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J Cell Biol. 2016 Mar 14;212(6):647-59. doi: 10.1083/jcb.201408089. Epub 2016 Mar 7.

ARHGEF17 is an essential spindle assembly checkpoint factor that targets Mps1 to kinetochores.

Author information

1
Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
2
Centre for Molecular and Cellular Imaging, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
3
Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany.
4
Molecular and Cellular Biology, Research Institute of Molecular Pathology, 1030 Vienna, Austria.
5
Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany jan.ellenberg@embl.de.

Abstract

To prevent genome instability, mitotic exit is delayed until all chromosomes are properly attached to the mitotic spindle by the spindle assembly checkpoint (SAC). In this study, we characterized the function of ARHGEF17, identified in a genome-wide RNA interference screen for human mitosis genes. Through a series of quantitative imaging, biochemical, and biophysical experiments, we showed that ARHGEF17 is essential for SAC activity, because it is the major targeting factor that controls localization of the checkpoint kinase Mps1 to the kinetochore. This mitotic function is mediated by direct interaction of the central domain of ARHGEF17 with Mps1, which is autoregulated by the activity of Mps1 kinase, for which ARHGEF17 is a substrate. This mitosis-specific role is independent of ARHGEF17's RhoGEF activity in interphase. Our study thus assigns a new mitotic function to ARHGEF17 and reveals the molecular mechanism for a key step in SAC establishment.

PMID:
26953350
PMCID:
PMC4792069
DOI:
10.1083/jcb.201408089
[Indexed for MEDLINE]
Free PMC Article

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