Thematic Review Series: Sphingolipids. Cross-talk at the crossroads of sphingosine-1-phosphate, growth factors, and cytokine signaling*

Abstract

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that mediates a wide array of biologic effects through its interaction with a family of five G protein-coupled receptors. Cytokines and growth factors interact with this signaling pathway in a variety of ways, including both activation and regulation of the expression of the enzymes that regulate synthesis and degradation of S1P. Not only do many growth factors and cytokines stimulate S1P production, leading to transactivation of S1P receptors, ligation of S1P receptors by S1P can also transactivate growth factor tyrosine kinase receptors and stimulate growth factor and cytokine signaling cascades. This review discusses the mechanisms involved in cross-talk between S1P, cytokines, and growth factors and the impact of that cross-talk on cell signaling and cell biology. The biological effects of sphingosine-1-phosphate (S1P) overlap with those of a wide array of cytokines and growth factors. There is increasing evidence that this overlap in functions relates to both the ability of growth factors and cytokines to transactivate S1P signaling cascades as well as the ability of S1P to transactivate growth factor and cytokine signaling cascades. This mutual pathway cross-talk affects cell growth, differentiation, and movement and is integral to a variety of normal processes as well as disease processes, including inflammation and cancer. This review will focus on the ways in which S1P and growth factor or cytokine signaling pathways interact. S1P S1P is a potent bioactive lipid that regulates processes that are essential to cellular homeostasis, including cell viability, differentiation, and motility (1-3). Most of its bestcharacterized actions are mediated through a family of five G protein-coupled receptors, (GPCRs) S1P 1-5 (4, 5). The S1P receptors couple to a variety of G proteins, allowing them to mediate many different biologic responses (6, 7).One mechanism for cross-talk between cytokine or growth factor pathways and S1P signaling involves regulation of S1P metabolism. Sphingolipid metabolism was the focus of a recent excellent review (3) and will not be discussed in detail here. Cellular levels of S1P are regulated by the activities of the enzymes that are responsible for its synthesis and degradation. In mammalian cells, two sphingosine kinases, SphK1 and SphK2, catalyze the phosphorylation of sphingosine to generate S1P (8). Although both isozymes phosphorylate sphingosine, they differ in their enzymatic properties, cellular location, and biological roles (9). SphK1 is generally regarded as providing pro-survival signals, whereas SphK2, at least when overexpressed, induces apoptosis in several cell types (10). S1P is degraded to sphingosine by specific S1P phosphatases (11) or cleaved to palmitaldehyde and phosphoethanolamine by S1P lyase (12). Thus, it is clear that S1P levels can potentially be altered by stimuli that affect activity or expression of any of these enzymes. However, the majority of cytokines and growth factors that coopt regu...

Role of sphingolipids in oestrogen signalling in breast cancer cells: an update

“…It was shown that production of S1P is stimulated by several growth factors during activation of proliferation (Lebman & Spiegel 2008. Clinical data confirmed the importance of sphingolipid signalling in human breast carcinomas (Ruckhäberle et al 2008.…”

“…Notably, sphingolipid metabolism is activated during normal cell growth and division not only to provide a basic supply of structural and functional metabolites but also to serve as second messengers (Lebman & Spiegel 2008, Aoyagi et al 2012. In this review, we analysed recent knowledge gained at the crossroads of sphingolipid and oestrogen signalling pathways in breast cancer cells (BCC).…”

Sphingosine‐1‐Phosphate is Involved in the Occlusive Arteriopathy of Pulmonary Arterial Hypertension

“…[37][38][39][40] SphK1 can be activated by several mediators, and S1P produced and released into the extracellular milieu promotes cell proliferation and survival by acting on its G protein-coupled receptors and by transactivating a spectrum of receptor tyrosine kinases, including those of plateletderived growth factor (PDGF), transforming growth factor β, epidermal growth factor, hepatocyte growth factor, and VEGF. 41 Importantly, constitutive activation of SphK1 in endothelial cells induces a proinflammatory and proangiogenic phenotype, 42 and SphK inhibitors block pathologic neovascularization in animal models. 43 Given that many of the aforementioned growth factor receptors and pathogenic processes have been implicated in the pathogenesis of occlusive lesions in PAH, 44 we examined the effect of exogenous S1P on rat PAECs and found that it stimulated cell proliferation.…”

Stress and expression of cyclooxygenases (cox1, cox2a, cox2b) and intestinal eicosanoids, in Atlantic salmon, Salmo salar L.

“…These are characterized by having a lower content of n-3 polyunsaturated fatty acids (PUFA), and a higher content of n-6 PUFA. The fatty acids are incorporated into cellular membranes in a ratio corresponding to their dietary content (Henderson and Tocher 1987), where they serve many central homeostatic and immunologic functions (de Pablo and de Cienfuegos 2000;Vance 2008;Lebman and Spiegel 2008). A significant part of these processes are mediated through the action of eicosanoids including prostaglandins (PG) and prostacyclins.…”