Molecular Mechanisms of Cell Signaling

细胞信号转导的分子机制

• 批准号: 10320606
• 负责人: ALEXANDRA C. NEWTON
• 金额: $ 1.87万
• 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/10320606
• 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.

总结/摘要 我们研究的总体愿景是全面了解 驱动细胞存活信号传导的两个主要制动器功能的分子机制， 蛋白激酶C（PKC）和PH结构域富含亮氨酸重复蛋白磷酸酶 （PHLPP，发音为"flip"）。PKC家族已被深入研究， 自20世纪80年代初发现它是一种受体以来， 促进肿瘤的佛波醇酯。这导致了佛波醇激活PKC 酯类促进致癌物诱导的肿瘤发生。尽管如此，PKC一直是一个难以捉摸的 尽管有几十年的研究，我们最近发现， 与传统思维不同，PKC是一种肿瘤抑制因子，而不是致癌基因，这就解释了为什么 30多年的PKC抑制剂临床试验不仅失败了，而且在某些情况下， 患者结局恶化。我们现在面临的挑战是， PKC同工酶通常作为致癌信号传导的制动器的机制。 我们对PKC的研究导致了PHLPP的发现，PHLPP是一种磷酸酶， 机制，也制动致癌信号，但关于这一点知之甚少 它的结构、功能和规则。我们的目标是解决我们的关键差距， 了解控制数量，活性和位置的分子机制 PHLPP在细胞中的作用。揭示PKC和PHLPP如何控制细胞的分子细节 信号传递将为新疗法铺平道路。