Sphingolipid metabolites: Members of a new class of lipid second messengers

Abstract

In the last decade, many studies have demonstrated that glycerophospholipid metabolites, such as diacylglycerol, inositol 1,4,5-trisphosphate (InsP3), phosphatidic acid, and arachidonic acid, function as second messengers in growth-signaling pathways (Irvine, 1982; Exton, 1990; Nishizuka, 1992; Berridge, 1993). The importance of intracellular signaling molecules derived from another major class of membrane lipids, sphingolipids, has only recently begun to be appreciated. Sphingolipids contain a long-chain sphingoid base backbone of which sphingosine is the most prominent; an amide-linked fatty acid with 16-24 methylene groups; and a polar head group (hydroxyl for ceramide, phosphorylcholine for sphingomyelin, or carbohydrate residues of varying complexity for glycosphingolipids) (Fig. 1). These ubiquitous lipids have long been implicated in cell growth and differentiation, oncogenesis, and cell-cell contact (reviewed in Hakomori, 1990; Olivera & Spiegel, 1992). They act as cell surface receptors for some viruses and bacteria; they can modulate the functions of certain growth factors; and may be effectors of protein kinases, ion transporters, and other membrane proteins. However, more recently it has become evident that the biological activity of sphingolipids resides not only in the more complex species (e.g., sphingomyelin, cerebrosides, gangliosides, and sulfatides), but also in their metabolic products, such as ceramide (Hannun, 1994; Kolesnick & Golde, 1994), sphingosine (Zhang et al., 1990a; Merrill, 1991) sphingosine1-phosphate (Zhang et al., 1991; Desai el at., 1992; Olivera & Spiegel, 1993; Spiegel, 1993; Mattie et al., 1994) lysosphingomyelin or sphingosylphosphorylcholine (Desai & Spiegel, 1991; Desai et al., 1993), and diand trimethylsphingosine (Igarashi et al., 1990; Hakomori & Igarashi, 1993). The second messenger functions of ceramide mediating the effects of several extracellular stimuli, including TNF-c~, vitamin D3, 7-interferon, and IL-1 and IL-2, has recently been the subject of excellent reviews (Hannun, 1994; Kolesnick & Golde, 1994) and will not be covered here. In this review, we will summarize current knowledge regarding the second messenger role of sphingosine and its metabolites, sphingosine-l-phosphate (SPP) 1 and sphingosylphosphorylcholine (SPC) 1, in the regulation of cellular processes and also discuss possible mechanisms underlying their action.

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