Nck and Crk in VEGF-Induced Endothelial Cells Migration

Nck 和 Crk 在 VEGF 诱导的内皮细胞迁移中的作用

• 批准号: 7554653
• 负责人: Dianne Cox
• 金额: $ 27.98万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7554653
• 关键词: Actins; Angiogenesis Inhibition; Angiogenic Factor; Animal Model; Attention; Binding; Blood capillaries; Cardiovascular Diseases; Cell Adhesion; Cell surface; Cell-Matrix Junction; Cells; Complex; Data; Development; Diabetic Retinopathy; Docking; Dominant-Negative Mutation; Endothelial Cells; F-Actin; FRS2 gene; Focal Adhesions; Goals; Guanosine Triphosphate Phosphohydrolases; Lead; Mediating; Molecular; Mutagenesis; Neoplasm Metastasis; Pathologic; Play; Process; Proteins; Psoriasis; Recruitment Activity; Rheumatoid Arthritis; Role; Scaffolding Protein; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Site; Vascular Endothelial Growth Factors; angiogenesis; antiangiogenesis therapy; cell motility; cofilin; depolymerization; inhibitor/antagonist; migration; new growth; p21 activated kinase; polymerization; receptor; research clinical testing; response; therapeutic angiogenesis; tissue regeneration; tumor growth

DESCRIPTION (provided by applicant): The growth of new blood capillaries from existing vessels (angiogenesis) is essential for development, tissue regeneration and remodeling. Angiogenesis also contributes to pathologic conditions including tumor growth and metastasis, diabetic retinopathy, rheumatoid arthritis, psoriasis, and cardiovascular diseases. Vascular Endothelial Growth Factor (VEGF) is a critical pro-angiogenic factor that stimulates multiple signal transduction pathways through binding to its receptor KDR. VEGF has received attention as a target for angiogenesis inhibition for several reasons, including the observations that blocking VEGF's actions by several experimental approaches inhibits the growth of tumors in animal models. Endothelial cell migration is a crucial step in angiogenesis; however, the cellular mechanisms that mediate this process remain unclear. Our preliminary data indicate that the cell signaling proteins Nck and Crk play important roles in VEGF-induced cell migration. Both proteins are recruited to KDR after VEGF treatment, although their interaction with receptor is indirect and mediated by the FRS2 scaffolding protein. The introduction of dominant negative (DN) inhibitors of Crk or Nck into endothelial cells has dramatic effects on VEGF-induced responses related to migration. The DNs inhibit focal complex turnover as they lead to a loss in the formation of new focal complexes and a significant increase in the size of existing focal complexes. This is accompanied by a loss in cell adhesion. The DNs also blocked VEGF-induced changes in F-actin dynamics. We plan to continue these studies by proposing three Specific Aims. AIM1 focuses on clarifying molecular aspects of how Nck and Crk are recruited to the cell surface after VEGF treatment. AIM 2 examines in detail the signaling pathway by which Nck regulates cell migration. AIM 3 asks how Crk functions in VEGF-induced cell migration.

描述（由申请人提供）：现有血管（血管生成）新血液毛细血管的生长对于发展，组织再生和重塑至关重要。血管生成还导致病理疾病，包括肿瘤生长和转移，糖尿病性视网膜病，类风湿关节炎，牛皮癣和心血管疾病。血管内皮生长因子（VEGF）是关键的促血管生成因子，通过与其受体KDR结合来刺激多个信号转导途径。 VEGF因几个原因而受到关注，作为血管生成抑制的靶标，包括通过几种实验方法阻止VEGF的作用的观察结果抑制了动物模型中肿瘤的生长。 内皮细胞迁移是血管生成的关键步骤。但是，介导该过程的细胞机制尚不清楚。我们的初步数据表明，细胞信号蛋白NCK和CRK在VEGF诱导的细胞迁移中起重要作用。 VEGF治疗后两种蛋白质都募集到KDR，尽管它们与受体的相互作用是间接的，并由FRS2脚手架蛋白介导。将CRK或NCK的显性负（DN）抑制剂引入内皮细胞中对VEGF诱导的与迁移相关的反应产生了巨大影响。 DNS会抑制局灶性复合物的转换，因为它们导致新焦点复合物的形成损失，并显着增加现有焦点复合物的大小。这伴随着细胞粘附的损失。 DNS还阻止了VEGF诱导的F-肌动力学变化。 我们计划通过提出三个具体目标来继续这些研究。 AIM1的重点是阐明VEGF处理后如何募集NCK和CRK到细胞表面的分子方面。 AIM 2详细检查了NCK调节细胞迁移的信号传导途径。 AIM 3询问CRK在VEGF诱导的细胞迁移中的功能。