Human Cancer Suppressor Functions of Protein Phosphatase 2A

摘要 该计划包括三个紧密相连的主题。主要主题是蛋白质。 磷酸酶2A(PP2A)，一种公认的肿瘤抑制因子。了解PP2A如何作为肿瘤发挥作用 出于几个原因，抑制者一直在挑战。首先，PP2A是一种异三聚体酶，由A、 B和C亚基，每个亚基都有几个成员，产生&gt；80个可能的PP2A全酶。基因组 特性研究表明，在人类中，许多PP2A亚单位是反复突变或缺失的 以破坏PP2A组装或催化活性的方式致癌。因此，PP2A是一种高度复杂的 多种多样的酶家族，使其肿瘤抑制功能的去卷积成为问题。本计划 开发了一种全球磷酸肽分析系统，该系统已开始识别新的PP2A底物和 承诺加快解卷其复杂和多样化的肿瘤抑制的性质的进展 角色。该计划的第二个主题是使用DNA肿瘤病毒癌蛋白作为智能探针来 了解PP2A抑癌基因的功能。该计划的所有成员都已经表明，PP2A是一个关键的 在细胞生长调节和转化中发挥作用，病毒癌蛋白与PP2A相互作用的方式 干扰PP2A的肿瘤抑制活性，促进转化。第三个主题以 全球约20%的癌症是由感染性病原体引起的。默克尔细胞多瘤病毒(MCPyV) 是大多数默克尔细胞癌(MCC)的明显原因，MCC是一种高度致命的皮肤癌。MCPyV编码了一个小的 T抗原(ST)，对MCC是必不可少的，并能自行转化人类细胞。MCPyV ST与 PP2A和该计划将调查默克尔ST-PP2A相互作用的功能输出，并搜索 对MCPyV促进MCC的机制的新见解。 该计划的目标是：(1)确定PP2A驱动的信号级联，有助于临床 肿瘤抑制的重要例子；(2)确定与癌症相关的PP2A底物。(三)想方设法 以恢复或激活突变的PP2A功能。四个项目中的每一个和功能蛋白质组学核心将 重点研究特定的PP2A干扰，无论是通过突变还是与癌蛋白的关联，如何靶向 控制癌症发展的途径。项目1将研究MCPyV ST对MTOR信号的影响 和DNA断裂修复。项目2将评估小鼠多瘤病毒与PP2A相互作用对 YAP-河马信号。项目3将研究影响PP2A-Aβ亚单位的肿瘤抑制活性 AKT和SRC信号通路。项目4将研究新检测到的特定扰动的作用 PP2A-STRIPAK复合体在肿瘤分子发病机制中的作用功能蛋白质组学核心将 确定相关PP2A复合体及其磷酸化蛋白底物的亚基组成。这 该计划将为PP2A在很大程度上尚未确定的癌症抑制作用带来重要的新见解。 我们希望确定由PP2A调控的抑制癌症发展的重要信号通路。

Summary This Program encompasses three tightly connected themes. The primary theme is centered on protein phosphatase 2A (PP2A), an established tumor suppressor. Understanding how PP2A serves as a tumor suppressor has been challenging for several reasons. First, PP2A is a heterotrimeric enzyme composed of A, B and C subunits, each with several members giving rise to > 80 possible PP2A holoenzymes. Genome characterization studies show that many of the PP2A subunits are recurrently mutated or deleted in human cancers in a manner that disrupts PP2A assembly or catalytic activity. Thus, PP2A is a highly complex and diverse enzyme family, making deconvolution of its tumor suppressing functions problematic. This Program has developed a global phosphopeptide analysis system that has begun to identify new PP2A substrates and promises to accelerate progress in deconvoluting the nature of its complex and diverse tumor suppression roles. The second theme of this Program is the use of DNA tumor virus oncoproteins as smart probes to understand PP2A tumor suppressor function. All members of this program have shown that PP2A is a critical player in cell growth regulation and transformation and that viral oncoproteins interact with PP2A in ways that interfere with PP2A tumor suppressing activity and contribute to transformation. The third theme begins with the knowledge that ~ 20% of global cancer is caused by infectious agents. Merkel cell polyomavirus (MCPyV) is the clear cause of most Merkel cell carcinomas (MCC), a highly lethal skin cancer. MCPyV encodes a small T antigen (ST) that is essential for MCC and can transform human cells on its own. MCPyV ST interacts with PP2A and this Program will investigate the functional output of Merkel ST - PP2A interactions and search for novel insights into the mechanisms by which MCPyV contributes to MCC. The goals of this Program are: (1) To identify PP2A-driven signaling cascades that contribute to clinically important examples of tumor suppression; (2) To identify cancer-relevant PP2A substrates. (3) To seek ways to restore or activate mutant PP2A function. Each of the four Projects and the Functional Proteomics Core will focus on how specific PP2A perturbation, whether by mutation or association with oncoproteins, targets pathways that control cancer development. Project 1 will study the affects of MCPyV ST on MTOR signaling and DNA break repair. Project 2 will assess the effects of murine polyomavirus interactions with PP2A upon YAP - Hippo signaling. Project 3 will study the tumor suppressor activity of the PP2A-Aβ subunit that influences AKT and SRC signaling pathways. Project 4 will study the newly detected role of specific perturbations of the PP2A-STRIPAK complex in the molecular pathogenesis of cancer. The Functional Proteomics Core will identify the subunit composition of relevant PP2A complexes and their phospho-protein substrates. This Program will bring important, new insights into the largely uncharacterized cancer suppressor role of PP2A. We expect to identify important signaling pathways regulated by PP2A to suppress cancer development.