Signal Transduction

Phospholipids are substrate molecules for a wide range of lipid-derived signaling molecules, including diacylglycerol (DAG), phosphatidic acid (PA), 20:4n6, eicosanoid products, PAF, and lysophospha-tidic acid, generated by the action of PLA2, PLC, and PLD. The activation of these enzymes is complex, partly because of the large number of isoforms present within a cell and also because of the interdependence and coordination of their regulation. For instance, the bacterial peptide formyl-methio-nyl-leucyl phenylalanine (FMLP) binds to its receptor on neutrophils and activates the G-protein-regulated PLC^. PLC^ hydrolyses PI-4,5-P2 to form DAG, an activator of traditional Ca2+-depen-dent PKC isoforms, and inositol trisphosphate, which stimulates intracellular Ca2+ mobilisation. In addition, FMLP activates PC-specific PLD and cyto-plasmic PLA2. PLD generates PA, which also has signaling responses, including stimulation of NADPH oxidase activity, but which is also readily interconverted with DAG. Alkenyl species of PE are probably the major substrates for cytoplasmic PLA2, which is specific for molecular species containing 20:4n-6. This multitude of responses to a single agonist is highly coordinated and is typical of lipid signaling mechanisms in general. The activation of the various phospholipase enzymes is tightly regulated by a variety of protein kinases, phosphatases, and regulatory proteins, such that their responses are sequential rather than simultaneous.

Evidence suggests that phospholipid structure contributes to the coordinated regulation of phos-pholipase activation. PI-4,5-P2, the substrate for PLC, is an obligate activator of ADP ribosylation factor-dependent PLD; consequently PI-4,5-P2 must be regenerated after the transient activation of PLC, before maximal activation of PLD can be achieved. In addition, individual phospholipids can act as binding sites for a wide range of signaling proteins and enzymes, enabling their coordinated regulation at the membrane. Perhaps the best characterised of these systems is the generation of trace amounts of 3-phosphorylated PI, typically PI-3,4,5-P3, when PI-3-kinase is activated by insulin and growth factors. Signaling proteins containing appropriate binding motifs (plecstrin homology or PH domains) then bind to PI-3,4,5-P3 and initiate signaling cascades. The prototype of such protein is protein kinase B (PKB) also know as Akt. PKB undergoes a confor-mational change when bound to PI-3,4,5-P3, becomes phosphorylated, and then is active in the regulation of cell proliferation.

The mechanisms of action of dietary lipid modulation on these signaling pathways are largely unknown. There is good evidence that eating a diet rich in fish oil (containing 22:6n-3 and 22:5n-3) attenuates neutrophil-mediated inflammatory reactions. Part of this antiinflammatory nutritional effect may be to reduce the content of phospholipid species containing 20:4n-6, thus decreasing available substrate for synthesis of eicosanoid and leukotriene products derived from 20:4n-6. Alternatively, it may also result in part from the modulation of the spectrum of molecular species of DAG and PA generated by the various PLC and PLD enzymes. In this paradigm, altering the composition of substrate phospholipid will result in the formation of different DAG or PA species, which then have differential actions on target kinase enzymes. Because inositol phospholipids are generally composed of the 18:0120:4 species, activation of PLC1 will form DAG18:0/20:4, whereas hydrolysis of PC will generate predominately mono-unsaturated DAG species. It has been suggested, for instance, that individual isoforms of protein kinase C can be differentially regulated in response to different molecular species of DAG, thus providing a molecular basis for many nutritional effects on a wide range of cellular functions.

Despite extensive studies since the 1960s, remarkably little is understood about the fundamental reasons why cells expend considerable energy maintaining lineage-specific molecular species compositions of membrane phospholipids. Even for cell lines in culture, which can be grown successfully over many generations with grossly nonphysio-logical membrane phospholipid compositions, a degree of lineage specificity is maintained. The detailed metabolic processes that control membrane phospholipid composition are slowly being defined, and studies of the specificities and activities in intact cells of acyltransferase and phospholipid synthetic enzymes using gene transfection and sensitive analytical techniques such as ESI-MS will increase understanding of the fundamental mechanisms involved.

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