Role of the Shp-2 tyrosine phosphatase in signal transdu

可逆性酪氨酸磷酸化是细胞调节中的一个重要生化事件，由蛋白酪氨酸激酶(PTKs)和蛋白酪氨酸磷酸酶(PTPs)的相反活性控制。然而，与PTK的广泛关注相比，人们对PTP的调节机制和功能知之甚少。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研究表明，SHP-2参与了不同的信号通路，在细胞生长、分化、迁移和死亡的控制中起着积极或消极的调节作用。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)的活性。然而，PTP如何正向作用于受体PTK下游以增强ERK活性的诱导仍是一个谜。我们的最新数据提出了一个新的观点，即SHP-2与GAB1支架蛋白在多聚体蛋白复合体中协同工作，促进表皮生长因子激活Ras-Raf-MEK-ERK级联反应。在这次R29资助的竞争性更新中，我们建议通过鉴定其特定底物来确定SHP-2在RAS-ERK激活中作用的生化基础(S)。我们将进一步研究SHP-2在细胞质信号传递中的生理作用，特别是在RAS通路信息流的调节中，我们还将确定SHP-2蛋白的磷酸酶依赖和独立活性。最后，我们将确定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是如何被调控的，以及PTP活动是如何在细胞内信号传递过程中被执行的。

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.