ARHGEF17 is an essential spindle assembly checkpoint factor that targets Mps1 to kinetochores.
ARHGEF17 is an essential spindle assembly checkpoint factor that targets Mps1 to kinetochores.
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ARHGEF17是将MPS1靶向动力学的必不可少的主轴组件检查点因子。
DOI：
10.1083/jcb.201408089
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发表时间：
2016-03-14
期刊：
影响因子：
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通讯作者：
Ellenberg J
中科院分区：
文献类型：
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作者：
Isokane M;Walter T;Mahen R;Nijmeijer B;Hériché JK;Miura K;Maffini S;Ivanov MP;Kitajima TS;Peters JM;Ellenberg J
纺锤体组装检查点（SAC）确保细胞分裂期间基因组的稳定性。在这里，一个新的重要SAC因子，ARHGEF17，其特征在于定量成像，生物化学和生物物理实验，这表明它的目标是检查点激酶Mps1的动粒。为了防止基因组不稳定，有丝分裂退出被延迟，直到所有染色体通过纺锤体组装检查点（SAC）正确地附着到有丝分裂纺锤体。在这项研究中，我们表征了ARHGEF17的功能，该功能是在人类有丝分裂基因的全基因组RNA干扰筛选中鉴定的。通过一系列定量成像、生物化学和生物物理实验，我们发现ARHGEF 17对SAC活性至关重要，因为它是控制检查点激酶Mps1定位于动粒的主要靶向因子。这种有丝分裂功能由ARHGEF 17的中心结构域与Mps1的直接相互作用介导，Mps1由Mps1激酶的活性自动调节，ARHGEF 17是Mps1激酶的底物。这种有丝分裂特异性作用独立于ARHGEF 17在间期的RhoGEF活性。因此，我们的研究为ARHGEF17分配了一个新的有丝分裂功能，并揭示了SAC建立中关键步骤的分子机制。
The spindle assembly checkpoint (SAC) ensures genome stability during cell division. Here, a new essential SAC factor, ARHGEF17, is characterized by quantitative imaging, biochemical, and biophysical experiments, which show that it targets the checkpoint kinase Mps1 to kinetochores. 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.