Information on EC 2.7.1.91 - sphinganine kinase

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The expected taxonomic range for this enzyme is: Eukaryota

EC NUMBER
COMMENTARY
2.7.1.91
-
RECOMMENDED NAME
GeneOntology No.
sphinganine kinase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + sphinganine = ADP + sphinganine 1-phosphate
show the reaction diagram
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-
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ATP + sphinganine = ADP + sphinganine 1-phosphate
show the reaction diagram
catalytic mechanism
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ATP + sphinganine = ADP + sphinganine 1-phosphate
show the reaction diagram
overview on regulation
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ATP + sphinganine = ADP + sphinganine 1-phosphate
show the reaction diagram
Asp177 in C4 domain of isozyme SK1a is important for sphingosine substrate recognition
Q8CI15
ATP + sphinganine = ADP + sphinganine 1-phosphate
show the reaction diagram
catalytic mechanism, the catalytic domain contains the C1-C5 sequence stretches and the ATP-binding site
-
ATP + sphinganine = ADP + sphinganine 1-phosphate
show the reaction diagram
Lys103 is important in catalysis
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phospho group transfer
-
-
-
-
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
Metabolic pathways
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sphingolipid biosynthesis (plants)
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Sphingolipid metabolism
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sphingolipid recycling and degradation (yeast)
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sphingosine metabolism
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SYSTEMATIC NAME
IUBMB Comments
ATP:sphinganine 1-phosphotransferase
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SYNONYMS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dihydrosphingosine kinase
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-
-
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kinase, dihydrosphingosine (phosphorylating)
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SK
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-
-
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SK
Q9VYY8, Q9VZW0
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SK
Q9NRA0, Q9NYA1
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SK
Q8CI15
-
SK-1
Q9NYA1
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SK-1
Q8CI15
-
SK-1
Q91V26
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SK-2
Q9NRA0
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SK-2
Q6AYB2
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SK1
Q1HGK5
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SK2
Q9NRA0
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SK2
Q6AYB2
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sphingoid base kinase
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-
-
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sphingosine kinase
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sphingosine kinase
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sphingosine kinase
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sphingosine kinase
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sphingosine kinase
Q9VYY8, Q9VZW0
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sphingosine kinase
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sphingosine kinase
O88885
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sphingosine kinase
Q8CI15
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sphingosine kinase
Q9JIA7
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sphingosine kinase
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sphingosine kinase
Q6AYB2
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sphingosine kinase
Q91V26
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sphingosine kinase 1
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sphingosine kinase 1
Q9NYA1
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sphingosine kinase 1
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sphingosine kinase 1
Q8CI15
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sphingosine kinase 1
Q1HGK5
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sphingosine kinase 1
Q91V26
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sphingosine kinase 2
Q9NRA0
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sphingosine kinase 2
Q9JIA7
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sphingosine kinase type 1
Q8CI15
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sphingosine kinase type 2
Q9JIA7
-
sphingosine kinase-1
Q9NYA1
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sphingosine kinase-1
Q9NYA1
is a substrate for the cysteine protease cathepsin B
sphingosine kinase-1
Q8CI15
is a substrate for the cysteine protease cathepsin B
sphingosine kinase-1
Q91V26
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sphingosine kinase-1
Q91V26
is a substrate for the cysteine protease cathepsin B
sphingosine kinase-2
Q6AYB2
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SPHK
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-
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SPHK
Q9NRA0, Q9NYA1
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SPHK
O88885, Q9JIA7
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SPHK1
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SPHK1
Q8CI15
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SPHK1a
Q8CI15
stable enzyme form
SPHK1b
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unstable enzyme form
SPHK2
Q9NRA0
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SPHK2
Q9JIA7
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SPHK2
Q6AYB2
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kinase, sphingosine (phosphorylating)
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additional information
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the enzyme belongs to the subfamily of diacylglyceride kinases DAGKs
additional information
Q9NRA0, Q9NYA1
enzyme belongs to the SPHK superfamily
additional information
-
the enzyme belongs to the subfamily of diacylglyceride kinases DAGKs
additional information
O88885, Q9JIA7
enzyme belongs to the SPHK superfamily
CAS REGISTRY NUMBER
COMMENTARY
50864-48-7
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
several isozymes
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Manually annotated by BRENDA team
isozymes SgkA and SgkB encoded by the genes sgkA and sgkB
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Manually annotated by BRENDA team
isozyme Sk1; 2 isozymes Sk1 and Sk2 encoded by 2 genes Sk1 and Sk2
SwissProt
Manually annotated by BRENDA team
isozyme Sk2; 2 isozymes Sk1 and Sk2 encoded by 2 genes Sk1 and Sk2
SwissProt
Manually annotated by BRENDA team
2 isozymes SPHK1 and SPHK2
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Manually annotated by BRENDA team
2 isozymes SPHK1 and SPHK2, several splicing variants exist, overview
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Manually annotated by BRENDA team
enzyme is expressed as isoform SK1a of 42.5 kDa, and isoform SK1b, a 51 kDa protein identical to SK1a, but with an 86 amino acid N-terminal extension
SwissProt
Manually annotated by BRENDA team
isoform SK1
SwissProt
Manually annotated by BRENDA team
isoform SK2
SwissProt
Manually annotated by BRENDA team
isozyme Sk1; 2 isozymes SK1 and SK2
SwissProt
Manually annotated by BRENDA team
isozyme Sk2; 2 isozymes SK1 and SK2
SwissProt
Manually annotated by BRENDA team
isozyme SphK1
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-
Manually annotated by BRENDA team
isozyme SPHK1; 2 isozymes SPHK1 and SPHK2, several splicing variants
SwissProt
Manually annotated by BRENDA team
isozyme SPHK2; 2 isozymes SPHK1 and SPHK2, several splicing variants
SwissProt
Manually annotated by BRENDA team
isozymes SphK1 and SphK2
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Manually annotated by BRENDA team
patients with breast cancer
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Manually annotated by BRENDA team
patients with non-Hodgkin lymphomas
SwissProt
Manually annotated by BRENDA team
recombinant enzyme
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Manually annotated by BRENDA team
recombinant SPHK1, SPHK2
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Manually annotated by BRENDA team
SPHK2
SwissProt
Manually annotated by BRENDA team
Swiss 3T3 cell culture
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Manually annotated by BRENDA team
2 isozymes SPHK1 and SPHK2
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Manually annotated by BRENDA team
isoform SphK1a
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Manually annotated by BRENDA team
isozyme SK1 splicing variant a
SwissProt
Manually annotated by BRENDA team
isozyme SPHK1; 2 isozymes SPHK1 and SPHK2, several splicing variants
SwissProt
Manually annotated by BRENDA team
isozyme SPHK2; 2 isozymes SPHK1 and SPHK2, several splicing variants
SwissProt
Manually annotated by BRENDA team
male C57BL mice, 2 isozymes SPHK1 and SPHK2, isozyme SPHK1 exists in 2 splicing variants a and b
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Manually annotated by BRENDA team
SPHK2
SwissProt
Manually annotated by BRENDA team
plant
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Manually annotated by BRENDA team
mast-cell line RBL-2H3
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Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
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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
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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
-
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
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ATP + (2R)-2-amino-2-[5-(4-octylphenyl)-1H-imidazol-2-yl]propan-1-ol
ADP + (2R)-2-amino-2-[5-(4-octylphenyl)-1H-imidazol-2-yl]propyl dihydrogen phosphate
show the reaction diagram
-
-
product is a sphingosine 1-phosphate receptor prodrug
-
?
ATP + (2R)-2-amino-2-[5-(4-octylphenyl)-1H-imidazol-2-yl]propan-1-ol
ADP + (2R)-2-amino-2-[5-(4-octylphenyl)-1H-imidazol-2-yl]propyl dihydrogen phosphate
show the reaction diagram
-
approximately 20% the activity of sphingosine at isoformSPHK2
product is a sphingosine 1-phosphate receptor prodrug
-
?
ATP + (2R)-2-amino-4-(4-heptoxyphenyl)-2-methylbutan-1-ol
ADP + (2R)-2-amino-4-(4-heptoxyphenyl)-2-methylbutyl dihydrogen phosphate
show the reaction diagram
-
isoform SPHK2 is 6fold more efficient than SPHK1 in phosphorylating
product is a nanomolar agonist of sphingosine 1-phsphate receptor 1, whereas the (2S)-enantiomer is much weaker
-
?
ATP + (2R,3R)-3-amino-5-(4-heptoxyphenyl)-3-methylpentan-2-ol
ADP + (2R,3R)-3-amino-5-(4-heptoxyphenyl)-3-methylpentan-2-yl dihydrogen phosphate
show the reaction diagram
-
no substrate for SPHK1, phosphorylated by SPHK2 at low rates
product is a potent agonist of sphingosine 1-phsphate receptor 1
-
?
ATP + 1-O-hexadecyl-2-deoxy-2-amino-sn-glycerol
ADP + 1-O-hexadecyl-2-deoxy-2-amino-sn-glycerol 3-phosphate
show the reaction diagram
-
isozyme SPHK2, 10fold lower activity with isozyme SPHK1
-
-
?
ATP + 2-amino-2-[4-(4-octylphenyl)-1,3-oxazol-2-yl]propan-1-ol
ADP + 2-amino-2-[4-(4-octylphenyl)-1,3-oxazol-2-yl]propyl dihydrogen phosphate
show the reaction diagram
-
-
product is a sphingosine 1-phosphate receptor prodrug
-
?
ATP + 2-amino-2-[4-(4-octylphenyl)-1,3-oxazol-2-yl]propan-1-ol
ADP + 2-amino-2-[4-(4-octylphenyl)-1,3-oxazol-2-yl]propyl dihydrogen phosphate
show the reaction diagram
-
good substrate of isoform SPHK2
product is a sphingosine 1-phosphate receptor prodrug
-
?
ATP + 2-amino-2-[5-(4-octylphenyl)-1,2,4-oxadiazol-3-yl]propan-1-ol
ADP + 2-amino-2-[5-(4-octylphenyl)-1,2,4-oxadiazol-3-yl]propyl dihydrogen phosphate
show the reaction diagram
-
-
product is a sphingosine 1-phosphate receptor prodrug
-
?
ATP + 2-amino-2-[5-(4-octylphenyl)-1,2,4-oxadiazol-3-yl]propan-1-ol
ADP + 2-amino-2-[5-(4-octylphenyl)-1,2,4-oxadiazol-3-yl]propyl dihydrogen phosphate
show the reaction diagram
-
moderate activity at isoform SPHK2, it is the only alcohol in the series to have significant activity at isoform SPHK1
product is a sphingosine 1-phosphate receptor prodrug
-
?
ATP + 4,8-sphingadienine
ADP + 4,8-sphingadienine 1-phosphate
show the reaction diagram
-
high activity
-
-
ir
ATP + biotinyl-D-erythro-sphingosine
ADP + biotinyl-D-erythro-sphingosine 1-phosphate
show the reaction diagram
Q9NRA0, Q9NYA1
-
-
-
?
ATP + D-erythro-dihydrosphingosine
ADP + D-erythro-dihydrosphingosine 1-phosphate
show the reaction diagram
Q1HGK5
the activity of longrSK1 towards dihydrosphingosine is about 3.6fold higher than that of rSK1
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
ir
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
ir
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
show the reaction diagram
Q9NRA0, Q9NYA1
-
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
show the reaction diagram
Q1HGK5
-
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
show the reaction diagram
-
major substrate of isozyme SPHK1, also active with isozyme SPHK2
-
-
?
ATP + DELTA4-unsaturated long chain sphingosine
ADP + DELTA4-unsaturated long chain sphingosine 1-phosphate
show the reaction diagram
-
high activity
-
-
ir
ATP + dihydrosphingosine
ADP + dihydrosphingosine 1-phosphate
show the reaction diagram
Q9VYY8, Q9VZW0
-
-
-
?
ATP + dihydrosphingosine
ADP + dihydrosphingosine 1-phosphate
show the reaction diagram
Q9VYY8, Q9VZW0
C14 and C16 dihydrosphingosine substrates
-
-
?
ATP + DL-threo-dihydrosphingosine
ADP + DL-threo-dihydrosphingosine 1-phosphate
show the reaction diagram
-
-
-
-
?
ATP + DL-threo-dihydrosphingosine
ADP + DL-threo-dihydrosphingosine 1-phosphate
show the reaction diagram
-
isozyme SPHK2, no activity with isozyme SPHK1
-
-
?
ATP + fluorescein-labeled sphingosine
ADP + fluorescein-labeled sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
?
ATP + FTY720
ADP + FTY720 1-phosphate
show the reaction diagram
Q9NRA0, Q9NYA1
immunomodulatory drug, high activity with isozyme SPHK2, 7fold lower activity with isozyme SPHK1
-
-
?
ATP + FTY720
ADP + FTY720 1-phosphate
show the reaction diagram
O88885, Q9JIA7
immunomodulatory drug, high activity with isozyme SPHK2, lower activity with isozyme SPHK1
-
-
?
ATP + FTY720
ADP + FTY720 1-phosphate
show the reaction diagram
-
FTY720 is stereoselectively phosphorylated to the active principle (S)-FTY720-phosphate which binds to four of the five known sphingosine-1-phosphate receptors. The introduction of a second stereocenter in the amino alcohol head group of FTY720-like compounds has a strong effect on the phosphorylation efficiency and selectivity by SPHKs and on transiently decreasing peripheral lymphocyte counts in vivo
-
-
-
ATP + FTY720
ADP + ?
show the reaction diagram
-
-
-
-
?
ATP + N-[7-(4-nitrobenzo-2-oxa-1,3-diazole)]-6-aminocaproyl-D-erythro-sphingosine
ADP + N-[7-(4-nitrobenzo-2-oxa-1,3-diazole)]-6-aminocaproyl-D-erythro-sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
?
ATP + phytosphingosine
ADP + phytosphingosine 1-phosphate
show the reaction diagram
-
-
-
-
ir
ATP + phytosphingosine
ADP + phytosphingosine 1-phosphate
show the reaction diagram
-
-
-
-
?
ATP + phytosphingosine
ADP + phytosphingosine 1-phosphate
show the reaction diagram
-
low activity
-
-
?
ATP + phytosphingosine
ADP + phytosphingosine 1-phosphate
show the reaction diagram
-
phytosphingosine 1-phosphate is capable of regulating the turgor in guard cells/stomatal aperture via G-proteins, i.e. 4-hydroxysphinganine, moderate or low activity
-
-
ir
ATP + phytosphingosine
ADP + phytosphingosine 1-phosphate
show the reaction diagram
-
isozyme SPHK2, no activity with isozyme SPHK1
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
-
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
-
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
-
-
-
-
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
-
-
-
-
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
Q9NRA0, Q9NYA1
-
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
-
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
O88885, Q9JIA7
-
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
-
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
D-erythro-sphinganine, sphingosine metabolism
-
-
-
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
involved in regulation of GTP cyclohydrolase I and 6(r)-5,6,7,8-tetrahydrobiopterin
-
-
-
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
calcium mobilization through antigen receptors utilizes enzyme
-
-
-
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
overview on cellular functions
-
-
-
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
overview on cellular functions
-
-
-
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
plant
-
overview on cellular functions
-
-
-
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
involved in signal transduction in the nucleus
-
-
-
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
the lipid phosphate acts as a pleiotropic agent in cell signalling pathways, acts often in concert with ceramide 1-phosphate, enzyme is involved in the sphingomyelid pathway, overview
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
the lipid phosphate acts as a pleiotropic agent in cell signalling pathways, enzyme is involved in the sphingomyelid pathway, overview
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
Q9NRA0, Q9NYA1
2fold higher activity with isozyme SPHK1 compared to isozyme SPHK2
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
i.e. dihydrosphingosine, moderate or low activity
-
-
ir
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
SK2 has a higher substrate affinity to sphinganine than to sphingosine
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
Q9NRA0
-
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
r
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
O88885, Q9JIA7
-
-
-
-
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
Q9VYY8, Q9VZW0
-
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
Q8CI15
-
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
Q91V26
-
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
Q6AYB2
-
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
short-living product S1P is a bioactive lipid mediator in diverse cellular processes, e.g. regulation of cell differentiation, motility, and apoptosis both extracellularly via S1P family receptors and intracellularly
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
sphingosine 1-phosphate is a mediator in diverse biological processes such as cell differentiation, proliferation, motility, and apoptosis
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
sphingosine 1-phosphate is a potent bioactive sphingolipid, sphingolipid metabolism, overview
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
Q9VYY8, Q9VZW0
C14 and C16 sphingosine substrates
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
Q8CI15
involved in diverse biological functions
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
sphingosine 1-phosphate is capable of regulating the turgor in guard cells/stomatal aperture via G-proteins
-
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
sphingosine is a modulator of membrane signal transduction systems and a regulatory element of cardiac and skeletal muscle physiology
sphingosine 1-phosphate is a intracellular messenger molecule and ann extracellular ligand for specific membrane receptors
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
isozymes SPHK1 is about 100fold more active than isozyme SPHK2
-
-
?
GTP + sphinganine
GDP + sphinganine 1-phosphate
show the reaction diagram
-
isozyme SPHK1
-
-
?
additional information
?
-
-
isozyme SPHK1 is involved in responses to macrophages, the enzyme is involved in mast cell signalling, in neutrophil priming, and in prostaglandin biosynthesis via arachidonic acid production, overview, sphinganine 1-phosphate acts as an extracellular mediator by binding to specific members of the EDG-family of G-protein coupled receptors, and intracellularly as a messenger
-
-
-
additional information
?
-
Q9VYY8, Q9VZW0
requirement for Sk2 in normal reproductive function, product S1P signaling promotes cell proliferation, survival, and migration, enzyme reduces cellular levels of sphingosine and ceramide, sphingolipid metabolism, overview
-
-
-
additional information
?
-
-
sphinganine 1-phosphate acts as an extracellular mediator by binding to specific members of the EDG-family of G-protein coupled receptors, and intracellularly as a messenger
-
-
-
additional information
?
-
-
sphingosine 1-phosphate is responsible for resistance to the anticancer drug cisplatin
-
-
-
additional information
?
-
-
sphingosine and sphingosine 1-phosphate activate phospholipase D in mouse myoblasts
-
-
-
additional information
?
-
-
the enzyme is involved in many cellular processes, e.g. mast cell activation during inflammation, immunoactivation via intracellular Ca2+ and receptor activation and via neutrophil, macrophage, and monocyte activation, angiogenesis and control of cell adhesion molecule expression, anti-apoptosis, chemotaxis of leukocytes
-
-
-
additional information
?
-
-
the enzyme is involved in many cellular processes, e.g. mast cell activation during inflammation, immunoactivation via intracellular Ca2+ and receptor activation, angiogenesis and control of cell adhesion molecule expression, anti-apoptosis
-
-
-
additional information
?
-
-
FYT720 is no substrate of isozymes SphK1 and SphK2
-
-
-
additional information
?
-
Q9NRA0, Q9NYA1
isozyme SK1 shows high activity compared to isozyme SK2, development and optimization of a high-sensitive assay method utilizing biotinyl sphingosine and streptavidin-coated membranes with recombinant isozymes
-
-
-
additional information
?
-
Q9NRA0, Q9NYA1
isozyme SK2 shows low activity compared to isozyme SK1, development and optimization of a high-sensitive assay method utilizing biotinyl-sphingosine and streptavidin-coated membranes with recombinant isozymes
-
-
-
additional information
?
-
-
no activity with ceramide
-
-
-
additional information
?
-
-
no activity with ceramide, the 2 isozymes interact with a number of proteins, overview
-
-
-
additional information
?
-
-
substrate specificity of cytosolic and membrane enzymes, 4-hydroxy-8-sphingenine is a poor substrate
-
-
-
additional information
?
-
-
shows no activity towards DL-threo-dihydrosphingosine, dimethylsphingosine, C2-ceramide, dioleoylacylglycerol, or phosphatidylserine
-
-
-
additional information
?
-
Q1HGK5
long-rSK1 is involved in cell signaling
-
-
-
additional information
?
-
-
sphingosine kinase-mediated signalling plays a role in the innate and adaptive immune responses by altering migration of dendritic cells
-
-
-
additional information
?
-
Q1HGK5
no phosphorylation of with threo-dihydrosphingosine, N,N-dimethylsphingosine and N-acetyl-D-sphingosine
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
ir
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
show the reaction diagram
-
major substrate of isozyme SPHK1, also active with isozyme SPHK2
-
-
?
ATP + dihydrosphingosine
ADP + dihydrosphingosine 1-phosphate
show the reaction diagram
Q9VYY8, Q9VZW0
C14 and C16 dihydrosphingosine substrates
-
-
?
ATP + phytosphingosine
ADP + phytosphingosine 1-phosphate
show the reaction diagram
-
-
-
-
ir
ATP + phytosphingosine
ADP + phytosphingosine 1-phosphate
show the reaction diagram
-
phytosphingosine 1-phosphate is capable of regulating the turgor in guard cells/stomatal aperture via G-proteins
-
-
ir
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
-
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
-
-
-
-
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
Q9NRA0, Q9NYA1
-
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
O88885, Q9JIA7
-
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
D-erythro-sphinganine, sphingosine metabolism
-
-
-
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
involved in regulation of GTP cyclohydrolase I and 6(r)-5,6,7,8-tetrahydrobiopterin
-
-
-
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
calcium mobilization through antigen receptors utilizes enzyme
-
-
-
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
overview on cellular functions
-
-
-
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
overview on cellular functions
-
-
-
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
plant
-
overview on cellular functions
-
-
-
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
involved in signal transduction in the nucleus
-
-
-
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
the lipid phosphate acts as a pleiotropic agent in cell signalling pathways, acts often in concert with ceramide 1-phosphate, enzyme is involved in the sphingomyelid pathway, overview
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
show the reaction diagram
-
the lipid phosphate acts as a pleiotropic agent in cell signalling pathways, enzyme is involved in the sphingomyelid pathway, overview
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
short-living product S1P is a bioactive lipid mediator in diverse cellular processes, e.g. regulation of cell differentiation, motility, and apoptosis both extracellularly via S1P family receptors and intracellularly
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
sphingosine 1-phosphate is a mediator in diverse biological processes such as cell differentiation, proliferation, motility, and apoptosis
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
-
sphingosine 1-phosphate is a potent bioactive sphingolipid, sphingolipid metabolism, overview
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
Q9VYY8, Q9VZW0
C14 and C16 sphingosine substrates
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
Q8CI15
involved in diverse biological functions
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
sphingosine 1-phosphate is capable of regulating the turgor in guard cells/stomatal aperture via G-proteins
-
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
show the reaction diagram
-
sphingosine is a modulator of membrane signal transduction systems and a regulatory element of cardiac and skeletal muscle physiology
sphingosine 1-phosphate is a intracellular messenger molecule and ann extracellular ligand for specific membrane receptors
-
?
additional information
?
-
-
isozyme SPHK1 is involved in responses to macrophages, the enzyme is involved in mast cell signalling, in neutrophil priming, and in prostaglandin biosynthesis via arachidonic acid production, overview, sphinganine 1-phosphate acts as an extracellular mediator by binding to specific members of the EDG-family of G-protein coupled receptors, and intracellularly as a messenger
-
-
-
additional information
?
-
Q9VYY8, Q9VZW0
requirement for Sk2 in normal reproductive function, product S1P signaling promotes cell proliferation, survival, and migration, enzyme reduces cellular levels of sphingosine and ceramide, sphingolipid metabolism, overview
-
-
-
additional information
?
-
-
sphinganine 1-phosphate acts as an extracellular mediator by binding to specific members of the EDG-family of G-protein coupled receptors, and intracellularly as a messenger
-
-
-
additional information
?
-
-
sphingosine 1-phosphate is responsible for resistance to the anticancer drug cisplatin
-
-
-
additional information
?
-
-
sphingosine and sphingosine 1-phosphate activate phospholipase D in mouse myoblasts
-
-
-
additional information
?
-
-
the enzyme is involved in many cellular processes, e.g. mast cell activation during inflammation, immunoactivation via intracellular Ca2+ and receptor activation and via neutrophil, macrophage, and monocyte activation, angiogenesis and control of cell adhesion molecule expression, anti-apoptosis, chemotaxis of leukocytes
-
-
-
additional information
?
-
-
the enzyme is involved in many cellular processes, e.g. mast cell activation during inflammation, immunoactivation via intracellular Ca2+ and receptor activation, angiogenesis and control of cell adhesion molecule expression, anti-apoptosis
-
-
-
additional information
?
-
Q1HGK5
long-rSK1 is involved in cell signaling
-
-
-
additional information
?
-
-
sphingosine kinase-mediated signalling plays a role in the innate and adaptive immune responses by altering migration of dendritic cells
-
-
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ATP
-
binding site of SPHK1: involves Gly82, nucleotide binding also involved the SGDGX17-21K motif in the C2-region
ATP
Q9NRA0, Q9NYA1
binding site contains the GGDGX20K motif; binding site contain the GGDGX20K motif
ATP
Q9VYY8, Q9VZW0
;
GTP
-
utilized by isozyme SPHK1
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
-
30% of the stimulation with Mg2+
Ca2+
-
less stimulating than Mg2+, Mn2+
Ca2+
Q8CI15
Ca2+-dependent calmodulin binding of recombinant wild-type and mutant enzymes
Ca2+
Q1HGK5
both isoforms (longrSK1 and rSK1) require divalent cations for their activity, both enzymes show the highest activity with Mg2+, followed by Mn2+ and Ca2+
Cu
-
high affinity copper-binding protein
K+
-
increasing KCl concentration stimulates activity
KCl
-
activates
Mg2+
-
stimulation at concentration equimolar to ATP
Mg2+
-
ratio Mg2+:ATP is 5:1; required
Mg2+
-
ATP:Mg2+ ratio 2:1; optimum concentration: 10 mM; required
Mg2+
-
highest activity with
Mg2+
-
maximal activity at 5-10 mM
Mg2+
Q9NRA0, Q9NYA1
;
Mg2+
-
-
Mg2+
-
highest activity in the presence of Mg2+
Mg2+
Q1HGK5
both isoforms (longrSK1 and rSK1) require divalent cations for their activity, both enzymes show the highest activity with Mg2+, followed by Mn2+ and Ca2+
Mn2+
-
stimulation at concentration equimolar to ATP
Mn2+
-
40% of the stimulation with Mg2+
Mn2+
-
less stimulating than Mg2+
Mn2+
-
-
Mn2+
Q1HGK5
both isoforms (longrSK1 and rSK1) require divalent cations for their activity, both enzymes show the highest activity with Mg2+, followed by Mn2+ and Ca2+
Na+
-
increasing NaCl concentration stimulates activity
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2R)-2-amino-4-(4-octylphenyl)butan-1-ol
-
i.e. (R)-2-amino-4-(4-octylphenyl)butan-1-ol, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
(2R,3S)-2-[[(4-octylphenyl)amino]methyl]pyrrolidin-3-ol
-
inhibition of isoform Sk1
(2R,3S)-3-amino-4-morpholin-4-yl-1-phenylbutan-2-ol
-
i.e. (2R,3S)-3-amino-4-morpholino-1-phenylbutan-2-ol, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
(2R,3S,4E)-N-methyl-5-(4'-pentylphenyl)-2-aminopent-4-ene-1,3-diol
-
potent, water-soluble, isoenzyme-specific inhibitor of SphK1. The inhibitor decreases growth and survival of human leukemia U937 and Jurkat cells, and enhances apoptosis and cleavage of Bcl-2. Lethality of SK1-I is reversed by caspase inhibitors and by expression of Bcl-2. The specific inhibitor of SphK1 warrants attention as potential addition to the therapeutic armamentarium in leukemia
(2R,3S,4E)-N-methyl-5-(4-pentylphenyl)-2-aminopent-4-ene-1,3-diol
-
i.e. SK1-I, BML-258, isotype-specific SphK1 inhibitor. Treatment suppresses growth of LN229 and U373 glioblastoma cell lines and nonestablished human GBM6 cells. SK1-I also enhances glioblastoma multiforma cell death and inhibits their migration and invasion. Sk1-I enhances the survival of mice harboring LN229 intracranial tumors. SK1-I rapidly reduces phosphorylation of Akt but has no significant effect on activation of extracellular signal-regulated kinase 1/2
(2R,3S,4E)-N-methyl-5-(4-pentylphenyl)-2-aminopent-4-ene-1,3-diol
-
i.e. SK1-I, BML-258, isotype-specific SphK1 inhibitor. SK1-I markedly reduces the tumor growth rate of glioblastoma xenografts, inducing apoptosis and reducing tumor vascularization, and enhances the survival of mice harboring LN229 intracranial tumors
(2S)-2-amino-N-(4-octylphenyl)-4-hydroxybutanamide
-
inhibition of isoform Sk1
(2S,3R)-2-amino-4-(4-octylphenyl)butane-1,3-diol
-
i.e. (2S,3R)-2-amino-4-(4-octylphenyl)butane-1,3-diol, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
(2S,3R)-2-amino-N-(4-octylphenyl)-3-hydroxybutanamide
-
inhibition of isoform Sk1
(2S,3R,4E)-2-(dimethylamino)octadec-4-ene-1,3-diol
Q9NRA0, Q9NYA1
inhibits both isoforms SK1 and SK2. Treatment triples the levels of isoform SK1 mRNA, but only slightly increases isoform SK2 expression; inhibits both isoforms SK1 and SK2. Treatment triples the levels of isoform SK1 mRNA, but only slightly increases isoform SK2 expression
(2S,3S)-2-amino-4-(4-octylphenyl)butane-1,3-diol
-
i.e. (2S,3S)-2-amino-4-(4-octylphenyl)butane-1,3-diol, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
(2S,3S)-3-hydroxy-N-(4-octylbenzyl)pyrrolidine-2-carboxamide
-
inhibition of isoform Sk1
(2S,3S)-3-hydroxy-N-(4-octylphenyl)pyrrolidine-2-carboxamide
-
inhibition of isoform Sk1
(S)-FTY720 vinylphosphonate
Q9NYA1
uncompetitive with sphingosine and is a mixed inhibitor with respect to ATP
(S)-FTY720 vinylphosphonate
-
uncompetitive, binds to a putative allosteric site in the enzyme contingent on formation of the enzyme-sphingosine complex. (S)-FTY720 vinylphosphonate binding to and stabilization of the allosteric site might enhance the autoinhibitory effect on the enzymic activity
2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole
Q9NYA1
i.e. SKi, or SKI-II. Mixed inhibitor of sphingosine and ATP binding. N-terminal 86 amino-acid isoform variant SK1b shows reduced sensitivity to proteasomal degradation induced by 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole in comparison to isoform SK1a
2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole
-
mixed type inhibition
2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole
Q9NRA0, Q9NYA1
inhibits both isoforms SK1 and SK2. Treatment increases mRNAs for both isoforms SK1 and SK2 by about 4fold; inhibits both isoforms SK1 and SK2. Treatment increases mRNAs for both isoforms SK1 and SK2 by about 4fold
2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole
-
0.005 mM
2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole
-
the inhibition of SPHK affects acute eosinophilic inflammation induced in antigen-challenged mouse model
2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole
-
-
2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole
-
0.001-0.008 mM, specific inhibition
3-O-sulfogalactosylceramide
-
endogenous glycolipid sulfatide, binds to and inhibits the activity of isoform Sphk2 and the closely related ceramide kinase Cerk, but not isoform Sphk1. The lipid binding domain is mapped to the N-terminus of Sphk2, residues 1-175, a region of sequence that is absent in Sphk1, but aligns with a pleckstrin homology domain in Cerk
5-(4-chlorophenyl)-N-(pyridin-4-ylmethyl)tricyclo[3.3.1.13,7]decane-2-carboxamide
Q9NRA0, Q9NYA1
selective inhibition of isoform SK2
5-(4-chlorophenyl)-N-[2-(3,4-dihydroxyphenyl)ethyl]tricyclo[3.3.1.13,7]decane-2-carboxamide
Q9NRA0, Q9NYA1
inhibits both isoforms SK1 and SK2; inhibits both isoforms SK1 and SK2
B-5354c
-
SPHK1, SPHK2, noncompetitive to sphingosine
B-5354c
-
SphK1 inhibitor, induces apoptosis in a caspase-dependent manner by tilting the ceramide/sphingosine 1-phosphate rheostat toward ceramide. Pharmacologic SphK1 inhibition with B-5354c sensitizes LNCaP and PC-3 cells to docetaxel and camptothecin, respectively. In vivo, camptothecin and B-5354c alone display a limited effect on tumor growth in PC-3 cells, whereas in combination there is a synergy of effect on tumor size with a significant increase in the ceramide to sphingosine 1-phosphate sphingolipid ratio
B5354c
-
-
Bovine serum albumin
-
-
-
Bovine serum albumin
-
-
-
camptothecin
-
-
Cu2+
-
-
Cutsum
-
detergent, required for sphinganine suspension, 0.05 mg/ml gives optimal rates, inhibition above 1 mg/ml
-
D(+)threo-Sphinganine
-
-
D(+)threo-Sphinganine
-
-
D,L-threo-dihydrosphingosine
-
-
D,L-threo-dihydrosphingosine
-
0.005 mM, 64% inhibition
dihydrosphingosine
-
L-erythro-, L-threo- and D-threo-isomer
dihydrosphingosine
-
-
dihydrosphingosine
-
DL-threo-isomers
dimethylsphingosine
-
0.01 mM
dimethylsphingosine
-
potent competitive inhibitor
dimethylsphingosine
-
-
dimethylsphingosine
-
noncompetitive inhibitor
DL-threo-dihydrosphinganine
-
competitive inhibitor
DL-threo-dihydrosphingosine
-
competitive
DL-threo-dihydrosphingosine
-
-
DL-threo-dihydrosphingosine
-
-
DL-threo-dihydrosphingosine
-
slight inhibition
DL-threo-dihydrosphingosine
-
0.002 mM
DL-threo-dihydrosphingosine
-
potent competitive inhibitor
DL-threo-dihydrosphingosine
-
-
DL-threo-dihydrosphingosine
-
0.01 mM, significant inihibition
DL-threo-dihydrosphingosine
-
competitive inhibitor
DL-threo-dihydrosphingosine
-
0.005 mM, 25% inhibition
DL-threo-dihydrosphingosine
-
treatment of Jurkat and U-937 cells induces apoptosis and produces dramatic increases in SphK1 expression, the latter being a result of apoptotic stress
docetaxel
-
-
docetaxel
-
SphK1 inhibition by docetaxel is a two-step process involving an initial loss of enzyme activity followed by a decrease in SphK1 gene expression. Both pharmacological and siRNA-mediated SphK1 inhibition leads to a four-fold decrease in the docetaxel IC50 dose
EDTA
Q1HGK5
-
erythro-dihydrosphingosine
-
0.025 mM, dose-dependent inhibition
F-12509A
-
SPHK1, SPHK2, competitive to sphingosine
F-12509A
-
-
Fe2+
-
-
FTY720
-
0.005 mM, 73% inhibition; 0.005 mM, 8% inhibition
FTY720
Q9NYA1
i.e. fingolimod, competitive with sphingosine and uncompetitive with ATP
FTY720
-
competitive
galactosylceramide
-
0.01 mM, isoform SphK2, 84% of initial activity, isoform SphK1, 109% of initial activity
galactosylceramide 3-sulphate
-
0.01 mM, isoform SphK2, 37% of initial activity, isoform SphK1, 156% of initial activity
KCl
Q9JIA7
IC50 200 mM
KCl
-
1 mM
KCl
-
increasing KCl concentration profoundly inhibits activity
L(-)erythro-Sphinganine
-
-
L(-)threo-Sphinganine
-
-
L(-)threo-Sphinganine
-
-
L-erythro-sphingosine
-
0.005 mM, 41% inhibition; 0.005 mM, 43% inhibition
N,N,N-trimethylsphingosine
-
-
N,N-dimethylsphingosine
-
-
N,N-dimethylsphingosine
-
inhibition of isozymes SphK1 and SphK2
N,N-dimethylsphingosine
-
-
N,N-dimethylsphingosine
-
-
N,N-dimethylsphingosine
-
strong inhibition
N,N-dimethylsphingosine
-
0.005 mM
N,N-dimethylsphingosine
-
0.01 mM
N,N-dimethylsphingosine
-
the inhibition of SPHK affects acute eosinophilic inflammation induced in antigen-challenged mouse model
N,N-dimethylsphingosine
Q1HGK5
competitive inhibition with D-erythro-sphingosine as substrate
N,N-dimethylsphingosine
-
0.005 mM, 56% inhibition
N,N-dimethylsphingosine
-
inhibition of both isoforms Sphk1 and Sphk2. Treatment of Jurkat and U-937 cells results ina large increase in expression of SphK1 concomitant with induction of apoptosis
N,N-dimethylsphingosine
-
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
N,N-dimethylsphingosine
-
decreases MUC5AC expression up-regulated by IL-13 treatment and inhibits IL-13-induced ERK1/2 phosphorylation but neither p38 MAPK nor STAT6 phosphorylation
N-((2S,3S)-1,3-dihydroxy-4-phenylbutan-2-yl)tridecanamide
-
i.e. N-((2S,3S)-1,3-dihydroxy-4-phenylbutan-2-yl)tridecanamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-N-cyclohexylacetamide
Q9NRA0, Q9NYA1
selective inhibition of isoform SK1
N-ethylmaleimide
-
-
N-[(1R)-1-(hydroxymethyl)-3-phenylpropyl]tridecanamide
-
i.e. N-((R)-1-hydroxy-4-phenylbutan-2-yl)tridecanamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1R)-3-phenyl-1-(pyrrolidin-1-ylmethyl)propyl]decanamide
-
i.e. N-((R)-4-phenyl-1-(pyrrolidin-1-yl)butan-2-yl)decanamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S)-1-methyl-3-phenylpropyl]hexadecanamide
-
i.e. N-((R)-1-hydroxy-4-phenylbutan-2-yl)palmitamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S,2R)-2-hydroxy-1-(hydroxymethyl)-3-phenylpropyl]hexadecanamide
-
i.e. N-((2S,3R)-1,3-dihydroxy-4-phenylbutan-2-yl)palmitamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S,2R)-2-hydroxy-1-(hydroxymethyl)-3-phenylpropyl]tridecanamide
-
i.e. N-((2S,3R)-1,3-dihydroxy-4-phenylbutan-2-yl)tridecanamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S,2R)-2-hydroxy-3-phenyl-1-(pyrrolidin-1-ylmethyl)propyl]octadecanamide
-
i.e. N-((2S,3R)-3-hydroxy-4-phenyl-1-(pyrrolidin-1-yl)butan-2-yl)stearamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-3-phenylpropyl]hexadecanamide
-
i.e. N-((2S,3S)-1,3-dihydroxy-4-phenylbutan-2-yl)palmitamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S,2S)-2-hydroxy-1-(morpholin-4-ylmethyl)-3-phenylpropyl]decanamide
-
i.e. N-((2S,3S)-3-hydroxy-1-morpholino-4-phenylbutan-2-yl)decanamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S,2S)-2-hydroxy-3-phenyl-1-(pyrrolidin-1-ylmethyl)propyl]decanamide
-
i.e. N-((2S,3S)-3-hydroxy-4-phenyl-1-(pyrrolidin-1-yl)butan-2-yl)decanamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S,2S)-2-hydroxy-3-phenyl-1-(pyrrolidin-1-ylmethyl)propyl]octadecanamide
-
i.e. N-((2S,3S)-3-hydroxy-4-phenyl-1-(pyrrolidin-1-yl)butan-2-yl)stearamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
NaCl
Q9JIA7
IC50 200 mM
NaCl
-
increasing NaCl concentration profoundly inhibits activity
p-chloromercuribenzoate
-
-
phosphatidylinositol 4,5-bisphosphate
-
0.01 mM, isoform SphK2, 60% of initial activity, isoform SphK1, 90% of initial activity
phosphatidylinositol 4-phosphate
-
0.01 mM, isoform SphK2, 89% of initial activity, isoform SphK1, 175% of initial activity
phytosphingosine
-
0.0025 mM, 21% inhibition; 0.0025 mM, 64% inhibition
Ro-31-8220
-
-
S-12183a
-
-
-
S-12183b
-
-
-
SKI-II
-
isoform Sk1-specific inhibitor. Treatment markedly attenuates 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic acid-induced endothelial cell proliferation. 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic acid-induced activation of Akt kinase and transactivation of the epidermal growth factor receptor are also inhibited by SKI-II
sphingosine kinase inhibitor
-
can influence co-stimulatory molecules (CD40, CD80, CD86 and MHC class II) and cytokine production (IL-12 and IL-10) in murine bone marrow-derived dendritic cells. Sphingosine kinase inhibitor significantly inhibits co-stimulatory molecules in dendritic cells. Sphingosine kinase inhibitor suppresses IL-12 production by dendritic cells and IFN-gamma production by T cells
-
sphingosine kinase inhibitor II
-
-
-
Triton X-100
Q9JIA7
above 0.005%
Triton X-100
-
isozyme SPHK2
Triton X-100
-
the enyzme activity is higher with substrate solubilized by bovine serum albumin compared to Triton X-100
Triton X-100
-
-
Zn2+
-
-
Melatonin
-
melatonin decreases enzymic activity in PC-3 cells during hypoxia. In addition, Melatonin inhibits the stability of hypoxia inducible factor 1alpha in a time- and concentration-dependent manner and suppresses AKT/glycogen synthase kinase-3beta signaling pathway
additional information
-
not inhibitory: DL-threo-dihydrosphingosine
-
additional information
-
inhibitiors of isozyme SphK2 are cytotoxic, overview, inhibitory potency of the synthetic sphingosine analogues on isozymes SphK1 and SphK2, overview
-
additional information
-
isozyme SPHK2 is inhibited by high ionic strength
-
additional information
-
not inhibited by 0.25% Triton X-100
-
additional information
-
not inhibited by KCl
-
additional information
-
not inhibited by K+
-
additional information
-
isoform Sphk2 binds to phosphatidylinositol monophosphates but not to abundant cellular phospholipids
-
additional information
-
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
-
additional information
-
enzyme is an oligomeric protein containing noncooperative catalytic sites, the allosteric site exerts an autoinhibition of the catalytic site
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic acid
-
treatment markedly augments SK activity in HUVECs. At the concentration of 1 mM, 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic acid increases SK activity by 110% and the maximal effect on SK activation is observed at 20 min after 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic acid addition. Inhibition of SK by a specific inhibitor, SKI-II, markedly attenuates 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic acid-induced endothelial cell proliferation. 11,12-Epoxy-(5Z,8Z,14Z)-eicosatrienoic acid-induced activation of Akt kinase and transactivation of the epidermal growth factor receptor are also inhibited by SKI-II
12-O-tetradecanoylphorbol-13-acetate
-
50 nM, maximum increase in activity after 24 h
Bovine serum albumin
-
the enyzme activity is higher with substrate solubilized by bovine serum albumin compared to Triton X-100
-
Calmodulin
Q8CI15
Ca2+-dependent binding of recombinant wild-type and mutant enzymes
camptothecin
-
0.003 mM camptothecin induces marked elevation of SPHK activity, reaching a maximal level with approximately 250% of the control untreated cells at 36 h
cardiolipin
-
;
cholesterol
-
0.01 mM, isoform SphK2, 107% of initial activity
Cutsum
-
detergent, required for sphinganine suspension, 0.05 mg/ml gives optimal rates, inhibition above 1 mg/ml
-
endothelin-1
-
1 nM, 2.4fold and 2.7fold increase of activity after 5 and 10 min, respectively
G-protein-coupled receptor agonists
-
-
-
galactosylceramide
-
0.01 mM, isoform SphK2, 84% of initial activity, isoform SphK1, 109% of initial activity
galactosylceramide 3-sulfate
-
0.01 mM, isoform SphK2, 37% of initial activity, isoform SphK1, 156% of initial activity
growth factors
-
platelet- and nerve-derived growth factors
-
heregulin
-
heregulin stimulates SphK1 activity only in filamin A-expressing A7 melanoma cells but not in filamin A-deficient cells and induces its translocation and colocalization with filamin A at lamellipodia. SphK1 is required for heregulin-induced migration, lamellipodia formation, activation of PAK1, and subsequent filamin A phosphorylation. Sphingosine 1-phosphate directly stimulates PAK1 kinase. Heregulin also induces colocalization of S1P1, the promotility sphingosine 1-phosphate receptor, but not S1P2, with SphK1 and filamin A at membrane ruffles
-
histamine
-
0.001 mM, up to 5fold increase of activity after 20 h
immunoglobulins E and G
-
-
-
jasplakinolide
-
causes a 85% increase in SK activity
-
latrunculin B
-
causes a 38% increase in SK activity
muscarinic acetylcholine agonists
-
-
-
N,N-dimethylsphingosine
-
0.005 mM, activation to 106% of control
N-(1,3-dihydroxyisopropyl)-2-hexyl-3-oxo-decanamide
-
i.e. K6PC-5, induces intracellular Ca2+ concentration oscillations in HaCaT cells. The K6PC-5-induced intracellular Ca2+ oscillations are dependent on thapsigargin-sensitive Ca2+ stores and Ca2+ entry, but independent of the classical phospholipase C-mediated pathway. K6PC-5 enhances the expression of involucrin and filaggrin, specific differentiation-associated marker proteins in HaCaT cells, whereas transfection of SphK1 siRNA blocks the increase of involucrin
N-(1,3-dihydroxyisopropyl)-2-hexyl-3-oxo-decanamide
-
i.e. K6PC-5, activates SphK in a dose-dependent manner. K6PC-5 induces mobilization in hairless mouse epidermis. Both dimethylsphingosine and dihydroxysphingosine, SphK inhibitors, and transfection of SphK1-siRNA blocks K6PC-5-induced increases in intracellular Ca2+ concentration
phorbol 12-myristate 13-acetate
Q9NRA0, Q9NYA1
;
phosphatidic acid
-
;
phosphatidic acid
-
0.01 mM, isoform SphK2, 102% of initial activity, isoform SphK1, 265% of initial activity
phosphatidylinositol
-
;
phosphatidylinositol
-
0.01 mM, isoform SphK2,187% of initial activity
phosphatidylinositol 4-phosphate
-
0.01 mM, isoform SphK2, 89% of initial activity, isoform SphK1, 175% of initial activity
phosphatidylinositol bisphosphate
-
;
phosphatidylserine
-
;
phosphatidylserine
-
0.01 mM, isoform SphK2, 203% of initial activity
prolactin
-
-
-
sphingosine 1-phosphate
-
-
Thrombin
-
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
-
TNF-alpha
Q9NRA0, Q9NYA1
;
-
TNF-alpha
-
-
-
transforming growth factor beta1
-
5ng/ml
-
Triton X-100
-
isozyme SPHK1
Triton X-100
-
;
tumor necrosis factor-alpha
-
100 ng/ml
-
tumor necrosis factor-alpha
-
-
-
lipopolysaccharide
-
increases Sk1 transcription which is accompanied by increased SK activity and generation of sphingosine 1-phosphate. Sphingosine 1-phosphate is able to cause increases in COX-2 and PGE2 levels in RAW cells
additional information
Q9NRA0, Q9NYA1
solubilization in Triton X-100 results in higher activity compared to bovine serum albumin
-
additional information
-
selective activation mechanism of isozymes, overview, isozyme SPHK2 is activated by high ionic strength
-
additional information
-
the enzyme is stimulated by the phytohormone abscisic acid in guard cells and mesophyll cell protoplasts
-
additional information
-
SPHK2 is not activated by transforming growth factor beta1
-
additional information
-
not activated by histamine or 12-O-tetradecanoylphorbol-13-acetate
-
additional information
-
not activated by prolactin
-
additional information
-
not affected by bovine serum albumin; not affected by bovine serum albumin; not stimulated by phosphatidylcholine or phosphatidylethanolamine
-
additional information
-
under hypoxia, isoform Sk2 shows an increase in protein level and activity, which correlates with the release of shingosine 1-phosphate into the medium
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.063
ATP
Q8CI15
pH 7.4, 37C, recombinant mutant E179Q
0.07 - 0.1
ATP
-
-
0.072
ATP
Q8CI15
pH 7.4, 37C, recombinant wild-type enzyme
0.077
ATP
-
-
0.077
ATP
Q8CI15
pH 7.4, 37C, recombinant mutant D175N
0.088
ATP
Q8CI15
pH 7.4, 37C, recombinant mutant D177N
0.095
ATP
Q8CI15
pH 7.4, 37C, recombinant mutant E181Q
0.0034
D(+)erythro-sphinganine
Q9JIA7
-
0.005
D(+)erythro-sphinganine
-
-
0.072
D(+)erythro-sphinganine
-
-
0.1
D(+)erythro-sphinganine
-
-
0.0034 - 0.0138
D-erythro-sphingosine
-
isozyme SPHK2
0.005 - 0.0156
D-erythro-sphingosine
-
isozyme SPHK1
0.016
D-erythrosphinganine
-
as bovine serum albumin complex
0.02
DL-erythro-dihydrosphingosine
-
-
0.018
FTY720
Q9NRA0, Q9NYA1
pH 7.4, 30C, recombinant isozyme SPHK2; pH 7.4, 30C, recombinant isozyme SPHK2
0.024
FTY720
O88885, Q9JIA7
pH 7.4, 30C, recombinant isozyme SPHK2; pH 7.4, 30C, recombinant isozyme SPHK2
0.692
FTY720
O88885, Q9JIA7
about, pH 7.4, 30C, recombinant isozyme SPHK1a; about, pH 7.4, 30C, recombinant isozyme SPHK1a
0.785
FTY720
Q9NRA0, Q9NYA1
about, pH 7.4, 30C, recombinant isozyme SPHK1; about, pH 7.4, 30C, recombinant isozyme SPHK1
1
nitrobenzoxadiazole-labeled sphingosine
-
pH 7.4, 35C, presence of 10 microM 3-O-sulfogalactosylceramide
1.7
nitrobenzoxadiazole-labeled sphingosine
-
pH 7.4, 35C; pH 7.4, 35C, presence of 25 microM 3-O-sulfogalactosylceramide
3.6
nitrobenzoxadiazole-labeled sphingosine
-
pH 7.4, 35C, presence of 4 microM 3-O-sulfogalactosylceramide
0.09
sphinganine
-
-
0.005
sphingosine
-
-
0.0076
sphingosine
-
in 50 mM HEPES, pH 7.4, 10 mM KCl, 15 mM MgCl2, 0.1% Triton X-100, 20% glycerol, 2 mM orthovanadate, 2 mM dithiothreitol, 10 mM NaF, and 1 mM deoxypyridoxine
0.01
sphingosine
Q8CI15
pH 7.4, 37C, recombinant wild-type enzyme and mutant E181Q
0.013
sphingosine
O88885, Q9JIA7
pH 7.4, 30C, recombinant isozyme SPHK1a; pH 7.4, 30C, recombinant isozyme SPHK1a; pH 7.4, 30C, recombinant isozyme SPHK2; pH 7.4, 30C, recombinant isozyme SPHK2
0.0138
sphingosine
-
-
0.014
sphingosine
Q9NRA0, Q9NYA1
pH 7.4, 30C, recombinant isozyme SPHK2; pH 7.4, 30C, recombinant isozyme SPHK2
0.0156
sphingosine
-
-
0.016
sphingosine
Q9NRA0, Q9NYA1
pH 7.4, 30C, recombinant isozyme SPHK1; pH 7.4, 30C, recombinant isozyme SPHK1
0.026
sphingosine
Q8CI15
pH 7.4, 37C, recombinant mutant E179Q
0.037
sphingosine
Q8CI15
pH 7.4, 37C, recombinant mutant D175N
0.108
sphingosine
Q8CI15
pH 7.4, 37C, recombinant mutant D177N
1
L(-)threo-Sphinganine
-
-
additional information
additional information
-
simple quantitative radio-assay
-
additional information
additional information
-
assay for measurement of intracellular levels of free sphingoid bases
-
additional information
additional information
Q9NRA0, Q9NYA1
substrate kinetic analysis; substrate kinetic analysis
-
additional information
additional information
Q8CI15
kinetics, recombinant wild-type and mutant enzymes
-
additional information
additional information
Q9NRA0, Q9NYA1
kinetics, isozymes SPHK1 and SPHK2; kinetics, isozymes SPHK1 and SPHK2
-
additional information
additional information
O88885, Q9JIA7
kinetics, isozymes SPHK1 and SPHK2; kinetics, isozymes SPHK1 and SPHK2
-
additional information
additional information
-
kinetics
-
additional information
additional information
-
enzyme is an oligomeric protein containing noncooperative catalytic sites, the allosteric site exerts an autoinhibition of the catalytic site
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.01
(2R,3S,4E)-N-methyl-5-(4'-pentylphenyl)-2-aminopent-4-ene-1,3-diol
-
-
0.014
(2S,3R,4E)-2-(dimethylamino)octadec-4-ene-1,3-diol
Q9NRA0, Q9NYA1
pH not specified in the publication, temperature not specified in the publication
0.016
(2S,3R,4E)-2-(dimethylamino)octadec-4-ene-1,3-diol
Q9NRA0, Q9NYA1
pH not specified in the publication, temperature not specified in the publication
0.0145
(S)-FTY720 vinylphosphonate
-
pH 7.4, 30C
0.0079
2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole
Q9NRA0, Q9NYA1
pH not specified in the publication, temperature not specified in the publication
0.016
2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole
Q9NRA0, Q9NYA1
pH not specified in the publication, temperature not specified in the publication
0.017
2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole
-
pH 7.4, 30C, competitive inhibition
0.048
2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole
-
pH 7.4, 30C, uncompetitive inhibition
0.0093
5-(4-chlorophenyl)-N-(pyridin-4-ylmethyl)tricyclo[3.3.1.13,7]decane-2-carboxamide
Q9NRA0, Q9NYA1
pH not specified in the publication, temperature not specified in the publication
0.0031
5-(4-chlorophenyl)-N-[2-(3,4-dihydroxyphenyl)ethyl]tricyclo[3.3.1.13,7]decane-2-carboxamide
Q9NRA0, Q9NYA1
pH not specified in the publication, temperature not specified in the publication
0.0042
5-(4-chlorophenyl)-N-[2-(3,4-dihydroxyphenyl)ethyl]tricyclo[3.3.1.13,7]decane-2-carboxamide
Q9NRA0, Q9NYA1
pH not specified in the publication, temperature not specified in the publication
0.001
ADP
-
-
0.0022
B-5354c
-
SPHK2
0.004
B-5354c
-
SPHK1
0.0037
B5354c
-
-
0.005 - 0.018
D,L-threo-dihydrosphingosine
-
-
0.005
D,L-threo-dihydrosphingosine
-
-
0.006
D,L-threo-dihydrosphingosine
-
-
0.005
dimethylsphingosine
-
-
0.01
DL-threo-dihydrosphingosine
-
-
0.004
F-12509A
-
SPHK1
0.004
F-12509A
-
-
0.0055
F-12509A
-
SPHK2
0.002
FTY720
-
pH 7.4, 30C
0.00033
N,N-dimethylsphingosine
Q1HGK5
rSK1
0.003
N,N-dimethylsphingosine
-
SPHK1
0.0058
N,N-dimethylsphingosine
Q1HGK5
long-rSK1
0.008
N,N-dimethylsphingosine
-
-
0.0086
N,N-dimethylsphingosine
-
SPHK2
0.01
N,N-dimethylsphingosine
-
-
0.012
N,N-dimethylsphingosine
Q9JIA7
-
0.00028
N-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-N-cyclohexylacetamide
Q9NRA0, Q9NYA1
pH not specified in the publication, temperature not specified in the publication
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00074
(2R,3S)-2-[[(4-octylphenyl)amino]methyl]pyrrolidin-3-ol
-
pH 7.5, 22C
0.00005
(2S)-2-amino-N-(4-octylphenyl)-4-hydroxybutanamide
-
pH 7.5, 22C
0.00065
(2S,3R)-2-amino-N-(4-octylphenyl)-3-hydroxybutanamide
-
pH 7.5, 22C
0.00043
(2S,3S)-3-hydroxy-N-(4-octylbenzyl)pyrrolidine-2-carboxamide
-
pH 7.5, 22C
0.000062
(2S,3S)-3-hydroxy-N-(4-octylphenyl)pyrrolidine-2-carboxamide
-
pH 7.5, 22C
0.0005
2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole
-
-
0.0024
dimethylsphingosine
-
at 37C, in the presence of 0.25% Triton X-100
0.0024
DL-threo-dihydrosphingosine
-
at 37C, in the presence of 0.25% Triton X-100
200
KCl
Q9JIA7
IC50 200 mM
200
NaCl
Q9JIA7
IC50 200 mM
0.0002
Ro-31-8220
-
at 37C, in the presence of 0.25% Triton X-100
0.0025
S-12183a
-
-
-
0.0016
S-12183b
-
-
-
0.00055
U-73122
-
at 37C, in the presence of 0.25% Triton X-100
0.0021
Y-27632
-
at 37C, in the presence of 0.25% Triton X-100
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.000002
-
skeletal muscle homogenate
0.000018
-
sperm acrosome, SPHK1
0.00003
-
liver homogenate
0.00004 - 0.00005
-
homogenates of kidney, colon, stomach, pancreas, and heart
0.00006 - 0.00007
-
homogenates of testis, brain, and platelet
0.00009
-
homogenates of small intestine and spleen
0.00016
-
thymus homogenate
0.00024
-
lung homogenate
0.00375
-
-
0.184
Q9NRA0, Q9NYA1
native isozyme SK1 in cell extract
19.34
Q9NRA0, Q9NYA1
purified recombinant isozyme SK1
43.4
Q9NRA0, Q9NYA1
recombinant isozyme SK1 in cell extract of recombinant cells
additional information
-
activity of mutant strains
additional information
Q8CI15
Vmax of recombinant wild-type and mutant enzymes
additional information
-
-
additional information
Q9NRA0, Q9NYA1
Vmax of different splicing variants of both isozymes; Vmax of different splicing variants of both isozymes
additional information
O88885, Q9JIA7
Vmax of different splicing variants of both isozymes; Vmax of different splicing variants of both isozymes
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
6.6 - 7.5
-
-
7.2
Q9VYY8, Q9VZW0
assay at; assay at
7.4
Q8CI15
assay at
7.4
-
assay at; assay at
7.4
O88885, Q9JIA7
assay at; assay at
7.5
Q9JIA7
-
7.5
-
assay at
7.5
-
assay at
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
6 - 8.5
-
pH 6: about 55% of maximum activity, pH 8.5: about 40% of maximum activity
6 - 9
-
pH 6: about 35% of maximum activity, pH 9: about 70% of maximum activity
6.5 - 8
Q9JIA7
-
6.8 - 7.4
-
greater than 60% of maximum activity
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
30
Q9NRA0, Q9NYA1
assay at; assay at
30
O88885, Q9JIA7
assay at; assay at
37
Q9NRA0, Q9NYA1
assay at; assay at
37
-
assay at
37
-
assay at
37
Q8CI15
assay at
37
Q9VYY8, Q9VZW0
assay at; assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
gracilis muscle resistance artery. Pressure-dependent activation and translocation of isoform Sk1 by ERK1/2 is critically dependent on its serine225 phosphorylation site
Manually annotated by BRENDA team
-
higher activity of isozyme SPHK1, low activity of isozyme SPHK2
Manually annotated by BRENDA team
-
isozymes SPHK1 and SPHK2
Manually annotated by BRENDA team
-
secretion of sphinganine 1-phosphate
Manually annotated by BRENDA team
-
LPS stimulates Sphk activity
Manually annotated by BRENDA team
-
isozymes SPHK1 and SPHK2
Manually annotated by BRENDA team
-
major isozyme is SPHK1
Manually annotated by BRENDA team
-
quite low activity of isozyme SPHK1 and isozyme SPHK2
Manually annotated by BRENDA team
-
white matter, cerebellum, cerebrum, red nucleus, cerebral peduncle
Manually annotated by BRENDA team
Q1HGK5
expression of long-rSK1 mRNA
Manually annotated by BRENDA team
-
melanoma B16 cells, variant F10, Swiss 3T3, balb/c 3T3 clone A31
Manually annotated by BRENDA team
-
major isozyme is SPHK1
Manually annotated by BRENDA team
Q9VYY8, Q9VZW0
expression pattern of Sk1 during embryogenesis
Manually annotated by BRENDA team
Q9VYY8, Q9VZW0
expression pattern of Sk2 during embryogenesis
Manually annotated by BRENDA team
-
dermal microvascular endothelial cell
Manually annotated by BRENDA team
-
vascular and aorta endothelial cell
Manually annotated by BRENDA team
-
in airway epithelium of a mouse asthmatic model, both SphK and MUC5AC expression are increased and proteins co-localize
Manually annotated by BRENDA team
-
in bronchial epithelial cells, SphK1 and MUC5AC expression is increased by IL-13 treatment at both protein and mRNA levels, whereas SphK2 expression is not changed
Manually annotated by BRENDA team
-
SPHK2 is expressed in the synovial fibroblasts of the synovial tissues obtained from the knee joints of rheumatiod patients. In the cultured synovial fibroblasts from these patients, SPHK2 is more highly expressed than that in the human macrophage cell line, THP-1 and human dermal fibroblasts. SPHK2 is expressed in and around the nucleus and transferred to the cytoplasm and cell surface by the administration of epidermal growth factor, associated with the increased expression of sphingosine 1-phosphate. A sphingosine analogue, FTY720, which is activated by phosphorylation specifically by SPHK2, mediates apoptotic signaling of the cultured synovial fibroblasts
Manually annotated by BRENDA team
-
major isozyme is SPHK1
Manually annotated by BRENDA team
Q1HGK5
expression of long-rSK1 mRNA, no expression of rSK1 mRNA
Manually annotated by BRENDA team
-
isozyme SPHK1 and isozyme SPHK2
Manually annotated by BRENDA team
-
isozymes SPHK1 and SPHK2
Manually annotated by BRENDA team
Q1HGK5
expression of long-rSK1 mRNA
Manually annotated by BRENDA team
-
of peripheral blood
Manually annotated by BRENDA team
-
high activity of isozyme SPHK2, low activity of isozyme SPHK1
Manually annotated by BRENDA team
-
low activity of isozyme SPHK1, high activity of isozyme SPHK2
Manually annotated by BRENDA team
Q1HGK5
expression of long-rSK1 mRNA, no expression of rSK1 mRNA
Manually annotated by BRENDA team
-
high activity of isozyme SPHK1, low activity of isozyme SPHK2
Manually annotated by BRENDA team
-
high activity, isozymes SPHK1 and SPHK2
Manually annotated by BRENDA team
Q1HGK5
expression of long-rSK1 mRNA
Manually annotated by BRENDA team
-
isozymes SPHK1 and SPHK2
Manually annotated by BRENDA team
-
low activity of isozyme SPHK1 and isozyme SPHK2
Manually annotated by BRENDA team
-
from bone marrow. N,N-dimethyl-D-erythro-sphingosine inhibits osteoclastogenesis a sphingosine kinase independently of sphingosine kinase
Manually annotated by BRENDA team
-
secretion of sphinganine 1-phosphate
Manually annotated by BRENDA team
-
mouse calvaria osteoblast cell
Manually annotated by BRENDA team
-
use in mouse xenograft model
Manually annotated by BRENDA team
-
renal mesangial cell
Manually annotated by BRENDA team
-
follicular thyroid cell
Manually annotated by BRENDA team
-
neonatal cardiac myocyte
Manually annotated by BRENDA team
-
during gestation, isoforms Sphk1 and Sphk2 are co-expressed. The levels and activity of SphK1/2 are modest at midgestation , increase at day 19 and progressively decline to low at postpartum. Inhibition of protein kinase C and ERK reduces SphK1/2 activity. In primary cultures of myometrial cells from day 19 pregnant rats, induction of COX2 is mediated by 4-phorbol 12,13-dibutyrate and IL-1 through sequential activation of protein kinase C, ERK1/2, and SphK1. Sphingosine 1-phosphate produced by SphK1 is released in the medium. In day 12 myometrial tissues, the release of sphingosine 1-phosphate is markedly reduced in association with low levels of SphK1 and COX2
Manually annotated by BRENDA team
-
podocyte cell line
Manually annotated by BRENDA team
-
sphingolipids and the sphingosine kinase inhibitor, SKI II, induce BCL-2-independent apoptosis in human prostatic adenocarcinoma cells
Manually annotated by BRENDA team
-
very low activity
Manually annotated by BRENDA team
-
low activity, isozymes SPHK1 and SPHK2
Manually annotated by BRENDA team
-
isozymes SPHK1 and SPHK2
Manually annotated by BRENDA team
-
low activity, isozymes SPHK1 and SPHK2
Manually annotated by BRENDA team
-
gracilis muscle resistance artery. Pressure-dependent activation and translocation of isoform Sk1 by ERK1/2 is critically dependent on its serine225 phosphorylation site
Manually annotated by BRENDA team
-
SPHK1, exclusively in the acrosome, spermatozoa contain 5 sphingosine 1-phosphate receptors
Manually annotated by BRENDA team
-
high activity, isozymes SPHK1 and SPHK2
Manually annotated by BRENDA team
-
isozyme SPHK1, low activity of isozyme SPHK2
Manually annotated by BRENDA team
-
isozymes SPHK1 and SPHK2
Manually annotated by BRENDA team
Q1HGK5
expression of long-rSK1 mRNA
Manually annotated by BRENDA team
-
in the cultured synovial fibroblasts from rheumatoid arthritis patients, SPHK2 is more highly expressed than in the human macrophage cell line, THP-1 and human dermal fibroblasts
Manually annotated by BRENDA team
-
high activity
Manually annotated by BRENDA team
-
epidermal growth factor regulates plasminogen activator inhibitor-1 by a pathway involving c-Src, PKCdelta, and sphingosine kinase 1 in glioblastoma cells
Manually annotated by BRENDA team
-
N,N-dimethyl-D-erythro-sphingosine induces apoptotic cell death via modulation of mitochondrial membrane potential, c-Jun N-terminal protein kinase, p38 MAP kinase, extracellular signal-regulated kinase, and Akt kinase, but not through inhibition of sphingosine kinase or protein -kinase C in U937 cells
Manually annotated by BRENDA team
-
secretion of sphinganine 1-phosphate
Manually annotated by BRENDA team
additional information
-
tissue distribution
Manually annotated by BRENDA team
additional information
Q9JIA7
tissue distribution
Manually annotated by BRENDA team
additional information
-
isozyme tissue distribution
Manually annotated by BRENDA team
additional information
-
isozyme tissue distribution patterns
Manually annotated by BRENDA team
additional information
-
the 2 genes Sk1 and Sk2 show overlapping but distinct temporal and spatial expression patterns
Manually annotated by BRENDA team
additional information
-
tissue distribution of isozyme SPHK1 and isozyme SPHK2 expression and activity, overview
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
of sperm, SPHK1
-
Manually annotated by BRENDA team
-
SPHK2 is expressed in and around the nucleus and transferred to the cytoplasm and cell surface by the administration of epidermal growth factor, associated with the increased expression of sphingosine 1-phosphate
Manually annotated by BRENDA team
-
isozymes Sk1 and Sk2, predominantly
Manually annotated by BRENDA team
-
major part of isozyme SPHK1 and isozyme SPHK2
Manually annotated by BRENDA team
-
the cytosolic enzyme is 20fold less active than the membrane-associated enzyme
Manually annotated by BRENDA team
-
majority of enzyme activity
Manually annotated by BRENDA team
-
enzymes cycles between trans-Golgi network and late endosomes, facing the cytosol
Manually annotated by BRENDA team
-
enzyme is constitutively exported
-
Manually annotated by BRENDA team
-
enzymes cycles between trans-Golgi network and late endosomes, facing the cytosol
Manually annotated by BRENDA team
-
75% of total activity in leaves, associated with, the cytosolic enzyme is 20fold less active than the membrane-associated enzyme
Manually annotated by BRENDA team
-
about 30% of total activity
Manually annotated by BRENDA team
-
subcellular localization depends on the tissue type
Manually annotated by BRENDA team
-
deleting the N-terminal domain with residues 1-175 reduces Sphk2 membrane localisation in cells
Manually annotated by BRENDA team
-
both nuclear envelope and nucleoplasm
Manually annotated by BRENDA team
-
SPHK2 is expressed in and around the nucleus and transferred to the cytoplasm and cell surface by the administration of epidermal growth factor, associated with the increased expression of sphingosine 1-phosphate
Manually annotated by BRENDA team
-
activation of Gq protein-coupled receptors induces a profound, rapid and long-lasting translocation of isoform SphK1 to the plasma membrane
Manually annotated by BRENDA team
-
about 70% of total activity
-
Manually annotated by BRENDA team
-
subcellular localization depends on the tissue type
-
Manually annotated by BRENDA team
additional information
-
subcellular localization depends on the tissue type
-
Manually annotated by BRENDA team
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
30000
-
SDS-PAGE
673671
34000
-
SDS-PAGE
674746
39000
-
SDS-PAGE
672410
42000
-
SDS-PAGE, splice variant SK-1a
672377
43000
-
-
674084
43000
-
SDS-PAGE
674746
43000
-
SDS-PAGE
674843
43300
-
calculated from sequence of cDNA; calculated from sequence of cDNA
674746
49000
-
gel filtration
492171
49000
-
SDS-PAGE; SDS-PAGE
672834
51000
-
SDS-PAGE, splice variant SK-1b
672377
64000
-
-
674084
190000
-
gel filtration
492162
additional information
-
lesser amounts of immunoreactive protein migrate in the 45-48 kDa range
674843
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
?
-
x * 45000, SDS-PAGE, x * 96000, SDS-PAGE
?
Q1HGK5
x * 49800, calculated from sequence
monomer
-
1 * 43000, SDS-PAGE
oligomer
-
-
monomer
-
1 * 49000, SDS-PAGE
additional information
-
relationship to diacylglyceride kinases, NAD+ kinases and 6-phosphofructokinases
additional information
-
structure analysis of the 2 isozymes, schematic map, the enzyme contains 5 sequences stretches C1-C5 typical for lipid kinases, but the enzyme does not contain distinct domains for catalysis or substrate binding, overview
additional information
-
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
additional information
-
isoform SK1 interacts with subunit 7 of cytosolic chaperonin CCT, i.e. chaperonin containing t-complex polypeptide, also called TRiC for TCP-1 ring complex, a hexadecameric chaperonin that binds unfolded polypeptides. Other CCT/TRiC subunits also associate with SK1 in HEK293T cell lysates in an ATP-sensitive manner. CCT/TRiC binds specifically to newly translated SK1. Depletion of functional CCT/TRiC through the use of RNA interference in HeLa cells or temperature sensitive CCT mutants reduces cellular SK1 activity
additional information
-
oligomeric protein containing noncooperative catalytic sites, the allosteric site exerts an autoinhibition of the catalytic site
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
-
isozyme SPHK1 is phosphorylated at Ser225 by extracellular signal-regulated kinases 1 and 2, i.e. ERK1 and 2, and by cyclin dependent kinase 2, i.e. CDK2, recombinant isozyme SPHK1 in HEK293 cells is phosphorylated by ERK1 after stimulation with TNF-alpha, mechanism, overview, phosphorylation activates the enzyme by up to 14fold
phosphoprotein
-
in muscle resistance artery, pressure-dependent activation and translocation of isoform Sk1 by ERK1/2 is critically dependent on its serine225 phosphorylation site
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
homology modeling based of Staphylococcus aureus diacylglycerol kinase, PDB entry 2QV7, and docking of substrate sphinganine 1-phosphatre to the model con taining bound ADP; homology modeling based of Staphylococcus aureus diacylglycerol kinase, PDB entry 2QV7, and docking of substrate sphinganine 1-phosphatre to the model con taining bound ADP
Q9NRA0, Q9NYA1
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
-
10% glycerol, 0.05% Triton X-100, 0.5 M NaCl, stable for 30 min
492164
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
extensive dialysis or dilution in potassium phosphate buffer, 100 mM, pH 7.4, results especially during the early stages of purification in rapid loss of activity
-
repeated freezing and thawing results in 20-30% loss of activity
-
ORGANIC SOLVENT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Glycerol
-
stable when stored at -20C in the presence of 50% glycerol
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-20C, 100 mM phosphate buffer, pH 7.4, 1 mM 2-mercaptoethanol, 1 mM EDTA, 20% glycerol, stable for several months
-
-18C, stable for at least 3 weeks
-
-20C, 50% glycerol, remains stable
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
partial, multiple forms
-
G-Sepharose column chromatography
-
isozyme SPHK1
-
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
phylogenetic analysis
-
overexpression of gene sgkA leads to increased resistance to the anticancer drug cisplatin and altered growth behaviour
-
gene Sk1, DNA and amino acid sequence determination and analysis, 2 splicing variants, location on the X chromosome, functional overexpression of Sk1 in the yeast strain JSK398; gene Sk2, DNA and amino acid sequence determination and analysis, a single intron, location on chromosome 3, functional overexpression of Sk2 in the yeast strain JSK398
Q9VYY8, Q9VZW0
3- to 5fold overexpression in HUVEC cell
-
DNA and amino acid sequence determination and analysis
-
expressed in C2C12 cells; expressed in KK/Ay type 2 diabetic mice
-
expressed in Escherichia coli
-
expressed in HEK-293 cells
-
expressed in HEK-293T cells
-
expression in HEK-293 cell
-
expression in HEK-293 cell line
-
expression of FLAG-tagged isozyme in HEK293 cells; expression of FLAG-tagged isozyme in HEK293 cells, expression of His-tagged isozyme in Sf9 insect cells via baculovirus infection system
Q9NRA0, Q9NYA1
isozymes SPHK1 and SPHK2, DNA and amino acid sequence determination and analysis
-
isozymes SPHK1 and SPHK2, several splicing variants are differently active, expression in HEK293 cells as EGFP-fusion proteins; isozymes SPHK1 and SPHK2, several splicing variants are differently active, expression in HEK293 cells as EGFP-fusion proteins
Q9NRA0, Q9NYA1
overexpression of isoform Sk1 in HUVEC cell
-
transfection of A498 kidney adenocarcinoma cells; transfection of A498 kidney adenocarcinoma cells
Q9NRA0, Q9NYA1
transient expression in murine C2C12 myoblasts in the cytosolic fraction, in Golgi-enriched and endosome/plasma membrane fraction of transfected cells, the over-expressed SphK1 is localized at plasma membrane, as well as at internal membranes, SphK1 partially colocalized with caveolin-1, known to be an integral plasma membrane protein, secretion of extracellularly produced sphingosine 1-phosphate
-
transient expression of HA-tagged isozymes SphK1 and SphK2 in CHO-K1 cells
-
overview
-
-
Q9JIA7
DNA and amino acid sequence determination and analysis
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expressed in HEK -293T cells and embryonal carcinoma cells; expressed in HEK -293T cells and embryonal carcinoma cells
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expressed in NIH3T3 cells
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expressed in the adenovirus shuttle vector pAdlox
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expression of FLAG-tagged isozyme SK1 splicing variant a in HEK293 cells
Q8CI15
expression of isoform SphK1a in HEK-293 cell
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isozymes SPHK1 and SPHK2, expression in HEK293 cells as EGFP-fusion proteins; isozymes SPHK1 and SPHK2, expression in HEK293 cells as EGFP-fusion proteins
O88885, Q9JIA7
overexpression in C2C12 cell
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overexpression of isozymes SPHK1 and SPHK2 in cytosol of HEK293 cells
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overview
plant
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cloning and characterization of an isoform of rat SK1 with an N-terminal extension (long-rSK1). When the long-rSK1 is transfected in COS-7 cells, SK activity is 53fold increased. Substrate specificity and dependency on divalent cations of long-rSK1 are similar to those of rSK1
Q1HGK5
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
SphK1 inhibition by docetaxel is a two-step process involving an initial loss of enzyme activity followed by a decrease in SphK1 gene expression. Both pharmacological and siRNA-mediated SphK1 inhibition leads to a four-fold decrease in the docetaxel IC50 dose
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hypoxia increases SK1 mRNA levels, protein expression, and enzyme activity, followed by intracellular sphingosine 1-phosphate production and sphingosine 1-phosphate release. Knockdown of hypoxia-inducible factor HIF-2 by small interfering RNA abolishes the induction of SK1 and the production of extracellular shpingosine 1-phosphate after CoCl2 treatment, whereas HIF-1 small interfering RNA results in an increase of HIF-2 and of SK1 protein levels. HIF-2 binds the SK1 promoter
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in bronchial epithelial cells, SphK1 and MUC5AC expression is increased by IL-13 treatment at both protein and mRNA levels, whereas SphK2 expression is not changed. Inhibitor N,N-dimethylsphingosine decreases MUC5AC expression up-regulated by IL-13 treatment and inhibits IL-13-induced ERK1/2 phosphorylation but neither p38 MAPK nor STAT6 phosphorylation
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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
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the expression of IL-1 correlates with the expression of SphK1 in glioblastoma cells. IL-1 up-regulates SphK1 mRNA levels, protein expression, and activity in both primary human astrocytes and various glioblastoma cell lines, it does not affect SphK2 expression. The IL-1-induced SphK1 up-regulation can be blocked by the inhibition of c-Jun N-terminal kinase, the overexpression of the dominant-negative c-Jun(TAM67), and the down-regulation of c-Jun expression by small interference RNA. Activation of SphK1 expression by IL-1 occurs on the level of transcription and is mediated via a novel AP-1 element located within the first intron of the sphk1 gene
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transforming growth factor TGF-beta2 activates the promoter of isoform Sk1, resulting in upregulation of its mRNa and protein expression
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treatment with inhibitors N,N-dimethylsphingosine or DL-threo-dihydrosphingosine or with doxorubicin leads to increase in expression as a result of apoptotic stress. The caspase inhibitor ZVAD reduces not only doxorubicin-induced lethality but also the increased expression of SphK1 and secretion of sphingosine 1-phosphate
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knockdown of isoform SK2 expression results in overexpression of isoform SK1 in several cell lines. Treatment with inhibitor (2S,3R,4E)-2-(dimethylamino)octadec-4-ene-1,3-diol triples the levels of isoform SK1 mRNA, but only slightly increases isoform SK2 expression. Treatment with inhibitor 2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole increases mRNAs for both isoforms SK1 and SK2 by about 4fold
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both lipopolysaccharide and thrombin increase mouse lung microvascular permeability and result in a delayed activation of SPHK1 that is coupled to the onset of restoration of pulmonary microvessel permeability
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inhibition of protein kinase C-alpha, signal transducers and activators of transcription 3 and c-Jun NH2-terminal kinase inhibition suppresses SPHK1 expression in v-Src-transformed NIH-3T3 cells, whereas their overexpression increases SPHK1 mRNA. Modulation of AUF1 and HuR by their overexpression or siRNA reveals that SPHK1 mRNA in v-Src- and mock-NIH3T3 is regulated reciprocally by these factors
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dihydrotestosterone triggers cell growth in steroid-deprived MC-3T3 cells, associated with a rapid stimulation of isoform SphK1 and activation of both Akt and ERK signaling pathways. This mechanism relies on functional androgen receptor/PI3K/Akt nongenotropic signaling as pharmacological antagonists can block SphK1 stimulation by dihydrotestosterone and its consequences. SphK1 inhibition also blocks cell proliferation, while ERK inhibition has no impact
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treatment with lipopolysaccharid causes significantly enhances isoform SphK1 expression within 6 h, which declines back to baseline levels by 24 h. Expression of isoform SphK2 is gradually induced following lipopolysaccharide treatment and is elevated within 24 h
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treatment with lipopolysaccharide increases the SphK1 mRNA and protein expression in microglia leading to altered expression and production of proinflammatory cytokines and nitric oxide. 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
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v-Src-transfected cells show both increased SPHK1 mRNA and enzyme activity. Inhibition of protein kinase C-alpha, signal transducers and activators of transcription 3 and c-Jun NH2-terminal kinase inhibition suppresses SPHK1 expression in v-Src-transformed NIH-3T3 cells, whereas their overexpression increases SPHK1 mRNA. Modulation of AUF1 and HuR by their overexpression or siRNA reveals that SPHK1 mRNA in v-Src- and mock-NIH3T3 is regulated reciprocally by these factors
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
G113A
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increased catalytic activity
G82D
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catalytically inactive mutant
G82D
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dominant-negative SK1 mutant, removes the capacity of Ang-1 to inhibit endothelial cell permeability
G82D
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dominant-negative SK1mutant, displays substantially attenuated 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic acid-induced endothelial cell proliferation, migration, and tube formation in vitro and Matrigel plug angiogenesis in vivo
G82D
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over-expression inhibits the TNF-induced vascular cell adhesion molecule VCAM-1 and E selectin and inhibits PMN adhesion
H121E
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reduced activity by 20%
N121E
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the mutation reduces cleavage by cathepsin B at the mutation site, reduced activity by 20%
S225A
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the mutation prevents ERK1/2-mediated phosphorylation and membrane localization of SK1
S225A
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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 endothelial cell permeability
Y123A
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reduced activity by 40%
S225A
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expression in resistance artery smooth muscle cells reduces resting and myogenic tone, resting Ca2+, pressure-induced Ca2+ elevations, and Ca2+ sensitivity. Lack of function of S225A can only partly be overcome by forced localization to the plasma membrane
D175N
Q8CI15
site-directed mutagenesis, about 50% of wild-type enzyme activity
D175N/D177N
Q8CI15
site-directed mutagenesis, less than 5% of wild-type enzyme activity
D177N
Q8CI15
site-directed mutagenesis, less than 10% of wild-type enzyme activity
D177N/E179Q
Q8CI15
site-directed mutagenesis, nearly inactive mutant
E179Q
Q8CI15
site-directed mutagenesis, about 30% of wild-type enzyme activity
E181Q
Q8CI15
site-directed mutagenesis, about 30% of wild-type enzyme activity
G82D
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catalytically inactive mutant
S225A
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the mutation prevents ERK1/2-mediated phosphorylation and membrane localization of SK1
G82D
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dominant-negative mutant, calcium entry to cells is decreased in mutant lines. Exogenous sphingosine 1-phosphate restores calcium entry
additional information
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disruption mutants of genes sgkA and sgkB, single mutants with reduced activity, or double mutants nearly inactive, show increased sensitivity to the anticancer drug cisplatin and altered growth behaviour
additional information
Q9VYY8, Q9VZW0
complementation of yeast enzyme-deficient mutant strain by both Sk1 and Sk2
additional information
Q9VYY8, Q9VZW0
complementation of yeast enzyme-deficient mutant strain by both Sk1 and Sk2, a Drosophila melanogaster null Sk2 transposon insertion mutant shows elevated long chain base levels, impaired flight performance, and diminished ovulation, phenotype analysis
H122A
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the mutation reduces cleavage by cathepsin B at the mutation site, reduced activity by 60%
additional information
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deletion mutants in highly conserved regions, truncation mutants
additional information
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isoform SphK2 contains a lipid binding domain at the N-terminal residues 1-175, a region of sequence that is absent in Sphk1. Deleting the N-terminal domain reduces Sphk2 membrane localisation in cells
additional information
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deletion of 21 amino acids from the COOH-terminus of isoform SphK1, expression of residues 1-363, results in about 2.2fold increase in catalytic activity relative to wild-type SphK1, which is independent of the phosphorylation state of Serine 225 and stimulation by phorbol-12,13-myristic acid. HEK-293 cells stably expressing the truncated protein exhibit enhanced cell growth under serum-deprived cell culture conditions. A further truncated mutant, residues 1-315, displays about 20% of wild-type activity
G82D
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catalytically inactive. Overexpression in myoblast cells significantly increases cell growth and delays the beginning of myogenesis
additional information
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site-directed mutagenesis at Cys-4 and Cys-5 residues results in increased sphingosine kinase activity
H122Y
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no detectable difference in activity compared to the wild type enzyme
additional information
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spontaneous mutants with reduced enzyme activity
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
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involved in signal transduction by TRAF2, tumor necrosis factor-alpha receptor-associated factor 2
medicine
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isozyme SPHK1 is a potential therapeutic target in the treatment of inflammatory and autoimmune diseases
medicine
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anti-tumor therapy
medicine
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potential therapeutic target in anti-cancer therapy
medicine
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89% of human colon cancer samples tested stain positively for SphK1, whereas normal colon mucosa has negative or weak staining. Adenomas have higher expression of SphK1 versus normal mucosa, and colon cancers with metastasis have higher expression of SphK1 than those without metastasis
medicine
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adenovirus-mediated SPK1 gene transfer promotes recovery of the surgically damaged mesothelial cell layer and prevents postoperative peritoneal adhesion formation
medicine
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isoform Sk1 expression is increased in the podocytes of kidney sections of patients with diabetic nephropathy
medicine
Q9NYA1
isoform SphK1 protein and mRNA levels are higher in clinical tissue samples of patients with non-Hodgkin lymphomas than in reactive lymphoid hyperplasias, with a clear trend towards increasng levels with increasing clinicla grade
medicine
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levels of SPHK1mRNA and protein are higher in gastric cancer cell lines than in normal gastric epithelial cells. SPHK1 protein level is up-regulated in gastric cancer lesions compared with that in the paired adjacent noncancerous tissues. Gastric cancer tissues from 65.7% of patients reveals high level of SPHK1protein expression in contrast to the undetectable or marginally detectable expression of SPHK1 in the adjacent noncancerous gastric tissues. Significantly different expression levels of SPHK1 are found in patients at different clinical stages. Patients with higher SPHK1expression have shorter overall survival time, whereas those with lower SPHK1 expression survive longer
medicine
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patients with breast cancer that express higher CerS2 or 4 mRNA levels tend to show no changes in sphingosine kinase 1 levels, and likewise patients that express no change in CerS2 or CerS4 mRNA levels tend to express higher levels of sphingosine kinase 1. Results suggest an important role for the CerS genes in breast cancer etiology or diagnosis
medicine
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pharmacologic SphK1 inhibition with B-5354c sensitizes LNCaP and PC-3 cells to docetaxel and camptothecin, respectively. In vivo, camptothecin and B-5354c alone display a limited effect on tumor growth in PC-3 cells, whereas in combination there is a synergy of effect on tumor size with a significant increase in the ceramide to sphingosine 1-phosphate sphingolipid ratio
medicine
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sphingosine analogue FTY720, which is activated by phosphorylation specifically by SPHK2, mediates apoptotic signaling of cultured synovial fibroblasts
medicine
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SphK1 inhibition by docetaxel is a two-step process involving an initial loss of enzyme activity followed by a decrease in SphK1 gene expression. Both pharmacological and siRNA-mediated SphK1 inhibition leads to a four-fold decrease in the docetaxel IC50 dose
medicine
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SPHK1in astrocytoma cell lines is elevated at both mRNA and protein levels, and the SPHK1 mRNA and protein are significantly up-regulated by up to 6.8- and 40fold, respectively, in primary astrocytomas compared with those in the adjacent noncancerous brain tissues. 41.2% of paraffin-embedded archival astrocytoma biopsies exhibit high expression of SPHK1. The up-regulation of SPHK1 is significantly correlated with the histologic grade of astrocytoma and patients with high SPHK1 level exhibit shorter survival time
medicine
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synthesis of shingosine kinase substrates as sphingosine 1-phosphate receptor prodrugs, with varying activities at the five sphingosine 1-phosphate receptors
medicine
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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
medicine
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the synovial fluid levels of sphingosine 1-phosphate are significantly higher in patients with rheumatoid arthritis than in those with osteoarthritis. Small chronic increases in SK1 activity in the endothelial cells enhance the ability of the cells to support inflammation and undergo angiogenesis, and sensitize the cells to inflammatory cytokines. The SK1 signaling pathway is activated in rheumatoid arthritis
medicine
Q9NYA1
the expression level and properties of N-terminal 86 amino-acid isoform variant of sphingosine kinase 1, SK1b, in prostate cancer cells reduce its sensitivity to proteasomal degradation induced by 2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole in comparison to isoform SK1a. The reduced sensitivity of SK1b to proteasomal degradation in response to 2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole results in specific changes in ceramide and S1P levels that lead to apoptosis of androgen-sensitive but not androgen-independent LNCaP prostate cancer cells
medicine
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targeting SPHK may provide a novel therapeutic tool to treat bronchial asthma
medicine
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after 4 weeks of systemic ovalbumin sensitization and local airway challenge, airway responsiveness increases less in SphK1-/- compared with wild-type mice, whereas pulmonary vascular responsiveness is greatly increased and does not differ between strains. Acute lung inflammation leads to an increase in eosinophils and mRNA expression for sphingosine 1-phosphate phosphatase 2 and sphingosine 1-phosphate lyase in lungs of wild-type but not SphK1-/- mice. After repetitive allergen exposure for 8 weeks, airway responsiveness is not augmented in SphK1-/- or wild-type mice, but pulmonary vascular responsiveness is increased in both strains, with significantly higher vascular responsiveness in SphK1-/- mice compared with that seen in wild-type mice
medicine
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chronic activation of SPHK1-S1P signalling results in both pathological cardiac remodelling through reactive oxygen species mediated by S1P3 and favourable cardioprotective effects
medicine
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in a mouse model of streptozotocin-induced diabetic nephropathy, isoform Sk1 and connective tisuue grwoth factor CTGF are upregulated in podocytes. In Sk1 deficient mice, exacerbation of diesease is detected by increased albuminuria and CTGF expression when compared to wild-type
medicine
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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
medicine
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In the azoxymethane murine model of colon cancer, SphK1 and sphingosine 1-phosphate are significantly elevated in colon cancer tissues compared to normal mucosa. Blood levels of sphingosine 1-phosphate are higher in mice with colon cancers than in those without cancers. SphK1-/- mice subjected to azoxymethane have significantly less aberrant crypt foci formation and significantly reduced colon cancer development
medicine
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synthesis of shingosine kinase substrates as sphingosine 1-phosphate receptor prodrugs, with varying activities at the five sphingosine 1-phosphate receptors. Substrate (2R)-2-amino-2-[5-(4-octylphenyl)-1H-imidazol-2-yl]propan-1-ol causes lymphopenia for more than 20h
medicine
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treatment of wild-type and Sphk1 null mouse hearts by ischaemic postconditioning. Postconditioning consisting of 5 s of ischaemia and 5 s of reperfusion for three cycles after the index ischaemia, protects hearts against ischaemia/reperfusion injury, recovery of left ventricular developed pressure and maximum velocity of increase or decrease of left ventricular pressure are elevated and left ventricular end-diastolicpressure is decreased, infarction size is reduced from 40% in the control group to 29% of the risk area in the postconditioning group. Phosphorylation of Akt and extracellular signal-regulated kinases is increased at 10 min of reperfusion. The protection induced by postconditioning is abolished in Sphk1 null mouse hearts
medicine
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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