ReviewRegulation and biological activities of the autotaxin–LPA axis
Introduction
Lysophosphatidic acid (LPA; mono-acylglycerol-3-phosphate), consisting of a single acyl chain, a glycerol backbone and a phosphate headgroup, is the smallest and structurally simplest glycerophospholipid and arguably also one of the most interesting. In addition to its vital role as a precursor in phospholipid biosynthesis, LPA functions as an intercellular lipid mediator with multiple actions, particularly as an inducer of cell proliferation, migration and survival. LPA acts via specific G protein-coupled receptors (GPCRs) on the cell surface to activate a great variety of signaling pathways. The outcome of LPA signaling depends on cellular context and impinges on biological processes as diverse as wound healing, neurogenesis and tumor progression, to name a few.
Since the initial discovery of LPA as a serum-borne growth factor that signals in a GPCR-dependent manner [1], [2], [3], much progress has been made in the characterization of LPA signaling pathways, the identification of several LPA-specific GPCRs and the biological activities of LPA (see [4] for an historic overview of the LPA field). Yet, knowledge of how and where bioactive LPA normally is produced has long been elusive, not least because of the complexity of the enzymatic networks that control phospholipid synthesis and degradation in general. A major step forward was made by the discovery [5], [6] that the LPA-producing lysophospholipase D (lysoPLD) in serum is identical to autotaxin (ATX; also known as NPP2), a widely expressed nucleotide pyrophosphatase/phosphodiesterase (NPP) first identified in the early 1990s as an ‘autocrine motility factor’ for tumor cells [7].
The main purpose of this review is to summarize current knowledge about ATX as the major LPA-producing phospholipase. We will first provide a brief update on the activities of LPA and then focus on ATX with emphasis on its regulation and emerging role in cancer and other pathologies; finally, we will discuss the importance of ATX in vascular development as revealed by gene targeting studies in mice.
Section snippets
Biological activities of LPA
The major physiological and pathophysiological effects of LPA are summarized in Table 1. The list is based on many studies in cell culture and, to a lesser extent, experimental animals; it will undoubtedly expand by further analysis of the ATX–LPA receptor axis in vivo, particularly by loss-of-function analyses in specific tissues. The multitude of activities of LPA is consistent with the broad tissue distribution of LPA receptors (see below) and their coupling to at least three distinct
LPA production and degradation
One long-standing issue has been the question of how and where bioactive LPA normally is produced and how its levels are controlled. Obviously, there must be a tightly controlled balance between de novo synthesis and subsequent degradation of LPA. It is now clear that LPA is produced and degraded extracellularly through the action of lysoPLD/ATX and lipid phosphatases, respectively (Fig. 1). Serum LPA levels gradually increase following platelet activation; this ‘platelet-derived’ LPA
Concluding remarks
While much has recently been learned about ATX as the major LPA-generating exo-enzyme and our understanding of LPA action has progressed rapidly, the exact in vivo functions of the ATX–LPA axis remain to be elucidated. Targeted deletion of ATX and LPA receptors in mice has revealed essential roles of ATX and LPA in diverse biological processes. ATX was found to be essential for blood vessel formation during development, whereas LPA receptor signaling has been implicated in olfaction, initiation
Acknowledgements
We thank our colleagues in the Netherlands Cancer Institute for fruitful discussions. Research related to this review is supported by the Dutch Cancer Society.
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