The role of specific PP2A complexes in human cell transformation

描述（由申请人提供）：虽然激酶癌基因是癌症发展的良好特征驱动因素，但对磷酸酶在转化中的作用知之甚少。丝氨酸-苏氨酸蛋白磷酸酶2A （PP2A）参与多种信号通路的调节，可能具有肿瘤抑制作用。PP2A是一种异源三聚体蛋白复合物，三个亚基中的每一个都有几个同工异构体，形成了一个不同的相关酶家族，调节特定的生理功能。PP2A异源三聚体的多样性使之前建立特定PP2A亚基细胞功能的努力变得复杂。我建议采用三层方法对癌症进展中的PP2A复合物进行系统表征。使用功能丧失实验，我计划评估特定PP2A复合物在人类细胞转化中的贡献。通过使用基因组规模的方法，我将确定人类癌症中特定PP2A调节亚基的改变。然后，我将专注于通过定向蛋白质组学方法和细胞转化分析来破译特定PP2A复合物在肿瘤抑制中的分子作用。

DESCRIPTION (provided by applicant): Although kinase oncogenes are well-characterized drivers of cancer development, much less is known regarding the role of phosphatases in transformation. The serine-threonine protein phosphatase 2A (PP2A) is implicated in the regulation of numerous signaling pathways and may function as a tumor suppressor. PP2A is a heterotrimeric protein complex, and several isoforms exist for each of the three subunits, creating a diverse family of related enzymes that regulate specific physiological functions. The diversity of PP2A heterotrimers has complicated previous efforts to establish the cellular function of specific PP2A subunits. I propose to take a three-tiered approach toward a systematic characterization of PP2A complexes in cancer progression. Using loss of function experiments I plan to assess the contribution of particular PP2A complexes in human cell transformation. By using genome scale approaches, I will determine alterations of particular PP2A regulatory subunits in human cancers. I will then focus on deciphering the molecular roles of specific PP2A complexes in tumor suppression through a directed proteomics approach together with cell transformation assays. Public Health Relevance: These studies represent primary steps toward the identification of new targets that may have diagnostic and therapeutic potential in the treatment of cancer.