Regulation of oncogenic Akt ubiquitination and activation by diverse mechanisms in cancer

癌症中多种机制对致癌 Akt 泛素化和激活的调节

• 批准号: 10302409
• 负责人: Hui-Kuan Lin
• 金额: $ 49.86万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10302409
• 关键词: Address; Automobile Driving; Biochemical; Biological; Biological Process; Cancer Intervention; Cell Proliferation; Complex; Development; Dose; Event; Genetic; Goals; Growth Factor; Human; Insulin-Like Growth Factor I; Knock-in Mouse; Knowledge; Ligase; Link; Malignant Neoplasms; Mediating; Membrane; Metabolism; Methylation; Methyltransferase; Modeling; Modification; Mus; Oncogenic; Organoids; PRKDC gene; Patients; Pharmacology; Phosphorylation; Phosphotransferases; Play; Post-Translational Protein Processing; Process; Proteomics; Regulation; Research; Role; SETDB1 gene; Signal Pathway; Signal Transduction; TRAF6 gene; Technology; Treatment Factor; Tumor-Derived; Ubiquitination; Xenograft procedure; base; cancer initiation; cancer therapy; druggable target; frontier; innovation; insight; mouse model; novel; recruit; side effect; small molecule inhibitor; therapeutic target; tumor; tumor progression; tumor xenograft; tumorigenesis; ubiquitin-protein ligase

Summary The PI3K/Akt signaling is one of most important oncogenic events in human cancers. It regulates many aspects of biological functions including cell proliferation, survival, and metabolism important for cancer initiation and progression. While extensive efforts have been made in the last three decades to understand the downstream effectors responsible for the biological and oncogenic processes regulated by PI3K/Akt signaling, the upstream signals mediating PI3K/Akt signaling activation upon diverse growth factor stimulation is not well understood. Understanding and defining the upstream mechanisms responsible for PI3K/Akt signaling activation will not only provide new insight into how PI3K/Akt signaling activation is orchestrated, but also offer novel paradigms and therapeutic targets for cancer intervention. Although it has been well established that PIP3 is critical for the membrane recruitment and subsequent activation of Akt, our recent studies provide the evidence that Akt undergoes methylation and subsequent non-proteolytic K63-linked ubiquitination, which are crucial for Akt membrane recruitment and subsequent phosphorylation and activation upon stimulation with diverse growth factors, opening up a new frontier for Akt signaling regulation. Of note, we identified SETDB1 as a methyltransferase for Akt K64 methylation and TRAF6 ligase as an upstream E3 ligase triggering K63-linked ubiquitination and activation of Akt, and these events are required for cancer progression. However, the outstanding questions remained to be addressed are how SETDB1 and TRAF6 are activated or recruited to the Akt complex upon growth factor treatment to trigger Akt methylation and subsequent Akt ubiquitination and activation, thus promoting oncogenic processes. The goal of this study is to dissect the upstream regulatory mechanisms by which growth factors activate and recruit SETDB1 and TRAF6 ligase to Akt complex to elicit Akt methylation and subsequent Akt ubiquitination, define the mechanism by which Akt ubiquitination facilitates Akt membrane localization and activation, and finally explore the role of these regulatory modes in cancer development and develop small molecule inhibitors targeting these regulatory mechanisms. Our preliminary results revealed that SETDB1 and TRAF6 undergo novel posttranslational modifications, which are crucial for methylation, ubiquitination and activation of Akt by growth factors and oncogenic activity. We hypothesized that SETDB1 and TRAF6 undergo the novel posttranslational modification upon growth factor treatment, which recruits SETDB1 to the Akt complex and activates TRAF6 E3 ligase to facilitate Akt methylation and subsequent Akt ubiquitination and activation, thus leading to tumorigenesis. Our innovative hypothesis has been formulated based on our preliminary results and prior research. We proposed three specific aims to validate this provocative and paradigm-shifting concept using cutting-edge technologies including xenograft, organoids from genetic mouse tumor models and patient derived tumors, patient-derived models (PDX), knockin mouse models, genetic mouse tumor models and pharmacological approaches. This application is significant, therefore, because it is expected to provide the knowledge needed to develop pharmacologic strategies that will allow concurring cancers with aberrant PI3K/Akt activation. Our study will open up a new avenue for PI3K/Akt signaling regulation, but also offer new concepts and strategies for cancer targeting.

概括 PI3K/AKT信号传导是人类癌症中最重要的致癌事件之一。它规范了许多方面 生物学功能，包括细胞增殖，生存和代谢对于癌症开始和代谢 进展。在过去的三十年中，已经做出了广泛的努力，以了解下游 负责由PI3K/AKT信号调节的生物学和致癌过程，上游 在不同生长因子刺激时介导PI3K/AKT信号激活的信号尚不清楚。 理解和定义负责PI3K/AKT信号激活的上游机制不会 仅提供有关PI3K/AKT信号激活如何精心策划的新见解，但也提供新颖的范例 和癌症干预的治疗靶标。尽管已经确定PIP3对 膜募集和随后的AKT激活，我们最近的研究提供了AKT的证据 经过甲基化和随后的非蛋白水解K63连接的泛素化，这对于Akt至关重要 膜募集以及随后的磷酸化和激活，刺激随着不同的生长而激活 因素，为AKT信号调节打开了新的边界。值得注意的是，我们将setDB1确定为 Akt K64甲基化和TRAF6连接酶的甲基转移酶作为上游E3连接酶触发K63连接的上游E3连接酶 AKT的泛素化和激活，以及这些事件是癌症进展所必需的。但是， 尚待解决的问题是如何将SetDB1和TRAF6激活或招募到 Akt复合物进行生长因子处理以触发Akt甲基化和随后的Akt泛素化和 激活，从而促进致癌过程。这项研究的目的是剖析上游调节 生长因子激活和募集setDB1和traf6连接酶的机制引起了Akt复合物 Akt甲基化和随后的Akt泛素化，定义了Akt泛素化的机制 促进AKT膜的定位和激活，最后探讨这些调节模式在 癌症发展并发展针对这些调节机制的小分子抑制剂。我们的 初步结果表明，setDB1和traf6经历了新的翻译后修饰，这是 对于生长因子和致癌活性，对Akt的甲基化，泛素化和激活至关重要。我们 假设SetDB1和Traf6在生长因子上进行了新的翻译后修饰 治疗，将SETDB1募集到AKT复合物并激活TRAF6 E3连接酶以促进Akt 甲基化以及随后的Akt泛素化和激活，从而导致肿瘤发生。我们的创新性 假设是根据我们的初步结果和先前的研究提出的。我们提出了三个 具体旨在使用尖端技术来验证这种挑衅和范式转移概念 包括异种移植物，遗传小鼠肿瘤模型的类器官和患者衍生的肿瘤，患者衍生 模型（PDX），敲击小鼠模型，遗传小鼠肿瘤模型和药理学方法。这 因此，应用是重要的，因为它有望提供开发所需的知识 药理学策略将允许同意具有异常PI3K/AKT激活的癌症。我们的研究愿意 为PI3K/AKT信号法规开放新的途径，但也提供了新的概念和策略 定位。