Structural and biophysical characterization of Tie receptor/integrin interactions

Tie 受体/整合素相互作用的结构和生物物理特征

• 批准号: 8589369
• 负责人: Annamarie C Dalton
• 金额: $ 3.34万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8589369
• 关键词: Ablation; Adhesions; Adult; Affect; Agonist; Angiogenesis Inhibitors; Angiogenic Switch; Angiopoietin-1; Angiopoietin-2; Angiopoietins; Area; Binding; Biochemical; Biological; Blood capillaries; Cell Surface Receptors; Cell Survival; Cell physiology; Cells; Cellular Membrane; Co-Immunoprecipitations; Complex; Conflict (Psychology); Confocal Microscopy; Cryoelectron Microscopy; Crystallography; Cues; Cytoplasm; Development; Electron Microscopy; Endothelial Cells; Environment; Eph Family Receptors; Ephrins; Extracellular Domain; Extracellular Matrix; Family; Fibronectins; Fluorescence Resonance Energy Transfer; Genetic; Goals; Growth Factor; Growth Factor Receptors; Growth and Development function; Human; Imaging Techniques; Integrin Binding; Integrins; Knowledge; Learning; Life; Ligands; Mediating; Membrane; Methods; Modeling; Molecular; Nature; Neoplasm Metastasis; Pathologic Neovascularization; Phosphorylation; Process; Receptor Activation; Receptor Protein-Tyrosine Kinases; Regulation; Reporting; Research; Resolution; Role; Signal Transduction; Solid Neoplasm; Stimulus; Structure; Therapeutic; Therapeutic Human Experimentation; Tyrosine Kinase Domain; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vitronectin; Wound Healing; angiogenesis; base; capillary; cellular imaging; extracellular; interest; migration; prevent; public health relevance; receptor; response; success; therapeutic target; tumor; tumor growth; vasculogenesis

DESCRIPTION: Pathological angiogenesis is an essential component of tumor growth, development, and metastasis for which few therapeutic options exist. Although a great deal about angiogenesis has been learned over the past several decades, it remains unclear how integral membrane receptors cooperate with one another to influence cellular signaling in response to extracellular cues. Two important families of receptors in angiogenesis, the Ties and Integrins, respond to the extracellular environment via outside-in and, in the case of Integrins, inside- out signaling. Recently, it was reported that the endothelial specific tyrosine kinase receptor, Tie2, forms complexes with two of the endothelial Integrins heterodimers, ¿5¿1 and ¿v¿3, providing a convenient clarification for the integration of extracellular stimuli. However, our preliminary studies suggest that Integrins bind to both Tie1 and Tie2 on the cellular membrane, and that binding occurs strictly through the extracellular domains. To elucidate the biological role of these interactions, biochemical and biophysical methods including co-immunoprecipitation, confocal microscopy, and FRET will be used to follow receptor/Integrin association in response to the Tie2 ligands Angiopoietin-1 and -2 as well as the Integrin ligands fibronectin, and vitronectin. Furthermore, structural determination either through x-ray crystallography or cryo-electron microscopy of an Integrin/Tie complex will identify the basis for growth factor receptor-integrin signal transduction.

描述：病理性血管生成是肿瘤生长、发展和转移的一个重要组成部分，目前几乎没有治疗选择。虽然在过去的几十年里已经了解了很多关于血管生成的知识，但仍然不清楚整合的膜受体如何相互合作以影响细胞信号传导以响应细胞外信号。血管生成中两个重要的受体家族，即Tie和整联蛋白，通过由外向内的信号传导响应细胞外环境，并且在整联蛋白的情况下，通过由内向外的信号传导响应细胞外环境。最近，据报道，内皮特异性酪氨酸激酶受体Tie 2与两种内皮整合素异二聚体<$5 <$1和<$v <$3形成复合物，为细胞外刺激的整合提供了方便的解释。然而，我们的初步研究表明，整合素结合Tie 1和Tie 2的细胞膜上，并严格通过细胞外结构域发生的结合。为了阐明这些相互作用的生物学作用，将使用生物化学和生物物理学方法，包括免疫共沉淀、共聚焦显微镜和FRET来跟踪响应于Tie 2配体血管生成素-1和-2以及整合素配体纤连蛋白和玻连蛋白的受体/整合素缔合。此外，通过整联蛋白/Tie复合物的X射线晶体学或冷冻电子显微镜的结构测定将鉴定生长因子受体-整联蛋白信号转导的基础。