Abstract
Phosphatidic acid (PA) is a simple glycerophospholipid with a well-established role as an intermediate in phospholipid biosynthesis. In addition to its role in lipid biosynthesis, PA has been proposed to act as a signaling molecule that modulates several aspects of cell biology including membrane transport. PA can be generated in eukaryotic cells by several enzymes whose activity is regulated in the context of signal transduction and enzymes that can metabolize PA thus terminating its signaling activity have also been described. Further, several studies have identified PA binding proteins and changes in their activity are proposed to be mediators of the signaling activity of this lipid. Together these enzymes and proteins constitute a PA signaling toolkit that mediates the signaling functions of PA in cells. Recently, a number of novel genetic models for the analysis of PA function in vivo and analytical methods to quantify PA levels in cells have been developed and promise to enhance our understanding of PA functions. Studies of several elements of the PA signaling toolkit in a single cell type have been performed and are presented to provide a perspective on our understanding of the biochemical and functional organization of pools of PA in a eukaryotic cell. Finally, we also provide a perspective on the potential role of PA in human disease, synthesizing studies from model organisms, human disease genetics and analysis using recently developed PLD inhibitors.
Highlights
AND HISTORICAL PERSPECTIVEPhosphatidic acid (PA) is the simplest glycerophospholipid whose oldest known function is to serve as the backbone for the synthesis of a number of classes of glycerophospholipids
PA produced by phospholipase D (PLD) has been shown to bind and modulate the activity of several proteins involved in synaptic vesicle endo and exocytosis such as NSF, PI4P5K, and syntaxin-1A (Manifava et al, 2001; Lam et al, 2007; Mima and Wickner, 2009; Roach et al, 2012)
And pertinent to the topic of this review, phospholipase D has been reported to be phosphorylated by Ribosomal S6 kinase 2 (RSK2) and analysis in neural cell lines has suggested that this phosphorylation by RSK2 controls PLD1 activity and NGF induced neurite outgrowth; this study has proposed that PA may regulate vesicular transport in the growing neurite (Ammar et al, 2013, 2015)
Summary
Phosphatidic acid (PA) is the simplest glycerophospholipid whose oldest known function is to serve as the backbone for the synthesis of a number of classes of glycerophospholipids. It consists of two fatty acyl chains esterified at positions sn-1 and sn-2 of glycerol and a free phosphate group at sn-3 (Figure 1) reviewed in Athenstaedt and Daum (1999). It has become apparent that PA is produced by biochemical reactions that are well understood as part of signal transduction pathways that mediate information transfer in eukaryotic cells. In this review we focus on those functions of PA that relate to its ability to regulate membrane transport events in eukaryotic cells
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