Molecular Mechanisms of Cell Signaling

摘要/摘要 我们研究的总体愿景是全面了解 驱动细胞生存信号主要刹车功能的分子机制，蛋白质 蛋白激酶C(PKC)及其负性调节因子--PH域富含亮氨酸的重复蛋白 磷酸酶(PHLPP)。在癌症的背景下，PKC家族已经被深入研究 自20世纪80年代初发现它是促进肿瘤的佛波醇酯的受体以来。 这导致了佛波酯激活PKC促进致癌物诱导的教条 肿瘤发生学。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 研究的成果。2015年，我们逆转了一个主要的范式，表明PKC通常会抑制， 而不是增强致癌信号。这项建议旨在了解下游 PKC同工酶抑制癌基因信号转导的底物和分子机制 建立在癌症中恢复PKC的方法。此外，我们的目标是了解监管机构 它的负调控因子PHLPP的机制，我们在一项有针对性的研究中发现 使PKC上的保守位点去磷酸化的磷酸酶和相关的激酶，如 AKT。PHLPP既是一种肿瘤抑制因子，也是一种癌基因，而很多都是 对其底物、下游信号通路和功能的了解相对较少 了解其自身的监管机制。这项建议旨在了解结构和 PHLPP的调控机制，以抑制PHLPP的靶向特异性作用，特别是AS 一种恢复PKC的方法。拟议研究的首要挑战是填补我们在 了解调控PKC和PKC及其信号转导的分子机制 PHLPP为了利用这种理解来开发有效的治疗方法，当这些 在疾病中，机制被打乱。

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.