Abstract
ABSTRACTLysophosphatidic acid (LPA) is emerging as an angiogenic factor, because knockdown of the enzyme that produces it (autotaxin, also known as ENPP2) and its receptors cause severe developmental vascular defects in both mice and fish. In addition, overexpression of autotaxin in mice causes 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, also known as PPAP2B), and showed that LPP3 was localized in specific cell–cell contact sites of endothelial cells and suppresses LPA signalling through the LPA6 receptor (also known as LPAR6). In HEK293 cells, overexpression of LPP3 dramatically suppressed activation of LPA6. In human umbilical vein endothelial cells (HUVECs), LPA induced actin stress fibre formation through LPA6, which was substantially upregulated by LPP3 knockdown. LPP3 was localized to cell–cell contact sites and was missing in non-contact sites to which LPA-induced actin stress fibre formation mediated by LPA6 was restricted. Interestingly, the expression of LPP3 in HUVECs was dramatically increased after forskolin treatment in a process involving Notch signalling. These results indicate that LPP3 regulates and localizes LPA signalling in endothelial cells, thereby stabilizing vessels through Notch signalling for proper vasculature.
Highlights
Lysophosphatidic acid (LPA) regulates a wide variety of cellular processes in vertebrates, including migration, adhesion, proliferation, differentiation and cell death, and thereby influences multiple in vivo events ranging from organogenesis to development of cancer (Ishii et al, 2004; Lin et al, 2010)
LPA is mainly produced by autotaxin (ATX, known as ENPP2), an extracellular enzyme that converts lysophospholipids to LPA, and exerts its action through at least six G-protein-coupled receptors (LPA1–LPA6, known as LPAR1–LPAR6) specific to LPA (Chun et al, 2010)
To understand regulation of LPA signalling, we examined the roles of LPA and LPP3 using human umbilical vein endothelial cells (HUVECs)
Summary
Lysophosphatidic acid (LPA) regulates a wide variety of cellular processes in vertebrates, including migration, adhesion, proliferation, differentiation and cell death, and thereby influences multiple in vivo events ranging from organogenesis to development of cancer (Ishii et al, 2004; Lin et al, 2010). To understand regulation of LPA signalling, we examined the roles of LPA and LPP3 using human umbilical vein endothelial cells (HUVECs). We found that LPA dramatically induced the formation of actin stress fibres and intracellular gaps (Fig. 1A), and increased the permeability of the cells (Fig. 1B).
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