THE ROLE OF NEDD4-1 IN IGF-1R SIGNALING

NEDD4-1 在 IGF-1R 信号转导中的作用

• 批准号: 8316173
• 负责人: Junran Zhang
• 金额: $ 32.58万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-08 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316173
• 关键词: Binding; Biological Markers; Cancer Cell Growth; Cancer Patient; Cell Proliferation; Cell Survival; Cell physiology; Cells; Clinical Trials; Cultured Cells; DNA; Data; Development; Drug Delivery Systems; Embryonic Development; Fc Receptor; Goals; Growth; Guidelines; Human; Insulin-Like Growth Factor I; Knock-out; Knowledge; Ligase; Maintenance; Malignant Neoplasms; Metabolism; Modeling; Molecular; Mus; Oncogenic; Outcome; PTEN gene; Phosphorylation; Play; Proteins; Receptor Inhibition; Receptor Signaling; Regulation; Research; Role; SS DNA BP; Screening procedure; Signal Pathway; Signal Transduction; Testing; Ubiquitination; Work; Xenograft Model; base; cancer cell; cancer therapy; cell growth; improved; insight; new therapeutic target; novel; novel strategies; overexpression; protein expression; receptor; replication factor A; response; treatment planning; tumor; tumorigenesis

DESCRIPTION (provided by applicant): NEDD4-1 is an E3 ubiquitination ligase that is frequently over-expressed in human cancers. NEDD4-1 plays an important role in tumorigenesis. Although it has been suggested that NEDD4-1 functions as an oncogenic protein by facilitation of Akt activation, the molecular mechanisms by which NEDD4-1 activates Akt remain largely unknown. We found that NEDD4-1 activates Akt via regulation of IGF-1R signaling. Strikingly, we also found that activation of Akt by NEDD4-1 is negatively regulated by replication protein A (RPA), a single strand DNA (ssDNA) binding protein which is generally believed to play a critical role in DNA metabolism. Thus, we are proposing a study to test the central hypothesis that NEDD4-1 plays a role in cell proliferation via activation of IGF-1R signaling and this pathway is inhibited by RPA. Therefore, growth of cells overexpressing NEDD4-1 is specifically suppressed by IGF-1R inhibition through IGF-1R antibody and/or RPA. Three interrelated specific aims are proposed to test our hypothesis. Aim 1 will identify the role of NEDD4-1 in cell proliferation via regulation of IGF-1R signaling. Aim 2 will delineate how NEDD4-1 dependent IGF-1R signaling is regulated by RPA. Aim 3 will determine the antitumor activity of blocking IGF-1R signaling in cells over-expressing NEDD4-1. We anticipate to (1) define the molecular mechanisms by which NEDD4-1 promotes cell proliferation via regulation of IGF-1R signaling; (2) identify a novel function of RPA in suppression of IGF-1R signaling via interaction with NEDD4-1; (3) find that the growth of cancer cells over-expressing NEDD4-1 can be specifically targeted by IGF-1R inhibition through RPA and/or IGF-1R antibody. The expected results will fundamentally advance our understanding of the molecular mechanism underlying NEDD4-1 associated cancer development. In addition, identification of a novel function of RPA in suppression of IGF-1R signaling will facilitate the development of novel drugs targeting NEDD4-1 or IGF-1R. Moreover, the expected result will improve guidance for cancer treatment plans based on better predictions of tumor response to IGR-1R inhibition by identification of cancer patients with NEDD4-1 over-expression.

描述（由申请人提供）：NEDD4-1 是一种 E3 泛素化连接酶，在人类癌症中经常过度表达。 NEDD4-1在肿瘤发生中发挥重要作用。尽管有人认为 NEDD4-1 通过促进 Akt 激活而发挥致癌蛋白的作用，但 NEDD4-1 激活 Akt 的分子机制仍然很大程度上未知。我们发现 NEDD4-1 通过调节 IGF-1R 信号传导激活 Akt。引人注目的是，我们还发现 NEDD4-1 对 Akt 的激活受到复制蛋白 A (RPA) 的负调控，RPA 是一种单链 DNA (ssDNA) 结合蛋白，通常被认为在 DNA 代谢中发挥着关键作用。因此，我们提出一项研究来检验中心假设，即 NEDD4-1 通过激活 IGF-1R 信号传导在细胞增殖中发挥作用，并且该途径被 RPA 抑制。因此，过表达NEDD4-1的细胞的生长通过IGF-1R抗体和/或RPA被IGF-1R抑制特异性抑制。提出了三个相互关联的具体目标来检验我们的假设。目标 1 将确定 NEDD4-1 通过调节 IGF-1R 信号传导在细胞增殖中的作用。目标 2 将描述 RPA 如何调节 NEDD4-1 依赖性 IGF-1R 信号传导。目标 3 将确定在过度表达 NEDD4-1 的细胞中阻断 IGF-1R 信号传导的抗肿瘤活性。我们期望 (1) 定义 NEDD4-1 通过调节 IGF-1R 信号传导促进细胞增殖的分子机制； (2) 鉴定 RPA 通过与 NEDD4-1 相互作用抑制 IGF-1R 信号传导的新功能； (3)发现过表达NEDD4-1的癌细胞的生长可以通过RPA和/或IGF-1R抗体特异性抑制IGF-1R。预期结果将从根本上增进我们对 NEDD4-1 相关癌症发展分子机制的理解。此外，鉴定 RPA 在抑制 IGF-1R 信号传导方面的新功能将有助于开发针对 NEDD4-1 或 IGF-1R 的新药物。此外，预期结果将通过识别 NEDD4-1 过度表达的癌症患者来更好地预测肿瘤对 IGR-1R 抑制的反应，从而改善对癌症治疗计划的指导。