FOCAL ADHESION TYROSINE KINASES AND CELL SIGNALING

局部粘附酪氨酸激酶和细胞信号传导

• 批准号: 6311494
• 负责人: J THOMAS PARSONS
• 金额: $ 1.8万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6311494
• 关键词: affinity chromatography; biological signal transduction; cell adhesion; cell differentiation; cell migration; extracellular matrix; integrins; intermolecular interaction; metabolism; mitogens; oncogenes; protein structure function; protein tyrosine kinase; second messengers; site directed mutagenesis

The long term goals of this revised project are to understand the nature of cellular signalling events mediated by cellular receptors that recognize components of the extracellular matrix and/or other cell surface molecules. We will focus specifically on the role of tyrosine phosphorylation in regulating these pathways, seeking to define the molecular mechanisms by which tyrosine kinases contribute to the regulation and control of such pathways. The proposed experiments build and extend the progress made during the past four years. We have identified a novel protein tyrosine kinase, that is associated with cellular focal adhesions, designated Focal Adhesion Kinase, FAK. Evidence from our own laboratory as well as other has indicated that FAK plays a role in regulating signalling events initiated by interactions of surface integrins with extracellular matrix. In addition, our own studies have demonstrated a stable association of FAK with pp60src in src transformed cells. We outline three specific aims: First, we will define and characterize the mechanisms that lead to activation of FAK in response to engagement of integrins with defined extracellular ligands. These studies will include an analysis of the interaction of FAK with cytoplasmic domains of specific integrins and components of focal adhesions as well as possible functional interactions with proteins that regulate mitogen and hormone activated signal transduction pathways. Second, we will examine the role of FAK in the regulation of the formation and/or breakdown of cellular focal adhesions, in the regulation of other cellular activities (e.g., adhesion, cell spreading, cell migration) and the possible control of second messenger pathways. In these studies we will investigate the phenotypic and biochemical properties of cells expressing variant FAK proteins and attempt to correlate known defects in FAK activity with alterations in cellular metabolism. Finally, we will characterize the function interactions between FAK and pp60src in src transformed cells and extend this paradigm to the analysis of possible interactions of FAK and pp60src or other src family kinases in normal cells. These experiments seek to delineate the role of pp60src in the structural perturbation of focal adhesions in transformed cells and explore the possibility that FAK regulates or is regulated by src family kinases in normal cells.

这个修改后的项目的长期目标是了解 由细胞受体介导的细胞信号事件 识别细胞外基质和/或其他细胞的成分 表面分子。我们将特别关注酪氨酸的作用。 在调节这些通路中的磷酸化，试图定义 酪氨酸激酶参与血管紧张素转换酶的分子机制 对这类途径的调控。建议的实验建立 并延续过去四年取得的进展。我们有 发现了一种新的蛋白酪氨酸激酶，它与 细胞局灶性粘连，指定为粘着斑激酶，FAK。 来自我们自己的实验室以及其他实验室的证据表明，FAK 在调节由交互启动的信令事件方面发挥作用 表面整合素与细胞外基质的结合。此外，我们自己的 研究表明，FAK与src中pp60src之间存在稳定的相关性。 转化的细胞。我们概述了三个具体目标：第一，我们将 定义并描述导致FAK激活的机制 对整合素与确定的细胞外配体的接触的反应。 这些研究将包括分析哥伦比亚革命武装力量与 特定整合素的胞质结构域和焦点组分 粘连以及可能与蛋白质的功能相互作用 调节有丝分裂原和激素激活的信号转导通路。 第二，我们将研究FAK在监管 调节中细胞灶性粘连的形成和/或破坏 其他细胞活动(例如，黏附、细胞扩散、细胞 迁徙)和对第二信使通路的可能控制。在……里面 这些研究我们将调查表型和生化 表达不同FAK蛋白的细胞特性及尝试 FAK活性的已知缺陷与细胞内的变化相关 新陈代谢。最后，我们将描述功能交互的特征 在src转换单元中的fak和pp60src之间，并扩展此范例 对FAK和pp60src或其他src可能相互作用的分析 正常细胞中的家族激酶。这些实验试图描绘出 Pp60src在大鼠局灶性粘连结构扰动中的作用 转化细胞并探索FAK调节或 在正常细胞中受src家族激酶的调节。