Rosenfeldt H M, Hobson J P, Milstien S, Spiegel S
Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, DC 20007, USA.
Biochem Soc Trans. 2001 Nov;29(Pt 6):836-9. doi: 10.1042/0300-5127:0290836.
EDG-1, encoded by the endothelial differentiation gene-1, is a heterotrimeric guanine nucleotide binding protein-coupled receptor (GPCR) for sphingosine-1-phosphate (SPP) that has been shown to stimulate angiogenesis and cell migration in cultured endothelial cells. Unexpectedly, EDG-1 knockout embryos had a normal blood vessel network, vasculogenesis and angiogenesis, but died in utero owing to massive haemorrhaging as a result of failure of smooth muscle cells and pericytes to migrate around the circumference and reinforce endothelial tubes [Liu, Wada, Yamashita, Mi, Deng, Hobson, Rosenfeldt, Nava, Chae, Lee, et al. (2000) J. Clin. Invest. 106, 951-961]. This vascular maturation defect is similar to the phenotype of mice homozygous for disrupted alleles of platelet-derived growth factor B-subunit homodimer (PDGF-BB) or its receptor PDGFR-beta. We found that fibroblasts from EDG-1 null embryos did not migrate toward PDGF or SPP, and inhibition of motility correlated with defective activation of the small guanosine triphosphatase Rac, which is required for lamellipodia formation and directional locomotion [Hobson, Rosenfeldt, Barak, Olivera, Poulton, Caron, Milstien, and Spiegel (2001) Science 291, 1800-1803]. Moreover, we showed that PDGF-directed cell migration requires both sphingosine kinase activation and expression of EDG-1, suggesting a functional link between PDGF signalling and EDG-1. Indeed, treatment of wild-type cells with PDGF transactivated EDG-1 as determined by translocation of beta-arrestin and phosphorylation of EDG-1. These findings reveal a new paradigm for receptor cross-communication in which activation of a GPCR by a receptor tyrosine kinase is critical for cell motility. Our observations might also clarify the role of EDG-1 in vascular maturation and angiogenesis.
内皮分化基因 -1（endothelial differentiation gene-1）编码的EDG-1是一种异源三聚体鸟嘌呤核苷酸结合蛋白偶联受体（GPCR），可作用于1-磷酸鞘氨醇（SPP），已证实在培养的内皮细胞中能刺激血管生成和细胞迁移。出乎意料的是，EDG-1基因敲除胚胎具有正常的血管网络、血管发生和血管生成，但由于平滑肌细胞和周细胞无法围绕血管圆周迁移并强化内皮管，导致大量出血，最终在子宫内死亡[刘、和田、山下、米、邓、霍布森、罗森费尔特、纳瓦、蔡、李等人（2000年）《临床研究杂志》106卷，951 - 961页]。这种血管成熟缺陷类似于血小板衍生生长因子B亚基同二聚体（PDGF-BB）或其受体PDGFR-β等位基因破坏的纯合小鼠的表型。我们发现，来自EDG-1基因缺失胚胎的成纤维细胞不会向PDGF或SPP迁移，运动抑制与小GTP酶Rac的激活缺陷相关，而Rac是片状伪足形成和定向运动所必需的[霍布森、罗森费尔特、巴拉克、奥利韦拉、波尔顿、卡隆、米尔斯坦和斯皮格尔（2001年）《科学》291卷，1800 - 1803页]。此外，我们表明PDGF介导的细胞迁移既需要鞘氨醇激酶激活，也需要EDG-1的表达，这表明PDGF信号传导与EDG-1之间存在功能联系。事实上，通过β-抑制蛋白的转位和EDG-1的磷酸化测定，用PDGF处理野生型细胞可使EDG-1反式激活。这些发现揭示了一种受体交叉通讯的新模式，即受体酪氨酸激酶激活GPCR对细胞运动至关重要。我们的观察结果也可能阐明EDG-1在血管成熟和血管生成中的作用。
