Molecular Mechanisms of Cell Signaling

细胞信号转导的分子机制

• 批准号: 9488036
• 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/9488036
• 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全面了解 驱动细胞生存信号两大刹车功能的分子机制，蛋白质 Kinas C(PKC)和PH域富含亮氨酸重复蛋白磷酸酶(PHLPP， 发音为‘flip’)。在癌症的背景下，PKC家族已经被深入研究 自从20世纪80年代初发现它是促进肿瘤的佛波醇的受体以来 酯类化合物。这导致了佛波酯激活PKC促进致癌物的教条- 诱导肿瘤形成。尽管如此，PKC一直是一个难以捉摸的化疗靶点 几十年的研究。我们最近发现，与传统思维相反，PKC是一种 肿瘤抑制物，而不是癌基因，从而解释了为什么30多年来对PKC的临床试验 抑制剂不仅失败了，而且在某些情况下，还恶化了患者的预后。我们现在是 挑战在于理解PKC同工酶的分子机制，通常， 作为致癌信号的刹车。我们在PKC方面的工作导致了PHLPP的发现，一种 磷酸酶，通过不同的机制，也抑制致癌信号，但关于 人们对它的结构、功能和调控知之甚少。我们的目标是攻克关键 我们对控制量、活性和分子机制的理解存在差距 PHLPP在细胞中的位置。揭示PKC和PHLPP如何控制的分子细节 细胞信号将为新的治疗方法铺平道路。