LPP3 localizes LPA6 signalling to non-contact site in endothelial cells

Abstract

Lysophosphatidic acid (LPA) is an emerging angiogenic factor, as knockdown of its producing enzyme, autotaxin and receptors caused severe developmental vascular defects in both mice and fish. In addition, overexpression of autotaxin in mice caused similar vascular defects, indicating that the extracellular amount of LPA must be tightly regulated. Here, we focused on an LPA-degrading enzyme, lipid phosphate phosphatase 3 (LPP3), and showed that LPP3 was localized in specific cell-cell contact sites of endothelial cells and suppresses LPA signalling via LPA6 receptor. In HEK293 cells, overexpression of LPP3 dramatically suppressed activation of LPA6. In human umbilical vein endothelial cells (HUVECs), LPA induced actin stress fiber formation via LPA6, which was prominently up-regulated by LPP3 knockdown. LPP3 was localized to cell-cell contact sites and was missing in non-contact sites to which LPA-induced actin stress fiber formation mediated by LPA6 was restricted. Interestingly, the expression of LPP3 in HUVECs was dramatically increased after forskolin-treatment, in which Notch signalling was involved. These results indicate that LPP3 regulates and localizes LPA signalling in endothelial cells thereby stabilizing vessels via Notch signalling for proper vasculature.