Abstract
Autotaxin (ATX), or ecto-nucleotide pyrophosphatase/phosphodiesterase-2, is a secreted lysophospholipase D (lysoPLD) that hydrolyzes extracellular lysophospholipids into the lipid mediator lysophosphatidic acid (LPA), a ligand for specific G protein-coupled receptors. ATX-LPA signaling is essential for development and has been implicated in a great diversity of (patho)physiological processes, ranging from lymphocyte homing to tumor progression. Structural and functional studies have revealed what makes ATX a unique lysoPLD, and how secreted ATX binds to its target cells. The ATX catalytic domain shows a characteristic bimetallic active site followed by a shallow binding groove that can accommodate nucleotides as well as the glycerol moiety of lysophospholipids, and by a deep lipid-binding pocket. In addition, the catalytic domain has an open tunnel of unknown function adjacent to the active site. Here, we discuss our current understanding of ATX structure-function relationships and signaling mechanisms, and how ATX isoforms use distinct mechanisms to target LPA production to the plasma membrane, notably binding to integrins and heparan sulfate proteoglycans. We also briefly discuss the development of drug-like inhibitors of ATX.
Highlights
Autotaxin (ATX), or ecto-nucleotide pyrophosphatase/phosphodiesterase-2, is a secreted lysophospholipase D that hydrolyzes extracellular lysophospholipids into the lipid mediator lysophosphatidic acid (LPA), a ligand for specific G protein-coupled receptors
Autotaxin (ATX), known as ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP)2, is a secreted lysophospholipase D that belongs to the ENPP family
The ENPP family consists of seven members with structurally related catalytic domains that hydrolyze phosphodiester bonds in various substrates, including nucleoside triphosphates, lysophospholipids, and choline phosphate esters [1,2,3]
Summary
LPA acts on six distinct GPCRs (termed LPA1–6 or LPAR1–6), which are differentially expressed and show both overlapping and distinct signaling properties [12]. The classical LPA1–3 receptors belong to the so-called “endothelial differentiation gene” (Edg) family, which includes five GPCRs for the lipid mediator sphingosine 1-phosphate (S1P) [31]. Ether-linked 1-alkyl-LPA and 1-alkenyl-LPA species exist, but are much less abundant. Some LPA receptors (LPA3 and LPA6) prefer unsaturated 2-acyl-LPA as a ligand, while LPA5 exhibits a strong preference for ether-linked 1-alkyl-LPA species [13, 33]. Detailed accounts of LPA receptor signaling pathways, their impact on gene expression, and biological outcomes can be found elsewhere [6, 12, 34]
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