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Sphingolipids: second messengers, mediators and raft constituents in signaling

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Abstract

Recently, evidence has accumulated to show that sphingolipids exert an important function in signaling. These lipids serve as intracellular second messengers and as extracellular mediators. Furthermore, glycosylated sphingolipids are essential components of membrane rafts, which serve as platforms for the initiation of signaling cascades. Here, Eva Prieschl and Thomas Baumruker summarize current findings in leukocytes illustrating these different facets.

Section snippets

Ceramide, a second messenger in lymphocytes

A prototype molecule for the second messenger role of sphingolipids is ceramide. The transition from regarding these molecules as membrane constituents to regarding them as signals is illustrated best in neutrophils, where ceramide accumulates during phagocytosis, particularly as ceramide-1-phosphate (C1P). Elevated levels of this phospholipid promote the fusion of liposomes, which is now attributed to the signaling character, rather than the membrane constituent feature, of C1P. This implies a

Sphingolipids: constituents of signal-initiating rafts

Rafts serve as platforms for glycosylphosphatidylinositol (GPI)-anchored proteins (e.g. CD14, CD16b, CD24, CD48, CD58, CD59, CD67, CD73, CD87 and CD157), some transmembrane proteins [e.g. linker of activated T cells (LAT), CD4, CD8, CD26, CD36 and CD44], receptors [e.g. FceRI, FcaR and the B-cell receptor (BCR)] and doubly acylated protein tyrosine kinases of the Src family (Lyn, Lck, Fyn, Hck; reviewed in Ref. 3). The first two groups are incorporated into rafts in the endoplasmic reticulum

Conclusions and perspectives

Sphingolipids are involved in the initiation and transmission of signals in leukocytes, making them attractive drug candidates. Indeed, derivatives have been used as potential therapeutics for immuno-stimulation (α-galactosylceramide), immuno-suppression (ISP-1 also termed myriocin) and hematopoiesis (N-butyrylsphinganine). In addition, interfering with the enzymes involved in the anabolism and catabolism of sphingolipids might lead to a shift in the balance between counter-regulatory

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