Lipid phosphate phosphatase (LPP3) and vascular development

Abstract

Lipid phosphate phosphatases (LPP) are integral membrane proteins with broad substrate specificity that dephosphorylate lipid substrates including phosphatidic acid, lysophosphatidic acid, ceramide 1-phosphate, sphingosine 1-phosphate, and diacylglycerol pyrophosphate. Although the three mammalian enzymes (LPP1-3) demonstrate overlapping catalytic activities and substrate preferences in vitro, the phenotypes of mice with targeted inactivation of the Ppap2 genes encoding the LPP enzymes reveal nonredundant functions. A specific role for LPP3 in vascular development has emerged from studies of mice lacking Ppap2b. A meta-analysis of multiple, large genome-wide association studies identified a single nucleotide polymorphism in PPAP2B as a novel predictor of coronary artery disease. In this review, we will discuss the evidence that links LPP3 to vascular development and disease and evaluate potential molecular mechanisms. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.

Figure 1. Predicted topology of lipid phosphate phosphatases

The LPP members are predicted to have six transmembrane spanning regions and an active site composed of regions on the extracellular or abluminal surface of the membrane.

Figure 2. Proposed role of lipid phosphate phosphatases in regulating lysophospholipid signaling

Bioactive lysophosphatidic acid (LPA) production is the result of autoxatin mediated hydrolysis of lysophopshatidyl choline (LPC) generated at least in part from phosphatidyl choline (PC). Extracellular LPA can act via its G-protein coupled receptors to elicit intracellular signaling and/or be degraded by surface LPPs to receptor inactive monoacyl glycerol.