University of Utah, Eccles Institute of Human Genetics, Salt Lake City, UT 84112, USA.
Circ Res. 2011 Sep 16;109(7):770-4. doi: 10.1161/CIRCRESAHA.111.247239. Epub 2011 Jul 28.
Netrin-4 regulates vascular development. Identity of netrin-4 endothelial receptor and its subsequent cell functions is controversial. We previously demonstrated that the inhibition of netrin-1 canonical receptors, Unc5B and neogenin, expressed by lymphatic endothelial cells, do not suppress netrin-4-induced cell signaling and functions. Netrin family members were shown to signal through a range of receptors, including integrins (such as α3β1, α6β1, and α6β4) in nonendothelial cells.
We tested whether integrins are netrin-4 receptors in the endothelium.
The α6β1 integrin is expressed by endothelial cells, and binds netrin-4 in a dose-dependent manner. Inhibition of α6 or β1 integrin subunits suppresses netrin-4-induced endothelial cell migration, adhesion, and focal adhesion contact. Netrin-4-stimulated phosphorylation of Src kinase family, effectors of endothelial cell migration, is also abolished by α6 or β1 inhibition. Finally, netrin-4 and α6β1 integrin expression colocalize in mouse embryonic, intestine, and tumor vasculature.
The α6β1 integrin is a netrin-4 receptor in lymphatic endothelium and consequently represents a potential target to inhibit netrin-4-induced metastatic dissemination.
轴突导向因子 Netrin-4 可调节血管发育。Netrin-4 的内皮细胞受体及其后续细胞功能的身份仍存在争议。我们之前的研究表明，淋巴管内皮细胞表达的 Netrin-1 经典受体 Unc5B 和 neogenin 的抑制作用并不能抑制 Netrin-4 诱导的细胞信号转导和功能。轴突导向因子家族成员可通过一系列受体（如非内皮细胞中的整合素（如 α3β1、α6β1 和 α6β4））发出信号。
我们测试整合素是否为内皮细胞中的 Netrin-4 受体。
α6β1 整合素在血管内皮细胞中表达，并以剂量依赖的方式与 Netrin-4 结合。α6 或 β1 整合素亚基的抑制作用可抑制 Netrin-4 诱导的内皮细胞迁移、黏附和焦点黏附接触。α6 或 β1 抑制作用还可消除 Netrin-4 刺激的 Src 激酶家族（内皮细胞迁移的效应物）磷酸化。最后，Netrin-4 和 α6β1 整合素表达在小鼠胚胎、肠道和肿瘤血管中发生共定位。
α6β1 整合素是淋巴管内皮细胞中的 Netrin-4 受体，因此代表了抑制 Netrin-4 诱导的转移扩散的潜在靶点。
