Geretti Elena, Shimizu Akio, Klagsbrun Michael
Department of Surgery, Vascular Biology Program, Children's Hospital and Harvard Medical School, Karp Building 12210, 300 Longwood Ave., Boston, MA, 02115, USA.
Angiogenesis. 2008;11(1):31-9. doi: 10.1007/s10456-008-9097-1. Epub 2008 Feb 19.
Neuropilins (NRP) play a central role in neuronal and blood vessel development as receptors for two ligand types, the semaphorin (SEMA) family of axon guidance modulators and the VEGF family of angiogenesis stimulators. The role of NRPs in axon guidance is well documented but a role in blood vessel development is less so. NRPs mediate normal developmental angiogenesis as shown in mouse and zebrafish models, and pathological angiogenesis in tumors and retinal disease. The ability of two disparate ligand families to bind to the same receptor is unusual but may be explainable by analysis of neuropilin structure. There are two NRP genes, nrp1 and nrp2. The NRPs have a relatively large extracellular domain consisting of sub domains, which are ligand binding sites. VEGF(165) binds to the b1b2 subdomain, SEMA3A and SEMA3F also bind to b1b2 but to a1a2 as well. Mutagenesis studies have identified NRP amino acids that bind VEGF(165) but not SEMA3F. These NRP structural elements might dictate differential SEMA and VEGF(165) binding properties, which in turn regulate angiogenesis. This article reviews the latest information of NRP structure and how structure influences angiogenesis. In addition, the role of NRPs in human cancer is addressed.
神经纤毛蛋白（NRP）作为两类配体的受体，在神经元和血管发育中发挥核心作用。这两类配体分别是轴突导向调节剂的信号素（SEMA）家族和血管生成刺激因子的血管内皮生长因子（VEGF）家族。NRP在轴突导向中的作用已有充分记载，但在血管发育中的作用则了解较少。在小鼠和斑马鱼模型中已证实，NRP介导正常的发育性血管生成以及肿瘤和视网膜疾病中的病理性血管生成。两个不同的配体家族能够结合同一受体，这种情况并不常见，但通过对神经纤毛蛋白结构的分析或许可以解释。有两个NRP基因，即nrp1和nrp2。NRP具有一个相对较大的细胞外结构域，该结构域由多个亚结构域组成，这些亚结构域就是配体结合位点。VEGF（165）与b1b2亚结构域结合，SEMA3A和SEMA3F也与b1b2结合，但同时也与a1a2结合。诱变研究已确定了NRP中与VEGF（165）结合但不与SEMA3F结合的氨基酸。这些NRP结构元件可能决定了信号素和VEGF（165）的不同结合特性，进而调节血管生成。本文综述了NRP结构的最新信息以及结构如何影响血管生成。此外，还探讨了NRP在人类癌症中的作用。
