Sphingolipids in mammalian cell signalling

Abstract

Sphingolipids and their metabolites, ceramide, sphingosine and sphingosine-1-phosphate, are involved in a variety of cellular processes including differentiation, cellular senescence, apoptosis and proliferation. Ceramide is the main second messenger, and is produced by sphingomyelinase-induced hydrolysis of sphingomyelin and by de novo synthesis. Many stimuli, e. g. growth factors, cytokines, G protein-coupled receptor agonists and stress (UV irradiation) increase cellular ceramide levels. Sphingomyelin in the plasma membrane is located primarily in the outer (extracellular) leaflet of the bilayer, whilst sphingomyelinases are found at the inner (cytosolic) face and within lysosomes/endosomes. Such cellular compartmentalisation restricts the site of ceramide production and subsequent interaction with target proteins. Glycosphingolipids and sphingomyelin together with cholesterol are major components of specialised membrane microdomains known as lipid rafts, which are involved in receptor aggregation and immune responses. Many signalling molecules, for example Src family tyrosine kinases and glycosylinositolphosphate-anchored proteins, are associated with rafts, and disruption of these domains affects cellular responses such as apoptosis. Sphingosine and sphingosine-1-phosphate derived from ceramide are also signalling molecules. In particular, sphingosine-1-phosphate is involved in proliferation, differentiation and apoptosis. Sphingosine-1-phosphate can act both extracellularly through endothelial-differentiating gene (EDG) family G protein-coupled receptors and intracellularly through direct interactions with target proteins. The importance of sphingolipid signalling in cardiovascular development has been reinforced by recent reports implicating EDG receptors in the regulation of embryonic cardiac and vascular morphogenesis.

Isc1p Plays a Key Role in Hydrogen Peroxide Resistance and Chronological Lifespan through Modulation of Iron Levels and Apoptosis

“…Sphingolipids such as ceramide, sphingosine, and sphingosine-1-phosphate are important signaling molecules conserved during evolution, with roles in differentiation, senescence, cell cycle arrest, apoptosis, and stress responses Ohanian and Ohanian, 2001). Data published in recent years have established a link between sphingolipid signaling and redox regulation.…”

Sphingolipid therapy in myocardial ischemia–reperfusion injury

“…Glycosphingolipids can be further subdivided in neutral (cerebrosides) or acidic fractions (gangliosides and sulfatides). It is become evident that the biological activity of sphingolipids resides not only in their complex structures (e.g., gangliosides and sulfatides) but also in their derivatives and metabolites such as ceramide, sphingosine and N-methylated products (i.e, N,N-dimethylsphingosine (DMS) [17]. Sphingolipid and its metabolites have been found to play an important role in a number of biological and pathological processes including myocardial ischemia reperfusion injury [18].…”

Yeast genome-wide drug-induced haploinsufficiency screen to determine drug mode of action

“…4E). Higher ceramide concentrations reduced the extent of the rescue (data not shown), possibly because ceramide is known to induce apoptosis at higher concentrations (13,20). These results indicate that modulation of ceramide levels by dhMotC is relevant to its mechanism of action in yeast and mammalian cells alike.…”

“…Sphingolipids are essential components of all eukaryotic cells, playing both structural and regulatory roles (13,14). The first committed step of sphingolipid synthesis is the condensation of serine and palmitoyl CoA to 3-ketodihydrosphingosine catalyzed by serine palmitoyl transferase, composed of subunits encoded by LCB1 and LCB2.…”

“…One explanation is that dhMotC might have additional targets in human cells that are not present in yeast. Alternatively, because ceramide has been implicated in the regulation of numerous cellular pathways including apoptosis, senescence and cell-cycle arrest (13,20), it is possible that rescue by exogenous ceramide is limited by its intrinsic toxicity. Nevertheless, this result provides crucial evidence that drug-induced haploinsufficiency studies in yeast can reveal pathways targeted by drugs in human cells.…”