Abstract
Lipid phosphate phosphatases (LPPs) regulate cell signaling by modifying the concentrations of lipid phosphates versus their dephosphorylated products. The ecto-activity regulates the availability of extracellular lysophosphatidate (LPA) and sphingosine 1-phosphate (S1P) and thereby signaling by their respective receptors. LPP products (monoacylglycerol or sphingosine) are taken up by cells and rephosphorylated to produce LPA and S1P, respectively, which activate intracellular signaling cascades. The proposed integrin binding domain on the external surface of LPP3 modifies cell/cell interactions. Expression of LPPs on internal membranes controls signaling depending on the access of lipid phosphates to their active sites. Different LPPs perform distinct functions, probably based on integrin binding, their locations, and their abilities to metabolize different lipid phosphates in vivo.
Highlights
Lipid phosphate phosphatases (LPPs) regulate cell signaling by modifying the concentrations of lipid phosphates versus their dephosphorylated products
This work did not evaluate LPA turnover, which could be a self-regulating process because both LPA and sphingosine 1-phosphate (S1P) are product inhibitors of ATX [35]. This observation shows that the regulation of LPA and S1P metabolism can interact at the levels of both ATX and the LPPs
The results demonstrate the rapid turnover of circulating LPA and the physiological role of LPP1 in regulating this process
Summary
Extracellular LPA and S1P are metabolized mainly by the ecto-activities of the LPPs [1, 2, 21]. Ecto-LPP1 activity promotes uptake of sphingosine derived from S1P by human lung endothelial cells [30] This increases intracellular S1P formation through sphingosine kinase-1 [30]. LPP1 dephosphorylates exogenous C1P [22] to produce ceramides that can be converted to C1P once they enter the cell This mechanism could explain how exogenous C1P increases intracellular C1P, activating cytosolic PLA2 and leading to arachidonate and prostaglandin E2 production [34]. Despite this weight of evidence for the importance of ecto-LPP activities, it has been questioned whether the LPPs regulate cell signaling based on conceptual problems.
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