1. ARHGEF17 is an essential spindle assembly checkpoint factor that targets Mps1 to kinetochores
- Author
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Tomoya S. Kitajima, Thomas Walter, Jan Ellenberg, Kota Miura, Jan-Michael Peters, Stefano Maffini, Robert Mahen, Bianca Nijmeijer, Jean-Karim Hériché, Miroslav P Ivanov, Mayumi Isokane, Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), European Molecular Biology Laboratory [Heidelberg] (EMBL), MPI-DS, Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Mines Paris - PSL (École nationale supérieure des mines de Paris), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
- Subjects
0301 basic medicine ,Genome instability ,MESH: Signal Transduction ,Cell cycle checkpoint ,MESH: Cell Line, Tumor ,Biology ,MESH: Protein-Tyrosine Kinases ,MESH: Cell Cycle Checkpoints ,MESH: Protein-Serine-Threonine Kinases ,03 medical and health sciences ,0302 clinical medicine ,MESH: Cell Cycle Proteins ,MESH: Rho Guanine Nucleotide Exchange Factors ,MESH: Spindle Apparatus ,Mitosis ,MESH: Humans ,Kinetochore ,MESH: Kinetochores ,[INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV] ,Cell Biology ,11 Medical And Health Sciences ,06 Biological Sciences ,MESH: Mitosis ,[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,Spindle apparatus ,Cell biology ,Spindle checkpoint ,030104 developmental biology ,Mitotic exit ,[INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV] ,MESH: HeLa Cells ,Interphase ,[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
International audience; 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.
- Published
- 2016
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