Human Cancer Suppressor Functions of Protein Phosphatase 2A

总结 该计划包括三个紧密相连的主题。第一个主题是蛋白质 磷酸酶2A（PP 2A），一种已确立的肿瘤抑制因子。了解PP 2A如何作为肿瘤 抑制器由于几个原因而受到挑战。首先，PP 2A是由A， B和C亚基，每个亚基有几个成员，产生> 80种可能的PP 2A全酶。基因组 表征研究表明，许多PP 2A亚基在人类中反复突变或缺失， 以破坏PP 2A组装或催化活性的方式治疗癌症。因此，PP 2A是一种高度复杂且 不同的酶家族，使得其肿瘤抑制功能的去卷积成问题。这个程序 开发了一个全球磷酸肽分析系统，该系统已开始识别新的PP 2A底物， 有望加速其复杂多样的肿瘤抑制性质的去卷积进展 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， 了解PP 2A肿瘤抑制功能。该计划的所有成员都表明，PP 2A是一个关键的 在细胞生长调节和转化中起作用，病毒癌蛋白与PP 2A相互作用， 干扰PP 2A肿瘤抑制活性并有助于转化。第三个主题开始于 全球约20%的癌症是由传染性病原体引起的。默克尔细胞多瘤病毒 是大多数默克尔细胞癌（MCC）的明确原因，MCC是一种高度致命的皮肤癌。MCPyV编码一个小的 T抗原（ST）是MCC所必需的，可以自行转化人类细胞。MCPyV ST与 PP 2A和本计划将调查默克尔ST -PP 2A相互作用的功能输出，并寻找 新的见解MCPyV有助于MCC的机制。 本项目的目标是：（1）识别PP 2A驱动的信号级联，其有助于临床上的 肿瘤抑制的重要实例;（2）鉴定癌症相关的PP 2A底物。(3)设法 以恢复或激活突变型PP 2A功能。四个项目和功能蛋白质组学核心将 重点关注PP 2A特异性干扰，无论是通过突变还是与癌蛋白的结合， 控制癌症发展的途径。项目1将研究MCPyV ST对MTOR信号传导的影响 和DNA断裂修复项目2将评估鼠多瘤病毒与PP 2A相互作用对 雅普-河马信号。项目3将研究PP 2A-A β亚基的肿瘤抑制活性， AKT和SRC信号通路。项目4将研究新发现的地球大气中特定扰动的作用， PP 2A-STRIPAK复合物在癌症分子发病机制中的作用功能蛋白质组学核心将 鉴定相关PP 2A复合物及其磷蛋白底物的亚基组成。这 该计划将为PP 2A在很大程度上未表征的癌症抑制作用带来重要的新见解。 我们希望确定由PP 2A调控的重要信号通路，以抑制癌症的发展。

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.