Valenzuela D M, Griffiths J A, Rojas J, Aldrich T H, Jones P F, Zhou H, McClain J, Copeland N G, Gilbert D J, Jenkins N A, Huang T, Papadopoulos N, Maisonpierre P C, Davis S, Yancopoulos G D
Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):1904-9. doi: 10.1073/pnas.96.5.1904.
The angiopoietins have recently joined the members of the vascular endothelial growth factor family as the only known growth factors largely specific for vascular endothelium. The angiopoietins include a naturally occurring agonist, angiopoietin-1, as well as a naturally occurring antagonist, angiopoietin-2, both of which act by means of the Tie2 receptor. We now report our attempts to use homology-based cloning approaches to identify new members of the angiopoietin family. These efforts have led to the identification of two new angiopoietins, angiopoietin-3 in mouse and angiopoietin-4 in human; we have also identified several more distantly related sequences that do not seem to be true angiopoietins, in that they do not bind to the Tie receptors. Although angiopoietin-3 and angiopoietin-4 are strikingly more structurally diverged from each other than are the mouse and human versions of angiopoietin-1 and angiopoietin-2, they appear to represent the mouse and human counterparts of the same gene locus, as revealed in our chromosomal localization studies of all of the angiopoietins in mouse and human. The structural divergence of angiopoietin-3 and angiopoietin-4 appears to underlie diverging functions of these counterparts. Angiopoietin-3 and angiopoietin-4 have very different distributions in their respective species, and angiopoietin-3 appears to act as an antagonist, whereas angiopoietin-4 appears to function as an agonist.
血管生成素最近加入了血管内皮生长因子家族，成为仅有的主要对血管内皮具有特异性的已知生长因子。血管生成素包括一种天然存在的激动剂血管生成素-1以及一种天然存在的拮抗剂血管生成素-2，二者均通过Tie2受体发挥作用。我们现在报告我们尝试使用基于同源性的克隆方法来鉴定血管生成素家族的新成员。这些努力已导致鉴定出两种新的血管生成素，小鼠中的血管生成素-3和人类中的血管生成素-4；我们还鉴定出了一些亲缘关系较远的序列，它们似乎并非真正的血管生成素，因为它们不与Tie受体结合。尽管血管生成素-3和血管生成素-4在结构上彼此的差异比小鼠和人类版本的血管生成素-1和血管生成素-2之间的差异更为显著，但正如我们对小鼠和人类中所有血管生成素进行的染色体定位研究所显示的那样，它们似乎代表了同一基因座的小鼠和人类对应物。血管生成素-3和血管生成素-4的结构差异似乎是这些对应物功能差异的基础。血管生成素-3和血管生成素-4在各自物种中的分布非常不同，血管生成素-3似乎起拮抗剂的作用，而血管生成素-4似乎起激动剂的作用。
