Structural and Systematic Biology of PP2A and Cancer Treatment.

描述（由申请人提供）：蛋白磷酸酶2A （PP2A）是哺乳动物细胞中主要的丝氨酸/苏氨酸蛋白磷酸酶，参与多个过程。PP2A活性的放松通常会导致致癌转化，这导致了PP2A是一个重要的肿瘤抑制因子的概念。由于其多亚基组成及其与许多调节蛋白相互作用的能力，PP2A的结构和调控仍然知之甚少。申请人的长期目标是使用结构方法推断PP2A调控的机制，并使用蛋白质组学方法完善我们对其在细胞功能中的作用的了解。这一信息将促进潜在的基于PP2A的癌症治疗策略的发展。本研究的直接目标是1)解决PP2A a - c核心二聚体复合物中PP2A甲基转移酶（PMT）和甲基酯酶（PME）的结构，从而阐明催化亚基可逆甲基化的机制，这是PP2A调控所必需的过程，并提供期待已久的a - c复合物的结构信息；ii)利用结构和生化方法阐明细胞抑制蛋白I1PP2A和I2PP2A抑制PP2A磷酸酶活性的机制，并研究PME、alpha4蛋白、I1PP2A和I2PP2A中存在的共同多酸基序的作用；iii)解析受小分子抑制剂（如冈田酸）影响的细胞中的蛋白质磷酸化谱，以及受甲基化过程、α 4蛋白、I1PP2A、I2PP2A和一些调节b亚基的影响。它们对细胞生长、增殖的影响也将在癌细胞系上进行测试。PP2A的活性在癌细胞中经常被下调。下调PP2A功能的抑制蛋白如PME、alpha4蛋白、11PP2A、I2PP2A等是癌症治疗干预的极佳靶点。蛋白质组学数据应该有助于鉴定最有希望作为靶标的PP2A调控元件，结构数据应该为PP2A的调控和功能提供最终的清晰度，并有助于设计具有最大潜在治疗用途的治疗化合物，以减缓或停止致癌细胞的生长、增殖和转移。

DESCRIPTION (provided by applicant): Protein phosphatase 2A (PP2A) is a major Ser/Thr protein phosphatase in mammalian cells that is involved in multiple processes. Deregulation of PP2A activity often leads to oncogenic transformation, which has led to the notion that PP2A is an important tumor suppressor. Due to its multi-subunit composition and its ability to interact with numerous regulatory proteins, the structure and regulation of PP2A remains poorly understood. The long-term goal of the applicant is to deduce the mechanism of PP2A regulation using a structural approach and to refine our knowledge of its roles in cell function using proteomic methods. This information will facilitate the development of potential PP2A based strategies for cancer therapy. The immediate goals of this research are i) to solve the structure of PP2A methyltransferase (PMT) and methylesterase (PME) in complex with the PP2A A-C core dimer and thereby elucidate the mechanism of reversible methylation of the catalytic subunit, a process that is essential for PP2A regulation, and to provide the long-awaited structural information for A-C complex; ii) to elucidate the mechanism of cellular inhibitory proteins I1PP2A and I2PP2A to inhibit the phosphatase activity of PP2A using structural and biochemical approach, and to investigate the roles of the common poly-acidic motif existed in PME, alpha4 protein, I1PP2A and I2PP2A; and iii) to resolve the protein phosphorylation profiles in cells affected by small molecule inhibitors such as okadaic acid, and by the methylation process, by alpha4 protein, I1PP2A, I2PP2A and some of the regulatory B-subunits. Their effects on cell growth, proliferation will also be tested on carcinoma cell lines. The activity of PP2A is often down regulated in cancer cells. The inhibitory proteins that down regulate PP2A function, such as PME, alpha4 protein, 11PP2A and I2PP2A are excellent targets for therapeutic intervention of cancer. The proteomic data should facilitate the identification of the regulatory element of PP2A that has the greatest promise for use as a target, and the structural data should provide ultimate clarity to PP2A regulation and function, and facilitate the design of therapeutic compounds that have the greatest potential therapeutic use for slowing or halting the growth, proliferation, and metastasis of oncogenic cells.