Disease relevance of Sphk1

• These signalling events downstream of lpR activation were inhibited to varying degrees by pertussis toxin (PTX) pretreatment or by the inhibition of sphingosine kinase (SK), a rate-limiting enzyme in the biosynthesis of S1P from sphingosine [1].
• Strongly positive SK1 staining was found in 21/28 (75%) of rat colon adenocarcinomas induced by AOM, whereas no positive SK1 staining was observed in normal mucosa [2].
• Nerve growth factor (NGF), a neurotrophic factor for pheochromocytoma PC12 cells, induced a biphasic increase in the activity of sphingosine kinase, the enzyme that catalyzes the formation of SPP [3].
• This stimulatory effect of hypoxia on VSM cell growth was significantly inhibited by pretreatment of cells with D-erythro-N,N-dimethylsphingosine, an inhibitor of sphingosine kinase [4].

High impact information on Sphk1

• Stimulation of sphingosine kinase 1 (SphK1), the enzyme that phosphorylates sphingosine to form sphingosine-1-phosphate (S1P), is part of the functional TrkA signaling repertoire [5].
• Sphingosine kinase 1 (SphK1) and formation of S1P, which leads to transactivation of S1P receptors and their downstream signaling pathways, regulates mast-cell functions initiated by cross-linking of the high-affinity immunoglobulin E (IgE) receptor FcepsilonRI [6].
• We report that prosaposin treatment induced extracellular signal-regulated kinases (ERKs) and sphingosine kinase activity, increased DNA synthesis, and prevented cell apoptosis [7].
• To further substantiate a role for SPP in the cytoprotective actions of NGF, we found that N, N-dimethylsphingosine, a competitive inhibitor of sphingosine kinase, also induced apoptosis and interfered with the survival effect of NGF [3].
• Sphingosine kinase 1 (SK1) phosphorylates sphingosine to generate sphingosine 1-phosphate (S1P) [8].

Biological context of Sphk1

• Here, we identify rat Sphk1, using multiple alternative first exons for the subtypes, and demonstrate that there is a CpG island bearing T-DMR [9].
• CpG island of rat sphingosine kinase-1 gene: tissue-dependent DNA methylation status and multiple alternative first exons [9].
• Prosaposin treatment induces PC12 entry in the S phase of the cell cycle and prevents apoptosis: activation of ERKs and sphingosine kinase [7].
• Sphingosine kinase shows substrate specificity for D-erythro-sphingosine and does not catalyze the phosphorylation of phosphatidylinositol, diacylglycerol, ceramide, DL-threo-dihydrosphingosine, or N,N-dimethylsphingosine [10].
• Furthermore, inhibition of sphingosine kinase accelerated TG-induced cell death, and exogenous sphingosine 1-phosphate (S1P) protected cells from FCCP-induced cell death by about 60% [11].

Anatomical context of Sphk1

• These results suggest that astrocyte lpR signalling mechanisms likely involve both Gi- and Gq-coupled GPCRs and that receptor-mediated activation of SK leads to intracellular generation of S1P, which in turn amplifies the lpR signalling in a paracrine/autocrine manner [1].
• Therefore, we examined the expression of SK1 and COX-2 in rat colon tumors induced by azoxymethane (AOM) and the relationship of these two proteins in normal and malignant intestinal epithelial cells [2].
• These results indicate that, in these cells, depletion of intracellular nonmitochondrial or mitochondrial Ca(2+) stores causes cell death, that TG activates phospholipase A(2) and sphingosine kinase, and that arachidonic acid induces neurite outgrowth, whereas S1P delays cell death [11].
• Phorbol ester treatment resulted in an increase in sphingosine kinase 1 activity in the membranes, accompanied by a significant increase in extracellular S1P [12].
• Novel role of sphingosine kinase 1 as a mediator of neurotrophin-3 action in oligodendrocyte progenitors [13].

Associations of Sphk1 with chemical compounds

• Sphingosine kinase 1 is an intracellular effector of phosphatidic acid [8].
• This 385-fold purified sphingosine kinase bound tightly to calmodulin-Sepharose and could be eluted in high yield with EGTA in the presence of 1 M NaCl [10].
• Reduction in cellular synthesis of S1P by adding the sphingosine kinase inhibitor dimethyl sphingosine during medium conditioning reduced the ability of conditioned medium to cause actin rearrangements [14].
• The cell cycle effect was blocked by the antioxidants ADPC and ascorbate, the superoxide scavenger Tiron, and the sphingosine kinase inhibitor L-cycloserine, but not by inhibitors of nitric oxide synthase [15].
• Studies with sphingosine kinase inhibitors and overexpression of sphingosine kinase revealed a partial contribution of this pathway to depolarisation-induced noradrenaline release and Ca(2+) increase [16].

Other interactions of Sphk1

• We report that SK1, which is ordinarily a cytosolic enzyme, translocates in vivo and in vitro to membrane compartments enriched in phosphatidic acid (PA), the lipid product of phospholipase D. This translocation depends on direct interaction of SK1 with PA, because recombinant purified enzyme shows strong affinity for pure PA coupled to Affi-Gel [8].
• On the other hand, sphingosine, a substrate for sphingosine kinase which forms intracellular S1P, was a very weak activator for the expression of either FGF-2 or Egr-1 [17].
• S1P was able to activate ERK1/2 without a detectable increase in the intracellular content of the lipid, but sphingosine, a substrate of sphingosine kinase, which is an enzyme for S1P generation in the cells, hardly affected the ERK1/2 activation in spite of a marked elevation of intracellular S1P accumulation [18].
• Essential requirement for sphingosine kinase activity in eNOS-dependent NO release and vasorelaxation [19].
• Sphingosine kinase activity was increased by prosaposin treatment [7].

Analytical, diagnostic and therapeutic context of Sphk1

• The increase in SK1 and COX-2 expression in AOM-induced rat colon adenocarcinoma was confirmed at the level of mRNA by real-time RT-PCR [2].
• Purified sphingosine kinase has an apparent molecular mass of approximately 49 kDa under denaturing conditions on SDS-polyacrylamide gel, which is similar to the molecular mass determined by gel filtration, suggesting that the active form is a monomer [10].

References