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

破译泛素化和磷酸化途径之间的生理作用和相互作用，以指导靶向癌症治疗

• 批准号: 10240580
• 负责人: Wenyi Wei
• 金额: $ 105万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10240580
• 关键词: Acetylation; Alternative Splicing; Antineoplastic Agents; Attention; Award; Biochemical Genetics; Biological Markers; Cell Cycle; Cell Cycle Regulation; Cell physiology; Cellular Metabolic Process; Complex; Cullin Proteins; Development; Disease; Drug Targeting; Enzymes; Event; FRAP1 gene; Functional disorder; Genes; Goals; Heart; Human; Human Genome; Laboratories; Lead; Light; Malignant Neoplasms; Mediating; Methylation; Modification; Molecular; Multienzyme Complexes; Oncogenic; Pathologic; Pathway interactions; Phosphorylation; Phosphotransferases; Physiological; Post-Translational Protein Processing; Proteins; Proteome; Research; Resources; Role; Signal Pathway; Signal Transduction; Therapeutic; Ubiquitination; base; career; cell type; combat; genetic approach; human disease; in vivo; inhibitor/antagonist; innovation; insight; new therapeutic target; next generation; novel; novel therapeutic intervention; novel therapeutics; programs; proteostasis; targeted cancer therapy; tumor; tumorigenesis; ubiquitin-protein ligase

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. !

抽象的 在人类基因组中鉴定的25,000个基因中的绝大多数受到替代剪接，并且 他们的蛋白质产品通常经过翻译后修饰，包括但不限于 泛素化，磷酸化，甲基化和乙酰化，从而大大增加了功能多样性 人类蛋白质组。但是，因蛋白质修饰失调引起的异常细胞信号传导事件 通常会导致蛋白质稳态和细胞功能改变，以促进人类疾病的发展 包括癌症。与这些修饰有关肿瘤发生的关键作用，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标。为此，我的实验室的核心一直专注于研究 两种主要多组分蛋白酶的调节机制和生理功能 复合物：基于库林的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通路的相互作用，以控制细胞周期调节和 肿瘤发生。我的研究计划的长期目标是了解异常细胞信号通路 包括磷酸化和泛素化会影响肿瘤发生，这引导了新型的鉴定 治疗人类癌的药物靶标。在过去的十三年中，我的实验室有 在细胞周期和癌症信号传导中建立了原始，尖端研究的杰出记录 字段。在此提案中，我通过进一步破译泛素化在调节中的作用来扩展我们的研究 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，从而提供机械洞察力和发展抑制剂的理由 针对包括E3连接酶和激酶在内的细胞信号通路的关键模块，以增强我们的能力 产生高度针对性的癌症疗法。为了实现这些目标，一个主要主题是使用两种生化 以及了解SKP2的致癌作用以及FBW7在 通过泛素化介导的途径调节细胞代谢的一部分。第二个主要主题 建议旨在研究Gator2介导的泛素化的生理和病理影响 Gator1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性 针对这些信号通路的机会。因此，这个享有声望的奖项将为我们提供 使用高度创新的方法来解决诸如理解之类的挑战性问题的必要资源 肿瘤发生的分子和细胞机制揭示了靶向癌症的新途径 更有效。在我职业的这个阶段获得这一享有声望的奖项，我的实验室可以 更多地专注于创新的实验室研究，以继续使突破性发现产生影响 下一代癌症治疗剂的发展。 呢