Function and regulation of the spindle positioning checkpoint (SPOC) kinase Kin4 of budding yeast

芽殖酵母纺锤体定位检查点（SPOC）激酶Kin4的功能和调控

• 批准号: 200342907
• 负责人: Professorin Dr. Gislene Pereira
• 金额: --
• 依托单位: Centre for Organismal Studies (COS)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/200342907?language=en
• 关键词: Function; regulation; spindle; positioning; checkpoint

The ability of cells to undergo asymmetric cell divisions and to form daughter cells of distinct cell fates is a conserved mechanism that is involved in the generation of cell diversity in multiand unicellular organisms. In most cell types the position of the spindle plays a crucial role in determining whether a cell will divide asymmetrically or symmetrically. A couple of years ago, I and others have identified the spindle position checkpoint (SPOC) as an essential mechanism that senses the position of the spindle in respect to the division axis of a budding yeast cell. If the spindle is misaligned the SPOC delays both the transition out of mitosis and cytokinesis.So far, only five SPOC components have been identified: the kinases Cdc5 (polo-like kinase), Elm1 and Kin4, the Bfa1-Bub2 GAP complex, and the PP2A subunit Rts1. The Kin4 kinase is a key SPOC component that counteracts the inactivation of Bfa1-Bub2 GAP complex by Cdc5 polo kinase. Rts1 and Elm1 regulate the localisation and activity of Kin4 kinase, respectively. Interestingly, a similar checkpoint mechanism involving the homologue of Kin4 might exist in Drosophila stem cells. The im-portance of this checkpoint for cell cycle regulation in higher eukaryotes is just emerging.Kin4 kinase functions at the centre of the SPOC coordinating correct spindle alignment and exit from mitosis. However, relatively little is know about how the position of the spindle controls Kin4 kinase. This project therefore aims to unravel the molecular mechanisms that regulate localisation and activity of Kin4 kinase under normal cell cycle progression and upon SPOC activation.

细胞经历不对称细胞分裂并形成不同细胞命运的子代细胞的能力是一种保守的机制，参与了多细胞和单细胞生物体中细胞多样性的产生。在大多数细胞类型中，纺锤体的位置在决定细胞是不对称分裂还是对称分裂中起着至关重要的作用。几年前，我和其他人已经确定纺锤体位置检查点(SPOC)是感知纺锤体相对于萌芽酵母细胞分裂轴的位置的基本机制。到目前为止，只鉴定了5个SPOC组分：CDC5(Polo-like kinase)，Elm1和Kin4，Bfa1-Bub2间隙复合体，以及PP2A亚单位RTS1。Kin4是一个关键的SPOC组分，它能中和Cdc5 Polo激酶对Bfa1-Bub2间隙复合体的失活。RTS1和Elm1分别调节Kin4激酶的定位和活性。有趣的是，在果蝇干细胞中可能存在与Kin4同源物有关的类似检查点机制。在高等真核生物中，这一检查点对细胞周期调控的重要性才刚刚出现，它位于SPOC的中心，协调正确的纺锤体排列和退出有丝分裂。然而，对于纺锤体的位置如何控制Kin4激酶，我们知之甚少。因此，本项目旨在揭示在正常细胞周期进程和SPOC激活时调节Kin4激酶定位和活性的分子机制。