Disease relevance of sphingosine

• The Rho signalling pathway is activated, for example, by bioactive sphingolipids such as sphingosine-1-phosphate (SPP) or by overexpression of Rho family members in tumorigenesis and metastases [1].
• In vivo, calcineurin mediates prolonged dephosphorylation of Slm1 and Slm2 during heat stress, and this response can be mimicked by exogenous addition of the sphingoid base phytosphingosine [2].
• We present data showing that rhabdomyosarcoma cell lines, independent of lineage (alveolar rhabdomyosarcoma and embryonal rhabdomyosarcoma), are particularly sensitive to the induction of apoptosis as a result of an elevation in the cellular levels of sphingosine (D-erythro-sphingosine) [3].
• Pertussis toxin antagonized the SPP effects on insulin release [4].
• Retinoblastoma protein dephosphorylation induced by D-erythro-sphingosine [5].

High impact information on sphingosine

• Alteration of the 4-sphingenine scaffolds of ceramides in keratinocyte-specific Arnt-deficient mice affects skin barrier function [6].
• Mammalian S1P phosphatase (SPP-1), which degrades S1P to terminate its actions, was recently cloned based on homology to a lipid phosphohydrolase that regulates the levels of phosphorylated sphingoid bases in yeast [7].
• In a screen to detect proteins involved in ubiquitin-dependent receptor internalization, we identified the sphingoid base-regulated serine-threonine kinase Ypk1 [8].
• These results suggest that Pkh1/2p kinases are part of a sphingoid base-mediated signaling pathway that is required for the internalization step of endocytosis [9].
• We show that overexpression of either one of the two kinases Pkh1p or Pkh2p, that are homologous to mammalian 3-phosphoinositide-dependent kinase-1 (PDK1), can specifically suppress the sphingoid base synthesis requirement for endocytosis [9].

Chemical compound and disease context of sphingosine

• Induction of apoptosis and potentiation of ceramide-mediated cytotoxicity by sphingoid bases in human myeloid leukemia cells [10].
• The effects of SPP were mimicked by sphingosylphosphorylcholine (SPPC) and strongly attenuated by pertussis toxin (PTX) [11].
• The sphingoid base sphinganine induces apoptosis in HT-29 human colon cancer cells more potently than other bioactive sphingolipid metabolites sphingosine and C2-ceramide tested in our previous study [12].
• This PGE2-induced inhibition was attenuated by 30 min pretreatment with the protein kinase C (PKC) antagonists 1 microM staurosporine or 100 microM D-sphingosine but was insensitive to pertussis toxin (PTX) [13].
• Evaluation of cellular morphology via fluorescence microscopy and quantitation of fragmented low-molecular weight DNA using the diphenylamine assay demonstrated that sphingoid bases and C(2)-ceramide cause chromatin and nuclear condensation as well as fragmentation of DNA, suggesting these lipids kill colon cancer cells by inducing apoptosis [14].

Biological context of sphingosine

• Interestingly, sphingoid base synthesis is required for proper actin organization, but is not required for receptor phosphorylation [15].
• Increased protein kinase or decreased PP2A activity bypasses sphingoid base requirement in endocytosis [16].
• Based on sequence homology with LBP1, a lipid phosphohydrolase that regulates the levels of phosphorylated sphingoid bases in yeast, we report here the cloning, identification, and characterization of a mammalian SPP phosphatase (mSPP1) [17].
• Induction of apoptosis by sphingoid long-chain bases in Aspergillus nidulans [18].
• In the present study, we investigated the effects of short chain ceramides and sphingoid bases on phagocytosis of IgG-opsonized erythrocytes (EIgG) by suspended PMNs activated with fMLP [19].

Anatomical context of sphingosine

• In yeast, sphingoid base synthesis is required for the internalization step of endocytosis and organization of the actin cytoskeleton [9].
• Analysis of C(18) sphingoid bases derived from 16:0 indicated that, despite a 50% reduction in exported 16:0, the mutant cells maintained wild-type levels of sphingoid bases, presumably at the expense of other cell components [20].
• At 37 degrees C in lcb1-100 cells, a more severe defect occurs in sphingoid base synthesis, and targeting of newly synthesized Pma1 to the plasma membrane is impaired [21].
• This phosphorylated sphingoid base is not only an intermediary catabolite, but also a bioactive lipid with important functions, including stimulation of cell proliferation in Swiss 3T3 fibroblasts and inhibition of tumor cell motility [22].
• Our results suggest that platelets may maintain the integrity of endothelial cells by incorporating Sph and releasing Sph-1-P [23].

Associations of sphingosine with other chemical compounds

• Central to this signalling pathway is the phosphorylation of the sphingoid long chain base, sphingosine, which yields sphingosine-1-phosphate [24].
• Combination of exogenous sphingomyelin with ceramide, glucosylceramide, GM3, or sphingoid bases did not show any synergistic or additive effect on the SPB-1 cell growth enhancement, compared with sphingomyelin alone [25].
• Strains deleted in sphingoid base kinases, sphingoid phosphate phosphatase, lyase, or dihydrosphingosine hydroxylase were found to display the cell cycle arrest [26].
• Phytosphingosine (PHS), a sphingoid long chain base, is hypothesized to be a lipid activator of Pkh1 and thereby controls the activity of Ypk1/2 [27].
• The effects of N-acetyl-conjugated sphingols (C2 ceramides) on phosphatidylcholine-specific phospholipase D and phosphatidic acid phosphohydrolase were markedly different from the effects of the related sphingoid bases [28].

Gene context of sphingosine

• Phosphorylation by Pho85 cyclin-dependent kinase acts as a signal for the down-regulation of the yeast sphingoid long-chain base kinase Lcb4 during the stationary phase [29].
• Interestingly, cell cycle recovery from the transient arrest was found to be dependent upon the sphingoid base kinases (LCB4, LCB5) [26].
• Both genes functionally and biochemically complement a yeast sphingosine kinase mutant, express predominantly cytosolic activities, and are capable of phosphorylating a range of endogenous and non-endogenous sphingoid base substrates [30].
• We observed concentration- and time-dependent activation of PAK1 by sphingosine and several related long chain sphingoid bases but not by ceramides or a variety of other lipids [31].
• Tsc3p is apparently not required for any essential process besides stimulation of serine palmitoyltransferase at 37 degrees C, since providing sphingoid bases to the growth medium reverses the temperature-sensitive growth phenotype of the tsc3 delta mutant [32].

Analytical, diagnostic and therapeutic context of sphingosine

• FTY720 was rationally designed by modification of myriocin, a naturally occurring sphingoid base analog that causes immunosuppression by interrupting sphingolipid metabolism [33].
• Using measurements with the Ca2+-sensitive fluorescent dye fura-2 and the whole-cell patch-clamp technique, we found that D-erythro-sphingosine, a metabolite arising during the de novo synthesis of cellular sphingolipids, activated TRPM3 [34].
• In the present study, we have isolated four O-methyl ethers of C18-sphingosine by medium pressure liquid chromatography of their diacetate derivatives, i.e., (2S,3R,4E)-1-acetoxy-2-acetamido-3-methoxy-4-octadecene, its (2S,3S) epimer, (2R,3E,5R)-1-acetoxy-2-acetamido-5-methoxy-3-octadecene, and its (2R,5S) epimer [35].
• Sphingoid bases were characterized by gas-liquid chromatography of aldehydes formed upon periodate oxidation [36].
• A fraction enriched in sphingoid bases was isolated by preparative thin-layer chromatography and reacted with 2,4-dinitrofluorobenzene [37].

References