Nck and Crk in VEGF-Induced Endothelial Cells Migration

描述（由申请人提供）：现有血管的新毛细血管生长（血管生成）对发育、组织再生和重塑至关重要。血管生成也有助于病理条件，包括肿瘤的生长和转移，糖尿病视网膜病变，风湿性关节炎，牛皮癣和心血管疾病。血管内皮生长因子（Vascular Endothelial Growth Factor， VEGF）是一种重要的促血管生成因子，通过与其受体KDR结合刺激多种信号转导途径。VEGF作为抑制血管生成的靶点受到关注有几个原因，包括观察到通过几种实验方法阻断VEGF的作用可以抑制动物模型中肿瘤的生长。

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.