The Role of PP2A in Yeast Cell Cycle Progression

描述(申请人提供)：蛋白磷酸酶2A是真核生物中的一种主要的蛋白质丝氨酸/苏氨酸磷酸酶，其活性与许多细胞过程有关。PP2A全酶是由一个催化亚基(PP2Ac)和两个调节亚基(A和B)组成的异三聚体蛋白质复合体。然而，最近在酵母和哺乳动物细胞中的研究发现了一种新的PP2A复合体，它包含催化亚基和细胞蛋白，在酵母中称为Tap42，在哺乳动物中称为a-4蛋白。在酵母中，Tap42-PP2Ac复合体是TOR信号通路的一部分，已被证明是细胞生长所必需的。然而，这种复合体在控制细胞生长和增殖中的重要作用尚不清楚。在我们的初步研究中，我们发现Tap42-PP2Ac复合体参与控制细胞周期中的肌动蛋白细胞骨架、细胞壁完整性和G2/M转变，这三个事件以前被认为是由PP2A全酶控制的。这一发现对PP2A在这些过程中的作用提出了新的解释，并为剖析PP2A调节这些过程的机制提供了新的线索。根据我们的初步研究结果，我们提出了以下特定的目标来研究Tap42-PP2Ac在这些过程中的作用：特定的目标1.检验Rom2是Tap42-PP2Ac复合体在细胞壁完整性途径中的直接靶点的假设。具体目的2.研究Mpk1下调细胞壁完整性途径的反馈机制。具体目的3.验证Tap42-PP2Ac复合体通过转录因子Fkh1/2调控G2基因表达的假说。这项研究是我们长期目标的一部分，目的是了解PP2A在细胞生长控制中的作用。

DESCRIPTION (provided by applicant): Protein phosphatase 2A is a major protein ser/thr phosphatase in eukaryotes, whose activity has been implicated in numerous cellular processes. The PP2A holoenzyme is a heterotrimeric protein complex that is comprised of one catalytic subunit (PP2Ac) and two regulatory subunits (A and B). However, recent studies in both yeast and mammalian cells have identified a novel PP2A complex that contains the catalytic subunit and a cellular protein, named Tap42 in yeast and a-4 protein in mammals. In yeast, the Tap42-PP2Ac complex is part of the TOR signaling pathway, and has been shown to be essential for cell growth. However, the essential role for this complex in controlling cell growth and proliferation is unknown. In our preliminary study, we found that the Tap42-PP2Ac complex was involved in controlling the actin cytoskeleton, cell wall integrity and the G2/M transition during the cell cycle, three events that were previously believed to be controlled by the PP2A holoenzyme. This finding suggests new interpretations for the role of PP2A in these processes, and offers new clues for dissecting the mechanisms by which PP2A regulates these processes. Based on the results of our preliminary studies, we propose the following specific aims to examine the role of the Tap42-PP2Ac in these processes: Specific Aim 1. To test the hypothesis that Rom2 is the direct target of the Tap42-PP2Ac complex in the cell wall integrity pathway. Specific Aim 2. To examine the putative feedback mechanism by which Mpk1 downregluates the cell wall integrity pathway. Specific Aim 3. To test the hypothesis that the Tap42-PP2Ac complex controls the G2 gene expression through the Fkh1/2 transcription factors. This study is part of our long-term goals to understand the role of PP2A in cell growth control.