Disease relevance of Sphk1

• The immunosuppressant FTY720 was phosphorylated and elicited lymphopenia in the Sphk1 null mice showing that SPHK1 is not required for the functional activation of this sphingosine analogue prodrug [1].
• Concomitantly, epithelial cell proliferation in the polyps was significantly attenuated, suggesting that Sphk1 regulates adenoma progression [2].
• Our findings suggest that Sphk1 plays a critical role in intestinal tumor cell proliferation and that inhibitors of Sphk1 may be useful in the control of intestinal cancer [2].
• CONCLUSIONS: Overall, these studies demonstrate that inhibitors of SK attenuate the effects of proliferative and inflammatory stimuli on RECs both in vitro and in vivo, and so could be significant therapeutics in the treatment of diabetic retinopathy [3].
• All three structurally diverse SK inhibitors tested showed antitumor activity in mice without exhibiting toxicity [4].

High impact information on Sphk1

• Cross-linking of the high-affinity receptor for IgE (FcepsilonRI) in RBL-2H3 and bone marrow-derived mast cells activates sphingosine kinase (SphK), which leads to generation and secretion of the potent sphingolipid mediator, sphingosine-1-phosphate (S1P) [5].
• Concomitantly, epithelial cell proliferation and the expression of the G(1)/S cell cycle regulator CDK4 and c-myc were diminished in the polyps of Apc(Min/)(+) Sphk1(-/)(-) mice [2].
• In rat intestinal epithelial (RIE) cells in vitro, Sphk1 overexpression enhanced cell cycle traverse at the G(1)/S boundary [2].
• Sphingosine kinase type 2 is essential for lymphopenia induced by the immunomodulatory drug FTY720 [6].
• The data show that transcriptional up-regulation of the sphingosine kinase gene (SPHK1) is a recurrent event associated with the tumorigenic phenotype of these transgenic proerythroblasts [7].

Chemical compound and disease context of Sphk1

• Involvement of sphingosine kinase in TNF-alpha-stimulated tetrahydrobiopterin biosynthesis in C6 glioma cells [8].
• Here we show that sphingosine kinase 1 knockout mice exhibit normal inflammatory cell recruitment during thioglycollate-induced peritonitis and that sphingosine kinase 1-null neutrophils respond normally to formyl peptide [9].
• This effect is: (i) blocked by inhibitors of sphingosine kinase, (ii) unaffected by inhibitors of G(i)-proteins (pertussis toxin), (iii) recapitulated by sphingosine, (iv) can also be induced by lysophosphatidic acid [10].

Biological context of Sphk1

• Depletion of SK-1 by siRNA drastically reduced the effect of ATP and UTP on cell migration but not on cell proliferation [11].
• Sphingosine kinase type 1 (SphK1) and its product sphingosine-1-phosphate have been shown to promote cell growth and inhibit apoptosis of tumor cells [12].
• Non-coding RNA directed DNA demethylation of Sphk1 CpG island [13].
• Incubation of endothelial cells with FTY720 resulted in phosphorylation by sphingosine kinase activity and formation of FTY720-P [14].
• We demonstrate that inactivation of the S1P producing enzyme, sphingosine kinase, leads to cell death in cardiac tissue which is rescued by exogenous S1P treatment [15].

Anatomical context of Sphk1

• The results with these Sphk1 null mice reveal that some key physiologic processes that require S1P receptor signaling, such as vascular development and proper lymphocyte distribution, can occur in the absence of SPHK1 [1].
• We recently demonstrated [Ancellin, Colmont, Su, Li, Mittereder, Chae, Stefansson, Liau and Hla (2002) J. Biol. Chem. 277, 6667-6675] that Sphk1 activity is constitutively secreted by vascular endothelial cells [16].
• Extracellular nucleotides induce migration of renal mesangial cells by upregulating sphingosine kinase-1 expression and activity [11].
• After FcepsilonRI triggering, enhanced sphingosine kinase activity was associated with FcepsilonRI in sphingolipid-enriched rafts of mast cells [17].
• Using fibroblasts from embryonic mice devoid of functional S1PRs, we also demonstrated that, in contrast to exogenous S1P, intracellular S1P formed by overexpression of sphingosine kinase type 1 promoted growth and survival independent of its GPCRs [18].

Associations of Sphk1 with chemical compounds

• SK activity was measured by an in vitro kinase assay using sphingosine as substrate.Key results:Nucleotide stimulation caused biphasic activation of SK-1, but not SK-2 [11].
• In mast cells, induction of sphingosine kinase and generation of sphingosine-1-phosphate have been linked to the initial rise in Ca(2+), released from internal stores, and to degranulation [17].
• Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720 [1].
• Site-directed mutagenesis at these Cys residues resulted in increased sphingosine kinase activity, suggesting that the modification is inhibitory to the enzyme [19].
• Asp177 in C4 domain of mouse sphingosine kinase 1a is important for the sphingosine recognition [20].

Regulatory relationships of Sphk1

• In addition, SK inhibitors were shown to block TNFalpha-induced expression of adhesion proteins, suppress VEGF-induced vascular leakage in an in vivo mouse model, and reduce retinal vascular leakage in the rat diabetic retinopathy model [3].
• Sphingosine kinase expression regulates apoptosis and caspase activation in PC12 cells [21].

Other interactions of Sphk1

• Aminoacylase 1 is a sphingosine kinase 1-interacting protein [12].
• We previously reported that fumonisin B(1) caused sphingosine kinase (SPHK) induction along with the increase of serine palmitoyltransferase (SPT) [22].
• Early activation of sphingosine kinase in mast cells and recruitment to FcepsilonRI are mediated by its interaction with Lyn kinase [17].
• Sphingosine kinase type 1 induces G12/13-mediated stress fiber formation, yet promotes growth and survival independent of G protein-coupled receptors [18].
• Sphingosine kinase 1 is a negative regulator of CD4+ Th1 cells [23].

Analytical, diagnostic and therapeutic context of Sphk1

• Sphingosine kinase-1 (SK-1) protein expression was detected by Western blot analysis and mRNA expression quantified by real-time PCR [11].
• Sphingosine kinase activation mediates ischemic preconditioning in murine heart [24].
• Because protein kinase C (PKC)epsilon activation is necessary for myocardial ischemic preconditioning (IPC) and PKC activators increase SK activity, we tested the hypothesis that SK may be a central mediator of IPC [24].
• Roles of AKT and sphingosine kinase in the antiapoptotic effects of bile duct ligation in mouse liver [25].
• In the collagen-induced arthritis model of rheumatoid arthritis, sphingosine kinase 1 knockout mice developed arthritis with normal incidence and severity [9].

References