title: ARHGEF17 is an essential spindle assembly checkpoint factor that targets Mps1 to kinetochores.
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.
authors.affiliation: Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Isokane
authors.affiliation: Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Walter
authors.affiliation: Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Mahen
authors.affiliation: Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Nijmeijer
authors.affiliation: Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
authors.forename: Jean-Karim
authors.initials: JK
authors.lastname: Hériché
authors.affiliation: Centre for Molecular and Cellular Imaging, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
authors.forename: Kota
authors.initials: K
authors.lastname: Miura
authors.affiliation: Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany.
authors.forename: Stefano
authors.initials: S
authors.lastname: Maffini
authors.affiliation: Molecular and Cellular Biology, Research Institute of Molecular Pathology, 1030 Vienna, Austria.
authors.forename: Miroslav Penchev
authors.initials: MP
authors.lastname: Ivanov
authors.affiliation: Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
authors.forename: Tomoya S
authors.initials: TS
authors.lastname: Kitajima
authors.affiliation: Molecular and Cellular Biology, Research Institute of Molecular Pathology, 1030 Vienna, Austria.
authors.forename: Jan-Michael
authors.initials: JM
authors.lastname: Peters
authors.affiliation: Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany jan.ellenberg@embl.de.
authors.forename: Jan
authors.initials: J
authors.lastname: Ellenberg
mesh_terms: D059447:Cell Cycle Checkpoints / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000378:metabolism* / Q000502:physiology*; D008938:Mitosis / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D008941:Spindle Apparatus / Q000378:metabolism* / Q000502:physiology
chemical_list: C577226:ARHGEF17 protein, human; D018797:Cell Cycle Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human