Ceramide-1-Phosphate in Cell Survival and Inflammatory Signaling

  • Antonio Gómez-Muñoz
  • Patricia Gangoiti
  • María H. Granado
  • Lide Arana
  • Alberto Ouro
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 688)


An important metabolite of ceramide is ceramide-1-phosphate (C1P). This lipid second messenger was first demonstrated to be mitogenic for fibroblasts and macrophages and later shown to have antiapoptotic properties. C1P is also an important mediator of the inflammatory response, by stimulating the release of arachidonic acid through activation of group IVA cytosolic phospholipase A2, the initial rate-limiting step of eicosanoid biosynthesis. C1P is formed from ceramide by the action of a specific ceramide kinase (CerK), which is distinct from the sphingosine kinases that synthesize sphingosine-1-phosphate. CerK is specific for natural ceramides with the erythro configuration in the base component and esterified to long-chain fatty acids. CerK can be activated by different agonists, including interleukin 1-beta, macrophage colony stimulating factor, or calcium ions. Most of the effects of C1P so far described seem to take place in intracellular compartments; however, the recent observation that C1P stimulates cell migration implicates a specific plasma membrane receptor that is coupled to a Gi protein. Therefore, C1P has a dual regulatory capacity acting as an intracellular second messenger to regulate cell survival, or as extracellular receptor ligand to stimulate chemotaxis.


Pleckstrin Homology Domain Ceramide Accumulation Acid SMase SMase Activity Ulatory Molecule 


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  1. 1.
    Zhang J, Xu M. Apoptotic DNA fragmentation and tissue homeostasis. Trends Cell Biol 2002; 12:84–9.PubMedCrossRefGoogle Scholar
  2. 2.
    Vaux DL, Korsmeyer SJ. Cell death in development. Cell 1999; 96:245–54.PubMedCrossRefGoogle Scholar
  3. 3.
    Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science 1995; 267:1456–62.PubMedCrossRefGoogle Scholar
  4. 4.
    Merrill AH Jr, Jones DD. An update of the enzymology and regulation of sphingomyelin metabolism. Biochim Biophys Acta 1990; 1044:1–12.PubMedGoogle Scholar
  5. 5.
    Merrill AH Jr, Schmelz EM, Dillehay DL et al. Sphingolipids—the enigmatic lipid class: biochemistry, physiology and pathophysiology. Toxicol Appl Pharmacol 1997; 142:208–25.PubMedCrossRefGoogle Scholar
  6. 6.
    Merrill AH Jr. Cell regulation by sphingosine and more complex sphingolipids. J Bioenerg Biomembr 1991; 23:83–104.PubMedGoogle Scholar
  7. 7.
    Merrill AH Jr. De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway. J Biol Chem 2002; 277:25843–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Spiegel S, Merrill AH Jr. Sphingolipid metabolism and cell growth regulation. Faseb J 1996; 10:1388–97.PubMedGoogle Scholar
  9. 9.
    Kolesnick R, Golde DW. The sphingomyelin pathway in tumor necrosis factor and interleukin-1 signaling. Cell 1994; 77:325–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Kolesnick RN. 1,2-Diacylglycerols but not phorbol esters stimulate sphingomyelin hydrolysis in GH3 pituitary cells. J Biol Chem 1987; 262:16759–62.PubMedGoogle Scholar
  11. 11.
    Kolesnick RN, Hemer MR. Characterization of a ceramide kinase activity from human leukemia (HL-60) cells. Separation from diacylglycerol kinase activity. J Biol Chem 1990; 265:18803–8.PubMedGoogle Scholar
  12. 12.
    Kolesnick RN, Goni FM, Alonso A. Compartmentalization of ceramide signaling: physical foundations and biological effects. J Cell Physiol 2000; 184:285–300.PubMedCrossRefGoogle Scholar
  13. 13.
    Hannun YA. The sphingomyelin cycle and the second messenger function of ceramide. J Biol Chem 1994; 269:3125–8.PubMedGoogle Scholar
  14. 14.
    Hannun YA, Loomis CR, Merrill AH Jr et al. Sphingosine inhibition of protein kinase C activity and of phorbol dibutyrate binding in vitro and in human platelets. J Biol Chem 1986; 261:12604–9.PubMedGoogle Scholar
  15. 15.
    Hannun YA, Obeid LM. Ceramide: an intracellular signal for apoptosis. Trends Biochem Sci 1995; 20:73–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Hannun YA. Functions of ceramide in coordinating cellular responses to stress. Science 1996; 274:1855–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Hannun YA, Obeid LM. The Ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind. J Biol Chem 2002; 277:25847–50.PubMedCrossRefGoogle Scholar
  18. 18.
    Brann AB, Scott R, Neuberger Y et al. Ceramide signaling downstream of the p75 neurotrophin receptor mediates the effects of nerve growth factor on outgrowth of cultured hippocampal neurons. J Neurosci 1999; 19:8199–206.PubMedGoogle Scholar
  19. 19.
    Goodman Y, Mattson MP. Ceramide protects hippocampal neurons against excitotoxic and oxidative insults and amyloid beta-peptide toxicity. J Neurochem 1996; 66:869–72.PubMedCrossRefGoogle Scholar
  20. 20.
    Ping SE, Barrett GL. Ceramide can induce cell death in sensory neurons, whereas ceramide analogues and sphingosine promote survival. J Neurosci Res 1998; 54:206–13.PubMedCrossRefGoogle Scholar
  21. 21.
    Plummer G, Perreault KR, Holmes CF et al. Activation of serine/threonine protein phosphatase-1 is required for ceramide-induced survival of sympathetic neurons. Biochem J 2005; 385:685–93.PubMedCrossRefGoogle Scholar
  22. 22.
    Song MS, Posse de Chaves EI. Inhibition of rat sympathetic neuron apoptosis by ceramide. Role of p75NTR in ceramide generation. Neuropharmacology 2003; 45:1130–50.PubMedCrossRefGoogle Scholar
  23. 23.
    Dressler KA, Mathias S, Kolesnick RN. Tumor necrosis factor-alpha activates the sphingomyelin signal transduction pathway in a cell-free system. Science 1992; 255:1715–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Gómez-Muñoz A. Modulation of cell signalling by ceramides. Biochim Biophys Acta 1998; 1391:92–109.PubMedGoogle Scholar
  25. 25.
    Mathias S, Dressler KA, Kolesnick RN. Characterization of a ceramide-activated protein kinase: stimulation by tumor necrosis factor alpha. Proc Natl Acad Sci USA 1991; 88:10009–13.PubMedCrossRefGoogle Scholar
  26. 26.
    Mathias S, Kolesnick R. Ceramide: a novel second messenger. Adv Lipid Res 1993; 25:65–90.PubMedGoogle Scholar
  27. 27.
    Okazaki T, Bielawska A, Bell RM et al. Role of ceramide as a lipid mediator of 1 alpha,25-dihydroxyvitamin D3-induced HL-60 cell differentiation. J Biol Chem 1990; 265:15823–31.PubMedGoogle Scholar
  28. 28.
    Menaldino DS, Bushnev A, Sun A et al. Sphingoid bases and de novo ceramide synthesis: enzymes involved, pharmacology and mechanisms of action. Pharmacol Res 2003; 47:373–81.PubMedCrossRefGoogle Scholar
  29. 29.
    Gulbins E, Kolesnick R. Raft ceramide in molecular medicine. Oncogene 2003; 22:7070–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Adams JM 2nd, Pratipanawatr T, Berria R et al. Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. Diabetes 2004; 53:25–31.PubMedCrossRefGoogle Scholar
  31. 31.
    Schmitz-Peiffer C. Protein kinase C and lipid-induced insulin resistance in skeletal muscle. Ann N Y Acad Sci 2002; 967:146–57.PubMedCrossRefGoogle Scholar
  32. 32.
    Stratford S, Hoehn KL, Liu F et al. Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. J Biol Chem 2004; 279:36608–15.PubMedCrossRefGoogle Scholar
  33. 33.
    Sun L, Xu L, Henry FA et al. A new wound healing agent—sphingosylphosphorylcholine. J Invest Dermatol 1996; 106:232–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Spiegel S, Foster D, Kolesnick R. Signal transduction through lipid second messengers. Curr Opin Cell Biol 1996; 8:159–67.PubMedCrossRefGoogle Scholar
  35. 35.
    Spiegel S, Milstien S. Sphingosine 1-phosphate, a key cell signaling molecule. J Biol Chem 2002; 277:25851–4.PubMedCrossRefGoogle Scholar
  36. 36.
    Spiegel S, Olivera A, Carlson RO. The role of sphingosine in cell growth regulation and transmembrane signaling. Adv Lipid Res 1993; 25:105–29.PubMedGoogle Scholar
  37. 37.
    Spiegel S, Milstien S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol 2003; 4:397–407.PubMedCrossRefGoogle Scholar
  38. 38.
    Gómez-Muñoz A. Ceramide-1-phosphate: a novel regulator of cell activation. FEBS Lett 2004; 562:5–10.PubMedCrossRefGoogle Scholar
  39. 39.
    Gómez-Muñoz A, Duffy PA, Martin A et al. Short-chain ceramide-1-phosphates are novel stimulators of DNA synthesis and cell division: antagonism by cell-permeable ceramides. Mol Pharmacol 1995; 47:833–9.PubMedGoogle Scholar
  40. 40.
    Gómez-Muñoz A, Frago LM, Alvarez L et al. Stimulation of DNA synthesis by natural ceramide 1-phosphate. Biochem J 1997; 325 (Pt 2):435–40.PubMedGoogle Scholar
  41. 41.
    Goni FM, Alonso A. Sphingomyelinases: enzymology and membrane activity. FEBS Lett 2002; 531:38–46.PubMedCrossRefGoogle Scholar
  42. 42.
    Cremesti AE, Goni FM, Kolesnick R. Role of sphingomyelinase and ceramide in modulating rafts: do biophysical properties determine biologic outcome? FEBS Lett 2002; 531:47–53.PubMedCrossRefGoogle Scholar
  43. 43.
    Merrill AH Jr, Sullards MC, Allegood JC et al. Sphingolipidomics: high-throughput, structure-specific and quantitative analysis of sphingolipids by liquid chromatography tandem mass spectrometry. Methods 2005; 36:207–24.PubMedCrossRefGoogle Scholar
  44. 44.
    Pettus BJ, Bielawska A, Kroesen BJ et al. Observation of different ceramide species from crude cellular extracts by normal-phase high-performance liquid chromatography coupled to atmospheric pressure chemical ionization mass spectrometry. Rapid Commun Mass Spectrom 2003; 17:1203–11.PubMedCrossRefGoogle Scholar
  45. 45.
    Merrill AH Jr, Sullards MC, Wang E et al. Sphingolipid metabolism: roles in signal transduction and disruption by fumonisins. Environ Health Perspect 2001; 109(Suppl 2):283–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Van Overloop H, Denizot Y, Baes M et al. On the presence of C2-ceramide in mammalian tissues: possible relationship to etherphospholipids and phosphorylation by ceramide kinase. Biol Chem 2007; 388:315–24.PubMedCrossRefGoogle Scholar
  47. 47.
    Smith ER, Jones PL, Boss JM et al. Changing J774A.1 cells to new medium perturbs multiple signaling pathways, including the modulation of protein kinase C by endogenous sphingoid bases. J Biol Chem 1997; 272:5640–6.PubMedCrossRefGoogle Scholar
  48. 48.
    Gómez-Muñoz A, Hamza EH, Brindley DN. Effects of sphingosine, albumin and unsaturated fatty acids on the activation and translocation of phosphatidate phosphohydrolases in rat hepatocytes. Biochim Biophys Acta 1992; 1127:49–56.PubMedGoogle Scholar
  49. 49.
    Jamal Z, Martin A, Gómez-Muñoz A et al. Plasma membrane fractions from rat liver contain a phosphatidate phosphohydrolase distinct from that in the endoplasmic reticulum and cytosol. J Biol Chem 1991; 266:2988–96.PubMedGoogle Scholar
  50. 50.
    Natarajan V, Jayaram HN, Scribner WM et al. Activation of endothelial cell phospholipase D by sphingosine and sphingosine-1-phosphate. Am J Respir Cell Mol Biol 1994; 11:221–9.PubMedGoogle Scholar
  51. 51.
    Sakane F, Yamada K, Kanoh H. Different effects of sphingosine, R59022 and anionic amphiphiles on two diacylglycerol kinase isozymes purified from porcine thymus cytosol. FEBS Lett 1989; 255:409–13.PubMedCrossRefGoogle Scholar
  52. 52.
    Yamada K, Sakane F, Imai S et al. Sphingosine activates cellular diacylglycerol kinase in intact Jurkat cells, a human T-cell line. Biochim Biophys Acta 1993; 1169:217–24.PubMedGoogle Scholar
  53. 53.
    Wu J, Spiegel S, Sturgill TW. Sphingosine 1-phosphate rapidly activates the mitogen-activated protein kinase pathway by a G protein-dependent mechanism. J Biol Chem 1995; 270:11484–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Olivera A, Spiegel S. Sphingosine-1-phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens. Nature 1993; 365:557–60.PubMedCrossRefGoogle Scholar
  55. 55.
    Rabano M, Pena A, Brizuela L et al. Sphingosine-1-phosphate stimulates cortisol secretion. FEBS Lett 2003; 535:101–5.PubMedCrossRefGoogle Scholar
  56. 56.
    Brizuela L, Rabano M, Pena A et al. Sphingosine 1-phosphate: a novel stimulator of aldosterone secretion. J Lipid Res 2006; 47:1238–49.PubMedCrossRefGoogle Scholar
  57. 57.
    Chalfant CE, Spiegel S. Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling. J Cell Sci 2005; 118:4605–12.PubMedCrossRefGoogle Scholar
  58. 58.
    Lamour NF, Chalfant CE. Ceramide-1-phosphate: the “missing” link in eicosanoid biosynthesis and inflammation. Mol Interv 2005; 5:358–67.PubMedCrossRefGoogle Scholar
  59. 59.
    Hinkovska-Galcheva V, Boxer LA, Kindzelskii A et al. Ceramide 1-phosphate, a mediator of phagocytosis. J Biol Chem 2005; 280:26612–21.PubMedCrossRefGoogle Scholar
  60. 60.
    Hinkovska-Galcheva VT, Boxer LA, Mansfield PJ et al. The formation of ceramide-1-phosphate during neutrophil phagocytosis and its role in liposome fusion. J Biol Chem 1998; 273:33203–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Bajjalieh SM, Martin TF, Floor E. Synaptic vesicle ceramide kinase. A calcium-stimulated lipid kinase that copurifies with brain synaptic vesicles. J Biol Chem 1989; 264:14354–60.PubMedGoogle Scholar
  62. 62.
    Mitsutake S, Kim TJ, Inagaki Y et al. Ceramide kinase is a mediator of calcium-dependent degranulation in mast cells. J Biol Chem 2004; 279:17570–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Van Overloop H, Gijsbers S, Van Veldhoven PP. Further characterization of mammalian ceramide kinase: substrate delivery and (stereo)specificity, tissue distribution and subcellular localization studies. J Lipid Res 2006; 47:268–83.PubMedCrossRefGoogle Scholar
  64. 64.
    Boath A, Graf C, Lidome E et al. Regulation and traffic of ceramide 1-phosphate produced by ceramide kinase: comparative analysis to glucosylceramide and sphingomyelin. J Biol Chem 2008; 283:8517–26.PubMedCrossRefGoogle Scholar
  65. 65.
    Lamour NF, Stahelin RV, Wijesinghe DS et al. Ceramide kinase uses ceramide provided by ceramide transport protein: localization to organelles of eicosanoid synthesis. J Lipid Res 2007; 48:1293–304.PubMedCrossRefGoogle Scholar
  66. 66.
    Baumruker T, Bornancin F, Billich A. The role of sphingosine and ceramide kinases in inflammatory responses. Immunol Lett 2005; 96:175–85.PubMedCrossRefGoogle Scholar
  67. 67.
    Truett AP 3rd, King LE Jr. Sphingomyelinase D: a pathogenic agent produced by bacteria and arthropods. Adv Lipid Res 1993; 26:275–91.PubMedGoogle Scholar
  68. 68.
    Lee S, Lynch KR. Brown recluse spider (Loxosceles reclusa) venom phospholipase D (PLD) generates lysophosphatidic acid (LPA). Biochem J 2005; 391:317–23.PubMedCrossRefGoogle Scholar
  69. 69.
    Sugiura M, Kono K, Liu H et al. Ceramide kinase, a novel lipid kinase. Molecular cloning and functional characterization. J Biol Chem 2002; 277:23294–300.PubMedCrossRefGoogle Scholar
  70. 70.
    Kim TJ, Mitsutake S, Kato M et al. The leucine 10 residue in the pleckstrin homology domain of ceramide kinase is crucial for its catalytic activity. FEBS Lett 2005; 579:4383–8.PubMedCrossRefGoogle Scholar
  71. 71.
    Kim TJ, Mitsutake S, Igarashi Y. The interaction between the pleckstrin homology domain of ceramide kinase and phosphatidylinositol 4,5-bisphosphate regulates the plasma membrane targeting and ceramide 1-phosphate levels. Biochem Biophys Res Commun 2006; 342:611–7.PubMedCrossRefGoogle Scholar
  72. 72.
    Wijesinghe DS, Massiello A, Subramanian P et al. Substrate specificity of human ceramide kinase. J Lipid Res 2005; 46:2706–16.PubMedCrossRefGoogle Scholar
  73. 73.
    Pettus BJ, Bielawska A, Spiegel S et al. Ceramide kinase mediates cytokine-and calcium ionophore-induced arachidonic acid release. J Biol Chem 2003; 278:38206–13.PubMedCrossRefGoogle Scholar
  74. 74.
    Graf C, Zemann B, Rovina P et al. Neutropenia with Impaired Immune Response to Streptococcus pneumoniae in Ceramide Kinase-Deficient Mice. J Immunol 2008; 180:3457–66.PubMedGoogle Scholar
  75. 75.
    Tuson M, Marfany G, Gonzalez-Duarte R. Mutation of CERKL, a novel human ceramide kinase gene, causes autosomal recessive retinitis pigmentosa (RP26). Am J Hum Genet 2004; 74:128–38.PubMedCrossRefGoogle Scholar
  76. 76.
    Bornancin F, Mechtcheriakova D, Stora S et al. Characterization of a ceramide kinase-like protein. Biochim Biophys Acta 2005; 1687:31–43.PubMedGoogle Scholar
  77. 77.
    Rile G, Yatomi Y, Takafuta T et al. Ceramide 1-phosphate formation in neutrophils. Acta Haematol 2003; 109:76–83.PubMedCrossRefGoogle Scholar
  78. 78.
    Riboni L, Bassi R, Anelli V et al. Metabolic formation of ceramide-1-phosphate in cerebellar granule cells: evidence for the phosphorylation of ceramide by different metabolic pathways. Neurochem Res 2002; 27:711–6.PubMedCrossRefGoogle Scholar
  79. 79.
    Gangoiti P, Granado MH, Wang SW et al. Ceramide 1-phosphate stimulates macrophage proliferation through activation of the PI3-kinase/PKB, JNK and ERK1/2 pathways. Cell Signal 2008; 20:726–36.PubMedCrossRefGoogle Scholar
  80. 80.
    Pettus BJ, Bielawska A, Subramanian P et al. Ceramide 1-phosphate is a direct activator of cytosolic phospholipase A2. J Biol Chem 2004; 279:11320–6.PubMedCrossRefGoogle Scholar
  81. 81.
    Pettus BJ, Kitatani K, Chalfant CE et al. The coordination of prostaglandin E2 production by sphingosine-1-phosphate and ceramide-1-phosphate. Mol Pharmacol 2005; 68:330–5.PubMedGoogle Scholar
  82. 82.
    Nakamura H, Hirabayashi T, Shimizu M et al. Ceramide-1-phosphate activates cytosolic phospholipase A2alpha directly and by PKC pathway. Biochem Pharmacol 2006; 71:850–7.PubMedCrossRefGoogle Scholar
  83. 83.
    Subramanian P, Stahelin RV, Szulc Z et al. Ceramide 1-phosphate acts as a positive allosteric activator of group IVA cytosolic phospholipase A2 alpha and enhances the interaction of the enzyme with phosphatidylcholine. J Biol Chem 2005; 280:17601–7.PubMedCrossRefGoogle Scholar
  84. 84.
    Gómez-Muñoz A, Kong JY, Salh B et al. Ceramide-1-phosphate blocks apoptosis through inhibition of acid sphingomyelinase in macrophages. J Lipid Res 2004; 45:99–105.PubMedCrossRefGoogle Scholar
  85. 85.
    Shinghal R, Scheller RH, Bajjalieh SM. Ceramide 1-phosphate phosphatase activity in brain. J Neurochem 1993; 61:2279–85.PubMedCrossRefGoogle Scholar
  86. 86.
    Boudker O, Futerman AH. Detection and characterization of ceramide-1-phosphate phosphatase activity in rat liver plasma membrane. J Biol Chem 1993; 268:22150–5.PubMedGoogle Scholar
  87. 87.
    Waggoner DW, Gómez-Muñoz A, Dewald J et al. Phosphatidate phosphohydrolase catalyzes the hydrolysis of ceramide 1-phosphate, lysophosphatidate and sphingosine 1-phosphate. J Biol Chem 1996; 271:16506–9.PubMedCrossRefGoogle Scholar
  88. 88.
    Brindley DN, Waggoner DW. Mammalian lipid phosphate phosphohydrolases. J Biol Chem 1998; 273:24281–4.PubMedCrossRefGoogle Scholar
  89. 89.
    Long J, Darroch P, Wan KF et al. Regulation of cell survival by lipid phosphate phosphatases involves the modulation of intracellular phosphatidic acid and sphingosine 1-phosphate pools. Biochem J 2005; 391:25–32.PubMedCrossRefGoogle Scholar
  90. 90.
    Zhao Y, Usatyuk PV, Cummings R et al. Lipid phosphate phosphatase-1 regulates lysophosphatidic acid-induced calcium release, NF-kappaB activation and interleukin-8 secretion in human bronchial epithelial cells. Biochem J 2005; 385:493–502.PubMedCrossRefGoogle Scholar
  91. 91.
    Gijsbers S, Mannaerts GP, Himpens B et al. N-acetyl-sphingenine-1-phosphate is a potent calcium mobilizing agent. FEBS Lett 1999; 453:269–72.PubMedCrossRefGoogle Scholar
  92. 92.
    Hogback S, Leppimaki P, Rudnas B et al. Ceramide 1-phosphate increases intracellular free calcium concentrations in thyroid FRTL-5 cells: evidence for an effect mediated by inositol 1,4,5-trisphosphate and intracellular sphingosine 1-phosphate. Biochem J 2003; 370:111–9.PubMedCrossRefGoogle Scholar
  93. 93.
    Colina C, Flores A, Castillo C et al. Ceramide-1-P induces Ca2+ mobilization in Jurkat T-cells by elevation of Ins(1,4,5)-P3 and activation of a store-operated calcium channel. Biochem Biophys Res Commun 2005; 336:54–60.PubMedCrossRefGoogle Scholar
  94. 94.
    Jaworowski A, Wilson NJ, Christy E et al. Roles of the mitogen-activated protein kinase family in macrophage responses to colony stimulating factor-1 addition and withdrawal. J Biol Chem 1999; 274:15127–33.PubMedCrossRefGoogle Scholar
  95. 95.
    Hundal RS, Gómez-Muñoz A, Kong JY et al. Oxidized low density lipoprotein inhibits macrophage apoptosis by blocking ceramide generation, thereby maintaining protein kinase B activation and Bcl-XL levels. J Biol Chem 2003; 278:24399–408.PubMedCrossRefGoogle Scholar
  96. 96.
    Mitra P, Maceyka M, Payne SG et al. Ceramide kinase regulates growth and survival of A549 human lung adenocarcinoma cells. FEBS Lett 2007; 581:735–40.PubMedCrossRefGoogle Scholar
  97. 97.
    Graf C, Rovina P, Tauzin L et al. Enhanced ceramide-induced apoptosis in ceramide kinase overexpressing cells. Biochem Biophys Res Commun 2007; 354:309–14.PubMedCrossRefGoogle Scholar
  98. 98.
    Gómez-Muñoz A, Kong J, Salh B et al. Sphingosine-1-phosphate inhibits acid sphingomyelinase and blocks apoptosis in macrophages. FEBS Lett 2003; 539:56–60.PubMedCrossRefGoogle Scholar
  99. 99.
    Gómez-Muñoz A, Kong JY, Parhar K et al. Ceramide-1-phosphate promotes cell survival through activation of the phosphatidylinositol 3-kinase/protein kinase B pathway. FEBS Lett 2005; 579:3744–50.PubMedCrossRefGoogle Scholar
  100. 100.
    Testai FD, Landek MA, Goswami R et al. Acid sphingomyelinase and inhibition by phosphate ion: role of inhibition by phosphatidyl-myo-inositol 3,4,5-triphosphate in oligodendrocyte cell signaling. J Neurochem 2004; 89:636–44.PubMedCrossRefGoogle Scholar
  101. 101.
    Scheid MP, Huber M, Damen JE et al. Phosphatidylinositol (3,4,5)P3 is essential but not sufficient for protein kinase B (PKB) activation; phosphatidylinositol (3,4)P2 is required for PKB phosphorylation at Ser-473: studies using cells from SH2-containing inositol-5-phosphatase knockout mice. J Biol Chem 2002; 277:9027–35.PubMedCrossRefGoogle Scholar
  102. 102.
    Scheid MP, Woodgett JR. Unravelling the activation mechanisms of protein kinase B/Akt. FEBS Lett 2003; 546:108–12.PubMedCrossRefGoogle Scholar
  103. 103.
    Filippa N, Sable CL, Filloux C et al. Mechanism of protein kinase B activation by cyclic AMP-dependent protein kinase. Mol Cell Biol 1999; 19:4989–5000.PubMedGoogle Scholar
  104. 104.
    Sable CL, Filippa N, Hemmings B et al. cAMP stimulates protein kinase B in a Wortmannin-insensitive manner. FEBS Lett 1997; 409:253–7.PubMedCrossRefGoogle Scholar
  105. 105.
    Van Kolen K, Gilany K, Moens L et al. P2Y12 receptor signalling towards PKB proceeds through IGF-I receptor cross-talk and requires activation of Src, Pyk2 and Rap1. Cell Signal 2006; 18:1169–81.PubMedCrossRefGoogle Scholar
  106. 106.
    Gómez-Muñoz A, Waggoner DW, O’Brien L et al. Interaction of ceramides, sphingosine and sphingosine 1-phosphate in regulating DNA synthesis and phospholipase D activity. J Biol Chem 1995; 270:26318–25.PubMedCrossRefGoogle Scholar
  107. 107.
    Gómez-Muñoz A, Aboulsalham A, Kikuchi Y et al. Role of Sphingolipids in Regulating the Phospholipase D Pathway and Cell Division in Sphingolipid-mediated Signal Transduction (ed. Hannun YA) (New York, RG Landes Co 1997; 103–120).Google Scholar
  108. 108.
    Medzhitov R. Origin and physiological roles of inflammation. Nature 2008; 454:428–35.PubMedCrossRefGoogle Scholar
  109. 109.
    Serhan CN, Haeggstrom JZ, Leslie CC. Lipid mediator networks in cell signaling: update and impact of cytokines. Faseb J 1996; 10:1147–58.PubMedGoogle Scholar
  110. 110.
    Manna SK, Aggarwal BB. IL-13 suppresses TNF-induced activation of nuclear factor-kappa B, activation protein-1 and apoptosis. J Immunol 1998; 161:2863–72.PubMedGoogle Scholar
  111. 111.
    Newton R, Hart L, Chung KF et al. Ceramide induction of COX-2 and PGE(2) in pulmonary A549 cells does not involve activation of NF-kappaB. Biochem Biophys Res Commun 2000; 277:675–9.PubMedCrossRefGoogle Scholar
  112. 112.
    Hayakawa M, Jayadev S, Tsujimoto M et al. Role of ceramide in stimulation of the transcription of cytosolic phospholipase A2 and cyclooxygenase 2. Biochem Biophys Res Commun 1996; 220:681–6.PubMedCrossRefGoogle Scholar
  113. 113.
    Masini E, Giannini L, Nistri S et al. Ceramide: a key signaling molecule in a Guinea pig model of allergic asthmatic response and airway inflammation. J Pharmacol Exp Ther 2008; 324:548–57.PubMedCrossRefGoogle Scholar
  114. 114.
    Prasad VV, Nithipatikom K, Harder DR. Ceramide elevates 12-hydroxyeicosatetraenoic acid levels and upregulates 12-lipoxygenase in rat primary hippocampal cell cultures containing predominantly astrocytes. Neurochem Int 2008; 53:220–9.PubMedCrossRefGoogle Scholar
  115. 115.
    Goggel R, Winoto-Morbach S, Vielhaber G et al. PAF-mediated pulmonary edema: a new role for acid sphingomyelinase and ceramide. Nat Med 2004; 10:155–60.PubMedCrossRefGoogle Scholar
  116. 116.
    Wijesinghe DS, Subramanian P, Lamour NF et al. The chain length specificity for the activation of group IV cytosolic phospholipase A2 by ceramide-1-phosphate. Use of the dodecane delivery system for determining lipid-specific effects. J Lipid Res 2008; In press.Google Scholar
  117. 117.
    Wijesinghe DS, Lamour NF, Gómez-Muñoz A et al. Ceramide kinase and ceramide-1-phosphate. Methods Enzymol 2007; 434:265–92.PubMedCrossRefGoogle Scholar
  118. 118.
    Rader DJ, Daugherty A. Translating molecular discoveries into new therapies for atherosclerosis. Nature 2008; 451:904–13.PubMedCrossRefGoogle Scholar
  119. 119.
    Hendriks JJ, Teunissen CE, de Vries HE et al. Macrophages and neurodegeneration. Brain Res Rev 2005; 48:185–95.PubMedCrossRefGoogle Scholar
  120. 120.
    Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion and metastasis. Cell 2006; 124:263–6.PubMedCrossRefGoogle Scholar
  121. 121.
    Granado MH, Gangoiti P, Ouro A et al. Ceramide 1-phosphate (C1P) promotes cell migration Involvement of a specific C1P receptor. Cell Signal 2008; 21:405–12.PubMedCrossRefGoogle Scholar
  122. 122.
    Goldsmith M, Avni D, Levy-Rimler G et al. A ceramide-1-phosphate analogue, PCERA-1, simultaneously suppresses tumour necrosis factor-alpha and induces interleukin-10 production in activated macrophages. Immunology 2008.Google Scholar

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© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  • Antonio Gómez-Muñoz
    • 1
  • Patricia Gangoiti
    • 1
  • María H. Granado
    • 1
  • Lide Arana
    • 1
  • Alberto Ouro
    • 1
  1. 1.Department of Biochemistry and Molecular Biology, Faculty of Science and TechnologyUniversity of the Basque CountryBilbaoSpain

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