Deciphering the physiological role and interplay between ubiquitination and phosphorylation pathways to guide targeted cancer therapies

摘要 在人类基因组中发现的25,000个基因中，绝大多数都受到选择性剪接的影响，并且 他们的蛋白质产品经常被大量的翻译后修饰，包括但不限于 泛素化、磷酸化、甲基化和乙酰化，从而极大地增加了 人类蛋白质组。然而，蛋白质修饰的失调引起的细胞信号异常事件 常导致蛋白质动态平衡和细胞功能改变，促进人类疾病的发展 包括癌症。为了与这些修饰在控制肿瘤发生中的关键作用保持一致，抑制剂 调控这些翻译后修饰的靶向酶引起了广泛的关注，因为 生物标志物和抗癌药物靶点。为此，我的实验室的中心一直专注于研究 两种主要多组分蛋白质酶的调节机制和生理功能 复合体：基于cullin的E3泛素连接酶复合体和雷帕霉素复合体的哺乳动物靶标 (MTOR)，以及它们与其他细胞信号通路的相互作用，以调控细胞周期调节和 肿瘤发生学。我研究项目的长期目标是了解异常细胞信号通路是如何 包括磷酸化和泛素化对肿瘤发生的影响，这指导了新基因的鉴定 治疗人类癌症的药物靶点。在独立的过去13年里，我的实验室 在细胞周期和癌症信号方面的原创、尖端研究方面建立了出色的跟踪记录 菲尔兹。在这项提议中，我通过进一步破译泛素化在调节中的作用来扩大我们的研究 MTORC1信号通路以及泛素化和磷酸化信号之间的相互作用 控制肿瘤发生的途径，从而提供机制洞察力和开发抑制剂的原理 靶向细胞信号通路的关键模块，包括E3连接酶和激酶，以增强我们的能力 创造具有高度针对性的癌症疗法。为了实现这些目标，一个主要的主题是使用这两种生物化学 用遗传学方法了解Skp2的致癌作用和Fbw7的抑瘤作用 部分通过泛素化介导的途径调节细胞新陈代谢。这次会议的第二个主题是 建议研究GATOR2介导的泛素化对血管内皮细胞的生理和病理影响 体内肿瘤发展过程中的GATOR1信号事件，这将指导我们发现新的治疗方法 瞄准这些信号通路的机会。因此，这个享有盛誉的奖项将为我们提供 使用高度创新的方法解决挑战性问题的必要资源，如理解 肿瘤发生的分子和细胞机制有助于揭示肿瘤靶向的新途径 效率更高。在我职业生涯的这个阶段获得这个享有盛誉的奖项将使我的实验室 更多地专注于创新的实验室研究，继续取得突破性发现以影响 下一代癌症疗法的发展。 好了！

Abstract A vast majority of the 25,000 genes identified in the human genome are subjected to alternative splicing, and their protein products are often heavily modified with posttranslational modifications including but not limited to ubiquitination, phosphorylation, methylation, and acetylation, thereby vastly increasing the functional diversity of the human proteome. However, aberrant cell signaling events caused by dysregulation of protein modifications often lead to altered protein homeostasis and cellular function to facilitate the development of human diseases including cancer. In keeping with a critical role for these modifications to governing tumorigenesis, inhibitors targeting enzymes regulating these post-translational modifications have attracted extensive attention as biomarkers and anti-cancer drug targets. To this end, the heart of my laboratory has been focused on studying the regulatory mechanisms and physiological functions of two major multi-component protein enzyme complexes: Cullin-based E3 ubiquitin ligase complexes and the Mammalian Target of Rapamycin Complex (mTOR), as well as their interplay with other cell signaling pathways to govern cell cycle regulation and tumorigenesis. The long-term goal of my research program is to understand how aberrant cell signaling pathways including phosphorylation and ubiquitination influence tumorigenesis, which guides the identification of novel drug targets for treating human cancers. Over the past thirteen years of independence, my laboratory has established an outstanding track record of original, cutting-edge, research in the cell cycle and cancer signaling fields. In this proposal, I have expanded our research by further deciphering the role of ubiquitination in regulating the mTORC1 signaling pathway, as well as the interplay between ubiquitination and phosphorylation signaling pathways to govern tumorigenesis, thereby providing mechanistic insights and the rationale to develop inhibitors targeting key modules of cell signaling pathways including E3 ligases and kinases to enhance our capability of creating highly targeted cancer therapies. To achieve these goals, one major theme is to use both biochemical and genetic approaches to understand the oncogenic role of Skp2 and the tumor suppressive role of Fbw7 in part via modulating cell metabolism through ubiquitination-mediated pathways. The second major theme of this proposal aims to investigate the physiological and pathological impacts of GATOR2-mediated ubiquitination of GATOR1 signaling events during cancer development in vivo, which will guide us to uncover novel therapeutic opportunities targeting these signaling pathways. This prestigious award would therefore provide us the necessary resources to use highly innovative approaches to tackle challenging questions such as understanding the molecular and cellular mechanisms governing tumorigenesis to shed light on novel pathways to target cancer more effectively. Receiving this prestigious award at this stage of my career will allow my laboratory to concentrate more on innovative lab research to continue to make breakthrough discoveries to impact development of the next generation of cancer therapeutics. !