Lipid phosphate phosphatases (LPPs, encoded by the PPAP2 genes) are broad specificity enzymes that can de-phosphorylate lipid phosphate esters such as phosphatidic acid (PA), lysophosphatidic acid (LPA), and sphingosine-1- phosphate (SIP) that serve as critical intermediates in intracellular pathways of lipid metabolism and signaling (Fig. 1) (1). Of these substrates, LPA and SIP are also bio-active mediators that can be released or generated extra-cellularly and/or act on cell surface receptors to initiate a broad range of cellular responses (2). LPPs can localize to the cell surface with their active site facing the extracellular space allowing them to function as ecto enzymes (3, 4). Accordingly, it has been attractive to speculate that one function of these enzymes is to terminate the receptor-mediated signaling actions of LPA and SIP by dephos-phorylating them to generate the corresponding alcohols, which are not receptor-active. In support of this concept, overexpression of LPP1 or LPP3 increases the LPP activity of several intact cells, and this activity is decreased by silencing or genetic inactivation of the corresponding PPAP2A and PPAP2B genes (5-7).
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