Human sphingosine kinase: molecular cloning, functional characterization and tissue distribution

Melendez, Alirio J.; Carlos-Dias, Estelle; Gosink, Mark; Allen, Janet M.; Takács, László

doi:10.1016/s0378-1119(00)00205-5

Cited by 128 publications

(114 citation statements)

References 29 publications

Supporting

Mentioning

111

Contrasting

Order By: Relevance

“…SPHK activity is elevated by several stimuli, including platelet-derived growth factor, vascular endothelial growth factor, tumor necrosis factor-␣, and phorbol ester, which trigger an increase in cellular S1P levels (14). Sphk genes have been identified in mammals (15)(16)(17)(18), insects (19), plants (20), yeast (21), worm (22), and slime mold (23,24). Mammals carry two known SphK genes, which in mice are encoded by Sphk1 and Sphk2.…”

mentioning

confidence: 99%

Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720

Allende

Sasaki

Kawai

et al. 2004

Journal of Biological Chemistry

425

384

View full text Add to dashboard Cite

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. Sphk1 null mice were viable, fertile, and without any obvious abnormalities. Total SPHK activity in most Sphk1؊/؊ tissues was substantially, but not completely, reduced indicating the presence of multiple sphingosine kinases. S1P levels in most tissues from the Sphk1؊/؊ 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 of Sphk1؊/؊ mice. The immunosuppressant FTY720 was phosphorylated and elicited lymphopenia in the Sphk1 null mice showing that SPHK1 is not required for the functional activation of this sphingosine analogue prodrug. The results with these Sphk1 null 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.Sphingosine-1-phosphate (S1P) 1 is a signaling molecule that influences cellular functions including proliferation, survival, migration, adhesion molecule expression, and morphogenesis (1-4). S1P binds to members of the S1P receptor family (also known as EDG receptors) and, via G proteins, triggers multiple signaling pathways (5, 6). S1P has also been shown to function intracellularly mediating calcium homeostasis, cell growth, and suppression of apoptosis (7,8). In mammals, vascular development and lymphocyte trafficking are dependent on S1P receptor signaling (9 -13).Sphingosine kinase (SPHK) catalyzes the synthesis of S1P via the phosphorylation of sphingosine. SPHK activity is elevated by several stimuli, including platelet-derived growth factor, vascular endothelial growth factor, tumor necrosis factor-␣, and phorbol ester, which trigger an increase in cellular S1P levels (14). Sphk genes have been identified in mammals (15-18), insects (19), plants (20), yeast (21), worm (22), and slime mold (23, 24). Mammals carry two known SphK genes, which in mice are encoded by Sphk1 and Sphk2. The two enzymes contain five highly conserved regions (C1-C5) and an ATP binding site within a conserved lipid kinase catalytic domain (15, 16). SPHK1 has a predominantly cytoplasm localization but can be induced to localize to the inner leaflet of the plasma membrane. Interestingly in endothelial cells SPHK1 is secreted and is capable of producing S1P extracellularly (25). Sphk1 shows a tissue distribution and developmental expression pattern different from Sphk2, although both enzymes are widely expressed (16,26).The importance of S1P receptor signaling in lymphocyte trafficking was first illuminated by the activities of FTY720, a potent immunosuppressive agent. FT...

show abstract

mentioning

confidence: 99%

Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720

Allende

Sasaki

Kawai

et al. 2004

Journal of Biological Chemistry

425

384

View full text Add to dashboard Cite

show abstract

“…SK was originally cloned in budding yeast (16), and members of the SK family have subsequently been identified in plant (17), mouse (18), rat (19), and human (20). Each has a conserved lipid kinase catalytic domain that contains the ATPbinding site.…”

mentioning

confidence: 99%

“…The SK enzymes studied to date are capable of phosphorylating erythro-sphingosine, dihydrosphingosine, and phytosphingosine in an ATPdependent fashion and are inhibited by a growing number of compounds, including the two most well tested in biological systems, DL-threo-dihydrosphingosine (22) and N,N-dimethylsphingosine (23). SK activity is widely distributed in mouse and rat tissues and is primarily found in the cytosolic fraction (20,24,25). However, SK activity is also found to be associated with mitochondrial and microsomal fractions, and activated forms of SK are associated with the plasma membrane to which they have been demonstrated to translocate in several cell types (26,27).…”

mentioning

confidence: 99%

Characterization of the Drosophila Sphingosine Kinases and Requirement for Sk2 in Normal Reproductive Function

Herr

Fyrst²,

Creason

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Sphingosine kinase is a highly conserved enzyme that catalyzes the synthesis of sphingosine 1-phosphate and reduces cellular levels of sphingosine and ceramide. Although ceramide is pro-apoptotic and sphingosine is generally growth-inhibitory, sphingosine 1-phosphate signaling promotes cell proliferation, survival, and migration. Sphingosine kinase is thus in a strategic position to regulate important cell fate decisions which may contribute to normal animal development. To facilitate studies examining the potential role of sphingosine kinase and long chain base metabolism in Drosophila development, we characterized two putative Drosophila sphingosine kinase genes, Sk1 and Sk2. 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. The two genes demonstrate overlapping but distinct temporal and spatial expression patterns in the Drosophila embryo, and timing of expression is consistent with observed changes in long chain base levels throughout development. A null Sk2 transposon insertion mutant demonstrated elevated long chain base levels, impaired flight performance, and diminished ovulation. This is the first reported mutation of a sphingosine kinase in an animal model; the associated phenotypes indicate that Sk1 and Sk2 are not redundant in biological function and that sphingosine kinase is essential for diverse physiological functions in this organism.Sphingosine 1-phosphate (S1P) 1 is a bioactive sphingolipid metabolite that provides directional cues to migrating cells (1) and exerts proliferative and anti-apoptotic effects on many cell types (2). S1P signals are transduced through both extracellular (receptor-mediated) and intracellular mechanisms. Intracellularly, S1P signaling affects cytoskeletal organization, calcium homeostasis, DNA synthesis, and the apoptotic machinery. S1P is generated by the phosphorylation of sphingosine, a reaction catalyzed by sphingosine kinase (SK). It is eliminated through dephosphorylation catalyzed by either S1P phosphatase (S1PP) or type 2 phosphatidate phosphohydrolases or through its irreversible degradation to a long chain aldehyde and ethanolamine phosphate, catalyzed by sphingosine 1-phosphate lyase (SPL) (Fig. 1).SK is a member of a growing class of lipid kinases, including diacylglycerol kinases and phosphatidylinositol 3-kinases, that participate in cell signaling. Many studies have implicated SK activation and S1P generation in mediating angiogenesis, tumorigenicity, metastasis, cell proliferation, motility, lymphocyte trafficking, endocytosis, and survival (reviewed in Refs. 3-10). SK activation has been reported in response to many stimuli and regulates diverse functions such as heat stress response in yeast (11) and stomatal closure in Arabidopsis (12). Thus, SK activation appears to be a widely employed mechanism for propagating mitogenic and survival signals in eukaryotes. Known do...

show abstract

“…SKs are highly conserved throughout various organisms from plants to mammals [8]. Two isoforms, SK1 and SK2, have been cloned and characterized so far in mammals [9][10][11][12][13][14]. Although these two enzymes have a high degree of sequence similarity, they are different in kinetic properties and tissue distribution and originate from different genes [2,15].…”

Section: Introductionmentioning

confidence: 99%

“…Although these two isoforms are differ only in a few N-terminal amino acid residues, they show different characteristics including stability, intracellular distribution, and tissue distribution [20]. With respect to human SK1 [11,12,14], two additional variants were reported and enzymatic activity of these variants has been shown to be similar to that of SK1 [15]. While sequencing rat genomic DNA and cDNA, Imamura et al identified 8 alternatively spliced mRNAs with alternative first exons within a 3.7-kb CpG island [21,22].…”

Section: Introductionmentioning

confidence: 99%

Cloning and characterization of rat sphingosine kinase 1 with an N-terminal extension

Park

Lee

et al. 2007

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

Sphingosine kinase (SK) is an enzyme that converts sphingosine to sphingosine 1-phosphate, a lysophospholipid with various cellular functions. Here, we report cloning and characterization of a novel isoform of rat SK1 (rSK1) with an N-terminal extension (long-rSK1). Long-rSK1 is 458 amino acid-long and has a calculated molecular weight of 49.8 kDa. Deduced amino acid sequences of rat and human long-SK1 have high homology (71.3% identity and 78.9% similarity). Long-rSK1 mRNA is widely expressed throughout the tissues including brain, heart, lung, liver, kidney and spleen, whereas mRNA encoding rSK1 has been shown not to be expressed in heart or liver. When the longrSK1 was transfected in COS-7 cells, SK activity was 53-fold increased. Substrate specificity and dependency on divalent cations of long-rSK1 were similar to those of rSK1. Taken together, the fact that long-rSK1 with similar enzymatic characteristics to rSK1 displays differential tissue distribution may suggest an additional role of long-rSK1.

show abstract

Human sphingosine kinase: molecular cloning, functional characterization and tissue distribution

Cited by 128 publications

References 29 publications

Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720

Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720

Characterization of the Drosophila Sphingosine Kinases and Requirement for Sk2 in Normal Reproductive Function

Cloning and characterization of rat sphingosine kinase 1 with an N-terminal extension

Contact Info

Product

Resources

About