Molecular Mechanisms of Cell Signaling

细胞信号转导的分子机制

• 批准号: 10415752
• 负责人: ALEXANDRA C. NEWTON
• 金额: $ 65.99万
• 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 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10415752
• 关键词: Address; Automobile Driving; Carcinogens; Cell Survival; Disease; Enzymes; Family; Isoenzymes; Knowledge; Malignant Neoplasms; Molecular; Oncogenes; Oncogenic; PH Domain; Phorbol Esters; Phosphoric Monoester Hydrolases; Phosphotransferases; Protein Kinase C; Protein phosphatase; Public Health; Regulation; Research; Role; Signal Pathway; Signal Transduction; Signaling Protein; Site; Structure; Tumor Suppressor Proteins; Vision; comparative; effective therapy; leucine-rich repeat protein; 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 a major brake to cell survival signaling, protein kinase C (PKC), and its negative regulator, the PH domain Leucine-rich repeat Protein Phosphatase (PHLPP). 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. In 2015 we reversed a major paradigm by showing that PKC generally suppresses, rather than enhances, oncogenic signaling. This proposal aims to 1] understand the downstream substrates and molecular mechanisms by which PKC isozymes brake oncogenic signaling and 2] establish ways to restore PKC in cancer. Furthermore, we aim to understand the regulatory mechanisms of its negative regulator, PHLPP, which we discovered in a targeted search for a phosphatase that would dephosphorylate a conserved site on PKC and related kinases such as Akt. PHLPP functions both as a tumor suppressor and as an oncogene and whereas much is known about its substrates, downstream signaling pathways, and function, comparatively little is known about its own regulatory mechanisms. This proposal aims to understand the structure and regulatory mechanisms of PHLPP in order to inhibit target-specific roles of PHLPP, especially as a way to restore PKC. The overarching challenge of the proposed research is to fill gaps in our knowledge of the molecular mechanisms governing the regulation of, and signaling by, PKC and PHLPP in order to leverage this understanding to develop effective therapies when these mechanisms are disrupted in disease.

摘要/摘要 我们研究的总体愿景是对 分子机制驱动主要制动器对细胞存活信号，蛋白质的功能 激酶C（PKC）及其阴性调节剂，pH结构域富含亮氨酸的重复蛋白 磷酸酶（PHLPP）。 PKC家族在癌症的背景下进行了深入研究 自1980年代初期的发现以来，它是促肿瘤的凤凰酯的受体。 这导致了教条，即佛波尔酯激活PKC会促进致癌物诱导的 肿瘤发生。尽管如此，尽管数十年 研究。在2015年，我们通过表明PKC通常抑制，扭转了一个主要的范式 而不是增强致癌信号。该建议的目的是1]了解下游 PKC同工酶制动致癌信号和2]的底物和分子机制 建立恢复PKC癌症的方法。此外，我们旨在了解监管 其负调节器PHLPP的机制，我们在目标搜索中发现 磷酸酶将在PKC和相关激酶（例如 akt。 PHLPP既可以用作肿瘤抑制剂，又是癌基因，而很多是 知道其底物，下游信号通路和功能，相对较小的IS 知道自己的监管机制。该建议旨在了解结构和 PHLPP的调节机制是为了抑制PHLPP的目标特异性作用，尤其是 一种恢复PKC的方法。拟议研究的总体挑战是填补我们的空白 了解有关PKC和PKC的调节和信号传导的分子机制的了解 PHLPP以利用这种理解来开发有效的疗法 机制在疾病中受到破坏。