Novel posttranslational modification in LKB1 activation and cancer development

LKB1 激活和癌症发展中的新型翻译后修饰

• 批准号: 9099782
• 负责人: Hui-Kuan Lin
• 金额: $ 31.13万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9099782
• 关键词: Address; Apoptosis; Autophagocytosis; Binding; Biological Process; Biology; Cancer Patient; Cancer Prevention Intervention; Cell Survival; Cells; Clinical; Complex; Development; Disease; Drug resistance; EGF gene; Fatty Acids; Genetic; Glycolysis; Goals; Growth; Growth Factor Receptors; Health; Insulin-Like Growth Factor I; Lead; Link; Maintenance; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Metabolic stress; Metabolism; Modeling; Molecular; Molecular Conformation; Mus; NADP; Oncogenic; Pathway interactions; Patients; Phosphotransferases; Physiological; Play; Polyubiquitination; Post-Translational Protein Processing; Protein-Serine-Threonine Kinases; Proteins; Receptor Signaling; Research; Role; STK11 gene; Sampling; Scaffolding Protein; Signal Transduction; Staging; Stimulus; Stress; Testing; Therapeutic; Time; Ubiquitination; Xenograft procedure; aerobic glycolysis; cancer cell; cell motility; cell transformation; glucose uptake; in vivo; innovation; insight; liver cancer prevention; malignant breast neoplasm; mouse model; novel; overexpression; response; survival outcome; therapeutic target; tumor; tumor metabolism; tumor progression; tumorigenesis; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Cancer metabolism has recently emerged to play an important role in cancer development and drug resistance. A key regulator involved in cancer metabolism is serine/threonine kinase LKB1. It displays a "double-edged sword" role in cancer suppression and promotion and forms a heterotrimeric complex with two other proteins, the pseudokinase STRAD and the scaffolding protein MO25. Binding of LKB1 to these two protein promotes and stabilizes the activated conformation of LKB1. Although LKB1 has been shown to play a critical role in regulating cancer development, how LKB1 activation and activity are regulated is poorly defined. Our preliminary results revealed a novel mechanism by which LKB1 kinase activity is maintained. We showed LKB1 kinase activity is positively regulated by oncogenic Skp2, which forms a SCF complex with Skp1, Cul-1 and Rbx1 to constitute an E3 ligase. Interestingly, we found that Skp2 is a direct E3 ligase for LKB1, and Skp2-mediated ubiquitination of LKB1 is required for LKB1 activity. We hypothesized that K63-linked ubiquitination of LKB1 is essential for maintaining the integrity of LKB1-STRAD-MO25 complex, thereby regulating LKB1 activation. The goal of this study is to test this hypothetical model and to determine the role of this ubiquitination in cancer development. We will test our central hypothesis by pursuing three specific aims. Aim 1. To characterize the role of Skp2-mediated K63-linked ubiquitination of LKB1 in LKB1 activity. Rationale. Aim 2. To identify the role of LKB1 in regulating Akt signaling activation. Aim 3. To explore the interplays between Skp2 and LKB1 in oncogenic functions. In summary, our study has several novel discoveries with important clinical implications. First, we showed for the first time that K63-linked ubiquitination of LKB1 i critical for LKB1 kinase activity. Second, we found that LKB1 is required for oncogenic Akt activation in response to EGF, thereby providing an insight and paradigm for oncogenic Akt activation. Third, we showed that Skp2 E3 ligase is an E3 ligase for LKB1, which is critical for LKB1 activation. Fourth, our study may offer a novel insight and mechanism for oncogenic Skp2 in cell transformation and tumorigenesis by activating the LKB1-AMPK-ACC pathway. Finally, our study may not only reveal novel oncogenic function and mechanism for LKB1 in tumor maintenance, but also help identify LKB1-AMPK as potential therapeutic targets for cancer prevention and intervention.

描述（由申请人提供）：癌症代谢最近出现在癌症发展和耐药性中发挥重要作用。参与癌症代谢的关键调节因子是丝氨酸/苏氨酸激酶LKB 1。它在癌症抑制和促进中显示出“双刃剑”作用，并与另外两种蛋白质（假激酶STRAD和支架蛋白MO 25）形成异源三聚体复合物。LKB 1与这两种蛋白的结合促进并稳定LKB 1的活化构象。虽然LKB 1已被证明在调节癌症发展中发挥关键作用，但LKB 1的活化和活性如何调节尚不清楚。我们的初步结果揭示了一种新的机制，LKB 1激酶活性的维持。我们发现LKB 1激酶活性受致癌Skp 2的正调控，Skp 2与Skp 1、Cul-1和Rbx 1形成SCF复合物，构成E3连接酶。有趣的是，我们发现Skp 2是LKB 1的直接E3连接酶，并且Skp 2介导的LKB 1遍在蛋白化是LKB 1活性所需的。我们假设K63连接的LKB 1遍在蛋白化对于维持LKB 1-STRAD-MO 25复合物的完整性至关重要，从而调节LKB 1的激活。这项研究的目的是测试这个假设的模型，并确定这种泛素化在癌症发展中的作用。我们将通过追求三个具体目标来检验我们的中心假设。目标1.研究Skp 2介导的K63连接的LKB 1泛素化在LKB 1活性中的作用。理由。目标二。目的：探讨LKB 1在Akt信号转导中的作用。目标3。探讨Skp 2和LKB 1在肿瘤发生中的相互作用。总之，我们的研究有几个具有重要临床意义的新发现。首先，我们首次证明了LKB 1的K63连接的泛素化对LKB 1激酶活性至关重要。其次，我们发现LKB 1是响应EGF的致癌Akt激活所必需的，从而为致癌Akt激活提供了见解和范例。第三，我们发现Skp 2 E3连接酶是LKB 1的E3连接酶，这对LKB 1活化至关重要。第四，我们的研究可能为Skp 2通过激活LKB 1-AMPK-ACC通路参与细胞转化和肿瘤发生提供新的见解和机制。最后，我们的研究不仅可以揭示LKB 1在肿瘤维持中的新的致癌功能和机制，而且有助于确定LKB 1-AMPK作为癌症预防和干预的潜在治疗靶点。