Role of the Shp-2 tyrosine phosphatase in signal transdu

Shp-2 酪氨酸磷酸酶在信号转导中的作用

• 批准号: 6758525
• 负责人: Gen-Sheng Feng
• 金额: $ 38.03万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-03-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6758525
• 关键词: biological signal transduction; cell growth regulation; cell transformation; cell type; enzyme activity; epidermal growth factor; extracellular matrix; genetically modified animals; growth factor receptors; immunoaffinity chromatography; immunoprecipitation; laboratory mouse; mitogen activated protein kinase; northern blottings; phosphorylation; polymerase chain reaction; protein structure function; protein tyrosine kinase; protein tyrosine phosphatase; tissue /cell culture; western blottings

Reversible tyrosine phosphorylation, a major biochemical event in cell regulation, is controlled by the opposing activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). However, relatively little is known about the mechanism for regulation and functions of PTPs, as compared to the extensive attention received for PTKs. The goal of this project is to determine the role of Shp-2, a PTP with two src-homology 2 (SH2) domains, in intracellular signal transduction. Work from this laboratory and others implicates the involvement of Shp-2 in different signaling pathways as a positive or a negative regulator in the control of cell growth, differentiation, migration and death. In particular, Shp-2 acts to promote growth factor stimulation of extracellular signal regulated kinase (ERK) activity. However, it remains a mystery how a PTP can act positively downstream of a receptor PTK to enhance the induction of ERK activity. Our most recent data present a fresh view that Shp-2 works in concert with Gab1 scaffold protein in a multimeric protein complex, in promoting the activation of the Ras-Raf-MEK-ERK cascade by epidermal growth factor. In this competitive renewal of the previously funded R29 grant, we propose to determine the biochemical basis for Shp-2 function in Ras-ERK activation by identifying its specific substrate(s). We will further investigate the physiological role of Shp-2 in cytoplasmic signaling, particularly in the modulation of information flow along the Ras pathway, and we will also determine the phosphatase-dependent and independent activities of the Shp-2 protein. Finally, we will define the biological function of Shp-2 in different cell types. Results from this study will allow us understand better how PTPs are regulated and how PTP activities are executed during intracellular signal relay in general.

可逆酪氨酸磷酸化是细胞调节中的一个主要生化事件，由蛋白酪氨酸激酶 (PTK) 和蛋白酪氨酸磷酸酶 (PTP) 的相反活性控制。 然而，与 PTK 受到的广泛关注相比，人们对 PTP 的调节和功能机制知之甚少。 该项目的目标是确定 Shp-2（一种具有两个 src 同源 2 (SH2) 结构域的 PTP）在细胞内信号转导中的作用。 该实验室和其他实验室的工作表明，Shp-2 作为控制细胞生长、分化、迁移和死亡的正调节剂或负调节剂参与不同的信号传导途径。 特别是，Shp-2 可以促进生长因子刺激细胞外信号调节激酶 (ERK) 活性。 然而，PTP 如何在受体 PTK 下游发挥积极作用以增强 ERK 活性的诱导仍然是一个谜。 我们最新的数据提出了一个新的观点：Shp-2 与多聚蛋白复合物中的 Gab1 支架蛋白协同作用，促进表皮生长因子激活 Ras-Raf-MEK-ERK 级联。 在对先前资助的 R29 资助的竞争性更新中，我们建议通过识别其特定底物来确定 Ras-ERK 激活中 Shp-2 功能的生化基础。 我们将进一步研究Shp-2在细胞质信号传导中的生理作用，特别是在Ras途径信息流的调节中，我们还将确定Shp-2蛋白的磷酸酶依赖性和非依赖性活性。 最后，我们将定义Shp-2在不同细胞类型中的生物学功能。 这项研究的结果将使我们更好地了解 PTP 是如何调节的以及 PTP 活动在细胞内信号传递过程中是如何执行的。