Molecular Mechanisms of Cell Signaling

摘要/摘要 我们研究的总体愿景是全面了解 驱动细胞生存信号的两个主要刹车功能的分子机制， 蛋白激酶C(PKC)与PH域富含亮氨酸的重复蛋白磷酸酶 (PHLPP，发音为‘flip’)。PKC家族在 自20世纪80年代初发现它是肿瘤的受体以来，癌症的背景 促进肿瘤的佛波醇酯。这导致了一种教条，即佛波醇激活PKC 酯促进致癌物诱导的肿瘤形成。尽管如此，PKC一直是一个难以捉摸的 尽管进行了数十年的研究，但仍以化疗为靶点。我们最近证实，与之相反 传统观点认为，PKC是一种肿瘤抑制因子，而不是癌基因，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， 恶化了患者的预后。我们现在面临着理解分子的挑战 通常，PKC同工酶作为致癌信号的刹车机制。 我们对PKC的研究导致了PHLPP的发现，这是一种磷酸酶，由不同的 机制，也抑制致癌信号，但对此知之甚少 关于它的结构，功能和调节。我们的目标是解决我们的 对控制数量、活性和位置的分子机制的理解 在细胞内的PHLPP。揭示PKC和PHLPP如何控制细胞的分子细节 信号将为新的治疗方法铺平道路。

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.