Akt-mediated phosphorylation of the G protein-coupled receptor EDG-1 is required for endothelial cell chemotaxis
Akt-mediated phosphorylation of the G protein-coupled receptor EDG-1 is required for endothelial cell chemotaxis
复制标题
DOI：
10.1016/s1097-2765(01)00324-0
复制
发表时间：
2001-09-01
期刊：
影响因子：
16
通讯作者：
Hla, T
中科院分区：
文献类型：
--
作者：
Lee, MJ;Thangada, S;Hla, T
蛋白激酶 Akt 在细胞迁移中的作用尚不完全清楚。在这里，我们表明，1-磷酸鞘氨醇 (S1P) 诱导的内皮细胞迁移需要 Akt 介导的 G 蛋白偶联受体 (GPCR) EDG-1 磷酸化。激活的 Akt 与 EDG-1 结合并磷酸化 T-236 残基处的第三个细胞内环。 Akt 对 EDG-1 的反式激活不是 G(i) 依赖性信号转导所必需的，但对于 Rac 激活、皮质肌动蛋白组装和趋化性是必不可少的。事实上，T236AEDG-1 突变体隔离 Akt 并作为显性失活 GPCR 抑制 S1P 诱导的 Rac 激活、趋化性和血管生成。 Akt 对 GPCR 的反式激活可能构成特异性开关，将快速 G 蛋白依赖性信号整合到细胞迁移等长期细胞现象中。
The role of the protein kinase Akt in cell migration is incompletely understood. Here we show that sphingosine-1-phosphate (S1P)-induced endothelial cell migration requires the Akt-mediated phosphorylation of the G protein-coupled receptor (GPCR) EDG-1. Activated Akt binds to EDG-1 and phosphorylates the third intracellular loop at the T-236 residue. Transactivation of EDG-1 by Akt is not required for G(i)-dependent signaling but is indispensable for Rac activation, cortical actin assembly, and chemotaxis. Indeed, T236AEDG-1 mutant sequestered Akt and acted as a dominant-negative GPCR to inhibit S1P-induced Rac activation, chemotaxis, and angiogenesis. Transactivation of GPCRs by Akt may constitute a specificity switch to integrate rapid G protein-dependent signals into long-term cellular phenomena such as cell migration.