Disease relevance of Sgpp1

• Binding of SPP to Edg-1 resulted in inhibition of forskolin-stimulated cAMP accumulation, in a pertussis toxin-sensitive manner [1].
• Finally, SPP suppresses apoptosis of HL-60 and pheochromocytoma PC12 cells, which do not have specific SPP binding or expression of Edg-1 mRNA [1].
• The Rho signalling pathway is activated, for example, by bioactive sphingolipids such as sphingosine-1-phosphate (SPP) or by overexpression of Rho family members in tumorigenesis and metastases [2].
• Rapid [Ca2+]i responses were also observed in human transitional bladder carcinoma (J82) cells, monkey COS-1 cells, mouse NIH 3T3 cells, Chinese hamster ovary (CHO-K1) cells, and rat C6 glioma cells, whereas human HL-60 leukemia cells and human erythroleukemia cells failed to respond to SPP [3].
• In contrast to PC12 cells, C6 astroglioma cells secreted SPP, suggesting that SPP might be one of a multitude of known neurotrophic factors produced and secreted by glial cells [4].

High impact information on Sgpp1

• SPP induces the Gi/mitogen-activated protein kinase/cell survival pathway and the small GTPase Rho- and Raccoupled adherens junction assembly [5].
• Ceramidase, in concert with sphingosine kinase, metabolizes ceramide to sphingosine-1-phosphate (SPP), an inducer of proliferation [6].
• Sphingosine-1-phosphate (SPP), a sphingolipid metabolite found in high concentrations in platelets and blood, stimulates members of the endothelial differentiation gene (Edg) family of G protein-coupled receptors and triggers diverse effects, including cell growth, survival, migration, and morphogenesis [7].
• Remarkably, dihydro-S1P, although a good substrate for SPP-1 in situ, did not cause significant ceramide accumulation or increase apoptosis [8].
• Moreover, SPP-1 activity and protein appeared to be mainly enriched in the intracellular membranes with lower expression in the plasma membrane [8].

Chemical compound and disease context of Sgpp1

• Consistent with the coupling of Edg receptors to G proteins, SPP- and SPC-induced Ca2+ signaling was inhibited by pretreatment of the cells with pertussis toxin (PTx) [9].
• Moreover, this abrogation of caspase activation, which was prevented by the SPHK inhibitor N,N-dimethylsphingosine, was not affected by pertussis toxin treatment, indicating that the cytoprotective effect was likely not mediated by binding of SPP to cell surface G(i)-coupled SPP receptors [4].
• Here the first evidence is provided that in C2C12 myoblasts sphingosine 1-phosphate (SPP) rapidly and transiently induced membrane association of Rho A in a pertussis toxin-insensitive manner [10].

Biological context of Sgpp1

• Sphingosine and sphingosine-1-phosphate (SPP) are interconvertible sphingolipid metabolites with opposing effects on cell growth and apoptosis [11].
• This hydrophobic enzyme, which contains the type 2 lipid phosphohydrolase conserved sequence motif, shows substrate specificity for SPP [11].
• Based on sequence homology to murine SPP1, we cloned the human homolog [12].
• SPP1 exhibited apparent Michaelis-Menten kinetics with S1P as substrate with an apparent K(m) of 38.5 microm and optimum activity at pH 7 [12].
• Transfection of human embryonic kidney 293 and Chinese hamster ovary cells with murine or human SPP1 resulted in marked increases in SPP1 activity in membrane fractions that were used to examine its enzymological properties [12].

Anatomical context of Sgpp1

• Treatment of SPP-1 transfectants with S1P markedly increased ceramide levels, predominantly in the intracellular membranes, diminished survival, and enhanced apoptosis [8].
• Enforced expression of mSPP1 in NIH 3T3 fibroblasts not only decreased SPP and enhanced ceramide levels, it also markedly diminished survival and induced the characteristic traits of apoptosis [11].
• Activation of these channels occurred strictly when SPP was applied at the extracellular face of atrial myocyte plasma membrane as measured in cell-attached and inside-out patch clamp current recordings [3].
• Thus, EDG receptors are expressed in pancreatic islet beta-cells and G(i) seems to mediate the inhibition by SPP of adenylyl cyclase and cAMP formation and inhibition of the stimulation of insulin secretion by GLP-1 [13].
• In this report, pharmacological properties of the three G-protein-coupled receptors (GPCRs) for SPP, EDG-1, -3, and -5 are characterized using a Xenopus oocyte expression system, which lacks endogenous SPP receptors [14].

Associations of Sgpp1 with chemical compounds

• Membrane fractions from human embryonic kidney HEK293 cells transfected with mSPP1 markedly degraded SPP but not lysophosphatidic acid, phosphatidic acid, or ceramide-1-phosphate [11].
• 5. Similar to other LPPs, SPP1 activity was also independent of any cation requirements, including Mg(2+), and was not inhibited by EDTA but was markedly inhibited by NaF and Zn(2+) [12].
• Edg-1 binds SPP with remarkable specificity as only sphinganine-1-phosphate displaced radiolabeled SPP, while other sphingolipids did not [1].
• Sphingosine 1-phosphate (SPP) has recently emerged as an important lipid messenger and a ligand for the endothelial differentiation gene receptor family of proteins through which it mediates its biologic effects [15].
• Sphingosine, a metabolic precursor of SPP, also produced a slight increase in tyrosine phosphorylation of Crk [16].

Other interactions of Sgpp1

• We observed that enzymes that regulate S1P levels, sphingosine kinase and sphingosine-1-phosphate phosphatase, are expressed in the developing heart [17].
• Partially purified Myc-tagged mSPP1 was also highly active at dephosphorylating SPP [11].
• The presence of RXR not only allows the VDR to bind to the rOST VDRE, but also increases the binding affinity for the mSPP-1 VDRE [18].

Analytical, diagnostic and therapeutic context of Sgpp1

• Confocal microscopy surprisingly revealed that epitope-tagged SPP-1 is intracellular and colocalized with the ER marker calnexin [8].
• Moreover, DNA synthesis in Swiss 3T3 fibroblasts was significantly and specifically increased by microinjection of SPP [1].
• Using 125I-TAP in both immunoprecipitation and radioimmunoassays, it was found that an antiserum raised against SPP did not cross-react with 125I-TAP [19].

References