PR55-alpha controlled PP2A in the regulation of the Hippo/YAP pathway

PR55-α控制PP2A调节Hippo/YAP通路

• 批准号: 10461097
• 负责人: Ying Yan
• 金额: $ 30.7万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10461097
• 关键词: Anchorage-Independent Growth; Automobile Driving; Black race; CUL1 gene; Cancer Control; Cancer Etiology; Catalytic Domain; Cells; Cessation of life; Clinical; Complex; Critical Pathways; Data; Development; Disease; F-Box Proteins; Family; Genes; Holoenzymes; Human; In Vitro; KRAS oncogenesis; KRASG12D; Knowledge; Longevity; MAP Kinase Gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mus; Mutation; Neoplasm Metastasis; Oncogenic; PI3K/AKT; Pancreas; Pathogenesis; Pathway interactions; Patients; Pattern; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Protein Kinase; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Proteins; Regulation; Research; Retinal blind spot; Role; Seminal; Signal Transduction; Source; Specimen; Substrate Specificity; Survival Rate; TP53 gene; Testing; Tissues; Tumor Suppression; Tumorigenicity; Work; base; cancer initiation; conditional knockout; defined contribution; effective therapy; improved; innovation; interdisciplinary approach; knock-down; malignant phenotype; mouse model; new therapeutic target; novel; pancreatic cancer cells; pancreatic cancer model; pancreatic cancer patients; scaffold; support network; targeted treatment; tumor progression; tumorigenesis; ubiquitin-protein ligase

Abstract Pancreatic cancer (PC) is one of the most lethal cancers in the U.S. with a 5-year survival rate of 7%, which has essentially unchanged for the past 40 years. Despite extensive research, there are no effective targeted therapies for this disease, suggesting an insufficient understanding of oncogenic signaling networks in PC. While almost all of the signaling networks implicated in cancer rely on the cooperation of kinases and phosphatases to transduce signals promoting cancer, most efforts have only been put on the study of protein kinases in cancer while leaving protein phosphatases as a blind spot. PP2A is a family of heterotrimers that serve as the main source of Ser/Thr phosphatase activities in human cells, with each consisting of a scaffold subunit (Aα/β), a catalytic subunit (Cα/β), and one of many non-conserved regulatory (B) subunits (>27) that control the substrate specificities of PP2A complexes. Our preliminary studies identified PR55α, a regulatory subunit of PP2A, as an important new player in promoting malignant PC. In particular, our studies revealed that PR55 inhibits the MOB1/LATS auto-activation loop of the Hippo tumor suppression pathway, whose function is to induce the phosphorylation of YAP causing its cytoplasmic retention and proteasomal degradation. In line with the essential role of YAP signaling in Kras-driven PC development and progression, knockdown of PR55α impeded the anchorage-independent growth, tumorigenicity, and metastasis of PC cells. Our preliminary data also revealed that the stability of PR55α protein is negatively regulated by the tumor suppressor p53 and its target gene FBXL20, a substrate adaptor for the SCF (SKP1-CUL1-F-box protein) E3 ligase. Consistently, we observed that PR55α is elevated in PC specimens, where its expression correlates with poor patient survival. Based on these findings, we hypothesize that loss of p53 function results in the stabilization of PR55α protein, which, in turn, activates the YAP oncogenic signaling required for Kras-driving PC initiation and progression. We will test the hypothesis by three specific aims: Aim 1 to define the mechanism by which PR55α/PP2A promotes YAP activation and the significance of this cascade in oncogenesis and malignant potential of PC, Aim 2 to elucidate how p53 suppresses the level of PR55α, and Aim 3 to delineate the role of the PR55/YAP axis in pancreatic cancer development and progression in the KPC spontaneous mouse model. The work is innovative, as it will illuminate a critical pathway that promotes PC initiation and progression through PR55/PP2A activated YAP signaling, which is novel to both the PP2A field and the PC field. Successful completion of the proposed studies will yield an in-depth mechanistic understanding of the critical contribution of PR55/PP2A complex to the observed cooperation between Kras activation and the loss of the p53 tumor suppressor during PC development and progression. The acquired knowledge not only will improve the understanding of the role of PP2A in cancer but also will contribute to identifying novel therapeutic targets for improving the treatment of PC.

抽象的 胰腺癌 (PC) 是美国最致命的癌症之一，5 年生存率为 7%， 尽管进行了大量研究，但过去 40 年来基本没有变化。 这种疾病的治疗方法，表明对 PC 中致癌信号网络的了解不足。 几乎所有与癌症有关的信号网络都依赖于激酶和磷酸酶的合作 转导促进癌症的信号，目前大部分精力仅放在癌症中蛋白激酶的研究上 而留下蛋白磷酸酶作为盲点的是作为主要的异源三聚体家族。 人类细胞中 Ser/Thr 磷酸酶活性的来源，每个磷酸酶由支架亚基 (Aα/β)、 催化亚基 (Cα/β)，以及控制底物的许多非保守调节 (B) 亚基 (>27) 之一 我们的初步研究确定了 PP2A 的调节亚基 PR55α 是一个 特别是，我们的研究表明 PR55 会抑制 PC 的恶性生长。 Hippo肿瘤抑制途径的MOB1/LATS自动激活环路，其功能是诱导 YAP 的磷酸化导致其细胞质滞留和蛋白酶体降解符合基本要求。 YAP 信号在 Kras 驱动的 PC 发育和进展中的作用，PR55α 的敲低阻碍了 我们的初步数据还揭示了 PC 细胞的贴壁依赖性生长、致瘤性和转移。 PR55α蛋白的稳定性受到抑癌基因p53及其靶基因的负调控 FBXL20，SCF（SKP1-CUL1-F-box 蛋白）E3 连接酶的底物接头，我们一致观察到。 PR55α 在 PC 标本中升高，其表达与患者生存率较差相关。 研究结果表明，p53 功能的丧失会导致 PR55α 蛋白的稳定，反过来， 激活 Kras 驱动 PC 启动和进展所需的 YAP 致癌信号。 三个具体目标的假设：目标 1 定义 PR55α/PP2A 促进 YAP 的机制 激活以及该级联在 PC 的肿瘤发生和恶性潜能中的重要性，目的 2 阐明 p53 如何抑制 PR55α 的水平，目标 3 描述 PR55α/YAP 轴在胰腺中的作用 KPC 自发小鼠模型中的癌症发展和进展这项工作具有创新性，也将具有创新性。 阐明通过 PR55/PP2A 激活 YAP 促进 PC 启动和进展的关键途径 信令，这对于 PP2A 领域和 PC 领域来说都是新颖的，成功完成了拟议的研究。 将深入了解 PR55/PP2A 复合物对 在 PC 发育过程中观察到 Kras 激活与 p53 肿瘤抑制因子丢失之间的协同作用 所获得的知识不仅将提高对 PP2A 在癌症中的作用的理解。 但也将有助于确定新的治疗靶点，以改善 PC 的治疗。