Author: ["Yuya Yamagishi","Ching-Hui Yang","Yuji Tanno","Yoshinori Watanabe"]
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Abstract
The kinase MPS1 is a conserved and essential component of the spindle assembly checkpoint (SAC), but its relevant substrate in this context has remained uncertain. Watanabe and colleagues now show that, in fission yeast and human cells, MPS1 (Mph1 in fission yeast) phosphorylates the kinetochore protein KNL1 (Spc7), leading to kinetochore recruitment of BUB1, an event required for SAC activation. The genomic stability of all organisms depends on the precise partition of chromosomes to daughter cells. The spindle assembly checkpoint (SAC) senses unattached kinetochores and prevents premature entry to anaphase, thus ensuring that all chromosomes attach to opposite spindle poles (bi-orientation) during mitosis1. MPS1 is an evolutionarily conserved protein kinase required for the SAC and chromosome bi-orientation2,3,4. Yet, its primary cellular substrate has remained elusive. We show that fission yeast Mph1 (MPS1 homologue) phosphorylates the kinetochore protein Spc7 (KNL1/Blinkin homologue) at the MELT repeat sequences. This phosphorylation promotes the in vitro binding to the Bub1–Bub3 complex, which is required for kinetochore-based SAC activation (Mad1–Mad2–Mad3 localization) and chromosome alignment. Accordingly, a non-phosphorylatable spc7-12A mutation abolishes kinetochore targeting of Bub1–Bub3, whereas a phospho-mimetic spc7-12E mutation forces them to localize at kinetochores throughout the entire cell cycle, even in the absence of Mph1. Thus, MPS1/Mph1 kinase locating at the unattached kinetochores initially creates a mark, which is crucial for SAC activation and chromosome bi-orientation. This mechanism seems to be conserved in human cells.Cite this article
Yamagishi, Y., Yang, CH., Tanno, Y. et al. MPS1/Mph1 phosphorylates the kinetochore protein KNL1/Spc7 to recruit SAC components. Nat Cell Biol 14, 746–752 (2012). https://doi.org/10.1038/ncb2515 