Dynamic Autophosphorylation of Mps1 Kinase Is Required for Faithful Mitotic Progression

Wang, Xinghui; Yu, Huijuan; Xu, Leilei; Zhu, Tongge; Zheng, Fan; Fu, Chuanhai; Wang, Zhiyong; Dou, Zhen

doi:10.1371/journal.pone.0104723

Cited by 21 publications

(26 citation statements)

References 51 publications

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“…Upon inhibition of kinase activity, Mps1 localization on kinetochores is elevated significantly ( Fig. S4 A and B) (22,35,44,45). Therefore, we hypothesized that the abnormal accumulation of inactive Mps1 in kinetochores causes defects in kinetochore-MT attachments.…”

Section: Inactive Mps1 Accumulates Abnormally At Kinetochores Leadinmentioning

confidence: 98%

“…Inactivating Mps1 kinase activity causes strongly elevated kinetochore localization of Mps1 (22,35,44,45,47). However, the mechanism remains unknown.…”

Section: Inactive and Active Mps1 Kinases Exhibit Distinctly Differenmentioning

confidence: 99%

“…Second, the localization of active Mps1 depends on aurora B activity in a TPR domain-dependent manner and promotes Mps1 to phosphorylate its key kinetochore substrate, KNL1, which is essential for the downstream SAC signaling (59). Numerous reports demonstrate that active Mps1 has a higher turnover rate and lower signal intensity at kinetochores than does inactive Mps1 (22,35,(43)(44)(45). We envision that low-affinity localization ensures a prompt silencing of SAC when biorientation is achieved.…”

Section: Mis12cmentioning

confidence: 99%

“…The other possibility is that the direct phosphorylation of Ndc80/Hec1 by Mps1 changes the binding interface between Mps1 and Ndc80C (24). Finally, autophosphorylation sites outside the activation loop (and also outside the IRK) may participate in the regulation via an as yet uncharacterized mechanism (45). Thus, it would be of great interest to quantify the dynamics of Mps1 kinase activity at the kinetochore using a FRET-based optical sensor (53) and to establish the relationship between the temporal dynamics of Mps1 kinase activity and accurate attachment during mitosis.…”

Section: Mis12cmentioning

confidence: 99%

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

Dou

Liu

Wang

et al. 2015

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

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The spindle assembly checkpoint (SAC) is a conserved signaling pathway that monitors faithful chromosome segregation during mitosis. As a core component of SAC, the evolutionarily conserved kinase monopolar spindle 1 (Mps1) has been implicated in regulating chromosome alignment, but the underlying molecular mechanism remains unclear. Our molecular delineation of Mps1 activity in SAC led to discovery of a previously unidentified structural determinant underlying Mps1 function at the kinetochores. Here, we show that Mps1 contains an internal region for kinetochore localization (IRK) adjacent to the tetratricopeptide repeat domain. Importantly, the IRK region determines the kinetochore localization of inactive Mps1, and an accumulation of inactive Mps1 perturbs accurate chromosome alignment and mitotic progression. Mechanistically, the IRK region binds to the nuclear division cycle 80 complex (Ndc80C), and accumulation of inactive Mps1 at the kinetochores prevents a dynamic interaction between Ndc80C and spindle microtubules (MTs), resulting in an aberrant kinetochore attachment. Thus, our results present a previously undefined mechanism by which Mps1 functions in chromosome alignment by orchestrating Ndc80C-MT interactions and highlight the importance of the precise spatiotemporal regulation of Mps1 kinase activity and kinetochore localization in accurate mitotic progression.Mps1 kinase | spindle assembly checkpoint | chromosome alignment | kinetochore-microtubule attachment | reversine

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Section: Inactive Mps1 Accumulates Abnormally At Kinetochores Leadinmentioning

confidence: 98%

“…Inactivating Mps1 kinase activity causes strongly elevated kinetochore localization of Mps1 (22,35,44,45,47). However, the mechanism remains unknown.…”

Section: Inactive and Active Mps1 Kinases Exhibit Distinctly Differenmentioning

confidence: 99%

Section: Mis12cmentioning

confidence: 99%

Section: Mis12cmentioning

confidence: 99%

See 2 more Smart Citations

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

Dou

Liu

Wang

et al. 2015

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

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“…Different studies have implicated Mps1 in chromosome alignment, but the underlying molecular mechanism remains unclear [336,337,338,339]. Initially it was proposed that regulation of chromosome alignment by Mps1 acts through modulation of Aurora B kinase activity [337].…”

Section: Mechanisms Of Chromosome Congressionmentioning

confidence: 99%

Mechanisms of Chromosome Congression during Mitosis

Maiato

Gomes

Sousa

et al. 2017

Biology

160

176

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Chromosome congression during prometaphase culminates with the establishment of a metaphase plate, a hallmark of mitosis in metazoans. Classical views resulting from more than 100 years of research on this topic have attempted to explain chromosome congression based on the balance between opposing pulling and/or pushing forces that reach an equilibrium near the spindle equator. However, in mammalian cells, chromosome bi-orientation and force balance at kinetochores are not required for chromosome congression, whereas the mechanisms of chromosome congression are not necessarily involved in the maintenance of chromosome alignment after congression. Thus, chromosome congression and maintenance of alignment are determined by different principles. Moreover, it is now clear that not all chromosomes use the same mechanism for congressing to the spindle equator. Those chromosomes that are favorably positioned between both poles when the nuclear envelope breaks down use the so-called “direct congression” pathway in which chromosomes align after bi-orientation and the establishment of end-on kinetochore-microtubule attachments. This favors the balanced action of kinetochore pulling forces and polar ejection forces along chromosome arms that drive chromosome oscillatory movements during and after congression. The other pathway, which we call “peripheral congression”, is independent of end-on kinetochore microtubule-attachments and relies on the dominant and coordinated action of the kinetochore motors Dynein and Centromere Protein E (CENP-E) that mediate the lateral transport of peripheral chromosomes along microtubules, first towards the poles and subsequently towards the equator. How the opposite polarities of kinetochore motors are regulated in space and time to drive congression of peripheral chromosomes only now starts to be understood. This appears to be regulated by position-dependent phosphorylation of both Dynein and CENP-E and by spindle microtubule diversity by means of tubulin post-translational modifications. This so-called “tubulin code” might work as a navigation system that selectively guides kinetochore motors with opposite polarities along specific spindle microtubule populations, ultimately leading to the congression of peripheral chromosomes. We propose an integrated model of chromosome congression in mammalian cells that depends essentially on the following parameters: (1) chromosome position relative to the spindle poles after nuclear envelope breakdown; (2) establishment of stable end-on kinetochore-microtubule attachments and bi-orientation; (3) coordination between kinetochore- and arm-associated motors; and (4) spatial signatures associated with post-translational modifications of specific spindle microtubule populations. The physiological consequences of abnormal chromosome congression, as well as the therapeutic potential of inhibiting chromosome congression are also discussed.

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The cytotoxicity of microcystin-LR: ultrastructural and functional damage of cells

Ge,

Du,

Liu

et al. 2024

Arch Toxicol

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Dynamic Autophosphorylation of Mps1 Kinase Is Required for Faithful Mitotic Progression

Cited by 21 publications

References 51 publications

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

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

Mechanisms of Chromosome Congression during Mitosis

The cytotoxicity of microcystin-LR: ultrastructural and functional damage of cells

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