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

摘要 在人类基因组中鉴定的25，000个基因中，绝大多数都经历了选择性剪接， 它们的蛋白质产物通常被翻译后修饰严重修饰，包括但不限于 泛素化，磷酸化，甲基化和乙酰化，从而大大增加了功能的多样性， 人类蛋白质组然而，由蛋白质修饰的失调引起的异常细胞信号传导事件， 通常导致蛋白质稳态和细胞功能的改变，从而促进人类疾病的发展 包括癌症与这些修饰对控制肿瘤发生的关键作用一致，抑制剂 靶向调节这些翻译后修饰的酶引起了广泛的关注， 生物标志物和抗癌药物靶点。为此，我的实验室一直专注于研究 两种主要多组分蛋白酶调节机制和生理功能 复合物：基于Cullin的E3泛素连接酶复合物和雷帕霉素复合物的哺乳动物靶标 （mTOR），以及它们与其他细胞信号传导途径的相互作用，以控制细胞周期调控， 肿瘤发生我的研究项目的长期目标是了解异常的细胞信号通路 包括磷酸化和泛素化影响肿瘤发生，这指导了新的 治疗人类癌症的药物靶点。在过去十三年的独立，我的实验室已经 在细胞周期和癌症信号传导领域建立了卓越的原创性、前沿性研究记录 领域的在这个建议中，我通过进一步破译泛素化在调节细胞凋亡中的作用， 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，从而提供机制的见解和开发抑制剂的基本原理 靶向细胞信号传导途径的关键模块，包括E3连接酶和激酶，以增强我们的能力， 创造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生物化学和生物化学。 和遗传学方法来了解Skp2的致癌作用和Fbw7的肿瘤抑制作用， 部分通过泛素化介导的途径调节细胞代谢。第二个主题是 该提案旨在研究GATOR 2介导的泛素化对生理和病理的影响， GATOR 1在体内癌症发展过程中的信号传导事件，这将指导我们发现新的治疗方法， 针对这些信号通路的机会。因此，这一享有盛誉的奖项将为我们提供 利用高度创新的方法来解决具有挑战性的问题， 控制肿瘤发生的分子和细胞机制，以阐明靶向癌症的新途径 更有效地在我职业生涯的这个阶段获得这个著名的奖项将使我的实验室能够 更多地专注于创新实验室研究，继续取得突破性发现， 下一代癌症治疗的发展。 !

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. !