Human Mps1 kinase is required for the spindle assembly checkpoint but not for centrosome duplication

Fred Hutchinson Cancer Research Center, Seattle, Washington, United States
The EMBO Journal (Impact Factor: 10.43). 05/2002; 21(7):1723-32. DOI: 10.1093/emboj/21.7.1723
Source: PubMed


Budding yeast Mps1p kinase has been implicated in both the duplication of microtubule-organizing centers and the spindle assembly checkpoint. Here we show that hMps1, the human homolog of yeast Mps1p, is a cell cycle-regulated kinase with maximal activity during M phase. hMps1 localizes to kinetochores and its activity and phosphorylation state increase upon activation of the mitotic checkpoint. By antibody microinjection and siRNA, we demonstrate that hMps1 is required for human cells to undergo checkpoint arrest in response to microtubule depolymerization. In contrast, centrosome (re-)duplication as well as cell division occur in the absence of hMps1. We conclude that hMps1 is required for the spindle assembly checkpoint but not for centrosome duplication.

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Available from: Lionel Arnaud, Oct 03, 2015
    • "TTK (TTK protein kinase) TTK (alternatively MPS1), a serine/threonine protein kinase (Liu and Winey, 2012), was detected during the cell cycle to be localized to centrosomes, kinetochores, and nuclear pores (Liu et al., 2003 ). The protein is important for passing through the spindle assembly checkpoint (SAC) in meiosis I (Stucke et al., 2002). It ensures the proper connection to the chromosomes of the mitotic spindle . "
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    • "Silencing of Mps1 leads to failure of cells to arrest in mitosis in response to anti-mitotic drugs. Remarkably, combination of microtubule interfering agents and Mps1 inhibition even increases chromosomal segregation errors and cell death [26, 27]. Therefore, the combined increase of chromosomal segregation errors induced by combination of anti-mitotics with SAC inhibition constitutes an efficient strategy for eliminating tumor cells. "
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    • "The human Mps1 protein (also known as TTK) displays maximum expression and kinase activity in mitosis and exhibits dynamic subcellular localization throughout mitosis [9]–[10]. In the absence of Mps1, the SAC is compromised [9], [11]. It is likely that Mps1 executes its function by recruiting Mad1 and Mad2 to unattached kinetochores. "
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    ABSTRACT: The spindle assembly checkpoint (SAC) is a surveillance mechanism monitoring cell cycle progression, thus ensuring accurate chromosome segregation. The conserved mitotic kinase Mps1 is a key component of the SAC. The human Mps1 exhibits comprehensive phosphorylation during mitosis. However, the related biological relevance is largely unknown. Here, we demonstrate that 8 autophosphorylation sites within the N-terminus of Mps1, outside of the catalytic domain, are involved in regulating Mps1 kinetochore localization. The phospho-mimicking mutant of the 8 autophosphorylation sites impairs Mps1 localization to kinetochore and also affects the kinetochore recruitment of BubR1 and Mad2, two key SAC effectors, subsequently leading to chromosome segregation errors. Interestingly, the non-phosphorylatable mutant of the 8 autophosphorylation sites enhances Mps1 kinetochore localization and delays anaphase onset. We further show that the Mps1 phospho-mimicking and non-phosphorylatable mutants do not affect metaphase chromosome congression. Thus, our results highlight the importance of dynamic autophosphorylation of Mps1 in regulating accurate chromosome segregation and ensuring proper mitotic progression.
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