Molecular Immunology Unit, Pathophysiology, Infectiology & Immunology, Medical University of Vienna, Austria.
Circ Res. 2011 Mar 18;108(6):676-85. doi: 10.1161/CIRCRESAHA.110.234732. Epub 2011 Jan 27.
The urokinase plasminogen activator (uPA) system is among the most crucial pericellular proteolytic systems associated with the processes of angiogenesis. We previously identified an important regulator of the uPA system in the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R).
Here, we wanted to clarify whether and how did the soluble form of M6P/IGF2R (sM6P/IGF2R) contribute to modulation of the uPA system.
By using specific inhibitors and RNA interference, we show that the tumor necrosis factor α convertase (TACE, ADAM-17) mediates the release of the ectodomain of M6P/IGF2R from human endothelial cells. We demonstrate further that sM6P/IGF2R binds plasminogen (Plg) and thereby prevents Plg from binding to the cell surface and uPA, ultimately inhibiting in this manner Plg activation. Furthermore, peptide 18-36 derived from the Plg-binding site of M6P/IGF2R mimics sM6P/IGF2R in the inhibition of Plg activation and blocks cancer cell invasion in vitro, endothelial cell invasion in vivo, and tumor growth in vivo.
The interaction of sM6P/IGF2R with Plg may be an important regulatory mechanism to inhibit migration of cells using the uPA/uPAR system.
尿激酶型纤溶酶原激活物（uPA）系统是与血管生成过程相关的最重要的细胞周蛋白酶解系统之一。我们之前在甘露糖 6-磷酸/胰岛素样生长因子 2 受体（M6P/IGF2R）中鉴定了 uPA 系统的一个重要调节剂。
在这里，我们想澄清可溶性 M6P/IGF2R（sM6P/IGF2R）是否以及如何调节 uPA 系统。
通过使用特异性抑制剂和 RNA 干扰，我们表明肿瘤坏死因子 α 转化酶（TACE，ADAM-17）介导 M6P/IGF2R 的外显子从人内皮细胞中释放。我们进一步证明 sM6P/IGF2R 结合纤溶酶原（Plg），从而阻止 Plg 与细胞表面和 uPA 结合，最终以这种方式抑制 Plg 激活。此外，源自 M6P/IGF2R 的 Plg 结合位点的肽 18-36 在抑制 Plg 激活以及阻断体外癌细胞侵袭、体内内皮细胞侵袭和体内肿瘤生长方面模拟 sM6P/IGF2R。
sM6P/IGF2R 与 Plg 的相互作用可能是抑制细胞迁移的重要调节机制，其使用 uPA/uPAR 系统。
