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主要制动器功能的分子机制，蛋白质 激酶C（PKC）及其负调节因子PH结构域富含亮氨酸重复蛋白 磷酸酶（PHLPP）。PKC家族在癌症的背景下得到了深入的研究 因为在20世纪80年代早期发现它是促肿瘤佛波醇酯的受体。 这导致了佛波醇酯激活PKC促进致癌物诱导的细胞凋亡的教条。 肿瘤发生尽管如此，尽管几十年来，PKC一直是一个难以捉摸的化疗靶点， 的研究。在2015年，我们通过显示PKC通常抑制， 而不是增强致癌信号。该建议旨在1]了解下游 底物和分子机制，PKC同工酶制动致癌信号和2] 建立恢复癌症中PKC的方法。此外，我们的目标是了解监管 其负调节因子PHLPP的机制，我们在有针对性的搜索中发现了一个 一种磷酸酶，可以使PKC和相关激酶上的保守位点去磷酸化， Akt. PHLPP既作为肿瘤抑制基因又作为癌基因发挥作用， 关于它的底物、下游信号通路和功能， 了解自己的监管机制。本建议旨在了解结构和 PHLPP的调节机制，以抑制PHLPP的靶特异性作用，特别是作为 恢复PKC的方法拟议研究的首要挑战是填补我们的空白， 知识的分子机制管理的调节，并通过信号，蛋白激酶C和 PHLPP为了利用这种理解，当这些 在疾病中机制被破坏。

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.