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

基本信息

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
项目类别：
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

项目摘要

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）：最近出现了癌症代谢，在癌症发育和耐药性中发挥重要作用。参与癌症代谢的关键调节剂是丝氨酸/苏氨酸激酶LKB1。它在癌症抑制和促进中表现出“双刃剑”的作用，并与另外两种蛋白质形成异三聚体配合物，即假子酶Strad和脚手架蛋白MO25。 LKB1与这两种蛋白质的结合促进并稳定LKB1的活化构象。尽管已显示LKB1在调节癌症发展中起着至关重要的作用，但如何调节LKB1激活和活性的定义很差。我们的初步结果揭示了一种新的机制，通过该机制维持LKB1激酶活性。我们显示LKB1激酶活性受致癌性SKP2的阳性调节，该致癌性SKP2与SKP1，CUL-1和RBX1形成SCF复合物，构成E3连接酶。有趣的是，我们发现SKP2是LKB1的直接E3连接酶，LKB1活性需要SKP2介导的LKB1泛素化。我们假设LKB1的K63连接的泛素化对于维持LKB1-STRAD-MO25复合物的完整性至关重要，从而调节LKB1激活。这项研究的目的是测试这一假设模型，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特定目标来检验中心假设。目的1。表征LKB1在LKB1活性中SKP2介导的K63连接泛素化的作用。理由。目标2。确定LKB1在调节Akt信号激活中的作用。 AIM 3。探索致癌功能中SKP2和LKB1之间的相互作用。总而言之，我们的研究有一些新颖的发现，具有重要的临床意义。首先，我们首次表明LKB1 I对LKB1激酶活性至关重要的K63连接的泛素化。其次，我们发现响应于EGF的致癌Akt激活需要LKB1，从而为致癌Akt激活提供了洞察力和范式。第三，我们表明SKP2 E3连接酶是LKB1的E3连接酶，这对于LKB1激活至关重要。第四，我们的研究可以通过激活LKB1-AMPK-ACC途径来提供一种新颖的洞察力和机制在细胞转化和肿瘤发生中。最后，我们的研究不仅可能揭示了LKB1在肿瘤维持中的新型致癌功能和机制，而且还有助于将LKB1-AMPK鉴定为预防癌症预防和干预的潜在治疗靶标。