2.7.1.91: sphingosine kinase
This is an abbreviated version!
For detailed information about sphingosine kinase, go to the full flat file.
Word Map on EC 2.7.1.91
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2.7.1.91
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sphingosine-1-phosphate
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1-phosphate
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sphingolipids
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ceramide
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endothelial
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sirnas
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necrosis
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agonist
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metastasis
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artery
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erk
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phospholipase
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fingolimod
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fibrosis
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lymphocyte
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protein-coupled
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sphingomyelinase
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tnf
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pulmonary
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leukemia
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sphingomyelin
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anti-apoptotic
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s1p-induced
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stat3
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pertussis
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mapks
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pro-apoptotic
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mitogen
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sclerosis
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pkc
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rheostat
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signal-regulated
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caspase-3
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pro-survival
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platelet-derived
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lysophospholipids
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cardioprotective
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phytosphingosine
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drug development
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lymphopenia
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egress
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glucosylceramide
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medicine
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fumonisins
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s1p-mediated
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dihydroceramide
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mitogenesis
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pdgf-induced
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ceramide-induced
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lysophosphatidic
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fcepsilonri
- 2.7.1.91
- sphingosine-1-phosphate
- 1-phosphate
- sphingolipids
- ceramide
- endothelial
- sirnas
- necrosis
- agonist
- metastasis
- artery
- erk
- phospholipase
- fingolimod
- fibrosis
- lymphocyte
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protein-coupled
- sphingomyelinase
- tnf
- pulmonary
- leukemia
- sphingomyelin
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anti-apoptotic
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s1p-induced
- stat3
- pertussis
- mapks
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pro-apoptotic
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mitogen
- sclerosis
- pkc
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rheostat
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signal-regulated
- caspase-3
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pro-survival
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platelet-derived
- lysophospholipids
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cardioprotective
- phytosphingosine
- drug development
- lymphopenia
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egress
- glucosylceramide
- medicine
- fumonisins
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s1p-mediated
- dihydroceramide
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mitogenesis
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pdgf-induced
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ceramide-induced
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lysophosphatidic
- fcepsilonri
Reaction
Synonyms
dihydrosphingosine kinase, kinase, dihydrosphingosine (phosphorylating), kinase, sphingosine (phosphorylating), More, SGK, SK, SK-1, SK-2, SK1, SK2, sphinganine kinase, sphingoid base kinase, sphingosine kinase, sphingosine kinase 1, sphingosine kinase 2, sphingosine kinase type 1, sphingosine kinase type 2, sphingosine kinase-1, sphingosine kinase-2, SPHK, SPHK-1, SPHK1, SPHK1a, SPHK1b, SPHK2, SPK
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General Information
General Information on EC 2.7.1.91 - sphingosine kinase
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malfunction
metabolism
physiological function
additional information
activation-dependent increase of intracellular Ca2+ concentration, degranulation (release of alpha and dense granules), integrin alphaIIbbeta3 activation, and aggregation are all significantly increased in enzyme-deficient sphk1-/- platelets compared with wild-type sphk1+/+ platelets. While platelet adhesion and thrombus formation under arterial shear rates are significantly augmented in Sphk1-deficient platelets, bleeding time and blood count are unaffected in sphk1-/- mice
malfunction
deletion of any one of the conserved domains hSK1DELTA17-36, hSK1DELTA72-96, hSK1DELTA107-119, hSK1DELTA165-198, or hSK1DELTA338-344 results in loss of interaction with calcium-loaded, sepharose-bound calmodulin, presumably due to improper protein folding, and sphingosine kinase activity. Truncation of the C-terminal 41 residues (hSK1DELTA344-384) also results in misfolded, inactive protein. In contrast, deletion of 17 residues (hSK1 DELTA368-384) yields a protein with affinity for calcium-calmodulin with activity equivalent to the wild-type enzyme
malfunction
dysregulation of the sphingosine-1-phosphate pathway is linked to a number of immune system disorders
malfunction
loss of sphingosine kinase 1 potentiates induction of the chemokine RANTES (regulated on activation, normal T cell expressed and secreted, also known as CCL5) in HeLa cells stimulated with TNF-alpha despite RANTES induction being highly dependent on the NF-kappaB pathway. Analysis of the mechanism by which SK1 regulates RANTES induction, overview. Loss of SK1 strongly upregulates RANTES independently of effects on NF-kappaB activation, while loss of SK2 does not affect NF-kappaB pathway activation
malfunction
single SK1 and SK2 knockout mouse models show little phenotypic change
malfunction
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genetic deficiency of isoform sphk-1 in the intestine inhibits activation of the mitochondrial unfolded protein response
malfunction
isoform SPHK1 deletion reduces endoplasm reticulum stress and alleviates inflammation response in hydrogen peroxide-treated cells
malfunction
sphingosine kinase-1 silencing decreases the expression of various immunosuppressive factors in the tumor microenvironment to limit regulatory T cell infiltration
malfunction
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activation-dependent increase of intracellular Ca2+ concentration, degranulation (release of alpha and dense granules), integrin alphaIIbbeta3 activation, and aggregation are all significantly increased in enzyme-deficient sphk1-/- platelets compared with wild-type sphk1+/+ platelets. While platelet adhesion and thrombus formation under arterial shear rates are significantly augmented in Sphk1-deficient platelets, bleeding time and blood count are unaffected in sphk1-/- mice
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malfunction
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genetic deficiency of isoform sphk-1 in the intestine inhibits activation of the mitochondrial unfolded protein response
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the interconversion of sphingosine and sphingosine 1-phosphate is mediated in the forward direction by sphingosine kinase and in the opposing way by specific sphingosine 1-phosphate phosphatases and less specific lipid phosphate phosphatases
metabolism
the interconversion of sphingosine and sphingosine1-phosphate is mediated in the forward direction by sphingosine kinase and in the opposing way by specific sphingosine 1-phosphate phosphatases and less specific lipid phosphate phosphatases
metabolism
the interconversion of sphingosine and sphingosine1-phosphate is mediated in the forward direction by sphingosine kinase and in the opposing way by specific sphingosine 1-phosphate phosphatases and less specific lipid phosphate phosphatases
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a short period of ischaemic postconditioning protects wild-type mouse hearts against ischaemia/reperfusion injury. The cardiac protection induced by postcondition is abrogated in SphK1-KO mouse hearts
physiological function
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activation of Gq protein-coupled receptors induces a profound, rapid and long-lasting translocation of isoform SphK1 to the plasma membrane. Classical Gq signalling pathways, or phosphorylation at Ser225, phospholipase D and Ca2+/calmodulin are not involved in M3 receptor-induced SphK1 translocation in HEK-293 cells. Translocation is associated with Sphingosine 1-phosphate receptor internalization, which is dependent on catalytic activity of SphK1 and sphingosine 1-phosphate receptor binding and thus results from S1P receptor cross-activation
physiological function
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adenovirus-mediated SPK1 gene transfer to rat mesothelial cells increases the cellular SPK1 activity, and leads to enhanced migration. Median adhesion scores are significantly lower in the transfected group than in controls in both rat caecum and rat uterine horn models
physiological function
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adiponectin-induced COX-2 expression is reduced by treatment with a sphingosine kinase-1 inhibitor or siRNA targeting SphK-1. Treatment with a sphingosine-1-phosphate receptor antagonist also diminishes COX-2 expression in response to adiponectin stimulation
physiological function
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cell lines sensitive to daunorubicin show increased ceramide content, while cell lines resistant to daunorubicin do not when treated with low doses of drug. Upon daunorubicin treatment, sphinganine 1-phosphate decreases more in the sensitive cell lines than in the resistant cell lines. A sphinganine kinase inhibitor recovers the daunorubicin sensitivity of daunorubicin resistant cells. The modulation of isoform Sk1 gene expression by overexpression or using siRNA affects the daunorubicin sensitivity of cell lines
physiological function
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depletion of isoform Sk1 by siRNA or inhibitors leads to accelerated connective tissue growth factor CTGF induction, mediated by sphingosine 1-phosphate
physiological function
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endothelial cells overepressing isoform Sk1 show reduced cell survival under conditions of stress, enhanced caspase-3 activity, cell cycle inhibition, and cell-cell junction disruption
physiological function
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filamin A links SphK1 and S1P1 receptor to locally influence the dynamics of actin cytoskeletal structures by orchestrating the concerted actions of of SphK1, FLNa, and PAK1, each of which requires and/or regulates the actions of the others, at lamellipodia to promote cell movement
physiological function
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HUVEC cells with 3- to 5fold overexpression of isoform SK1 show an enhanced migratory capacity and a stimulated rate of capillary tube formation. The cells show constitutive activation, and a more augmented vascular cell adhesion molecule VCAM-1 and E selectin response to TNF compared with empty vector control cells
physiological function
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in a murine collagen-induced arthritis model, prophylactic i.p. administration of SphK1 siRNA significantly reduces the incidence, disease severity, and articular inflammation compared with control siRNA recipients. Treatment of SphK1 siRNA also down-regulates serum levels of sphingosine 1-phosphate, IL-6, TNF-alpha, IFN-gamma, and IgG2a anticollagen Ab. Ex vivo analysis demonstrates significant suppression of collagen-specific proinflammatory/Th1 cytokine IL-6, TNF-alpha, IFN-gamma release in SphK siRNA-treated mice. Mice received with SphK2 siRNA develop more aggressive disease, higher serum levels of IL-6, TNF-alpha, and IFN-gamma, and proinflammatory cytokine production to collagen in vitro when compared with control siRNA recipients
physiological function
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in cardiac fibroblasts, sphingosine 1-phosphate increases alpha-smooth muscle actin and collagen expression in a S1P2 receptor- and Rho-kinase-dependent manner. TGF-beta increases sphingosine kinase 1 expression and activity. TGF-beta-stimulated collagen production is inhibited by SphK1 or S1P2 siRNA, a SphK inhibitor, and an anti-S1P monoclonal antibody
physiological function
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in contrast to wild-type mice, Sphk1-/- mice show markedly enhanced pulmonary edema formation in response to lipopolysaccharide and PAR-1 activation. Increased SPHK1 activity and decreased intracellular S1P concentration precede the onset of lung microvascular barrier recovery. Knockdown of SPHK1 decreases basal sphingosine 1-phoshate production and Rac1 activity but increases basal endothelial permeability. In SPHK1-depleted cells, PAR-1 activation fails to induce Rac1 activation but augments RhoA activation and endothelial hyperpermeability response. Knockdown of S1P1 receptor in endothelial cells also enhances the increase in endothelial permeability following PAR-1 activation. Sphingosine 1-phosphate treatment of Sphk1-/- lungs or SPHK1-deficient endothelial cells restores endothelial barrier function
physiological function
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in SPHK1-deficient mice, absence of the enzyme abrogates MCP-1 production induced in dermal microvascular endothelial cells upon treatment with thrombin or PAR-1 activating peptide
physiological function
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inhibition of isoform Sk1 or the ATP-binding cassette ABCC1 multidrug transporter attenuates calcium entry to cells, the addition of exogenous sphingosine 1-phosphate restores calcium entry. Overexpression of wild-type isoform Sk1, but not sk2, enhances phosphatese inhibitor calyculin-evoked calcium entry, whereas calcium entry is decreased in cells transfected with the dominant-negative G82D Sk1 mutant
physiological function
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isoform Sk1 activity is causally associated with endocrine resistance in MCF-7 cells. Enforced overexpression of Sk1 results in enhanced cell proliferation and resistance to tamoxifen-induced cell growth arrest and apoptosis. Tamoxifen-resistant cells exhibit higher levels of Sk1 expression and activity. Inhibition of Sk1 by pharmaceutical inhibitors or the dominant-negative mutant G82D restores the antiproliferative and proapoptotic effect of tamoxifen. Silencing of isoform Sk1, but not Sk2, expression by siRNA also restores the tamoxifen responsiveness in the resistant cells
physiological function
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isoform Sk1 interacts with four-and-a-half LIM only protein FHL-2. Overexpression of FHL-2 in endothelial cells inhibits VEGF-induced Sk1 activity, phosphatidylinositol 3-kinase activity, and phosphorylation of Akt and eNOS. Overexpression of FHL-2 has no effect on sphinganine 1-phosphate induced Akt phosphorylation. VEGF stimulation decreases the binding of FHL-2 and Sk1. Depletion of FHL-2 by siRNA increases endothelial cell migration accompanied with Sk1 and Akt activation
physiological function
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isoform SphK1 deficient SphK1-/- mice are much more susceptible to lipopolysaccharide-induced lung injury than wild-type. Overexpression of wild-type SphK1 in lungs protects SphK1-/- mice from lung injury and attenuates the severity of the response to lipopolysaccharide. Overexpression of a ShpK1 kinase-dead mutant in SphK1-/- mouse lungs further exacerbates the response to lipopolysaccharide as well as the extent of lung injury. Wild-type isoform SphK2 overexpression also fails to provide protection and augments the degree of lipopolysaccharide-induced lung injury
physiological function
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knock-down of SK1 using siRNA is able to inhibit the TNF but not the lipopolysaccharide inflammatory response. Knock-down of SK1 enhances both TNF- and lipopolysaccharide-induced apoptosis
physiological function
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knockdown of SK1 expression by specific siRNA inhibits 11,12-epoxyeicosatrienoic acid-induced endothelial cell proliferation and migration, whereas SK2 siRNA knockdown is without effect
physiological function
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mice depleted of isoform SK1 have increased vascular leakiness, whereas mice transgenic for SK1 in endothelial cells show attenuation of leakiness
physiological function
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overexpression of isoform Sk1 in ML-1 cells results in increased expression of sphingosine 1-phosphate, which can be attenuated by inhibiting Sk1 activity and an ATP-binding cassette transporter. Overexpression of Sk1 enhances serum-induced migration of ML-1 cells. Inhibition of protein kinase Calpha attenuates migration in Sk1 overexpressing cells. Overexpressing cells show an impaired adhesion, slower cell growth, and up-regulation of ERK1/2 phosphorylation
physiological function
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overexpression of SK1 results in inhibition of permeability similar to that seen for Ang-1, which rapidly and transiently stimulates SK1 activity and phosphorylation, and induces an increase in intracellular sphingosine 1-phosphate concentration. Knockdown of SK1 by siRNA blocks Ang-1-mediated inhibition of permeability. Transfection with S225A, a nonphosphorylatable mutant of SK1, inhibits basal leakiness, and both S225A and a dominant-negative SK1 mutant remove the capacity of Ang-1 to inhibit endotheial cell permeability. These effects are independent of extracellular sphingosine 1-phosphate
physiological function
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short-term androgen removal induces a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that is not observed in the hormone-insensitive PC-3 cells. The addition of dihydrotestosterone to androgen-deprived LNCaP cells re-establishes cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 can markedly impede the effects of dihydrotestosterone. Long-term removal of androgen support in LNCaP and C4-2B cells results in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which is characterized by the acquisition of a neuroendocrine-like cell phenotype. Inhibition of the PI3K/Akt pathway by negatively impacting SphK1 activity can prevent neuroendocrine differentiation in both cell models, an event that can be mimicked by SphK1 inhibitors
physiological function
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siRNA of SPHK1 inhibits cell proliferation of v-Src-transformed NIH-3T3 cells
physiological function
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SK1-/- mice treated with dextran sulfate sodium have significantly less blood loss, weight loss, colon shortening, colon histological damage, and splenomegaly than wild-type mice. SK1-/- mice have no systemic inflammatory response, and wild-type but not SK1-/- mice treated with dextran sulfate sodium have significant increases in blood sphingosine 1-phosphate levels, colon SK1 message and activity, and colon neutrophilic infiltrate. Unlike wild-type mice, SK1-/- mice fail to show colonic COX-2 induction despite an exaggerated TNF-alpha response
physiological function
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SphK activity, SphK1 protein content and sphingosine 1-phosphate formation are enhanced in myoblasts that became confluent as well as in differentiating cells. Enforced expression of SphK1 reduces the myoblast proliferation rate, enhances the expression of myogenic differentiation markers and anticipates the onset of differentiated muscle phenotype. Down-regulation of SphK1 by specific silencing byRNA interference or overexpression of a catalytically inactive SphK1, significantly increases cell growth and delays the beginning of myogenesis. Exogenous addition of sphingosine 1-phosphate rescues the biological processes. Stimulation of myogenesis in SphK1-overexpressing myoblasts is abrogated by treatment with short interfering RNA specific for S1P2 receptor
physiological function
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SphK1 activity is stimulated under low oxygen conditions and regulated by reactive oxygen species. The SphK1-dependent stabilization of HIF-1alpha levels is mediated by the Akt/glycogen synthase kinase-3beta signaling pathway that prevents its von Hippel-Lindau proteinmediated degradation by the proteasome. The pharmacologic and RNA silencing inhibition of SphK1 activity prevents the accumulation of HIF-1A and its transcriptional activity in several human cancer cell lineages from prostate, brain, breast, kidney, and lung, suggesting a canonical pathway
physiological function
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SphK1 enforced expression in PC-3 and LNCaP cells shifts the lipid biostat toward prosurvival sphingosine 1-phosphate and protects against B-5354cinduced apoptosis
physiological function
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SphK1 siRNA reduces both the SphK1 mRNA and the protein levels by 70% and has no effect on SphK2 expression. The SphK2 siRNA is equally specific but somewhat less efficient at reducing SphK2 expression. Decreasing SphK1expression significantly decreases both TGFbeta-induced chemotactic migration and invasion, whereas decreasing SphK2 expression inhibits chemotactic migration less effectively and has no effect on chemotactic invasion. Decreased expression of SphKs also inhibits TGFbeta activation of ERK1/2. TGFbeta activation of sphingosine kinases and formation of sphinmgosine 1-phosphate contribute to non-Smad signaling
physiological function
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SphK1-/- mice subjected to azoxymethane treatment have significantly less aberrant crypt foci formation and significantly reduced colon cancer development than wild-type
physiological function
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SPHK1-transgenic mice overexpress SPHK1 in diverse tissues, with a nearly 20fold increase in enzymatic activity. The transgenic mice grow normally with normal blood chemistry, cell counts, heart rate, and blood pressure. Transgenic mice with high but not low expression levels of SPHK1 develop progressive myocardial degeneration and fibrosis, with upregulation of embryonic genes, elevated RhoA and Rac1 activity, stimulation of Smad3 phosphorylation, and increased levels of oxidative stress markers. Treatment of juvenile transgenic mice with pitavastatin, or deletion of S1P3, a major myocardial S1P receptor subtype both inhibit cardiac fibrosis with concomitant inhibition of SPHK1-dependent Smad-3 phosphorylation. In addition, the anti-oxidant N-2-mercaptopropyonylglycine, also inhibits cardiac fibrosis. In in vivo ischaemia/reperfusion injury, the size of myocardial infarct is 30% decreased in SPHK1-transgenic mice compared with wild-type mice
physiological function
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stimulation of the lung epithelial cell line A-549 by thrombin leads to transient increase of SPHK1 activity and elevation of intracellular sphingosine 1-phosphate, abrogation of this stimulation by SPHK1-specific siRNA, pharmacological inhibition, or expression of a dominant-negative SPHK1 mutant blocks the response to thrombin. PAR-1 or thrombin-induced cytokine production and adhesion factor expression of human umbilical vein endothelial cells is also dependent on SPHK1
physiological function
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suppression of SphK1 by its inhibitor, N,N-dimethylsphingosine, or siRNA results in decreased mRNA expression of TNF-alpha, IL-1beta and iNOS and release of TNF-alpha and nitric oxide in lipopolysaccharid-activated microglia
physiological function
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the growth of SphK2-deficient MCF-7 breast tumor xenografts is markedly delayed when compared with controls. Infiltration of macrophages in SphK2-deficient and control tumors is comparable. Tumor-associated macrophages from SphK2-deficient tumors display a pronounced anti-tumor phenotype, showing an increased expression of pro-inflammatory markers/mediators such as NO, TNF-alpha, IL-12 and MHCII and a low expression of anti-inflammatory IL-10 and CD206
physiological function
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the knockdown of SphK1 by siRNA in mast cells inhibits several signaling mechanisms and effector functions, triggered by FcepsilonRI stimulation and including Ca2+ signals, NFkappaB activation, degranulation, cytokine/chemokine, and eicosanoid production. Silencing SphK2 has no effect at all. Silencing SPHK1 in vivo, in different strains of mice, strongly inhibits mast cell-mediated anaphylaxis, including inhibition of vascular permeability, tissue mast cell degranulation, changes in temperature, and serum histamine and cytokine levels, whereas silencing SPHK2 has no effect and the mice develop anaphylaxis. In mast cells derived from SPHK1-/- and SPHK2-/- mice, the calcium response and degranulation, triggered by FcepsilonRI-cross-linking, is not different from that triggered in wild-type cells. IgE-mediated anaphylaxis in the knockout mice shows similar levels in temperature changes and serum histamine to that from wild-type mice
physiological function
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translocation and precise subcellular positioning of Sk1 is essential for full function, and two distinct sphingosin 1-phosphate pools, intra- and extracellular, contribute to the maintenance of vascular tone
physiological function
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under basal conditions, SK1, integrin alphaVbeta3 and CD31 exist as a heterotrimeric complex. Under conditions that affect endothelial cell survival such as loss of contact with the extracellular matrix or growth factor activation, more of this heterotrimeric complex forms. Increased heterotrimeric complex formation requires SK1 phosphorylation at serine 225 for, activation of integrin alphaVbeta3, and endothelial cell survival signals, including Bcl-X and nuclear factor-B pathways. beta3-Integrin depletion confirms the requirement for this heterotrimeric complex in SK1-mediated endothelial cell survival
physiological function
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under hypoxia, isoform Sk2 shows an increase in protein level and activity, which correlates with the release of shingosine 1-phosphate into the medium. Knockdown of Sk2 by siRNA releives chemoresistance of A-450 cells under hypoxia and conditioned medium obtained from Sk2 knock-down cells is only partly protective, while conditioned medium of cells with normal levels of Sk2, incubated for 24 h under hypoxia, protects naive A-549 cells from etoposide-induced cell death
physiological function
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when sphingosine kinase 1 is deleted in Sandhoff disease mice, a prototypical neuronopathic lysosomal storage disorder, a milder disease course occurs, with decreased proliferation of glial cells and less-pronounced astrogliosis. A similar result of milder disease course and reduced astroglial proliferation is obtained by deletion of the gene for the S1P(3) receptor, a G protein-coupled receptor enriched in astrocytes
physiological function
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wild-type mesangial cells respond to staurosporine with increased DNA fragmentation and caspase-3 processing, which is enhanced in SK1-/- cells. SK2-/- cells are highly resistant to staurosporine-induced apoptosis. The basal phosphorylation and activity of the anti-apoptotic protein kinase B and of its substrate Bad are decreased in SK1-/- but not in SK2-/- cells. Upon staurosporine treatment, phosphorylation of protein kinase B and Bad decrease in wild-type and SK1-/- cells, but remain high in SK2-/- cells. The anti-apoptotic Bcl-XL is significantly upregulated in SK2-/- cells
physiological function
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application of siRNA-SPHK1 and sphingosine kinase inhibitor effectively blocks the expression of hypoxia inducible factor 1alpha, phospho-AKT and vascular endothelial growth factor production in PC-3 cells under hypoxia
physiological function
expression of isoform SK1 artificially targeted to the endoplasmic reticulum or without targeting signal, but surprisingly not plasma membrane-targeted SK1, results in a dramatic increase in the phosphorylation of dihydrosphingosine. Knockdown of endogenous SK1 diminishes both dihydrosphingosine-1-phosphate and sphinganine 1-phosphate levels. Sphinganine 1-phosphate produced at the plasma membrane is degraded to the same extent as that produced in the endoplasmic reticulum indicating that there is an efficient mechanism for the transport of sphinganine 1-phosphate. Sphinganine 1-phosphate degradation is primarily driven by lyase cleavage of sphinganine 1-phosphate
physiological function
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mice with kidney-specific overexpression of enhanced green fluorescent protein fused to isoform SK1 have significantly improved renal function with lower plasma creatinine, renal necrosis, apoptosis, and inflammation. Overexpression of the fusion protein cultured human proximal tubule cells protects against peroxide-induced necrosis. Selective overexpression of the construct leads to increased HSP27 mRNA and protein expression in vivo and in vitro. Functional protection as well as induction of HSP27 with the construct overexpression in vivo is blocked with sphingosine-1-phosphate-1 receptor-1 antagonism
physiological function
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renal ischemia-reperfusion injury induces isoform SK1, but not SK2, in the kidneys. Knockout or pharmacological inhibition of isoform SK1 increases injury after renal ischemia-reperfusion injury
physiological function
D-erythro-sphingosine 1-phosphate elicits numerous cellular responses via a family of G-protein coupled receptors, as well as intracellular effectors
physiological function
isozymes sphingosine kinases 1 and 2 (SK1 and SK2) generate the bioactive lipid mediator sphingosine 1-phosphate and as such play a significant role in cell fate and in human health and disease, SK1 and SK2 have overlapping, yet in some cases opposing, effects, overview. D-erythro-Sphingosine 1-phosphate elicits numerous cellular responses via a family of G-protein coupled receptors, as well as intracellular effectors
physiological function
lipid kinase sphingosine kinase 1 catalyzes the conversion of sphingosine to sphingosine-1-phosphate, which plays a role in lymphocyte trafficking, angiogenesis, and response to apoptotic stimuli. As a central enzyme in modulating the sphingosine-1-phosphate levels in cells, the enzyme is an important regulator for diverse cellular functions
physiological function
sphingosine 1-phosphate is a pleiotropic signaling molecule that acts as a ligand for five G-protein coupled receptors (S1P1-5) whose downstream effects are implicated in a variety of important pathologies including sickle cell disease, cancer, inflammation, and fibrosis. The synthesis of S1P is catalyzed by sphingosine kinase (SphK) isoforms 1 and 2
physiological function
sphingosine 1-phosphate is a pleiotropic signaling molecule that acts as a ligand for five G-protein coupled receptors (S1P1-5) whose downstream effects are implicated in a variety of important pathologies including sickle cell disease, cancer, inflammation, and fibrosis. The synthesis of S1P is catalyzed by sphingosine kinase (SphK) isoforms 1 and 2. Isozyme SphK2 can localize in the nucleus to inhibit DNA synthesis and regulate HDAC1/2 activity
physiological function
sphingosine kinase 1 is a powerful negative regulator of platelet function counteracting degranulation, aggregation, and thrombus formation. In mast cells, intracellular Ca2+ is rapidly and transiently increased by spingosine kinase 1. Sphingosine 1-phosphate mobilizes intracellular Ca2+ in mast cells in an inositol triphosphate-dependent manner. In other cell types, sphingosine kinases regulate intracellular Ca2+ by influencing voltage-gated Ca2+ channels or by activating the store-operated calcium entry. Sphingosine kinases and sphingosine 1-phosphate further regulate platelet formation by megakaryopoiesis. They are effective by upregulating Src family kinases in megakaryocytes. Megakyocytes express the S1P multifunctional receptor S1pr1, and S1P signaling is an important prerequisite for proper thrombopoesis
physiological function
sphingosine kinase 1 produces the pro-survival sphingolipid sphingosine 1-phosphate and is implicated in inflammation, proliferation, and angiogenesis. The enzyme is required for activation of p38 MAPK, but is not required for transcriptional NF-kappaB activity following TNF treatment. But nuclear translocation of NF-kappaB subunits does not require enzyme SK1
physiological function
sphingosine-1-phosphate is a lipid second messenger formed upon phosphorylation of sphingosine by sphingosine kinase and plays a crucial role in natural killer cell proliferation, migration, and cytotoxicity
physiological function
isofom SPHK1 upregulation, induced by hydrogen peroxide, is responsible for cerebral IR injury through inducing endoplasm reticulum stress and inflammation response in a manner working through the nuclear factor-kappaB signaling pathway
physiological function
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isoform SPHK-1 activates the mitochondrial unfolded protein response
physiological function
sphingosine kinase-1 is a key regulator of anti-tumor immunity. Increased expression of the enzyme in tumor cells is significantly associated with shorter survival in metastatic melanoma patients treated with anti-programmed cell death protein-1
physiological function
the enzyme regulates the expression of interleukin-17A in activated microglia in cerebral ischemia/reperfusion
physiological function
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sphingosine kinase 1 is a powerful negative regulator of platelet function counteracting degranulation, aggregation, and thrombus formation. In mast cells, intracellular Ca2+ is rapidly and transiently increased by spingosine kinase 1. Sphingosine 1-phosphate mobilizes intracellular Ca2+ in mast cells in an inositol triphosphate-dependent manner. In other cell types, sphingosine kinases regulate intracellular Ca2+ by influencing voltage-gated Ca2+ channels or by activating the store-operated calcium entry. Sphingosine kinases and sphingosine 1-phosphate further regulate platelet formation by megakaryopoiesis. They are effective by upregulating Src family kinases in megakaryocytes. Megakyocytes express the S1P multifunctional receptor S1pr1, and S1P signaling is an important prerequisite for proper thrombopoesis
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physiological function
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isoform SPHK-1 activates the mitochondrial unfolded protein response
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additional information
analysis of the catalytic mechanism of the enzyme, residues G79, G80, G82, and K103 are important. Sequence comparison of human isozymes sphingosine kinases 1 and 2
additional information
analysis of the catalytic mechanism of the enzyme, residues G79, G80, G82, and K103 are important. Sequence comparison of human isozymes sphingosine kinases 1 and 2
additional information
analysis of the catalytic mechanism of the enzyme, sequence comparison of human isozymes sphingosine kinases 1 and 2
additional information
analysis of the catalytic mechanism of the enzyme, sequence comparison of human isozymes sphingosine kinases 1 and 2
additional information
modeling of the catalytic mechanism, overview. Residue Asp81 plays a critical role in the phosphoryl transfer step, but not in the binding of ATP
additional information
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modeling of the catalytic mechanism, overview. Residue Asp81 plays a critical role in the phosphoryl transfer step, but not in the binding of ATP
additional information
schematic model of the proposed mechanism of the phosphorylation of D-erythro-sphingosine catalyzed by isozyme SK1
additional information
schematic model of the proposed mechanism of the phosphorylation of D-erythro-sphingosine catalyzed by isozyme SK1