Glycerophosphoinositol-4-Phosphate in Intracellular Signalling

Abstract

Cell Membrane Lipids and Signal Transduction Over the past two decades, the build-up of a complex understanding of the metabolism of cell membrane lipids has seen the development of the roles of these lipids from solely ‘passive’ structural components of the membrane bilayer to ‘active’ regulators of cell function. These roles have included the fields of lipid-protein interaction, membrane biogenesis and membrane transport (for reviews see Casey, 1995; Liscovitch and Cantley, 1995; Milligan et al., 1995), but it is in that of signal transduction (for reviews see Bell and Burns, 1991; Nishizuka, 1992, 1995; Billah, 1993; Divecha and Irvine, 1995; Liscovitch and Cantley, 1995; Milligan et al., 1995; Corda and Falasca, 1996) where novel lipid second messengers continue to be described (Panayotou and Waterfield, 1992; Cuadrado et al., 1993; Hannun, 1994; Su et al., 1994; Moolenaar, 1995; Pushkareva et al., 1995; Falasca et al., 1996a). Thus membrane lipids are acted upon by intracellular phospholipases (phospholipase A2 (PLA2), phospholipase C (PLC) and phospholipase D), leading to the production of lipid second messengers that are involved in the modulation of different functional cellular responses (Exton, 1990; Dennis et al., 1991; Cockcroft and Thomas, 1992; Nishizuka, 1992; Berridge, 1993; Billah, 1993; Glaser et al., 1993; Iacovelli et al., 1993; Mayer and Marshall, 1993; Dennis, 1994; Divecha and Irvine, 1995; Lee and Rhee, 1995). Activation of one of these phospholipases, PLA2, leads to the mobilisation of arachidonic acid from an sn-2 linkage of phosphatidylcholine (PtdCho), phosphatidyl-ethanolamine (PtdEth) and phosphatidylinositol (PtdIns) in numerous mammalian cell types (Van den Bosch, 1980; Irvine, 1982), which, in turn, serves as a substrate for the production of other cellular second messengers, such as the prostaglandins and leukotrienes (Piomelli and Greengard, 1990; Piomelli, 1993; Khan et al., 1995). In the case of PLA2 activation, this is also accompanied by the formation of biologically active lysolipids that have been shown to be mitogens in several cell lines, including lysophosphatidic acid (LysoPtdCOOH; Moolenaar, 1995), lysophosphatidylinositol (LysoPtdIns; Falasca and Corda, 1994) and lysophosphatidylcholine (LysoPtdCho; Asaoka et al., 1991). These lysolipids themselves are the substrates for lysophospholipases that release the fatty acid from the sn-1 linkage, thus producing glycerophospholipids.