<i>N</i>‐Acetyl‐sphingenine‐1‐phosphate is a potent calcium mobilizing agent

Gijsbers, Sofie; Mannaerts, Guy P.; Himpens, Bernard; Veldhoven, Paul P. Van

doi:10.1016/s0014-5793(99)00735-8

Cited by 24 publications

(32 citation statements)

References 29 publications

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“…Failure of C 8 -Cer-1-P to induce intracellular Ca 2 ϩ mobilization has been confirmed recently in neutrophils (20). However, Gijsbers et al (24) and Hogback et al (25) reported that C 2 -Cer-1-P caused fast and transient intracellular rises in Ca 2 ϩ in both calf pulmonary artery endothelial cells and thyroid FRTL-5 cells, respectively, an action that might be related to the mitogenic effect of C 2 -Cer-1-P.…”

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confidence: 92%

Ceramide-1-phosphate blocks apoptosis through inhibition of acid sphingomyelinase in macrophages

Gómez-Muñoz

Kong

Salh

et al. 2004

Journal of Lipid Research

194

182

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. We now show that Cer-1-P prevents cell death in bone-marrow-derived macrophages (BMDMs) after withdrawal of macrophage colony-stimulating factor (M-CSF). Removal of M-CSF is known to induce apoptosis in these cells. Cer-1-P blocked activation of the caspase-9/caspase-3 pathway and prevented DNA fragmentation, indicating that the enhancement of cell survival was due to inhibition of apoptosis. M-CSF deprivation resulted in activation of acid sphingomyelinase (A-SMase), increased ceramide levels, and a decrease in intracellular Cer-1-P. Exogenously added Cer-1-P inhibited A-SMase in intact BMDMs at concentrations that also prevented apoptosis. Cer-1-P also inhibited A-SMase in cell homogenates, suggesting a possible direct physical interaction of Cer-1-P with the enzyme. In conclusion, these data demonstrate that Cer-1-P blocks apoptosis in BMDMs through inhibition of A-SMase, thereby reducing ceramide generation. This adds a new dimension to the understanding of the metabolic interrelationship of ceramides and Cer-1-P, and shows how altering the balance of intracellular levels of these mediators can affect cell survival. The breakdown of sphingomyelin (SM) produces bioactive sphingolipid metabolites, some of which are believed to act as second messengers that control critical cellular functions. For example, N -deacylation of SM generates sphingosine phosphocholine, which is mitogenic for fibroblasts (1). Stimulation of SMase activity produces ceramides, which can inhibit cell proliferation and are potent inducers of apoptosis (2-4). Ceramides have been shown to regulate several protein kinases, including ceramide-activated protein kinase (5, 6) and protein kinase C (7), or protein phosphatases of the 2 A family (8). In addition, ceramides are potent inhibitors of phospholipase D, both in cultured cells (9, 10) and in cell-free systems (11). Ceramides can be degraded by ceramidases to sphingosine, and this, in turn, can be phosphorylated by sphingosine kinase to produce sphingosine-1-phosphate (Sph-1-P). Both sphingosine and Sph-1-P have been implicated in the regulation of cell proliferation and death (12-15).Another important ceramide metabolite that can be generated through the action of ceramide kinase is ceramide-1-phosphate (Cer-1-P) (16, 17). Boudker and Futerman (18) characterized a phosphatase that specifically hydrolyzes Cer-1-P in plasma membranes, suggesting that ceramide and Cer-1-P can be interconverted in cells. More recently, Riboni et al. (19) observed that Cer-1-P can also be produced from the recycling of sphingosine produced from ganglioside catabolism, and Rile et al. (20) reported that Cer-1-P can be formed intracellularly in neutrophils. Critical biological functions have been attributed to Cer-1-P. We first found that short-chain acetyl (C 2 )-and octanoyl (C 8 )-Cer-1-P, as well as natural long-chain Cer-1-P, stimulated the incorporation of [ 3 H]thymidine into DNA in fibroblasts, and that this action did not involve conversion of Cer-1-P to Sph-1-P (21, 22). More recently, it was fo...

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confidence: 92%

Ceramide-1-phosphate blocks apoptosis through inhibition of acid sphingomyelinase in macrophages

Gómez-Muñoz

Kong

Salh

et al. 2004

Journal of Lipid Research

194

182

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“…C1Ps also failed to induce Ca 2+ mobilization in neutrophils [12], and A549 cells [7]. However, C 2 -C1P has been reported to induce Ca 2+ mobilization in calf pulmonary artery endothelial cells [13], thyroid FTRL-5 cells [14], and GH4C1 pituitary cells [15], and induction of ERK2 phosphorylation has been observed in osteoblasts [16]. The reason for these discrepancies is unknown at present, but it may be that the effects of C1P are cell type specific.…”

Section: Introductionmentioning

confidence: 99%

Ceramide‐1‐phosphate promotes cell survival through activation of the phosphatidylinositol 3‐kinase/protein kinase B pathway

et al. 2005

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In this report, we show for the first time that ceramide-1-phosphate (C1P) stimulates the phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (PKB) pathway, which is a major mechanism whereby growth factors promote cell survival. Also, C1P induced IjB phosphorylation, and enhanced the DNA binding activity of the transcription factor NF-jB. Apoptotic macrophages showed a marked reduction of Bcl-X L levels, and this was prevented by C1P. These findings suggest that C1P blocks apoptosis, at least in part, by stimulating the PI3-K/ PKB/ NF-jB pathway and maintaining the production of antiapoptotic Bcl-X L . Based on these and our previous observations, we propose a working model for C1P in which inhibition of acid sphingomyelinase and the subsequent decrease in ceramide levels would allow cell signaling through stimulation of the PI3-K/PKB pathway to promote cell survival.

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“…As the process of phagocytosis proceeds, cytoplasmic granules fuse with the phagosome membrane to deliver hydrolytic and antibacterial enzymes to the phagosome (4). Phagolysosome formation is dependent upon intracellular Ca 21 and requires the activity of a complex containing docking and fusion proteins (5,6).…”

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confidence: 99%

“…Ca 21 is a ubiquitous intracellular messenger controlling a diverse range of cellular processes, such as gene transcription, muscle contraction, cell proliferation, and apoptosis (7). Cytosolic Ca 21 signaling occurs through both Ca 21 release from intracellular stores and Ca 21 entry from the extracellular environment.…”

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confidence: 99%

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Ceramide kinase promotes Ca2+ signaling near IgG-opsonized targets and enhances phagolysosomal fusion in COS-1 cells

Hinkovska‐Galcheva

Clark

VanWay

et al. 2008

Journal of Lipid Research

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Ceramide-1-phosphate (C1P) is a novel bioactive sphingolipid formed by the phosphorylation of ceramide catalyzed by ceramide kinase (CERK). In this study, we evaluated the mechanism by which increased C1P during phagocytosis enhances phagocytosis and phagolysosome formation in COS-1 cells expressing hCERK. Stable transfectants of COS-1 cells expressing FcgRIIA or both FcgRIIA/ hCERK expression vectors were created. Cell fractionation studies demonstrated that hCERK and the transient receptor potential channel (TRPC-1) were enriched in caveolae fractions. Our data establish that both CERK and TRPC-1 localize to the caveolar microdomains during phagocytosis and that CERK also colocalizes with EIgG in FcgRIIA/hCERKbearing COS-1 cells. Using high-speed fluorescence microscopy, FcgRIIA/hCERK transfected cells displayed Ca 21 sparks around the phagosome. In contrast, cells expressing FcgRIIA under identical conditions displayed little periphagosomal Ca 21 signaling. The enhanced Ca 21 signals were accompanied by enhanced phagolysosome formation. However, the addition of pharmacological reagents that inhibit store-operated channels (SOCs) reduced the phagocytic index and phagolysosomal fusion in hCERK transfected cells. The higher Ca 21 signal observed in hCERK transfected cells as well as the fact that CERK colocalized with EIgG during phagocytosis support our hypothesis that Ca 21 signaling is an important factor for increasing phagocytosis and is regulated by CERK in a manner that involves SOCs/TRPCs.-Hinkovska-Galcheva, V

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N‐Acetyl‐sphingenine‐1‐phosphate is a potent calcium mobilizing agent

Cited by 24 publications

References 29 publications

Ceramide-1-phosphate blocks apoptosis through inhibition of acid sphingomyelinase in macrophages

Ceramide-1-phosphate blocks apoptosis through inhibition of acid sphingomyelinase in macrophages

Ceramide‐1‐phosphate promotes cell survival through activation of the phosphatidylinositol 3‐kinase/protein kinase B pathway

Ceramide kinase promotes Ca2+ signaling near IgG-opsonized targets and enhances phagolysosomal fusion in COS-1 cells

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