2.7.1.138: ceramide kinase
This is an abbreviated version!
For detailed information about ceramide kinase, go to the full flat file.
Word Map on EC 2.7.1.138
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2.7.1.138
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ceramide-1-phosphate
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sphingolipids
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1-phosphate
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sphingosine-1-phosphate
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ceramidase
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pleckstrin
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cerkl
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medicine
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ceramide-induced
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analysis
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diagnostics
- 2.7.1.138
- ceramide-1-phosphate
- sphingolipids
- 1-phosphate
- sphingosine-1-phosphate
- ceramidase
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pleckstrin
-
cerkl
- medicine
-
ceramide-induced
- analysis
- diagnostics
Reaction
Synonyms
acylsphingosine kinase, ceramide kinase, CERK, DCERK protein, hCERK, kinase, acylsphingosine (phosphorylating), More
ECTree
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General Information
General Information on EC 2.7.1.138 - ceramide kinase
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malfunction
metabolism
physiological function
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a mutation in ceramide kinase specifically leads to proteolysis of NORPA, consequent loss of phosphoinositide-specific phospholipase C activity, and failure in light signal transduction, a significant increase in ceramide, resulting from lack of ceramide kinase, perturbs the membrane microenvironment of phosphatidylinositol-4,5-bisphosphate, altering its distribution
malfunction
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capillary-like tube formation is significantly impaired in CerK-deficient cells or in wild type cells treated with NVP-231 as compared with untreated wild type cells, ceramide kinase ablation increases serum ceramide levels at the expense of dihydroceramide levels without affecting sphingosine, dihydrosphingosine, sphingosine-1-phosphate or dihydrosphingosine-1-phosphate levels, in both Cerk -/- and NVP-231-treated cells, the density of the cell monolayer area is in increased at the expense of the tube forming area
malfunction
genetic ablation of CERK reduces basal ceramide 1-phosphate levels. CERK-/- knockout mouse cells show 52-74% reduced ceramide 1-phosphate contents and significantly lower levels of multiple eicosanoids compared to wild-type. Induction of eicosanoid synthesis by calcium ionophore is significantly reduced in the CERK-/- primary mouse embryonic fibroblasts. The CERK-/- mouse has adapted to loss of CERK in regards to airway hyper-responsiveness as compared with CERK siRNA treatment. Eicosanoids produced by immortalized primary mouse embryonic fibroblasts, overview
malfunction
genetic ablation of CERK results in decreased levels of ceramide 1-phosphate in fibroblasts and inhibits the ability of fibroblasts to release arachidonic acid in response to mechanical trauma. Simulation of mechanical trauma of a wound by scratching a monolayer of fibroblasts from CERK+/+ mice demonstrates steadily increasing levels of arachidonic acid in a time-dependent manner in stark contrast to CERK-/- fibroblasts, reflected in scratch-induced eicosanoid levels. Loss of proper eicosanoid response translated into an abnormal migration pattern for the fibroblasts isolated from CERK-/-. Neither the wild-type nor the CERK-null fibroblasts demonstrated additional changes to the endogenous ceramide 1-phosphate content upon induction of mechanical trauma. The migratory response to wounding of CERK-/- fibroblasts can be rescued via the addition of exogenous eicosanoids
malfunction
loss of CerK sensitized cells towards stress-induced apoptosis, loss of CerK facilitates apoptosis induced by stress factors such as staurosporine or TNFalpha combined with cycloheximide. Cell treatment with enzyme inhibitor NVP-231 decreases DNA synthesis, but not agonist-stimulated arachidonic acid release or PGE2 synthesis, overview
malfunction
loss of CerK sensitized cells towards stress-induced apoptosis, loss of CerK facilitates apoptosis induced by stress factors such as staurosporine or TNFalpha combined with cycloheximide. Cell treatment with enzyme inhibitor NVP-231 decreases DNA synthesis, but not agonist-stimulated arachidonic acid release or PGE2 synthesis. Proliferation but not arachidonic acid release or PGE2 synthesis is reduced in CERK knockout cells, overview
malfunction
a specific inhibitor of ceramide kinase inhibits TGF-beta-induced migration of BM-MSCs and N-cadherin that is necessary for BM-MSCs migration in response to TGF-beta
malfunction
Arabidopsis thaliana cell-death mutant, accelerated cell death5 (acd5), which accumulates ceramides and exhibits spontaneous cell death late in development. NaCl enhances disease resistance and suppresses cell death in ceramide kinase mutants partly via a mechanism that depends on abscisic acid (ABA) and salicylic acid (SA) antagonistic interaction, and enhances disease resistance independent of pattern-triggered immune responses. 300 mM NaCl suppresses the cell-death phenotype of the acd5 mutant without inhibiting plant growth
malfunction
cells lacking acid sphingomyelinase (ASM) have decreased ceramide 1-phosphate production following TNF-alpha treatment, suggesting that ASM may be acting upstream of CERK. Effect of CERK knockdown on lipid levels of ceramide 1-phosphate, ceramide, and sphingosine, overview. Knockdown of CERK in the presence of ASM overexpression led to a decrease in CCL5 levels on the protein and message levels
malfunction
knockdown of CerK and overexpression of HA-tagged CerK down- and upregulated the formation of ceramide-1-phosphate (C1P), respectively. When knockdown or overexpression of CerK is performed, Ca2+-induced release of [3H] noradrenaline is reduced or enhanced, respectively, but neurite extension is not modified. A limited change in cellular sphingolipid levels by knockdown of CerK. The levels of ceramide, sphingomyelin, and monohexosylceramide, including their total levels and levels of their subspecies with irrespective of N-acyl chain lengths, and those of sphingosine, sphingomyelin 1-phosphate, and their dihydro-forms are not affected by the CerK knockdown in PC12 cells
malfunction
miR-34a targets CERK resulting in ceramide accumulation, activation of PP2A and the pJNK pathway in muscle and C2C12 myoblasts. Overexpression of miR-34a in C2C12 myoblasts leads to alterations in the insulin signaling pathway, which are rescued by its antagonism
malfunction
treatment with ceramide kinase inhibitor K1, or nSMase inhibitor GW4869, decreases dopamine uptake in PC-12 cells, although the application of FB1, a ceramide synthase inhibitor, does not affect dopamine uptake. Transfection of nSMase2 and CERK siRNA decrease the dopamine transporter (DAT) surface level in PC-12 cells. SM-derived ceramide 1-phosphate affects cell surface levels of DAT. Protein-protein interaction between nSMase2 and DAT occur in the mouse striatum. Treatment of CERK knockdown PC-12 cells with C8-ceramide partially rescues the nSMase2 siRNA-induced decrease in DA uptake by about 40%, while treatment of C8-ceramide 1-phosphate also partially rescues the CERK sRNA-induced decrease in DA utake by about 45%
malfunction
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genetic ablation of CERK reduces basal ceramide 1-phosphate levels. CERK-/- knockout mouse cells show 52-74% reduced ceramide 1-phosphate contents and significantly lower levels of multiple eicosanoids compared to wild-type. Induction of eicosanoid synthesis by calcium ionophore is significantly reduced in the CERK-/- primary mouse embryonic fibroblasts. The CERK-/- mouse has adapted to loss of CERK in regards to airway hyper-responsiveness as compared with CERK siRNA treatment. Eicosanoids produced by immortalized primary mouse embryonic fibroblasts, overview
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malfunction
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genetic ablation of CERK results in decreased levels of ceramide 1-phosphate in fibroblasts and inhibits the ability of fibroblasts to release arachidonic acid in response to mechanical trauma. Simulation of mechanical trauma of a wound by scratching a monolayer of fibroblasts from CERK+/+ mice demonstrates steadily increasing levels of arachidonic acid in a time-dependent manner in stark contrast to CERK-/- fibroblasts, reflected in scratch-induced eicosanoid levels. Loss of proper eicosanoid response translated into an abnormal migration pattern for the fibroblasts isolated from CERK-/-. Neither the wild-type nor the CERK-null fibroblasts demonstrated additional changes to the endogenous ceramide 1-phosphate content upon induction of mechanical trauma. The migratory response to wounding of CERK-/- fibroblasts can be rescued via the addition of exogenous eicosanoids
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malfunction
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treatment with ceramide kinase inhibitor K1, or nSMase inhibitor GW4869, decreases dopamine uptake in PC-12 cells, although the application of FB1, a ceramide synthase inhibitor, does not affect dopamine uptake. Transfection of nSMase2 and CERK siRNA decrease the dopamine transporter (DAT) surface level in PC-12 cells. SM-derived ceramide 1-phosphate affects cell surface levels of DAT. Protein-protein interaction between nSMase2 and DAT occur in the mouse striatum. Treatment of CERK knockdown PC-12 cells with C8-ceramide partially rescues the nSMase2 siRNA-induced decrease in DA uptake by about 40%, while treatment of C8-ceramide 1-phosphate also partially rescues the CERK sRNA-induced decrease in DA utake by about 45%
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malfunction
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miR-34a targets CERK resulting in ceramide accumulation, activation of PP2A and the pJNK pathway in muscle and C2C12 myoblasts. Overexpression of miR-34a in C2C12 myoblasts leads to alterations in the insulin signaling pathway, which are rescued by its antagonism
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metabolism
functional role of the ASM/CERK pathway in cancer cell migration, and of the ASM/CERK signaling axis in cytokines associated with EMT, cell migration, and invasiveness
metabolism
involvement of the lysosome pathway in CerK levels and ceramide 1-phosphate formation
metabolism
myostatin (Mstn) and microRNA miR-34a antagonism can help ameliorate ceramide accumulation and loss of insulin sensitivity in aging skeletal muscle
metabolism
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myostatin (Mstn) and microRNA miR-34a antagonism can help ameliorate ceramide accumulation and loss of insulin sensitivity in aging skeletal muscle
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ceramide kinase catalyzed formation of ceramide 1-phosphate may regulate angiogenesis by a novel mechanism that is independent of sphingosine-1-phosphate formation and signaling
physiological function
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ceramide kinase, is a novel regulator of phosphoinositide-specific phospholipase C signaling and photoreceptor homeostasis, DCERK has a diacylglycerol kinase domain and a Ca2+/calmodulin binding domain
physiological function
enzyme plays an important role in cellular events such as cell growth and inflammation
physiological function
ceramide kinase might act as an modulator for mild and chronic activation of mast cells, thus increasing sensitivity to cytoplasmic Ca2+. CERK-/- mice are less prone to exhibiting a passive cutaneous anaphylactic shock-reaction compared to wild-type mice, the differences are not significant. In bone marrow-derived mast cells from CERK-/- mice activated by cross-linking antigen /IgE, low concentrations of Ag+ have a reduced effect on degranulation. Similarly, when the cells are activated with calcium ionophore to focus on the downstream signaling of Ca2+-elevation, only a low concentration of ionophore has a reduced effect on degranulation
physiological function
ceramide kinase/ceramide 1-phosphate axis acts as molecular effector of the anti-proliferative action of 1alpha,25-dihydroxyvitamin D3 and its analogues. The inhibition of ceramide kinase by specific gene silencing or pharmacological inhibition, drastically reduces cell proliferation. 1alpha,25-Dihydroxyvitamin D3 and structural analogue ZK191784 treatment induce a significant decrease in ceramide kinase expression and ceramide 1-phosphate content, and an increase of ceramide. The treatment of SH-SY5Y cells with ZK159222, antagonist of 1alpha,25-dihydroxyvitamin D3 receptor, trichostatin A, inhibitor of histone deacetylases, and COUP-TFI-siRNA prevents the decrease of ceramide kinase expression elicited by 1alpha,25-dihydroxyvitamin D3 supporting the involvement of VDR/COUP-TFI/histone deacetylase complex in ceramide kinase regulation
physiological function
a role for ceramide kinase in the production of eicosanoids. The initial rate-limiting step in eicosanoid biosynthesis is started by the activation of group IVA phospholipase A, 2cPLA2alpha, which is activated by direct binding of the C2 domain to ceramide-1-phosphate
physiological function
ceramide kinase catalyzes the generation of the sphingolipid ceramide-1-phosphate, which regulates various cellular functions including cell growth and death, and inflammation. Ceramide kinase contributes to proliferation but not to prostaglandin E2 formation in renal mesangial cells and fibroblasts
physiological function
ceramide kinase catalyzes the generation of the sphingolipid ceramide-1-phosphate, which regulates various cellular functions including cell growth and death, and inflammation. Ceramide kinase contributes to proliferation but not to prostaglandin E2 formation in renal mesangial cells and fibroblasts
physiological function
ceramide kinase promotes tumor cell survival and mammary tumor recurrence. Ceramide kinase is required for mammary tumor recurrence following HER2/neu pathway inhibition and is spontaneously upregulated during tumor recurrence in multiple genetically engineered mouse models for breast cancer. CERK expression is associated with an increased risk of recurrence in women with breast cancer, Cerk promotes tumor cell survival in vivo
physiological function
CERK is required for eicosanoid biosynthesis in response to mechanical insult. Proper migration of fibroblasts is one of the necessary steps of wound healing, requirement for the CERK-derived ceramide 1-phosphate in the proper healing response of wounds
physiological function
CERK is required for eicosanoid biosynthesis in response to mechanical insult. Simulation of mechanical trauma of a wound demonstrates steadily increasing levels of arachidonic acid in a time-dependent manner reflected in scratch-induced eicosanoid levels. Proper migration of fi broblasts is one of the necessary steps of wound healing, requirement for the CERK-derived ceramide 1-phosphate in the proper healing response of wounds
physiological function
phosphorylated sphingolipids ceramide-1-phosphate and sphingosine-1-phosphate are key regulators of cell growth, survival, migration, and inflammation. Ceramide 1-phosphate produced by ceramide kinase is an activator of group IVA cytosolic phospholipase A2alpha (cPLA2alpha), the rate-limiting releaser of arachidonic acid used for pro-inflammatory eicosanoid production, which contributes to disease pathogenesis in asthma/airway hyper-responsiveness, cancer, atherosclerosis, and thrombosis. To modulate eicosanoid action and avoid the damaging effects of chronic inflammation, cells require efficient targeting, trafficking, and presentation of ceramide 1-phosphate to specific cellular sites. Nonvesicular trafficking by a ceramide-1-phosphate transfer protein, CPTP, regulates eicosanoids, mechanism, overview. CPTP prevents excess ceramide-1-phosphate accumulation after production by CERK, thereby regulating cPLA2alpha action, diminishing arachidonic acid release and downstream generation of pro-inflammatory eicosanoids
physiological function
ceramide kinase (CerK) phosphorylates ceramide to ceramide-1-phosphate (C1P). The activity of CerK is regulated by post-translational modifications including phosphorylation, CerK has a role in neuronal functions
physiological function
dopamine transporter trafficking is regulated by neutral sphingomyelinase 2/ceramide kinase (nSMase/CERK). The dopamine transporter (DAT) has an important role in the regulation of Dopamine (DA) reuptake. DAT recycling is regulated by ceramide kinase via the sphingomyelin pathway. Dopamine stimulates the formation of ceramide and increases nSMase activity in PC-12 cells, while treatment with a cell-permeable ceramide 1-phosphate (C1P) increases DA uptake. Endocytic recycling of DAT requires CERK
physiological function
endogenous bone marrow-derived mesenchymal stem cells (BM-MSCs) are mobilized into peripheral blood and injured tissues by various growth factors and cytokines that are expressed in the injured tissues, such as substance P (SP), stromal cell derived factor-1 (SDF-1), and transforming growth factor beta (TGF-beta). Extracellular bioactive lipid metabolites such as ceramide 1-phosphate and sphingosine 1-phosphate also modulate BM-MSC migration as SP, SDF-1, and TGF-beta. Ceramide kinase mediates the chemotactic migration of BM-MSCs in response to SP, SDF-1, or TGF-beta. Ceramide kinase regulates the migration of bone marrow-derived mesenchymal stem cells. The extracellular ceramide 1-phosphate regulates the migration of bone marrowderived multipotent mesenchymal stem cells (BM-MSCs) as well as macrophages, lung cancer cells, prostate cancer cells, and endothelial cells. Ceramide 1-phosphate generated by ceramide kinase is released extracellularly in order to induce cellular migration. Ceramide 1-phosphate also remains inside of cells in order to recruit cytosolic proteins and transduce signals. Ceramide kinase also regulates the expression of N-cadherin that is required for BM-MSCs migration induced by TGF-beta
physiological function
myostatin (Mstn) levels increase in aging mouse muscle and upregulate miR-34a, which inhibits CERK resulting in increased ceramide levels. This ceramide accumulation activates PP2A and pJNK causing hypophosphorylation of AKT and hyperphosphorylation of IRS1 (Ser307), respectively, impairing insulin signaling pathway and eventually inhibiting the sarcolemma localization of GLUT4. These changes can result in reduced glucose uptake and insulin resistance. CERK inhibition affects insulin signaling pathway in C2C12 myoblasts via ceramide accumulation. CERK inhibition with NVP231 results in hypophosphorylation of insulin signaling molecules (PI3K, AKT, AS160, and GSK3b) and hyperphosphorylation of IRS1 (Ser307) when compared with dimethyl sulfoxide treated control C2C12 myoblasts
physiological function
TNF-alpha induces the formation of ceramide 1-phosphate (C-1-P) in a CERK-dependent manner. Silencing of CERK blocks CCL5 production in response to TNF-alpha. ASM and CERK induce a highly concordant program of cytokine production and both are required for migration of breast cancer cells. ASM can produce ceramide which is then converted to ceramide 1-phosphate by CERK, and that ceramide 1-phosphate is required for production of CCL5 and several cytokines and chemokines, with roles in cell migration. Enzyme CERK is required for CCL5 production and sufficient to induce CCL5 in MCF-7 breast cancer cells
physiological function
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a role for ceramide kinase in the production of eicosanoids. The initial rate-limiting step in eicosanoid biosynthesis is started by the activation of group IVA phospholipase A, 2cPLA2alpha, which is activated by direct binding of the C2 domain to ceramide-1-phosphate
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physiological function
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CERK is required for eicosanoid biosynthesis in response to mechanical insult. Proper migration of fibroblasts is one of the necessary steps of wound healing, requirement for the CERK-derived ceramide 1-phosphate in the proper healing response of wounds
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physiological function
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dopamine transporter trafficking is regulated by neutral sphingomyelinase 2/ceramide kinase (nSMase/CERK). The dopamine transporter (DAT) has an important role in the regulation of Dopamine (DA) reuptake. DAT recycling is regulated by ceramide kinase via the sphingomyelin pathway. Dopamine stimulates the formation of ceramide and increases nSMase activity in PC-12 cells, while treatment with a cell-permeable ceramide 1-phosphate (C1P) increases DA uptake. Endocytic recycling of DAT requires CERK
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physiological function
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myostatin (Mstn) levels increase in aging mouse muscle and upregulate miR-34a, which inhibits CERK resulting in increased ceramide levels. This ceramide accumulation activates PP2A and pJNK causing hypophosphorylation of AKT and hyperphosphorylation of IRS1 (Ser307), respectively, impairing insulin signaling pathway and eventually inhibiting the sarcolemma localization of GLUT4. These changes can result in reduced glucose uptake and insulin resistance. CERK inhibition affects insulin signaling pathway in C2C12 myoblasts via ceramide accumulation. CERK inhibition with NVP231 results in hypophosphorylation of insulin signaling molecules (PI3K, AKT, AS160, and GSK3b) and hyperphosphorylation of IRS1 (Ser307) when compared with dimethyl sulfoxide treated control C2C12 myoblasts
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