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Статті в журналах з теми "Sphingosine kinases"

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Автор: Grafiati

Опубліковано: 10 грудня 2022

Оновлено: 28 січня 2023

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1

MYu, Pushkareva, A. Bielawska, D. Menaldiv, D. Liotta, and Y. A. Hannun. "Regulation of sphingosine-activated protein kinases: selectivity of activation by sphingoid bases and inhibition by non-esterified fatty acids." Biochemical Journal 294, no. 3 (September 15, 1993): 699–703. http://dx.doi.org/10.1042/bj2940699.

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Sphingosine has been shown to activate protein kinases in Jurkat T cell cytosol [Pushkareva, Khan, Alessenko, Sahyoun and Hannun (1992) J. Biol. Chem. 267, 15246-15251]. In this study, two sphingosine-activated protein kinases were distinguished by their substrate specificity, their dose-response to sphingosine and the specificity of their activation by sphingosine and dihydrosphingosine stereoisomers. A p32-sphingosine-activated protein kinase responded to low concentrations of D-erythrosphingosine with an initial activation observed at 2.5 microM and a peak activity at 10-20 microM. This kinase showed a modest specificity for D-erythro-sphingosine over other sphingosine stereoisomers, and a preference for sphingosines over dihydrosphingosines. Phosphorylation of a p18 substrate required higher concentrations of sphingosine (20-100 microM) and showed a significant preference for the erythro isomers of sphingosine and dihydrosphingosine over the threo isomers. The ability of other lipids to modulate sphingosine activation of these kinases was also examined. Oleic acid, but not oleic alcohol or the methyl ester, induced the phosphorylation of a distinct set of substrates (probably through the activation of protein kinase C), and inhibited sphingosine-induced phosphorylation with an IC50 of approximately 20 microM. Oleic anhydride failed to induce changes in basal protein phosphorylation but inhibited sphingosine-activated protein kinases, thus distinguishing the effects of fatty acids on protein kinase C from the inhibition of sphingosine-induced phosphorylation. These studies define two distinct sphingosine-activated protein kinases and reveal an important interaction between two classes of putative lipid second messengers.

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2

Santos, Webster L., and Kevin R. Lynch. "Drugging Sphingosine Kinases." ACS Chemical Biology 10, no. 1 (November 19, 2014): 225–33. http://dx.doi.org/10.1021/cb5008426.

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3

Porter, Hunter, Hui Qi, Nicole Prabhu, Richard Grambergs, Joel McRae, Blake Hopiavuori, and Nawajes Mandal. "Characterizing Sphingosine Kinases and Sphingosine 1-Phosphate Receptors in the Mammalian Eye and Retina." International Journal of Molecular Sciences 19, no. 12 (December 5, 2018): 3885. http://dx.doi.org/10.3390/ijms19123885.

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Sphingosine 1-phosphate (S1P) signaling regulates numerous biological processes including neurogenesis, inflammation and neovascularization. However, little is known about the role of S1P signaling in the eye. In this study, we characterize two sphingosine kinases (SPHK1 and SPHK2), which phosphorylate sphingosine to S1P, and three S1P receptors (S1PR1, S1PR2 and S1PR3) in mouse and rat eyes. We evaluated sphingosine kinase and S1P receptor gene expression at the mRNA level in various rat tissues and rat retinas exposed to light-damage, whole mouse eyes, specific eye structures, and in developing retinas. Furthermore, we determined the localization of sphingosine kinases and S1P receptors in whole rat eyes by immunohistochemistry. Our results unveiled unique expression profiles for both sphingosine kinases and each receptor in ocular tissues. Furthermore, these kinases and S1P receptors are expressed in mammalian retinal cells and the expression of SPHK1, S1PR2 and S1PR3 increased immediately after light damage, which suggests a function in apoptosis and/or light stress responses in the eye. These findings have numerous implications for understanding the role of S1P signaling in the mechanisms of ocular diseases such as retinal inflammatory and degenerative diseases, neovascular eye diseases, glaucoma and corneal diseases.

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4

Maceyka, Michael, Sheldon Milstien, and Sarah Spiegel. "Sphingosine kinases, sphingosine-1-phosphate and sphingolipidomics." Prostaglandins & Other Lipid Mediators 77, no. 1-4 (September 2005): 15–22. http://dx.doi.org/10.1016/j.prostaglandins.2004.09.010.

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5

Pitson, Stuart M., Paul A. B. Moretti, Julia R. Zebol, Reza Zareie, Claudia K. Derian, Andrew L. Darrow, Jenson Qi, et al. "The Nucleotide-binding Site of Human Sphingosine Kinase 1." Journal of Biological Chemistry 277, no. 51 (October 18, 2002): 49545–53. http://dx.doi.org/10.1074/jbc.m206687200.

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Sphingosine kinase catalyzes the formation of sphingosine 1-phosphate, a lipid second messenger that has been implicated in a number of agonist-driven cellular responses including mitogenesis, anti-apoptosis, and expression of inflammatory molecules. Despite the importance of sphingosine kinase, very little is known regarding its structure or mechanism of catalysis. Moreover, sphingosine kinase does not contain recognizable catalytic or substrate-binding sites, based on sequence motifs found in other kinases. Here we have elucidated the nucleotide-binding site of human sphingosine kinase 1 (hSK1) through a combination of site-directed mutagenesis and affinity labeling with the ATP analogue, FSBA. We have shown that Gly82of hSK1 is involved in ATP binding since mutation of this residue to alanine resulted in an enzyme with an ∼45-fold higherKm(ATP). We have also shown that Lys103is important in catalysis since an alanine substitution of this residue ablates catalytic activity. Furthermore, we have shown that this residue is covalently modified by FSBA. Our data, combined with amino acid sequence comparison, suggest a motif of SGDGX17–21K is involved in nucleotide binding in the sphingosine kinases. This motif differs in primary sequence from all previously identified nucleotide-binding sites. It does, however, share some sequence and likely structural similarity with the highly conserved glycine-rich loop, which is known to be involved in anchoring and positioning the nucleotide in the catalytic site of many protein kinases.

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6

Allende, Maria L., Teiji Sasaki, Hiromichi Kawai, Ana Olivera, Yide Mi, Gerhild van Echten-Deckert, Richard Hajdu, et al. "Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720." Journal of Biological Chemistry 279, no. 50 (September 30, 2004): 52487–92. http://dx.doi.org/10.1074/jbc.m406512200.

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Sphingosine-1-phosphate (S1P), a lipid signaling molecule that regulates many cellular functions, is synthesized from sphingosine and ATP by the action of sphingosine kinase. Two such kinases have been identified, SPHK1 and SPHK2. To begin to investigate the physiological functions of sphingosine kinase and S1P signaling, we generated mice deficient in SPHK1.Sphk1null mice were viable, fertile, and without any obvious abnormalities. Total SPHK activity in mostSphk1-/-tissues was substantially, but not completely, reduced indicating the presence of multiple sphingosine kinases. S1P levels in most tissues from theSphk1-/- mice were not markedly decreased. In serum, however, there was a significant decrease in the S1P level. Although S1P signaling regulates lymphocyte trafficking, lymphocyte distribution was unaffected in lymphoid organs ofSphk1-/- mice. The immunosuppressant FTY720 was phosphorylated and elicited lymphopenia in theSphk1null mice showing that SPHK1 is not required for the functional activation of this sphingosine analogue prodrug. The results with theseSphk1null mice reveal that some key physiologic processes that require S1P receptor signaling, such as vascular development and proper lymphocyte distribution, can occur in the absence of SPHK1.

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7

Hait, Nitai C., Carole A. Oskeritzian, Steven W. Paugh, Sheldon Milstien, and Sarah Spiegel. "Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases." Biochimica et Biophysica Acta (BBA) - Biomembranes 1758, no. 12 (December 2006): 2016–26. http://dx.doi.org/10.1016/j.bbamem.2006.08.007.

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8

Birchwood, Christine J., Julie D. Saba, Robert C. Dickson, and Kyle W. Cunningham. "Calcium Influx and Signaling in Yeast Stimulated by Intracellular Sphingosine 1-Phosphate Accumulation." Journal of Biological Chemistry 276, no. 15 (January 19, 2001): 11712–18. http://dx.doi.org/10.1074/jbc.m010221200.

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In mammalian cells, intracellular sphingosine 1-phosphate (S1P) can stimulate calcium release from intracellular organelles, resulting in the activation of downstream signaling pathways. The budding yeastSaccharomyces cerevisiaeexpresses enzymes that can synthesize and degrade S1P and related molecules, but their possible role in calcium signaling has not yet been tested. Here we examine the effects of S1P accumulation on calcium signaling using a variety of yeast mutants. Treatment of yeast cells with exogenous sphingosine stimulated Ca2+accumulation through two distinct pathways. The first pathway required the Cch1p and Mid1p subunits of a Ca2+influx channel, depended upon the function of sphingosine kinases (Lcb4p and Lcb5p), and was inhibited by the functions of S1P lyase (Dpl1p) and the S1P phosphatase (Lcb3p). The biologically inactive stereoisomer of sphingosine did not activate this Ca2+influx pathway, suggesting that the active S1P isomer specifically stimulates a calcium-signaling mechanism in yeast. The second Ca2+influx pathway stimulated by the addition of sphingosine was not stereospecific, was not dependent on the sphingosine kinases, occurred only at higher doses of added sphingosine, and therefore was likely to be nonspecific. Mutants lacking both S1P lyase and phosphatase (dpl1 lcb3double mutants) exhibited constitutively high Ca2+accumulation and signaling in the absence of added sphingosine, and these effects were dependent on the sphingosine kinases. These results show that endogenous S1P-related molecules can also trigger Ca2+accumulation and signaling. Several stimuli previously shown to evoke calcium signaling in wild-type cells were examined inlcb4 lcb5double mutants. All of the stimuli produced calcium signals independent of sphingosine kinase activity, suggesting that phosphorylated sphingoid bases might serve as messengers of calcium signaling in yeast during an unknown cellular response.

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9

Ding, Tiandi, HaiJiao Chen, Yan Li, Ying Li, Ying Zhi, Zhiqiang Qu, Qiang Sun, Qingqiang Yao, and Bo Liu. "Discovery of an SphK1 inhibitor: A hybrid approach involving a receptor–ligand-complex-based pharmacophore and docking-based virtual screening." Journal of Chemical Research 46, no. 2 (March 2022): 174751982210892. http://dx.doi.org/10.1177/17475198221089222.

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Sphingosine kinase is a lipid kinase that catalyzes the phosphorylation of sphingosine to sphingosine-1-phosphate. Sphingosine-1-phosphate is a bioactive lipid that regulates biological processes. The overexpression of sphingosine kinases is related to a variety of pathophysiological conditions. For example, SphK1 has been shown to be highly expressed in various cancer cells including ovarian, cervical, colon, stomach, lung, and brain cancer. Inhibition of sphingosine kinases is a promising way to treat diseases such as cancer. Through computer-aided drug design, we have discovered a new SphK1 inhibitor named Amb30572637 (SAMS10). In this report, we describe the discovery process and biological characteristics. In biochemical experiments, SAMS10 shows a prominent inhibitory effect on SphK1, with an IC50 value of 9.8 μM. Subsequent MTT experiments show that SAMS10 has anticancer effects toward A549, SKVO3, A375, and LOVO cell lines and has essentially no cytotoxicity against the healthy cell L929. SAMS10 has significant inhibitory activity against the A549 and LOVO cell lines, with IC50 values of 14.64 and 14.48 μM, respectively. It belongs to a moderately active SphK1 inhibitor with lower anticancer activity than the control compound cisplatin, but the effect of SAMS10 toward SphK1 and its anticancer activity indicate that it is a promising lead compound for the development of effective SphK1 anticancer inhibitors.

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10

Min, Junxia, David Traynor, Andrew L. Stegner, Lei Zhang, Marie H. Hanigan, Hannah Alexander, and Stephen Alexander. "Sphingosine Kinase Regulates the Sensitivity of Dictyostelium discoideum Cells to the Anticancer Drug Cisplatin." Eukaryotic Cell 4, no. 1 (January 2005): 178–89. http://dx.doi.org/10.1128/ec.4.1.178-189.2005.

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ABSTRACT The drug cisplatin is widely used to treat a number of tumor types. However, resistance to the drug, which remains poorly understood, limits its usefulness. Previous work using Dictyostelium discoideum as a model for studying drug resistance showed that mutants lacking sphingosine-1-phosphate (S-1-P) lyase, the enzyme that degrades S-1-P, had increased resistance to cisplatin, whereas mutants overexpressing the enzyme were more sensitive to the drug. S-1-P is synthesized from sphingosine and ATP by the enzyme sphingosine kinase. We have identified two sphingosine kinase genes in D. discoideum—sgkA and sgkB—that are homologous to those of other species. The biochemical properties of the SgkA and SgkB enzymes suggest that they are the equivalent of the human Sphk1 and Sphk2 enzymes, respectively. Disruption of the kinases by homologous recombination (both single and double mutants) or overexpression of the sgkA gene resulted in altered growth rates and altered response to cisplatin. The null mutants showed increased sensitivity to cisplatin, whereas mutants overexpressing the sphingosine kinase resulted in increased resistance compared to the parental cells. The results indicate that both the SgkA and the SgkB enzymes function in regulating cisplatin sensitivity. The increase in sensitivity of the sphingosine kinase-null mutants was reversed by the addition of S-1-P, and the increased resistance of the sphingosine kinase overexpressor mutant was reversed by the inhibitor N,N-dimethylsphingosine. Parallel changes in sensitivity of the null mutants are seen with the platinum-based drug carboplatin but not with doxorubicin, 5-fluorouracil, and etoposide. This pattern of specificity is similar to that observed with the S-1-P lyase mutants and should be useful in designing therapeutic schemes involving more than one drug. This study identifies the sphingosine kinases as new drug targets for modulating the sensitivity to platinum-based drugs.

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11

Marfe, Gabriella, Giovanna Mirone, Arvind Shukla, and Carla Stefano. "Sphingosine Kinases Signalling in Carcinogenesis." Mini-Reviews in Medicinal Chemistry 15, no. 4 (March 26, 2015): 300–314. http://dx.doi.org/10.2174/1389557515666150227105415.

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12

Ettmayer, Peter, Andreas Billich, Thomas Baumruker, Diana Mechtcheriakova, Heide Schmid, and Peter Nussbaumer. "Fluorescence-labeled sphingosines as substrates of sphingosine kinases 1 and 2." Bioorganic & Medicinal Chemistry Letters 14, no. 6 (March 2004): 1555–58. http://dx.doi.org/10.1016/j.bmcl.2003.12.099.

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13

Sanllehí, Pol, José-Luis Abad, Josefina Casas, and Antonio Delgado. "Inhibitors of sphingosine-1-phosphate metabolism (sphingosine kinases and sphingosine-1-phosphate lyase)." Chemistry and Physics of Lipids 197 (May 2016): 69–81. http://dx.doi.org/10.1016/j.chemphyslip.2015.07.007.

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14

Kwong, Eric K., Xiaojiaoyang Li, Phillip B. Hylemon, and Huiping Zhou. "Sphingosine Kinases/Sphingosine 1-Phosphate Signaling in Hepatic Lipid Metabolism." Current Pharmacology Reports 3, no. 4 (June 20, 2017): 176–83. http://dx.doi.org/10.1007/s40495-017-0093-2.

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15

Bonica, Joseph, Cungui Mao, Lina M. Obeid, and Yusuf A. Hannun. "Transcriptional Regulation of Sphingosine Kinase 1." Cells 9, no. 11 (November 8, 2020): 2437. http://dx.doi.org/10.3390/cells9112437.

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Once thought to be primarily structural in nature, sphingolipids have become increasingly appreciated as second messengers in a wide array of signaling pathways. Sphingosine kinase 1, or SK1, is one of two sphingosine kinases that phosphorylate sphingosine into sphingosine-1-phosphate (S1P). S1P is generally pro-inflammatory, pro-angiogenic, immunomodulatory, and pro-survival; therefore, high SK1 expression and activity have been associated with certain inflammatory diseases and cancer. It is thus important to develop an understanding of the regulation of SK1 expression and activity. In this review, we explore the current literature on SK1 transcriptional regulation, illustrating a complex system of transcription factors, cytokines, and even micro-RNAs (miRNAs) on the post transcriptional level.

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16

PYNE, Susan, and Nigel J. PYNE. "Sphingosine 1-phosphate signalling in mammalian cells." Biochemical Journal 349, no. 2 (July 10, 2000): 385–402. http://dx.doi.org/10.1042/bj3490385.

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Sphingosine 1-phosphate is formed in cells in response to diverse stimuli, including growth factors, cytokines, G-protein-coupled receptor agonists, antigen, etc. Its production is catalysed by sphingosine kinase, while degradation is either via cleavage to produce palmitaldehyde and phosphoethanolamine or by dephosphorylation. In this review we discuss the most recent advances in our understanding of the role of the enzymes involved in metabolism of this lysolipid. Sphingosine 1-phoshate can also bind to members of the endothelial differentiation gene (EDG) G-protein-coupled receptor family [namely EDG1, EDG3, EDG5 (also known as H218 or AGR16), EDG6 and EDG8] to elicit biological responses. These receptors are coupled differentially via Gi, Gq, G12/13 and Rho to multiple effector systems, including adenylate cyclase, phospholipases C and D, extracellular-signal-regulated kinase, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase and non-receptor tyrosine kinases. These signalling pathways are linked to transcription factor activation, cytoskeletal proteins, adhesion molecule expression, caspase activities, etc. Therefore sphingosine 1-phosphate can affect diverse biological responses, including mitogenesis, differentiation, migration and apoptosis, via receptor-dependent mechanisms. Additionally, sphingosine 1-phosphate has been proposed to play an intracellular role, for example in Ca2+ mobilization, activation of non-receptor tyrosine kinases, inhibition of caspases, etc. We review the evidence for both intracellular and extracellular actions, and extensively discuss future approaches that will ultimately resolve the question of dual action. Certainly, sphingosine 1-phosphate will prove to be unique if it elicits both extra- and intra-cellular actions. Finally, we review the evidence that implicates sphingosine 1-phosphate in pathophysiological disease states, such as cancer, angiogenesis and inflammation. Thus there is a need for the development of new therapeutic compounds, such as receptor antagonists. However, identification of the most suitable targets for drug intervention requires a full understanding of the signalling and action profile of this lysosphingolipid. This article describes where the research field is in relation to achieving this aim.

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17

Pyne, Nigel J., Melissa McNaughton, Stephanie Boomkamp, Neil MacRitchie, Cecilia Evangelisti, Alberto M. Martelli, Hui-Rong Jiang, Satvir Ubhi, and Susan Pyne. "Role of sphingosine 1-phosphate receptors, sphingosine kinases and sphingosine in cancer and inflammation." Advances in Biological Regulation 60 (January 2016): 151–59. http://dx.doi.org/10.1016/j.jbior.2015.09.001.

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18

Adams, David R., Susan Pyne, and Nigel J. Pyne. "Sphingosine Kinases: Emerging Structure–Function Insights." Trends in Biochemical Sciences 41, no. 5 (May 2016): 395–409. http://dx.doi.org/10.1016/j.tibs.2016.02.007.

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19

Billich, Andreas, and Peter Ettmayer. "Fluorescence-based assay of sphingosine kinases." Analytical Biochemistry 326, no. 1 (March 2004): 114–19. http://dx.doi.org/10.1016/j.ab.2003.11.018.

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20

Chan, Huasheng, and Stuart M. Pitson. "Post-translational regulation of sphingosine kinases." Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1831, no. 1 (January 2013): 147–56. http://dx.doi.org/10.1016/j.bbalip.2012.07.005.

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21

Yonamine, Ikuko, Takeshi Bamba, Niraj K. Nirala, Nahid Jesmin, Teresa Kosakowska-Cholody, Kunio Nagashima, Eiichiro Fukusaki, Jairaj K. Acharya, and Usha Acharya. "Sphingosine kinases and their metabolites modulate endolysosomal trafficking in photoreceptors." Journal of Cell Biology 192, no. 4 (February 14, 2011): 557–67. http://dx.doi.org/10.1083/jcb.201004098.

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Internalized membrane proteins are either transported to late endosomes and lysosomes for degradation or recycled to the plasma membrane. Although proteins involved in trafficking and sorting have been well studied, far less is known about the lipid molecules that regulate the intracellular trafficking of membrane proteins. We studied the function of sphingosine kinases and their metabolites in endosomal trafficking using Drosophila melanogaster photoreceptors as a model system. Gain- and loss-of-function analyses show that sphingosine kinases affect trafficking of the G protein–coupled receptor Rhodopsin and the light-sensitive transient receptor potential (TRP) channel by modulating the levels of dihydrosphingosine 1 phosphate (DHS1P) and sphingosine 1 phosphate (S1P). An increase in DHS1P levels relative to S1P leads to the enhanced lysosomal degradation of Rhodopsin and TRP and retinal degeneration in wild-type photoreceptors. Our results suggest that sphingosine kinases and their metabolites modulate photoreceptor homeostasis by influencing endolysosomal trafficking of Rhodopsin and TRP.

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22

Labesse, Gilles, Dominique Douguet, Liliane Assairi, and Anne-Marie Gilles. "Diacylglyceride kinases, sphingosine kinases and NAD kinases: distant relatives of 6-phosphofructokinases." Trends in Biochemical Sciences 27, no. 6 (June 2002): 273–75. http://dx.doi.org/10.1016/s0968-0004(02)02093-5.

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23

Mastrandrea, Lucy D. "Role of sphingosine kinases and sphingosine 1-phosphate in mediating adipogenesis." Journal of Diabetes Mellitus 03, no. 02 (2013): 52–61. http://dx.doi.org/10.4236/jdm.2013.32009.

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24

Wong, Lingkai, Sheryl S. L. Tan, Yulin Lam, and Alirio J. Melendez. "Synthesis and Evaluation of Sphingosine Analogues as Inhibitors of Sphingosine Kinases." Journal of Medicinal Chemistry 52, no. 12 (June 25, 2009): 3618–26. http://dx.doi.org/10.1021/jm900121d.

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25

Kharel, Yugesh, Thomas P. Mathews, Amanda M. Gellett, Jose L. Tomsig, Perry C. Kennedy, Morgan L. Moyer, Timothy L. Macdonald, and Kevin R. Lynch. "Sphingosine kinase type 1 inhibition reveals rapid turnover of circulating sphingosine 1-phosphate." Biochemical Journal 440, no. 3 (November 28, 2011): 345–53. http://dx.doi.org/10.1042/bj20110817.

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S1P (sphingosine 1-phosphate) is a signalling molecule involved in a host of cellular and physiological functions, most notably cell survival and migration. S1P, which signals via a set of five G-protein-coupled receptors (S1P1–S1P5), is formed by the action of two SphKs (sphingosine kinases) from Sph (sphingosine). Interfering RNA strategies and SphK1 (sphingosine kinase type 1)-null (Sphk1−/−) mouse studies implicate SphK1 in multiple signalling cascades, yet there is a paucity of potent and selective SphK1 inhibitors necessary to evaluate the effects of rapid onset inhibition of this enzyme. We have identified a set of submicromolar amidine-based SphK1 inhibitors and report using a pair of these compounds to probe the cellular and physiological functions of SphK1. In so doing, we demonstrate that our inhibitors effectively lower S1P levels in cell-based assays, but we have been unable to correlate SphK1 inhibition with changes in cell survival. However, SphK1 inhibition did diminish EGF (epidermal growth factor)-driven increases in S1P levels and Akt (also known as protein kinase B)/ERK (extracellular-signal-regulated kinase) phosphorylation. Finally, administration of the SphK1 inhibitor to wild-type, but not Sphk1−/−, mice resulted in a rapid decrease in blood S1P levels indicating that circulating S1P is rapidly turned over.

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26

Pyne, Susan, David R. Adams, and Nigel J. Pyne. "Sphingosine 1-phosphate and sphingosine kinases in health and disease: Recent advances." Progress in Lipid Research 62 (April 2016): 93–106. http://dx.doi.org/10.1016/j.plipres.2016.03.001.

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27

Gassowska, Magdalena, Magdalena Cieslik, Anna Wilkaniec, and Joanna B. Strosznajder. "Sphingosine Kinases/Sphingosine-1-Phosphate and Death Signalling in APP-Transfected Cells." Neurochemical Research 39, no. 4 (January 23, 2014): 645–52. http://dx.doi.org/10.1007/s11064-014-1240-3.

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28

Alemany, Regina, Chris J. van Koppen, Kerstin Danneberg, Michael ter Braak, and Dagmar Meyer zu Heringdorf. "Regulation and functional roles of sphingosine kinases." Naunyn-Schmiedeberg's Archives of Pharmacology 374, no. 5-6 (January 23, 2007): 413–28. http://dx.doi.org/10.1007/s00210-007-0132-3.

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29

Iwabuchi, Kazuhisa, Hitoshi Nakayama, Ami Oizumi, Yasushi Suga, Hideoki Ogawa, and Kenji Takamori. "Role of Ceramide from Glycosphingolipids and Its Metabolites in Immunological and Inflammatory Responses in Humans." Mediators of Inflammation 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/120748.

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Glycosphingolipids (GSLs) are composed of hydrophobic ceramide and hydrophilic sugar chains. GSLs cluster to form membrane microdomains (lipid rafts) on plasma membranes, along with several kinds of transducer molecules, including Src family kinases and small G proteins. However, GSL-mediated biological functions remain unclear. Lactosylceramide (LacCer, CDw17) is highly expressed on the plasma membranes of human phagocytes and mediates several immunological and inflammatory reactions, including phagocytosis, chemotaxis, and superoxide generation. LacCer forms membrane microdomains with the Src family tyrosine kinase Lyn and the Gαi subunit of heterotrimeric G proteins. The very long fatty acids C24:0 and C24:1 are the main ceramide components of LacCer in neutrophil plasma membranes and are directly connected with the fatty acids of Lyn and Gαi. These observations suggest that the very long fatty acid chains of ceramide are critical for GSL-mediated outside-in signaling. Sphingosine is another component of ceramide, with the hydrolysis of ceramide by ceramidase producing sphingosine and fatty acids. Sphingosine is phosphorylated by sphingosine kinase to sphingosine-1-phosphate, which is involved in a wide range of cellular functions, including growth, differentiation, survival, chemotaxis, angiogenesis, and embryogenesis, in various types of cells. This review describes the role of ceramide moiety of GSLs and its metabolites in immunological and inflammatory reactions in human.

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Ayub, Maria, Hee-Kyung Jin, and Jae-sung Bae. "Novelty of Sphingolipids in the Central Nervous System Physiology and Disease: Focusing on the Sphingolipid Hypothesis of Neuroinflammation and Neurodegeneration." International Journal of Molecular Sciences 22, no. 14 (July 8, 2021): 7353. http://dx.doi.org/10.3390/ijms22147353.

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For decades, lipids were confined to the field of structural biology and energetics as they were considered only structural constituents of cellular membranes and efficient sources of energy production. However, with advances in our understanding in lipidomics and improvements in the technological approaches, astounding discoveries have been made in exploring the role of lipids as signaling molecules, termed bioactive lipids. Among these bioactive lipids, sphingolipids have emerged as distinctive mediators of various cellular processes, ranging from cell growth and proliferation to cellular apoptosis, executing immune responses to regulating inflammation. Recent studies have made it clear that sphingolipids, their metabolic intermediates (ceramide, sphingosine-1-phosphate, and N-acetyl sphingosine), and enzyme systems (cyclooxygenases, sphingosine kinases, and sphingomyelinase) harbor diverse yet interconnected signaling pathways in the central nervous system (CNS), orchestrate CNS physiological processes, and participate in a plethora of neuroinflammatory and neurodegenerative disorders. Considering the unequivocal importance of sphingolipids in CNS, we review the recent discoveries detailing the major enzymes involved in sphingolipid metabolism (particularly sphingosine kinase 1), novel metabolic intermediates (N-acetyl sphingosine), and their complex interactions in CNS physiology, disruption of their functionality in neurodegenerative disorders, and therapeutic strategies targeting sphingolipids for improved drug approaches.

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Kirby, R. Jason, Ying Jin, Jian Fu, Jimena Cubillos, Debi Swertfeger, and Lois J. Arend. "Dynamic regulation of sphingosine-1-phosphate homeostasis during development of mouse metanephric kidney." American Journal of Physiology-Renal Physiology 296, no. 3 (March 2009): F634—F641. http://dx.doi.org/10.1152/ajprenal.90232.2008.

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Branching morphogenesis of the metanephric kidney is critically dependent on the delicate orchestration of diverse cellular processes including proliferation, apoptosis, migration, and differentiation. Sphingosine-1-phosphate (S1P) is a potent lipid mediator influencing many of these cellular events. We report increased expression and activity of both sphingosine kinases and S1P phosphatases during development of the mouse metanephric kidney from induction at embryonic day 11.5 to maturity. Sphingosine kinase activity exceeded S1P phosphatase activity in embryonic kidneys, resulting in a net accumulation of S1P, while kinase and phosphatase activities were similar in adult tissue, resulting in reduced S1P content. Sphingosine kinase expression was greater in the metanephric mesenchyme than in the ureteric bud, while the S1P phosphatase SPP2 was expressed at greater levels in the ureteric bud. Treatment of cultured embryonic kidneys with sphingosine kinase inhibitors resulted in a dose-dependent reduction of ureteric bud tip numbers and increased apoptosis. Exogenous S1P rescued kidneys from apoptosis induced by kinase inhibitors. Ureteric bud tip number was unaffected by exogenous S1P in kidneys treated with N, N-dimethylsphingosine, although tip number increased in those treated with d,l- threo-dihydrosphingosine. S1P1 and S1P2 were the predominant S1P receptors expressed in the embryonic kidney. S1P1 expression increased during renal development while expression of S1P2 decreased, and both receptors were expressed predominantly in the metanephric mesenchyme. These results demonstrate dynamic regulation of S1P homeostasis during renal morphogenesis and suggest that differential expression of S1P metabolic enzymes and receptors provides a novel mechanism contributing to the regulation of kidney development.

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Tanaka, Yuko, Seiichi Okabe, Tetsuzo Tauchi, Yoshikazu Ito, Tomohiro Umezu, Junko H. Ohyashiki, and Kazuma Ohyashiki. "Therapeutic Potential Of Targeting Sphingosine-1-Phosuphate and Sphingosine Kinases In Multiple Myeloma." Blood 122, no. 21 (November 15, 2013): 1894. http://dx.doi.org/10.1182/blood.v122.21.1894.1894.

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Abstract Multiple myeloma (MM) is one of the common hematological malignancies and is a uniformly fatal disorder of B cells characterized by accumulation of abnormal plasma cells in the bone marrow.Clinical progression of patients with MM is improved with the proteasome inhibitor (PI) (e.g. bortezomib) and the immunomodulatory drugs (IMiDs) such as thalidomide and lenalidomide. Although PI and IMiDs have considerably changed the treatment paradigm of MM, many patients show disease relapse due to developing into drug resistance of MM cells. Since the prognosis remains poor for patients with refractory disease, the new therapeutic strategies are required to treat against these patients. Sphingosine-1-phosphate (S1P) is a potent bioactive sphingolipid. Two isoforms of sphingosine kinases (SphKs), SK1 and SK2, catalyze the formation of the S1P in mammalian cells. SphKs have also been shown to be up-regulated in the variety of cancer types. SphKs/S1P/S1P receptor (S1PR) axis is involved in multiple biological processes. It has been reported that S1P is involved in cell proliferation, angiogenesis and inflammation. S1P is also involved in cancer progression including cell transformation, oncogenesis and cell survival in hematological malignancies such as multiple myeloma. Therefore, S1P and SphKs may present attractive targets for MM treatment. One of the S1P analog, fingolimod (FTY720), which is an orally active immunomodulatory drug, is developed for the treatment of multiple sclerosis. SKI-I, which is a non-lipid pan-SphK inhibitor and ABC294640, selective inhibitor of SK2, are currently investigated in a pivotal phase 1 clinical trial against solid tumors. In this study, we investigated the efficacy of fingolimod, SKI-I, and ABC294640 by using the MM cell lines, RPMI8226, MM1.S and MM1.R. 72 hours treatment of fingolimod exhibited cell growth inhibition of MM cell lines in a dose dependent manner. Treatment of SKI-I and ABC294640 also exhibited cell growth inhibition in a dose dependent manner. Since S1P is the ligand for a family of five G-protein-coupled receptors with distinct signaling pathways that regulate angiogenesis and chemotaxis, we next evaluated the chemotactic response of human umbilical vein endothelial cells (HUVEC). We found that 4 hours treatment of S1P significantly induced the migration of HUVECs compared to control medium. Treatment of HUVECs with fingolimod inhibited S1P-stimulated chemotaxis in a dose dependent manner. We also found that S1P-induced chemotaxis was abolished by the SKI-I and ABC294640. These results suggest that intracellular SK1 and SK2 may play the important role in S1P induced chemotaxis of HUVEC. We next investigated the S1P concentrations in MM patient by enzyme-linked immune sorbent assay (ELISA), because S1P is a potent tumorigenic growth factor that is likely released from tumor cells. We found that serum concentrations of S1P were significantly higher in patient with MM compared with normal samples. The average S1P levels of MM and normal control are 1503.431 and 1103.38 (p <0.05). We also found that conditioned medium from MM cell line had chemotactic activity for HUVECs. These results implicate that S1P may be a novel biomarker for early stage of MM and that S1P is an important bioactive sphingolipid involved in angiogenesis. In this study, we also demonstrate that fingolimod, SKI-I and ABC294640 have potent preclinical anti-tumor activity in MM. These agents possibly inhibit angiogenesis with relation to MM cell growth and offer unique opportunities for novel therapeutic strategies for the treatment of multiple myeloma. Disclosures: No relevant conflicts of interest to declare.

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Evangelisti, C., C. Evangelisti, F. Buontempo, A. Lonetti, E. Orsini, F. Chiarini, J. T. Barata, S. Pyne, N. J. Pyne, and A. M. Martelli. "Therapeutic potential of targeting sphingosine kinases and sphingosine 1-phosphate in hematological malignancies." Leukemia 30, no. 11 (July 27, 2016): 2142–51. http://dx.doi.org/10.1038/leu.2016.208.

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Pandey, Suveg, Kelly M. Banks, Ritu Kumar, Andrew Kuo, Duancheng Wen, Timothy Hla, and Todd Evans. "Sphingosine kinases protect murine embryonic stem cells from sphingosine-induced cell cycle arrest." STEM CELLS 38, no. 5 (January 29, 2020): 613–23. http://dx.doi.org/10.1002/stem.3145.

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Shu, Xiaodong, Weicheng Wu, Raymond D. Mosteller, and Daniel Broek. "Sphingosine Kinase Mediates Vascular Endothelial Growth Factor-Induced Activation of Ras and Mitogen-Activated Protein Kinases." Molecular and Cellular Biology 22, no. 22 (November 15, 2002): 7758–68. http://dx.doi.org/10.1128/mcb.22.22.7758-7768.2002.

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ABSTRACT Vascular endothelial growth factor (VEGF) signaling is critical to the processes of angiogenesis and tumor growth. Here, evidence is presented for VEGF stimulation of sphingosine kinase (SPK) that affects not only endothelial cell signaling but also tumor cells expressing VEGF receptors. VEGF or phorbol 12-myristate 13-acetate treatment of the T24 bladder tumor cell line resulted in a time- and dose-dependent stimulation of SPK activity. In T24 cells, VEGF treatment reduced cellular sphingosine levels while raising that of sphingosine-1-phosphate. VEGF stimulation of T24 cells caused a slow and sustained accumulation of Ras-GTP and phosphorylated extracellular signal-regulated kinase (phospho-ERK) compared with that after EGF treatment. Small interfering RNA (siRNA) that targets SPK1, but not SPK2, blocks VEGF-induced accumulation of Ras-GTP and phospho-ERK in T24 cells. In contrast to EGF stimulation, VEGF stimulation of ERK1/2 phosphorylation was unaffected by dominant-negative Ras-N17. Raf kinase inhibition blocked both VEGF- and EGF-stimulated accumulation of phospho-ERK1/2. Inhibition of SPK by pharmacological inhibitors, a dominant-negative SPK mutant, or siRNA that targets SPK blocked VEGF, but not EGF, induction of phospho-ERK1/2. We conclude that VEGF induces DNA synthesis in a pathway which sequentially involves protein kinase C (PKC), SPK, Ras, Raf, and ERK1/2. These data highlight a novel mechanism by which SPK mediates signaling from PKC to Ras in a manner independent of Ras-guanine nucleotide exchange factor.

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Wallington-Beddoe, Craig T., Kenneth F. Bradstock, and Linda J. Bendall. "Oncogenic properties of sphingosine kinases in haematological malignancies." British Journal of Haematology 161, no. 5 (March 25, 2013): 623–38. http://dx.doi.org/10.1111/bjh.12302.

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Aoki, Masayo, Hiroaki Aoki, Partha Mukhopadhyay, Eriko Katsuta, and Kazuaki Takabe. "The Roles of Sphingosine Kinases in Skin Aging." Journal of Investigative Dermatology 139, no. 4 (April 2019): 951–53. http://dx.doi.org/10.1016/j.jid.2018.06.192.

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38

Lee, Seulah, Joo Chan Lee, Lalita Subedi, Kyo Hee Cho, Sun Yeou Kim, Hyun-Ju Park, and Ki Hyun Kim. "Bioactive compounds from the seeds of Amomum tsaoko Crevost et Lemaire, a Chinese spice as inhibitors of sphingosine kinases, SPHK1/2." RSC Advances 9, no. 58 (2019): 33957–68. http://dx.doi.org/10.1039/c9ra07988b.

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Kharel, Yugesh, Mithun Raje, Ming Gao, Amanda M. Gellett, Jose L. Tomsig, Kevin R. Lynch, and Webster L. Santos. "Sphingosine kinase type 2 inhibition elevates circulating sphingosine 1-phosphate." Biochemical Journal 447, no. 1 (September 12, 2012): 149–57. http://dx.doi.org/10.1042/bj20120609.

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S1P (sphingosine 1-phosphate) is a pleiotropic lipid mediator involved in numerous cellular and physiological functions. Of note among these are cell survival and migration, as well as lymphocyte trafficking. S1P, which exerts its effects via five GPCRs (G-protein-coupled receptors) (S1P1–S1P5), is formed by the action of two SphKs (sphingosine kinases). Although SphK1 is the more intensively studied isotype, SphK2 is unique in it nuclear localization and has been reported to oppose some of the actions ascribed to SphK1. Although several scaffolds of SphK1 inhibitors have been described, there is a scarcity of selective SphK2 inhibitors that are necessary to evaluate the downstream effects of inhibition of this isotype. In the present paper we report a cationic amphiphilic small molecule that is a selective SphK2 inhibitor. In the course of characterizing this compound in wild-type and SphK-null mice, we discovered that administration of the inhibitor to wild-type mice resulted in a rapid increase in blood S1P, which is in contrast with our SphK1 inhibitor that drives circulating S1P levels down. Using a cohort of F2 hybrid mice, we confirmed, compared with wild-type mice, that circulating S1P levels were higher in SphK2-null mice and lower in SphK1-null mice. Thus both SphK1 and SphK2 inhibitors recapitulate the blood S1P levels observed in the corresponding null mice. Moreover, circulating S1P levels mirror SphK2 inhibitor levels, providing a convenient biomarker of target engagement.

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Wadgaonkar, Raj, Vipul Patel, Natalia Grinkina, Carol Romano, Jing Liu, Yutong Zhao, Saad Sammani, Joe G. N. Garcia, and Viswanathan Natarajan. "Differential regulation of sphingosine kinases 1 and 2 in lung injury." American Journal of Physiology-Lung Cellular and Molecular Physiology 296, no. 4 (April 2009): L603—L613. http://dx.doi.org/10.1152/ajplung.90357.2008.

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Two mammalian sphingosine kinase (SphK) isoforms, SphK1 and SphK2, possess identical kinase domains but have distinct kinetic properties and subcellular localizations, suggesting each has one or more specific roles in sphingosine-1-phosphate (S1P) generation. Although both kinases use sphingosine as a substrate to generate S1P, the mechanisms controlling SphK activation and subsequent S1P generation during lung injury are not fully understood. In this study, we established a murine lung injury model to investigate LPS-induced lung injury in SphK1 knockout (SphK1−/−) and wild-type (WT) mice. We found that SphK1−/− mice were much more susceptible to LPS-induced lung injury compared with their WT counterparts, quantified by multiple parameters including cytokine induction. Intriguingly, overexpression of WT SphK1 delivered by adenoviral vector to the lungs protected SphK1−/− mice from lung injury and attenuated the severity of the response to LPS. However, adenoviral overexpression of a SphK1 kinase-dead mutant (SphKKD) in SphK1−/− mouse lungs further exacerbated the response to LPS as well as the extent of lung injury. WT SphK2 adenoviral overexpression also failed to provide protection and, in fact, augmented the degree of LPS-induced lung injury. This suggested that, in vascular injury, S1P generated by SphK2 activation plays a distinctly separate role compared with SphK1-dependent S1P generation and survival signaling. Microarray and real-time RT-PCR analysis of SphK1 and SphK2 expression levels during lung injury revealed that, in WT mice, LPS treatment caused significantly enhanced SphK1 expression (∼5×) levels within 6 h, which declined back to baseline levels by 24 h posttreatment. In contrast, expression of SphK2 was gradually induced following LPS treatment and was elevated within 24 h. Collectively, our results for the first time demonstrate distinct functional roles of the two SphK isoforms in the regulation of LPS-induced lung injury.

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Miller, Anna V., Sergio E. Alvarez, Sarah Spiegel та Deborah A. Lebman. "Sphingosine Kinases and Sphingosine-1-Phosphate Are Critical for Transforming Growth Factor β-Induced Extracellular Signal-Regulated Kinase 1 and 2 Activation and Promotion of Migration and Invasion of Esophageal Cancer Cells". Molecular and Cellular Biology 28, № 12 (21 квітня 2008): 4142–51. http://dx.doi.org/10.1128/mcb.01465-07.

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ABSTRACT Transforming growth factor β (TGFβ) plays a dual role in oncogenesis, acting as both a tumor suppressor and a tumor promoter. These disparate processes of suppression and promotion are mediated primarily by Smad and non-Smad signaling, respectively. A central issue in understanding the role of TGFβ in the progression of epithelial cancers is the elucidation of the mechanisms underlying activation of non-Smad signaling cascades. Because the potent lipid mediator sphingosine-1-phosphate (S1P) has been shown to transactivate the TGFβ receptor and activate Smad3, we examined its role in TGFβ activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and promotion of migration and invasion of esophageal cancer cells. Both S1P and TGFβ activate ERK1/2, but only TGFβ activates Smad3. Both ligands promoted ERK1/2-dependent migration and invasion. Furthermore, TGFβ rapidly increased S1P, which was required for TGFβ-induced ERK1/2 activation, as well as migration and invasion, since downregulation of sphingosine kinases, the enzymes that produce S1P, inhibited these responses. Finally, our data demonstrate that TGFβ activation of ERK1/2, as well as induction of migration and invasion, is mediated at least in part by ligation of the S1P receptor, S1PR2. Thus, these studies provide the first evidence that TGFβ activation of sphingosine kinases and formation of S1P contribute to non-Smad signaling and could be important for progression of esophageal cancer.

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Magli, Elisa, Angela Corvino, Ferdinando Fiorino, Francesco Frecentese, Elisa Perissutti, Irene Saccone, Vincenzo Santagada, Giuseppe Caliendo, and Beatrice Severino. "Design of Sphingosine Kinases Inhibitors: Challenges and Recent Developments." Current Pharmaceutical Design 25, no. 9 (July 9, 2019): 956–68. http://dx.doi.org/10.2174/1381612825666190404115424.

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Background:Sphingosine kinases (SphKs) catalyze the phosphorylation of sphingosine to form the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P). S1P is an important lipid mediator with a wide range of biological functions; it is also involved in a variety of diseases such as inflammatory diseases, Alzheimer’s disease and cancer.Methods:This review reports the recent advancement in the research of SphKs inhibitors. Our purpose is also to provide a complete overview useful for underlining the features needed to select a specific pharmacological profile.Discussion:Two distinct mammalian SphK isoforms have been identified, SphK1 and SphK2. These isoforms are encoded by different genes and exhibit distinct subcellular localizations, biochemical properties and functions. SphK1 and SphK2 inhibition can be useful in different pathological conditions.Conclusion:SphK1 and SphK2 have many common features but different and even opposite biological functions. For this reason, several research groups are interested in understanding the therapeutic usefulness of a selective or non-selective inhibitor of SphKs. Moreover, a compensatory mechanism for the two isoforms has been demonstrated, thus leading to the development of dual inhibitors.

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Gao, Peng, Yuri K. Peterson, Ryan A. Smith, and Charles D. Smith. "Characterization of Isoenzyme-Selective Inhibitors of Human Sphingosine Kinases." PLoS ONE 7, no. 9 (September 10, 2012): e44543. http://dx.doi.org/10.1371/journal.pone.0044543.

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Billich, Andreas, Frederic Bornancin, Piroska Dévay, Diana Mechtcheriakova, Nicole Urtz, and Thomas Baumruker. "Phosphorylation of the Immunomodulatory Drug FTY720 by Sphingosine Kinases." Journal of Biological Chemistry 278, no. 48 (September 16, 2003): 47408–15. http://dx.doi.org/10.1074/jbc.m307687200.

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45

Mahoney, James A., and Ronald L. Schnaar. "Multivalent ganglioside and sphingosine conjugates modulate myelin protein kinases." Biochimica et Biophysica Acta (BBA) - Biomembranes 1328, no. 1 (August 1997): 30–40. http://dx.doi.org/10.1016/s0005-2736(97)00070-9.

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BRYAN, L. "Regulation and functions of sphingosine kinases in the brain." Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1781, no. 9 (September 2008): 459–66. http://dx.doi.org/10.1016/j.bbalip.2008.04.008.

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47

Mizugishi, Kiyomi, Tadashi Yamashita, Ana Olivera, Georgina F. Miller, Sarah Spiegel, and Richard L. Proia. "Essential Role for Sphingosine Kinases in Neural and Vascular Development." Molecular and Cellular Biology 25, no. 24 (December 15, 2005): 11113–21. http://dx.doi.org/10.1128/mcb.25.24.11113-11121.2005.

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ABSTRACT Sphingosine-1-phosphate (S1P), an important sphingolipid metabolite, regulates diverse cellular processes, including cell survival, growth, and differentiation. Here we show that S1P signaling is critical for neural and vascular development. Sphingosine kinase-null mice exhibited a deficiency of S1P which severely disturbed neurogenesis, including neural tube closure, and angiogenesis and caused embryonic lethality. A dramatic increase in apoptosis and a decrease in mitosis were seen in the developing nervous system. S1P1 receptor-null mice also showed severe defects in neurogenesis, indicating that the mechanism by which S1P promotes neurogenesis is, in part, signaling from the S1P1 receptor. Thus, S1P joins a growing list of signaling molecules, such as vascular endothelial growth factor, which regulate the functionally intertwined pathways of angiogenesis and neurogenesis. Our findings also suggest that exploitation of this potent neuronal survival pathway could lead to the development of novel therapeutic approaches for neurological diseases.

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Brindley, David N., Abdelkarim Abousalham, Yutaka Kikuchi, Chuen-Neu Wang, and David W. Waggoner. ""Cross talk" between the bioactive glycerolipids and sphingolipids in signal transduction." Biochemistry and Cell Biology 74, no. 4 (July 1, 1996): 469–76. http://dx.doi.org/10.1139/o96-051.

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Hydrolysis of phosphatidylcholine via receptor-mediated stimulation of phospholipase D produces phosphatidate that can be converted to lysophosphatidate and diacylglycerol. Diacylglycerol is an activator of protein kinase C, whereas phosphatidate and lysophosphatidate stimulate tyrosine kinases and activate the Ras–Raf–mitogen-activated protein kinase pathway. These three lipids can stimulate cell division. Conversely, activation of sphingomyelinase by agonists (e.g., tumor necrosis factor-α) causes ceramide production that inhibits cell division and produces apoptosis. If ceramides are metabolized to sphingosine and sphingosine 1-phosphate, then these lipids can stimulate phospholipase D and are also mitogenic. By contrast, ceramides inhibit the activation of phospholipase D by decreasing its interaction with the G-proteins, ARF and Rho, which are necessary for its activation. In whole cells, ceramides also stimulate the degradation of phosphatidate, lysophosphatidate, ceramide 1-phosphate, and sphingosine 1-phosphate through a multifunctional phosphohydrolase (the Mg2+-independent phosphatidate phosphohydrolase), whereas sphingosine inhibits phosphatidate phosphohydrolase. Tumor necrosis factor-α causes insulin resistance, which may be partly explained by ceramide production. Cell-permeable ceramides decrease insulin-stimulated glucose uptake in 3T3-L1 adipocytes after 2–24 h, whereas they stimulate basal glucose uptake. These effects do not depend on decreased tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 or the interaction of insulin receptor substrate-1 with phosphatidylinositol 3-kinase. They appear to rely on the differential effects of ceramides on the translocation of GLUT1- and GLUT4-containing vesicles. It is concluded that there is a significant interaction and "cross-talk" between the sphingolipid and glycerolipid pathways that modifies signal transduction to control vesicle movement, cell division, and cell death.Key words: ceramides, insulin resistance, phosphatidate, phospholipases, signal transduction.

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49

Lynch, Kevin R. "Building a better sphingosine kinase-1 inhibitor." Biochemical Journal 444, no. 1 (April 26, 2012): e1-e2. http://dx.doi.org/10.1042/bj20120567.

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Sphingosine 1-phosphate (S1P) is currently one of the most intensely studied lipid mediators. Interest in S1P has been propelled by the development of fingolimod, an S1P receptor agonist prodrug, which revealed both a theretofore unsuspected role of S1P in lymphocyte trafficking and that such modulation of the immune system achieves therapeutic benefit in multiple sclerosis patients. S1P is synthesized from sphingosine by two SphKs (sphingosine kinases) (SphK1 and SphK2). Manipulation of SphK levels using molecular biology and mouse genetic tools has implicated these enzymes, particularly SphK1, in a variety of pathological processes such as fibrosis, inflammation and cancer progression. The results of such studies have spurred interest in SphK1 as a drug target. In this issue of the Biochemical Journal, Schnute et al. describe a small molecule inhibitor of SphK1 that is both potent and selective. Such chemical tools are essential to learn whether targeting S1P signalling at the level of synthesis is a viable therapeutic strategy.

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Raeder, Evelin M. B., Pamela J. Mansfield, Vania Hinkovska-Galcheva, Lars Kjeldsen, James A. Shayman, and Laurence A. Boxer. "Sphingosine Blocks Human Polymorphonuclear Leukocyte Phagocytosis Through Inhibition of Mitogen-Activated Protein Kinase Activation." Blood 93, no. 2 (January 15, 1999): 686–93. http://dx.doi.org/10.1182/blood.v93.2.686.

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Abstract In the present study, we investigated the mechanism by which sphingosine and its analogues, dihydrosphingosine and phytosphingosine, inhibit polymorphonuclear leukocyte (PMN) phagocytosis of IgG-opsonized erythrocytes (EIgG) and inhibit ERK1 and ERK2 phosphorylation. We used antibodies that recognized the phosphorylated forms of ERK1 (p44) and ERK2 (p42) (extracellular signal-regulated protein kinases 1 and 2). Sphingoid bases inhibited ERK1 and ERK2 activation and phagocytosis of EIgG in a concentration-dependent manner. Incubation with glycine, N,N′-[1,2-ethanediylbis(oxy-2,1-phenylene)]bis[N-[2-[(acetyloxy)methoxy]-2-oxoethyl]]-bis[(acetyloxy)methyl]ester (BAPTA,AM), an intracellular chelator of calcium, failed to block either phagocytosis or ERK1 and ERK2 phosphorylation, consistent with the absence of a role for a calcium-dependent protein kinase C (PKC) in ERK1 and ERK2 phosphorylations. Western blotting demonstrated that sphingosine inhibited the translocation of Raf-1 and PKCδ from PMN cytosol to the plasma membrane during phagocytosis. These data are consistent with the interpretation that sphingosine regulates ERK1 and ERK2 phosphorylation through inhibition of PKCδ, and this in turn leads to inhibition of Raf-1 translocation to the plasma membrane. Consistent with this interpretation, the sphingosine-mediated inhibition of phagocytosis, ERK2 activation, and PKCδ translocation to the plasma membrane could be abrogated with a cell-permeable diacylglycerol analog. The increase in the diacylglycerol mass correlated with the translocation of PKCδ and Raf-1 to the plasma membrane by 3 minutes after the initiation of phagocytosis. Additionally, the diacylglycerol analog enhanced phagocytosis by initiating activation of PKCδ and its translocation to the plasma membrane. Because PMN generate sufficient levels of sphingosine by 30 minutes during phagocytosis of EIgG to inhibit phagocytosis, it appears that sphingosine can serve as an endogenous regulator of EIgG-mediated phagocytosis by downregulating ERK activation.

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