Molecular Mechanisms of Cell Signaling

细胞信号转导的分子机制

• 批准号: 9276457
• 负责人: ALEXANDRA C. NEWTON
• 金额: $ 63.62万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276457
• 关键词: Address; Automobile Driving; Carcinogens; Cell Survival; Cells; Clinical Trials; Disease; Family; Functional disorder; Isoenzymes; Location; Malignant Neoplasms; Molecular; Oncogenes; Oncogenic; PH Domain; Patient-Focused Outcomes; Phorbol Esters; Phosphoric Monoester Hydrolases; Protein Kinase C; Protein phosphatase; Proteins; Public Health; Regulation; Research; Signal Transduction; Signaling Molecule; Signaling Protein; Structure; Thinking; Tumor Suppressor Proteins; Vision; Work; cancer clinical trial; inhibitor/antagonist; leucine-rich repeat protein; novel therapeutics; protein activation; receptor; tumor; tumorigenesis

Summary/Abstract The overall vision of our research is to gain a comprehensive understanding of the molecular mechanisms driving the function of two major brakes to cell survival signaling, protein kinas C (PKC) and the PH domain Leucine-rich repeat Protein Phosphatase (PHLPP, pronounced `flip'). The PKC family has been intensely investigated in the context of cancer since the discovery in the early 1980s that it is a receptor for the tumor-promoting phorbol esters. This led to the dogma that activation of PKC by phorbol esters promotes carcinogen- induced tumorigenesis. Nonetheless, PKC has been an elusive chemotherapeutic target despite decades of research. We recently established that, contrary to conventional thinking, PKC is a tumor suppressor, not an oncogene, thus explaining why 30+ years of clinical trials with PKC inhibitors have not only failed but, in some cases, worsened patient outcome. We are now challenged with understanding the molecular mechanisms by which PKC isozymes, generally, serve as the brakes to oncogenic signaling. Our work on PKC led to the discovery of PHLPP, a phosphatase that, by different mechanisms, also brakes oncogenic signaling but about which considerably less is known regarding its structure, function, and regulation. We aim to tackle key gaps in our understanding of the molecular mechanisms that control the amount, activity, and location of PHLPP in the cell. Uncovering the molecular details of how PKC and PHLPP control cell signaling will pave the way for novel therapies.

摘要/摘要 我们研究的总体愿景是对 分子机制驱动两个主要制动器对细胞存活信号传导的功能，蛋白质 Kinas C（PKC）和pH结构域富含亮氨酸的重复蛋白磷酸酶（PHLPP， 发音为“翻转”）。 PKC家族在癌症的背景下进行了深入研究 自1980年代初期发现它是促肿瘤佛波尔的受体 酯。这导致了教条，即佛波酯对PKC的激活促进致癌 诱导肿瘤发生。尽管如此，尽管 数十年的研究。我们最近确定，与传统思维相反，PKC是一个 肿瘤抑制剂，而不是癌基因，从而解释了为什么PKC进行了30多年的临床试验 抑制剂不仅失败了，而且在某些情况下会恶化患者的结果。我们现在 在理解PKC同工酶通常的分子机制方面受到挑战 充当致癌信号的制动器。我们在PKC上的工作导致发现PHLPP，一个 磷酸酶，通过不同的机制，也是制动致癌信号的 关于其结构，功能和调节，已知少得多。我们的目标是解决钥匙 我们对控制数量，活性和 PHLPP在细胞中的位置。发现PKC和PHLPP如何控制的分子细节 细胞信号传导将为新疗法铺平道路。