内皮细胞趋化作用需要Akt介导的G蛋白偶联受体EDG-1磷酸化。

Akt-mediated phosphorylation of the G protein-coupled receptor EDG-1 is required for endothelial cell chemotaxis.

作者信息

Lee M J, Thangada S, Paik J H, Sapkota G P, Ancellin N, Chae S S, Wu M, Morales-Ruiz M, Sessa W C, Alessi D R, Hla T

机构信息

Center for Vascular Biology and Department of Physiology, University of Connecticut Health Center, Farmington, CT 06030, USA.

出版信息

Mol Cell. 2001 Sep;8(3):693-704. doi: 10.1016/s1097-2765(01)00324-0.

DOI:10.1016/s1097-2765(01)00324-0

PMID:11583630

Abstract

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.

摘要

蛋白激酶Akt在细胞迁移中的作用尚未完全明确。在此我们表明，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。活化的Akt与EDG-1结合并使第三个细胞内环的T(236)残基磷酸化。Akt对EDG-1的反式激活对于G(i)依赖性信号传导并非必需，但对于Rac激活、皮质肌动蛋白组装和趋化性却是不可或缺的。实际上，T236A EDG-1突变体隔离了Akt，并作为一种显性负性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一种特异性开关，将快速的G蛋白依赖性信号整合到诸如细胞迁移等长期细胞现象中。