences. Along the way, we have uncovered some features of these proteins that have previously gone unreported, and identified unexplored questions for future work. The dysregulation of mitotic kinases is associated with proliferative disorders such as cancer, and structural biology will continue to play a critical role in the development of chemical probes used to interrogate disease biology and applied to the treatment of patients.

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Characterization of Spindle Checkpoint Kinase Mps1 Reveals Domain with Functional and Structural Similarities to Tetratricopeptide Repeat Motifs of Bub1 and BubR1 Checkpoint Kinases

Cited by 36 publications

References 66 publications

Geldanamycin Combination with Colcemid Induces Mitotic Arrest through Stabilization of bubR1 Mitotic Kinase in Human Tumor Cells

Geldanamycin Combination with Colcemid Induces Mitotic Arrest through Stabilization of bubR1 Mitotic Kinase in Human Tumor Cells

Making an effective switch at the kinetochore by phosphorylation and dephosphorylation

On the molecular mechanisms of mitotic kinase activation

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