DiMaio Terri A, Sheibani Nader
Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI 53792-4673, USA.
Microvasc Res. 2008 Mar;75(2):188-201. doi: 10.1016/j.mvr.2007.10.001. Epub 2007 Oct 17.
Platelet endothelial cell adhesion molecule-1 (PECAM-1) is alternatively spliced generating eight isoforms that only differ in the length of their cytoplasmic domain. Multiple isoforms of PECAM-1 are present in the endothelium and their expression levels are regulated during vascular development and angiogenesis. However, the functional significance of PECAM-1 isoforms during these processes remains largely unknown. We recently showed that mouse brain endothelial (bEND) cells prepared from PECAM-1-deficient (PECAM-1-/-) mice differ in their cell adhesive and migratory properties compared to PECAM-1+/+ bEND cells. Here we demonstrate that the restoration of PECAM-1 expression in these cells affects their adhesive and migratory properties in an isoform-specific manner. Expression of Delta14&15 PECAM-1, the predominant isoform present in the mouse endothelium, in PECAM-1-/- bEND cells activated MAPK/ERKs, disrupted adherens junctions, and enhanced cell migration and capillary morphogenesis in Matrigel. In contrast, expression of Delta15 PECAM-1 in PECAM-1-/- bEND cells had minimal effects on their activation of MAPK/ERKs, migration, and capillary morphogenesis. The effects of PECAM-1 on cell adhesive and migratory properties were mediated in an isoform-specific manner, at least in part, through its interactions with intracellular signaling proteins, including SHP-2 and Src. These results suggest that the impact of PECAM-1 on EC adhesion, migration, and capillary morphogenesis is modulated by alternative splicing of its cytoplasmic domain.
血小板内皮细胞黏附分子-1（PECAM-1）可通过可变剪接产生8种异构体，这些异构体仅在其胞质结构域的长度上有所不同。PECAM-1的多种异构体存在于内皮细胞中，其表达水平在血管发育和血管生成过程中受到调控。然而，在这些过程中PECAM-1异构体的功能意义仍 largely unknown。我们最近发现，与PECAM-1+/+的脑内皮（bEND）细胞相比，从PECAM-1缺陷（PECAM-1-/-）小鼠制备的小鼠脑内皮细胞在细胞黏附和迁移特性上有所不同。在此我们证明，在这些细胞中恢复PECAM-1的表达以异构体特异性方式影响其黏附和迁移特性。Delta14&15 PECAM-1是小鼠内皮中存在的主要异构体，在PECAM-1-/-的bEND细胞中表达可激活MAPK/ERK，破坏黏附连接，并增强细胞在基质胶中的迁移和毛细血管形态发生。相比之下，在PECAM-1-/-的bEND细胞中表达Delta15 PECAM-1对其MAPK/ERK激活、迁移和毛细血管形态发生的影响最小。PECAM-1对细胞黏附和迁移特性的影响至少部分地以异构体特异性方式通过其与包括SHP-2和Src在内的细胞内信号蛋白的相互作用介导。这些结果表明，PECAM-1对内皮细胞黏附、迁移和毛细血管形态发生的影响是由其胞质结构域的可变剪接调节的。
