VEGF INDUCED SIGNAL TRANSDUCTION

描述：（申请人的描述） 血管生成（新毛细血管的形成）是一个重要的 包括发育在内的几个正常生理过程的组成部分， 伤口愈合 血管生成也有助于肿瘤的发生和扩散。 疾病，例如在癌症中，血管生成为肿瘤细胞提供了 必需的营养素，从而有助于肿瘤生长。 一个 对抗癌症的抗血管生成策略是有吸引力的，因为 将靶向内皮细胞， 在靶向肿瘤细胞时观察到。 血管内皮生长因子 血管内皮生长因子（VEGF）已被考虑作为血管生成抑制的靶点， 几个原因：肿瘤细胞的表达由于缺乏 营养素，VEGF的作用是特定的内皮细胞，并阻止 VEGF的作用将抑制小鼠中生长的肿瘤的生长。 关于VEGF激活的信号转导通路的信息是有限的。 此前，我们的实验室发现了KDR基因，并将其鉴定为 VEGF受体。 KDR是一种受体酪氨酸激酶， 四个自磷酸化位点。 本申请中提出的实验 有两个目标 首先，我们希望在分子水平上理解 KDR自身磷酸化如何招募细胞信号蛋白。 二是 设计实验来阐明特定的细胞后果， 受体/信号蛋白相互作用。 提出了四个具体目标， 实现这些目标。 具体目标1将确定是否有 自磷酸化位点除了先前报道的。 具体 目的2将检验激酶中受体自磷酸化的假设， 域是最大催化活性所必需的。 具体目标3 在阐明与受体相互作用的信号蛋白方面， 自磷酸化位点。 具体目标4旨在澄清 依赖于受体的内皮细胞反应 在特定的酪氨酸磷酸化。

DESCRIPTION: (Applicant's Description) Anglogenesis (the formation of new blood capillaries) is an important component of several normal physiological processes including development and wound healing. Angiogenesis also contributes to the onset and spread of disease, for example in cancer angiogenesis provides tumor cells with essential nutrients and thus contributes to tumor growth. An anti-angiogenesis strategy for fighting cancer is attractive because this would target endothelial cells and potentially avoid the drug resistance observed when targeting tumor cells. Vascular Endothelial Growth Factor (VEGF) has received consideration as a target for angiogenesis inhibition for several reasons: Its expression by tumor cells is augmented by a lack of nutrients, VEGF's actions are specific to endothelial cells, and blocking VEGF's actions will inhibit the growth of tumors grown in mice. Information on the signal transduction pathways activated by VEGF is limited. Previously, our laboratory discovered the KDR gene and identified it as a receptor for VEGF. KDR is a receptor tyrosine kinase and we have identified four autophosphorylation sites. The experiments proposed in this application are directed at two goals. First, we wish to understand at a molecular level how KDR autophosphorylation recruits cell signaling proteins. Second, we have designed experiments to clarify the cellular consequence of specific receptor/signaling protein interactions. Four Specific Aims are proposed to accomplish these goals. Specific Aim 1 will determine whether there are autophosphorylation sites in addition to the ones reported earlier. Specific Aim 2 will test the hypothesis that receptor autophosphorylation in the kinase domain is required for maximum catalytic activity. Specific Aim 3 is directed at clarifying the signaling proteins which interact with receptor autophosphorylation sites. Specific Aim 4 is directed at clarifying endothelial cellular response which are dependent upon receptor phosphorylation at specific tyrosines.