Modulation of ErbB Signaling

ErbB 信号传导的调制

• 批准号: 6613165
• 负责人: JIE WU
• 金额: $ 29.01万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6613165
• 关键词: athymic mouse; biological signal transduction; cell line; enzyme activity; enzyme induction /repression; enzyme inhibitors; epidermal growth factor; free radical oxygen; gene expression; growth factor receptors; guanine nucleotide binding protein; mitogen activated protein kinase; neoplasm /cancer therapy; paxillin; protein tyrosine phosphatase; site directed mutagenesis; tetracyclines

DESCRIPTION (provided by applicant): The overall goals of this project are to elucidate regulatory mechanisms of ErbB signaling components and to explore these molecules as molecular targets for cancer therapy. SHP2 protein tyrosine phosphatase (PTPase) mediates ErbB-induced Erk mitogen-activated protein (MAP) kinase activation and is involved in cytoskeletal reorganization and cell motility. However, how SHP2 mediates these responses is not well understood. It has been shown that Gab1 is a key SHP2 regulator in epidermal growth factor (EGF)-stimulated cells and that Src and Ras are activated by SHP2, but the mechanisms by which SHP2 activates Src and Ras have not been defined. Two models for SHP2-mediated Src activation are postulated and will be evaluated in Specific Aim I. The involvement of Src in EGF-induced Ras and Erk activation also will be analyzed. In Specific Aim II, the novel small interfering RNA (siRNA) technique for gene knockdown will be developed and used to analyze the role of Gab1, Gab2, and SHP2 in EGF-induced cellular responses. These include Src and Akt/PKB activation, temporal regulation of Ras-MAP kinase activation, gene expression, paxillin dephosphorylation, and cell growth and metastatic properties. Based on our preliminary observations, we postulate that Gab1 and related pleckstrin-homology (PH) domains are novel molecular targets for antagonizing ErbB signaling and PTEN mutation in human cancers. This hypothesis will be evaluated in Specific Aim III using doxycycline-inducible decoy constructs in stable cancer cell lines in vitro and in tumor xenografts. These studies will define a major ErbB and SHP2 signaling mechanism, greatly advance our understanding of the function of Gab proteins, uncover novel targets for molecular intervention of malignant signaling, and stimulate further development of new inhibitors targeting these signaling components for cancer treatment.

描述（由申请人提供）：该项目的总体目标是阐明 ErbB 信号成分的调节机制，并探索这些分子作为癌症治疗的分子靶标。 SHP2 蛋白酪氨酸磷酸酶 (PTPase) 介导 ErbB 诱导的 Erk 丝裂原激活蛋白 (MAP) 激酶激活，并参与细胞骨架重组和细胞运动。然而，SHP2 如何介导这些反应尚不清楚。研究表明，Gab1 是表皮生长因子 (EGF) 刺激细胞中关键的 SHP2 调节因子，并且 Src 和 Ras 被 SHP2 激活，但 SHP2 激活 Src 和 Ras 的机制尚未明确。假设了 SHP2 介导的 Src 激活的两种模型，并将在特定目标 I 中进行评估。还将分析 Src 在 EGF 诱导的 Ras 和 Erk 激活中的参与。在 Specific Aim II 中，将开发用于基因敲除的新型小干扰 RNA (siRNA) 技术，并用于分析 Gab1、Gab2 和 SHP2 在 EGF 诱导的细胞反应中的作用。这些包括 Src 和 Akt/PKB 激活、Ras-MAP 激酶激活的时间调节、基因表达、桩蛋白去磷酸化以及细胞生长和转移特性。根据我们的初步观察，我们假设 Gab1 和相关的 pleckstrin 同源 (PH) 结构域是拮抗人类癌症中 ErbB 信号传导和 PTEN 突变的新分子靶点。这一假设将在特定目标 III 中使用多西环素诱导的诱饵结构在体外稳定癌细胞系和肿瘤异种移植物中进行评估。这些研究将定义主要的 ErbB 和 SHP2 信号传导机制，极大地增进我们对 Gab 蛋白功能的理解，发现恶性信号传导分子干预的新靶点，并刺激针对这些信号传导成分用于癌症治疗的新抑制剂的进一步开发。