SIGNAL TRANSDUCTION BY THE EGF RECEPTOR

EGF 受体的信号转导

• 批准号: 2099083
• 负责人: Roger J Davis
• 金额: $ 20.15万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-02-01 至 1997-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2099083
• 关键词: SDS polyacrylamide gel electrophoresis; biological signal transduction; epidermal growth factor; growth factor; growth factor receptors; laboratory mouse; laboratory rabbit; phosphorylation; protein kinase; receptor sensitivity; western blottings

The overall goal of this research program is to understand the process of signal transduction by the epidermal growth factor (EGF) receptor. A specific focus of this proposal is to define the mechanism and significance of the phosphorylation of the EGF receptor at the negative regulatory site Ser (1046/7). It is anticipated that this research will add significant new information to two different areas of basic research in cell biology: 1)signal transduction by growth factor receptors; and 2) the molecular mechanism of receptor desensitization. Progress in this research will increase the understanding of the mechanisms that account for the increased cellular proliferation caused by growth factors. This information represents a basis for the design of rational therapeutic strategies for the control of proliferative diseases of epithelial tissues such as cancer of the cervix and breast. There are four Specific Aims: 1. To identify growth factor-stimulated protein kinases that cause the phosphorylation of the EGF receptor at Ser-1046/7. The molecular mechanism that accounts for the EGF-stimulated phosphorylation of the EGF receptor at Ser (1046/7) has not been established. The focus of this specific aim is to define the mechanism by which growth factors regulate the phosphorylation state of the EGF receptor at this site. 2. To test the hypothesis that the phosphorylation of the EGF receptor at Ser-1046/7 causes desensitization of EGF receptor signal transduction. Increased phosphorylation of the EGF receptor at Ser (1046/7) has been shown to correlate with EGF receptor desensitization. We will examine whether there is a causal relationship between EGF receptor phosphorylation at Ser (1046/7) and the process of desensitization. 3. To investigate the physiological significance of EGF receptor desensitization during signal transduction. Rapid desensitization of the EGF receptor occurs when cultured cells are incubated with low mitogenic concentrations of EGF. However, the biological significance of receptor desensitization during EGF-stimulated cellular proliferation has not been established. We shall test the hypothesis that receptor desensitization is relevant to the process of signal transduction in EGF-treated cells. 4. To test the hypothesis that the association of signalling molecules with the EGF receptor is regulated by phosphorylation at Ser-1046/7. The phosphorylation site Ser(1046/7) is located within an important effector domain at the COOH terminus of the EGF receptor that: a) binds to signalling molecules; and b) is required for signal transduction. We shall test the hypothesis that Ser(1046/7 phosphorylation regulates the association of proteins with the EGF receptor.

该研究计划的总体目标是了解过程 表皮生长因子（EGF）受体的信号转导。 该提案的一个具体重点是定义机制和 EGF受体在阴性的磷酸化的重要性 监管地点SER（1046/7）。 预计这项研究将会 在基础研究的两个不同领域中添加重要的新信息 在细胞生物学中：1）生长因子受体转导信号；和 2）受体脱敏的分子机制。 进步 研究将增加对说明机制的理解 对于由生长因子引起的细胞增殖增加。 这 信息代表了设计理性治疗的基础 控制上皮疾病的策略 诸如子宫颈癌和乳腺癌之类的组织。 有四个特定 目标： 1。确定生长因子刺激的蛋白激酶 在Ser-1046/7处EGF受体的磷酸化。 分子 解释了EGF的EGF刺激磷酸化的机制 Ser（1046/7）的受体尚未建立。 重点 具体目的是定义生长因素调节的机制 EGF受体在该部位的磷酸化状态。 2。检验EGF受体磷酸化的假设 在Ser-1046/7处导致EGF受体信号转导脱敏。 在SER（1046/7）处EGF受体的磷酸化增加已有 显示与EGF受体脱敏相关。 我们将检查 EGF受体之间是否存在因果关系 SER（1046/7）和脱敏过程。 3。研究EGF受体的生理意义 信号转导期间脱敏。 快速脱敏的 当培养的细胞与低丝分裂性孵育时，EGF受体发生 EGF的浓度。 但是，受体的生物学意义 在EGF刺激的细胞增殖过程中脱敏 已确立的。 我们应检验以下假设：受体脱敏 与EGF处理的细胞中信号转导的过程有关。 4。检验信号分子缔合的假设 用EGF受体在Ser-1046/7处受磷酸化调节。 这 磷酸化位点Ser（1046/7）位于重要的效应器中 EGF受体的COOH末端的域：a）与 信号分子； b）信号转导需要。 我们 应检验Ser的假设（1046/7磷酸化调节 蛋白质与EGF受体的关联。