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Molecular mechanisms of Tie2/Angiopoietin signaling initiation

Tie2/血管生成素信号传导启动的分子机制

基本信息

批准号：
9321086
负责人：
DIMITAR B NIKOLOV
金额：
$ 44.81万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9321086
关键词：
Agonist Angiopoietin-2 Angiopoietins Binding Biochemical Biological Biological Assay Biophysics Cell Line Cell surface Cells Characteristics Chemicals Complement Complex Crystallization Data Engineering Event Fluorescence Resonance Energy Transfer Glycoproteins Goals Individual Insecta Integrins Kinetics Length Ligands Ligation Lymphatic System Maintenance Mediating Mediator of activation protein Methods Molecular Monitor Phosphotransferases Play Production Property Protein Tyrosine Kinase Proteins Receptor Protein-Tyrosine Kinases Role Signal Transduction Spectrum Analysis Structure Surface System TIE-2 Receptor Techniques Thermodynamics Transmembrane Domain Vascular System Work X-Ray Crystallography analytical ultracentrifugation angiogenesis base biological systems biophysical analysis experimental study extracellular in vivo microcalorimetry milligram overexpression receptor

项目摘要

Abstract The angiopoietins are a small class of secreted glycoproteins that play key roles in the maturation and maintenance of the mammalian vascular and lymphatic systems. They exert their effects through the Tie receptor tyrosine kinases. All four angiopoietins (Ang1-4) directly bind Tie2, while none of them binds the related Tie1, although the latter has been shown to modulate the Ang/Tie2 signaling. Integrins, and in particular a5b1, are involved in regulating Ang1-dependent angiogenesis and were shown to directly interact with Tie2. The Ang/Tie signaling is unique among receptor kinase-ligand systems in that distinct angiopoietin ligands, although all highly homologous, may function as agonist or antagonist in a context dependent manner. A detailed understanding of the mechanisms of Angiopoietin/Tie signaling and their precise function during angiogenesis requires a comprehensive structural and biophysical analysis of the angiopoietins, of the Tie receptors and their co-receptors, as well as of their interactions. We will use X-ray crystallography, combined with other biophysical, biochemical and cell-biological techniques, to study these molecules. We have previously determined the structures of Tie2, Ang1, Ang2, as well as of the Tie2/Ang1 and Tie2/Ang2 complexes, revealing important and unique characteristics of Tie2 signaling initiation. We also performed FRET-based studies on live cells to monitor the Tie1/Tie2 interactions on the cell surface. An important conclusion of our experiments is that the distinct signaling properties of the individual angiopoietins are likely the result of Tie2 co-receptors that respond differently to the different ligands. Therefore, we now propose to study the molecular mechanisms by which co-receptors modulate, in a regulated and cell/context-dependent manner, the Ang/Tie2 signaling events. We specifically propose to investigate the roles of Tie1 and intergrin a5b1. Finally, our ultimate goal is to determine crystal structures of the complete Tie2 receptor, including its transmembrane region, alone and in complex with ligands and co- receptors, and we will work on the production and structural characterization of functional full-length Tie proteins. + PHS 398/2590 (Rev. 05/01)

抽象的血管生成素是一小类分泌性糖蛋白，在成熟过程中发挥关键作用和维持哺乳动物血管和淋巴系统。他们通过以下方式发挥作用领带受体酪氨酸激酶。所有四种血管生成素 (Ang1-4) 均直接结合 Tie2，而它们均不结合相关的 Tie1，尽管后者已被证明可以调节 Ang/Tie2 信号传导。整合素，并且在特别是 a5b1，参与调节 Ang1 依赖性血管生成，并被证明可以直接与 Tie2 互动。 Ang/Tie 信号传导在受体激酶-配体系统中是独一无二的，因为血管生成素配体虽然都高度同源，但在一定情况下可以充当激动剂或拮抗剂依赖方式。详细了解血管生成素/Tie信号传导机制及其作用血管生成过程中的精确功能需要对血管进行全面的结构和生物物理分析血管生成素、Tie 受体及其共受体及其相互作用。我们将使用X射线晶体学结合其他生物物理、生物化学和细胞生物学技术来研究这些分子。我们之前已经确定了 Tie2、Ang1、Ang2 以及 Tie2/Ang1 的结构和 Tie2/Ang2 复合物，揭示了 Tie2 信号传导起始的重要且独特的特征。我们还对活细胞进行了基于 FRET 的研究，以监测细胞表面的 Tie1/Tie2 相互作用。我们实验的一个重要结论是，个体的独特信号特性血管生成素可能是 Tie2 辅助受体对不同配体有不同反应的结果。因此，我们现在建议研究共受体调节的分子机制， Ang/Tie2 信号传导事件以受调节和细胞/环境依赖性的方式进行。我们特别建议研究 Tie1 和整合素 a5b1 的作用。最后，我们的最终目标是确定晶体结构完整的 Tie2 受体，包括其跨膜区域，单独的以及与配体和共体的复合物受体，我们将致力于功能性全长 Tie 的生产和结构表征蛋白质。 + PHS 398/2590（修订版 05/01）