Disease relevance of EDG1

• In CHO-AGR16 cells, but not in parental CHO cells, S1P stimulated the production of inositol phosphates and Ca2+ mobilization which was only 30% inhibited by pertussis toxin (PTX), different from the case of the recently identified S1P receptor EDG1 [1].
• These data suggest that novel EPCR ligation and S1P1 transactivation results in EC cytoskeletal rearrangement and barrier protection, components potentially critical to the improved survival of APC-treated patients with severe sepsis [2].
• Sphingosine 1-phosphate receptor expression profile in human gastric cancer cells: differential regulation on the migration and proliferation [3].
• Astrocytomas of various histologic grades expressed three types of sphingosine-1-phosphate receptors, S1P1, S1P2, and S1P3; however, no significant correlation with histologic grade or patient survival was detected [4].
• EDG1 receptor stimulation leads to cardiac hypertrophy in rat neonatal myocytes [5].

High impact information on EDG1

• Both EDG-1-and EDG-3-regulated signaling pathways are required for endothelial cell morphogenesis into capillary-like networks [6].
• We show here that sphingosine-1-phosphate (SPP), a platelet-derived bioactive lipid, activates the EDG-1 and -3 subtypes of G protein-coupled receptors on endothelial cells to regulate angiogenesis [6].
• A sphingosine-1-phosphate receptor regulates cell migration during vertebrate heart development [7].
• SPP activated the heterotrimeric guanine nucleotide binding protein (G protein)-coupled orphan receptor EDG-1, originally cloned as Endothelial Differentiation Gene-1 [8].
• Here we show that sphingosine-1-phosphate (S1P)-induced endothelial cell migration requires the Akt-mediated phosphorylation of the G protein-coupled receptor (GPCR) EDG-1 [9].

Chemical compound and disease context of EDG1

• Activation of the endothelial receptor EDG-1 by platelet-derived lipids LPA and SPP may be important in thrombosis and angiogenesis, conditions in which critical platelet-endothelial interactions occur [10].
• Additional studies revealed that the rVP1 treatment caused apoptosis of cancer cells, including MCF-7 (a breast carcinoma cell line with a functional deletion of the caspase-3 gene) and PC-3 (a sphingosine 1-phosphate receptor subtype 3-deficient androgen-independent prostate cancer cell line) [11].
• FTY720 (2-amino-2[2-(-4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) is a new sphingosine-1-phosphate receptor agonist being developed for multiple sclerosis and prevention of solid organ transplant rejection [12].
• Sphingosine-1-phosphate and the low affinity sphingosine-1-phosphate receptor agonist, sphingosylphosphorylcholine, induced a rapid, transient and nearly complete pertussis toxin-sensitive Ca2+ mobilization in human embryonic kidney (HEK-293) cells [13].

Biological context of EDG1

• In addition, phosphorylation by PMA and SSP were associated with a loss of EDG1 from the cell surface by distinct mechanisms [14].
• Activated protein C mediates novel lung endothelial barrier enhancement: role of sphingosine 1-phosphate receptor transactivation [2].
• SPP binds to EDG-1 with the dissociation constant of approximately 8 nM and induces signal transduction events such as mitogen-activated protein kinase (MAP kinase) activation, decrease of cAMP levels, remodeling of the actin cytoskeleton, among others [15].
• In vascular endothelial cells, cooperative signaling between EDG-1 and EDG-3 subtypes of SPP receptors results in adherens junction assembly, cell survival, morphogenesis into capillary-like networks, and angiogenesis [15].
• Cell migration was sensitive to both receptors, but cell survival was exclusively sensitive to S1P1 [16].

Anatomical context of EDG1

• Consistent with angiogenesis in general during decidualization, we believe EDG1 and EDG5 to be regulated by the embryo because no microvascular expression for these receptors was observed in oil-induced deciduomas [17].
• Detailed analysis by in situ hybridization (ISH) and immunohistochemistry (IHC) revealed strong EDG1 expression in cardiomyocytes and in endothelial cells of cardiac vessels [18].
• Unlike EDG3 and EDG5, which are expressed in the smooth muscle cell layer of the human aorta, no signal corresponding to EDG1 expression could be detected in the aorta [18].
• This is corroborated with the down-regulation of S1P1 in T cells stimulated with anti-CD3 plus anti-CD28 [19].
• The agonist-modulated targeting of EDG-1 to caveolae and its dynamic inhibitory interactions with caveolin identify new points for regulation of sphingolipid-dependent signaling in the vascular wall [20].

Associations of EDG1 with chemical compounds

• EDG3 is a functional receptor specific for sphingosine 1-phosphate and sphingosylphosphorylcholine with signaling characteristics distinct from EDG1 and AGR16 [21].
• EDG-1 is a prototypical member of a large family of GPCRs that interact with glycero- and sphingolysolipid phosphates, namely, SPP and lysophosphatidic acid (LPA) [15].
• In contrast to SPP, sphinganine-1-phosphate, which binds to and signals through SPP receptors EDG-1, EDG-3, and EDG-5, had no effect on chemotactic motility of MDA-MB-231 or MCF-7 cells [22].
• Subcellular fractionation of cell lysates resolved by ultracentrifugation in discontinuous sucrose gradients revealed that approximately 55% of the EDG-1 protein was recovered in fractions enriched in caveolin-1, a resident protein of caveolae [20].
• The sphingosine 1-phosphate receptor agonist FTY720 supports CXCR4-dependent migration and bone marrow homing of human CD34+ progenitor cells [23].

Physical interactions of EDG1

• Identification of the Hydrophobic Ligand Binding Pocket of the S1P1 Receptor [24].
• In addition, SPP also has been identified as the ligand for the G-protein-coupled receptors EDG-1, -3, -5, and -6 [25].

Regulatory relationships of EDG1

• In vitro assays revealed that G-protein-coupled receptor kinase 2 may be at least partially responsible for SSP-stimulated EDG1 phosphorylation observed in intact cells [14].

Other interactions of EDG1

• When assessed by Northern blots, EDG1, EDG3, and EDG5 displayed wide expression levels in decreasing order, respectively [18].
• MBD1, EDG1 and gene hypermethylation mechanism would play an important role in the pathogenesis of pancreatic carcinoma [26].
• Immunoprecipitation of S1P receptors from CEM fractions revealed complexes containing Tiam1 and S1P1 [27].
• Once exported, SPP interacts with the G-protein-coupled receptors (GPCR) of the EDG-1 family [15].
• Dual regulation of EDG1/S1P(1) receptor phosphorylation and internalization by protein kinase C and G-protein-coupled receptor kinase 2 [14].

Analytical, diagnostic and therapeutic context of EDG1

• Co-immunoprecipitation studies demonstrate an interaction between EPCR and S1P1 upon APC treatment [2].
• Because solid tumors expressing ECGF-1 could also be lysed by the CTL, ECGF-1 is an interesting target for immunotherapy of both hematologic and solid tumors [28].
• METHODS: We examined S1P1 messenger RNA (mRNA) and protein levels in RA synoviocytes and MH7A cells by reverse transcriptase-polymerase chain reaction and Western blotting [29].
• A monoselective sphingosine-1-phosphate receptor-1 agonist prevents allograft rejection in a stringent rat heart transplantation model [30].
• All samples appeared to yield intact RNA without significant degradation, and expression of the edg-1 gene was detected by the real time reverse transcriptase polymerase chain reaction in all cases [31].

References