A chemical tool box defines mitotic and interphase roles for Mps1 kinase - PubMed (original) (raw)

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A chemical tool box defines mitotic and interphase roles for Mps1 kinase

Weijie Lan et al. J Cell Biol. 2010.

Abstract

In this issue, three groups (Hewitt et al. 2010. J. Cell Biol. doi:10.1083/jcb.201002133; Maciejowski et al. 2010. J. Cell Biol. doi:10.1083/jcb.201001050; Santaguida et al. 2010. J. Cell Biol. doi:10.1083/jcb.201001036) use chemical inhibitors to analyze the function of the mitotic checkpoint kinase Mps1. These studies demonstrate that Mps1 kinase activity ensures accurate chromosome segregation through its recruitment to kinetochores of mitotic checkpoint proteins, formation of interphase and mitotic inhibitors of Cdc20, and correction of faulty microtubule attachments.

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Figures

Figure 1.

Figure 1.

Microtubule–kinetochore attachments. Four types of kinetochore–microtubule attachments are highlighted. (A) Monotelic attachment with only one kinetochore attached. Unattached kinetochores produce the mitotic checkpoint inhibitor that delays advance to anaphase by inactivating Cdc20, an activator of the ubiquitin ligase APC/C. (B) Syntelic attachment with both kinetochores attached to microtubules from the same pole. (C) Merotelic attachment with one kinetochore attached to microtubules from both poles. (D) Bioriented attachment (also known as amphitelic) with the two kinetochores of each chromatid pair attached to opposite spindle poles.

Figure 2.

Figure 2.

Mps1 functions at multiple steps to inhibit Cdc20–APC/C. (A) All three groups (Hewitt et al., 2010; Maciejowski et al., 2010; Santaguida et al., 2010) demonstrate that at unattached kinetochores, Mps1 kinase activity is required to recruit other mitotic checkpoint components, including Mad1, Mad2, Bub1, BubR1, Bub3, and the Rod–Zw10–Zwilch complex. Discrepancies exist on exactly which components depend on Mps1 activity (see Table I for details). (B) Hewitt et al. (2010) show that Mps1 kinase activity maintains the recruitment at unattached kinetochores of O-Mad2 to the stably bound Mad1–C-Mad2 template. The molecular mechanism is yet to be elucidated. Mps1 may dimerize and be activated by self phosphorylation at kinetochores followed by quick release into the cytosol. (C) Maciejowski et al. (2010) demonstrate that Mps1 kinase activity in the cytosol promotes the assembly and/or prevents the disassembly of Cdc20–APC/C inhibitory complexes. Although the relative abundance and contribution of specific Cdc20–APC/C inhibitory complexes are unclear, all inhibit Cdc20 to prevent polyubiquitination of the key mitotic regulators cyclin B and securin by APC/C, an event which targets them for degradation as an irreversible trigger for anaphase entry.

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References

    1. Abrieu A., Magnaghi-Jaulin L., Kahana J.A., Peter M., Castro A., Vigneron S., Lorca T., Cleveland D.W., Labbé J.C. 2001. Mps1 is a kinetochore-associated kinase essential for the vertebrate mitotic checkpoint. Cell. 106:83–93 10.1016/S0092-8674(01)00410-X - DOI - PubMed
    1. Chen S., Zhang Q., Wu X., Schultz P.G., Ding S. 2004. Dedifferentiation of lineage-committed cells by a small molecule. J. Am. Chem. Soc. 126:410–411 10.1021/ja037390k - DOI - PubMed
    1. Cimini D., Wan X., Hirel C.B., Salmon E.D. 2006. Aurora kinase promotes turnover of kinetochore microtubules to reduce chromosome segregation errors. Curr. Biol. 16:1711–1718 10.1016/j.cub.2006.07.022 - DOI - PubMed
    1. D’Alise A.M., Amabile G., Iovino M., Di Giorgio F.P., Bartiromo M., Sessa F., Villa F., Musacchio A., Cortese R. 2008. Reversine, a novel Aurora kinases inhibitor, inhibits colony formation of human acute myeloid leukemia cells. Mol. Cancer Ther. 7:1140–1149 10.1158/1535-7163.MCT-07-2051 - DOI - PubMed
    1. Dorer R.K., Zhong S., Tallarico J.A., Wong W.H., Mitchison T.J., Murray A.W. 2005. A small-molecule inhibitor of Mps1 blocks the spindle-checkpoint response to a lack of tension on mitotic chromosomes. Curr. Biol. 15:1070–1076 10.1016/j.cub.2005.05.020 - DOI - PubMed

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