CHARACTERIZATION OF NEUROPILIN, A NOVEL VEGF RECEPTOR

新型 VEGF 受体 NUROPILIN 的表征

• 批准号: 6044341
• 负责人: MICHAEL KLAGSBRUN
• 金额: $ 53.77万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-01-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6044341
• 关键词: angiogenesis factor; animal tissue; binding proteins; cardiovascular disorder; epidermal growth factor; fibroblast growth factor; gene expression; high performance liquid chromatography; human tissue; immunoprecipitation; in situ hybridization; mass spectrometry; molecular cloning; neoplastic transformation; northern blottings; polymerase chain reaction; prostate neoplasms; protein sequence; protein structure function; scintillation counter; syndecan; tissue /cell culture; transfection; transport proteins; tumor promoters; vascular endothelial growth factors; western blottings

DESCRIPTION (Adapted from Investigator's Abstract): A 130-kDa receptor for VEGF165, neuropilin-1 (NRP1), has been purified and expression cloned. NRP1 is a cell surface glycoprotein previously shown to be a receptor for the semaphorins/ collapsins, a family of chemorepulsive proteins that mediate neuronal guidance. NRP1 is expressed by endothelial cells (EC) as are other VEGF receptors (e.g. KDR) but also abundantly by tumor cells, such as breast and prostate carcinoma, where it is the only receptor capable of binding VEGF. Co-expression of NRP1 and KDR in EC results in increased chemotaxis towards VEGF165 when compared to EC expressing KDR alone, suggesting that NRP1 may be a co-receptor for KDR in EC and contribute to angiogenesis. Tumor cells bind VEGF165 and respond by increased motility. Thus, VEGF165 may have a dual function in tumor growth as an angiogenesis factor and as a factor acting directly on tumor cells. While VEGF165 interactions with NRP1 enhance EC motility, collapsin/ semaphorin 111, an inhibitor of axon motility, inhibits EC motility via NRP1 suggesting that these two ligands have opposing effects acting on the same receptor. NRP1, a naturally occurring secreted 90 kDa NRP1 ectodomain (sNRP1) has been cloned which contains a unique intron sequence. Thus, the distribution of sNRP1 can determined by in situ hybridization independent of intact NRP1. SNRP1 is an antagonist of VEGF165 activity. A second gene, NRP2, with 47% homology to NRP1 has been cloned and its properties relative to NRP1 are being investigated. How NRP1 gene expression and activity is regulated is virtually unknown. The overall goals of this proposal are to define the structure, function and regulation of NRP1 as a novel receptor for VEGF165. The aims of this proposal are: 1) to investigate VEGF165 and semaphorin/collapsin interactions with NRP1; 2) to investigate NRP1 expression and function in tumor cells; 3) to characterize the structure, function and distribution of a naturally occurring soluble NRP1 (sNRP1) receptor and 4) to investigate the regulation of NRP1 gene expression and activity.

描述（改编自研究者摘要）：130-kDa 受体 VEGF165，神经毡蛋白-1 (NRP1)，已被纯化并表达克隆。 NRP1 是 先前显示为细胞表面糖蛋白的受体 信号蛋白/塌陷蛋白，化学脉冲蛋白家族，介导 神经元引导。 NRP1 与其他细胞一样由内皮细胞 (EC) 表达 VEGF 受体（例如 KDR）也大量存在于肿瘤细胞中，例如乳腺癌 和前列腺癌，它是唯一能够结合 VEGF 的受体。 EC 中 NRP1 和 KDR 的共表达导致趋化性增加 与单独表达 KDR 的 EC 相比，VEGF165 表明 NRP1 可能是 EC 中 KDR 的共受体并有助于血管生成。肿瘤细胞结合 VEGF165 并通过增加运动性做出反应。因此，VEGF165可能具有双重作用。 作为血管生成因子和作用因子在肿瘤生长中发挥作用 直接作用于肿瘤细胞。 VEGF165 与 NRP1 相互作用增强 EC 运动性，collapsin/semaphorin 111，轴突运动抑制剂，抑制 EC 通过 NRP1 的运动表明这两种配体具有相反的作用 作用于同一个受体。 NRP1，一种天然分泌的 90 kDa NRP1 胞外域 (sNRP1) 已被克隆，其中包含独特的内含子序列。 因此，sNRP1的分布可以通过原位杂交来确定 独立于完整的NRP1。 SNRP1 是 VEGF165 活性的拮抗剂。一个 第二个基因 NRP2 与 NRP1 具有 47% 同源性，已被克隆及其特性 与 NRP1 的相关性正在研究中。 NRP1基因如何表达和活性 是否受到监管几乎是未知的。该提案的总体目标是 定义 NRP1 作为新型受体的结构、功能和调节 VEGF165。该提案的目的是：1) 研究 VEGF165 和 信号蛋白/塌陷蛋白与 NRP1 的相互作用； 2) 研究NRP1表达 以及在肿瘤细胞中的功能； 3) 结构、功能的表征 天然存在的可溶性 NRP1 (sNRP1) 受体的分布和 4) 研究NRP1基因表达和活性的调控。