Molecular Mechanisms of Cell Signaling

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，蛋白质 激酶C（PKC）和PH结构域富含亮氨酸的重复蛋白磷酸酶（PHLPP， 发音为“flip”）。PKC家族在癌症的背景下得到了深入的研究 自从20世纪80年代早期发现它是促肿瘤的佛波醇的受体以来， 酯盐酸盐的褪这导致了佛波醇酯激活PKC促进致癌物质的教条- 诱发肿瘤发生。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。我们最近确定，与传统思维相反，PKC是一种 肿瘤抑制基因，而不是癌基因，从而解释了为什么30多年的PKC临床试验 抑制剂不仅失败，而且在某些情况下使患者的结果恶化。我们现在 挑战在于理解PKC同工酶的分子机制，通常， 作为致癌信号的制动器。我们对PKC的研究导致了PHLPP的发现， 一种磷酸酶，通过不同的机制，也能抑制致癌信号，但 关于它的结构、功能和管理，我们知道的要少得多。我们的目标是解决关键问题 我们对控制蛋白质数量、活性和 PHLPP在细胞中的位置。揭示PKC和PHLPP如何控制的分子细节 细胞信号将为新疗法铺平道路。

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.