Genomes and Genes
Summary: A family of G-protein-coupled receptors that bind to specific LYSOPHOSPHOLIPIDS such as lysophosphatidic acid and lysosphinglipids such as sphingosine-1-phosphate. They play an important role in the formation and function of the CARDIOVASCULAR SYSTEM.
- MacLennan A, Devlin B, Marks L, Gaskin A, Neitzel K, Lee N. Antisense studies in PC12 cells suggest a role for H218, a sphingosine 1-phosphate receptor, in growth-factor-induced cell-cell interaction and neurite outgrowth. Dev Neurosci. 2000;22:283-95 pubmed..Finally, and in agreement with a S1P receptor role for H218, we find that the antisense-H218 cells display less S1P-induced neurite retraction than control cells. ..
- Lee M, Thangada S, Claffey K, Ancellin N, Liu C, Kluk M, et al. Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate. Cell. 1999;99:301-12 pubmed..Indeed, SPP synergized with polypeptide angiogenic growth factors in the formation of mature neovessels in vivo. These data define SPP as a novel regulator of angiogenesis. ..
- Jin Y, Knudsen E, Wang L, Bryceson Y, Damaj B, Gessani S, et al. Sphingosine 1-phosphate is a novel inhibitor of T-cell proliferation. Blood. 2003;101:4909-15 pubmed..These results show differential effects of S1P on polyclonal T-cell proliferation and cytokine secretion. ..
- Spiegel S, Milstien S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol. 2003;4:397-407 pubmed..These S1P receptors are differentially expressed, coupled to various G proteins, and regulate angiogenesis, vascular maturation, cardiac development and immunity, and are important for directed cell movement. ..
- Sugimoto N, Takuwa N, Okamoto H, Sakurada S, Takuwa Y. Inhibitory and stimulatory regulation of Rac and cell motility by the G12/13-Rho and Gi pathways integrated downstream of a single G protein-coupled sphingosine-1-phosphate receptor isoform. Mol Cell Biol. 2003;23:1534-45 pubmed..These results indicate that integration of counteracting signals from the Gi- and the G12/13-Rho pathways directs either positive or negative regulation of Rac, and thus cell migration, upon activation of a single S1P receptor isoform. ..
- Hobson J, Rosenfeldt H, Barak L, Olivera A, Poulton S, Caron M, et al. Role of the sphingosine-1-phosphate receptor EDG-1 in PDGF-induced cell motility. Science. 2001;291:1800-3 pubmed..Our results reveal a role for receptor cross-communication in which activation of a GPCR by a receptor tyrosine kinase is critical for cell motility. ..
- Matloubian M, Lo C, Cinamon G, Lesneski M, Xu Y, Brinkmann V, et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature. 2004;427:355-60 pubmed..These findings establish that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs. ..
- Van Brocklyn J, Tu Z, Edsall L, Schmidt R, Spiegel S. Sphingosine 1-phosphate-induced cell rounding and neurite retraction are mediated by the G protein-coupled receptor H218. J Biol Chem. 1999;274:4626-32 pubmed..Moreover, the identification of these two additional SPP receptors indicates that a family of highly specific receptors exists that mediate different responses to SPP. ..
- Kluk M, Colmont C, Wu M, Hla T. Platelet-derived growth factor (PDGF)-induced chemotaxis does not require the G protein-coupled receptor S1P1 in murine embryonic fibroblasts and vascular smooth muscle cells. FEBS Lett. 2003;533:25-8 pubmed..These data question the generality of the concept that S1P1 GPCR is a critical downstream component of PDGF-induced chemotaxis. ..
- Molderings G, Bonisch H, Hammermann R, Gothert M, Bruss M. Noradrenaline release-inhibiting receptors on PC12 cells devoid of alpha(2(-)) and CB(1) receptors: similarities to presynaptic imidazoline and edg receptors. Neurochem Int. 2002;40:157-67 pubmed..Polymerase chain reaction (PCR) experiments on cDNA from PC12 mRNA suggest mRNA expression of lysophospholipid receptors encoded by the genes edg2, edg3, edg5 and edg7, but not of receptors encoded by edg1, edg4, edg6 and ..
- Ancellin N, Colmont C, Su J, Li Q, Mittereder N, Chae S, et al. Extracellular export of sphingosine kinase-1 enzyme. Sphingosine 1-phosphate generation and the induction of angiogenic vascular maturation. J Biol Chem. 2002;277:6667-75 pubmed..These findings suggest that S1P is made in the extracellular milieu and that extracellular export of SK contributes to the action of S1P in the vascular system. ..
- Cremers B, Flesch M, Kostenis E, Maack C, Niedernberg A, Stoff A, et al. Modulation of myocardial contractility by lysophosphatidic acid (LPA). J Mol Cell Cardiol. 2003;35:71-80 pubmed..This newly discovered action of LPA might be of pathophysiological importance in conditions like myocardial ischemia or inflammatory disorders when LPA release is enhanced. ..
- Lee M, Evans M, Hla T. The inducible G protein-coupled receptor edg-1 signals via the G(i)/mitogen-activated protein kinase pathway. J Biol Chem. 1996;271:11272-9 pubmed..These data suggest that the G(i)/mitogen-activated protein kinase pathway is a major signaling pathway regulated by the orphan receptor edg-1. ..
- Im D. Linking Chinese medicine and G-protein-coupled receptors. Trends Pharmacol Sci. 2003;24:2-4 pubmed..Two recent studies have elucidated that the mechanism of action of FTY720 is via a subset of G-protein-coupled receptors for the lysophospholipid mediator sphingosine-1-phosphate. ..
- Kono M, Mi Y, Liu Y, Sasaki T, Allende M, Wu Y, et al. The sphingosine-1-phosphate receptors S1P1, S1P2, and S1P3 function coordinately during embryonic angiogenesis. J Biol Chem. 2004;279:29367-73 pubmed..Our results indicate that the S1P(1), S1P(2) and S1P(3) receptors have redundant or cooperative functions for the development of a stable and mature vascular system during embryonic development. ..
- Paik J, Skoura A, Chae S, Cowan A, Han D, Proia R, et al. Sphingosine 1-phosphate receptor regulation of N-cadherin mediates vascular stabilization. Genes Dev. 2004;18:2392-403 pubmed..S1P-induced trafficking and activation of N-cadherin provides a novel mechanism for the stabilization of nascent blood vessels by mural cells and may be exploited to control angiogenesis and vascular diseases. ..
- Kohno T, Matsuyuki H, Inagaki Y, Igarashi Y. Sphingosine 1-phosphate promotes cell migration through the activation of Cdc42 in Edg-6/S1P4-expressing cells. Genes Cells. 2003;8:685-97 pubmed..This motility was mediated through the activation of a member of the Rho family of small GTPases, Cdc42. These results support a role for Sph-1-P signalling via Edg-6 in the pathways involved in cell motility. ..
- Kothapalli R, Kusmartseva I, Loughran T. Characterization of a human sphingosine-1-phosphate receptor gene (S1P5) and its differential expression in LGL leukemia. Biochim Biophys Acta. 2002;1579:117-23 pubmed..This gene is present in brain, spleen, and peripheral blood mononuclear cells (PBMC) and is overexpressed in leukemic LGL. ..
- Laychock S, Tian Y, Sessanna S. Endothelial differentiation gene receptors in pancreatic islets and INS-1 cells. Diabetes. 2003;52:1986-93 pubmed..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. ..
- Meyer zu Heringdorf D, Lass H, Kuchar I, Lipinski M, Alemany R, Rümenapp U, et al. Stimulation of intracellular sphingosine-1-phosphate production by G-protein-coupled sphingosine-1-phosphate receptors. Eur J Pharmacol. 2001;414:145-54 pubmed
- Liu C, Hla T. The mouse gene for the inducible G-protein-coupled receptor edg-1. Genomics. 1997;43:15-24 pubmed..However, the activity of the 5'-flanking region was suppressed by the repressor activity within the first intron. These data provide the basis for the further characterization of the regulation of the orphan GPR edg-1. ..
- Fallon K, Havlioglu N, Hamilton L, Cheng T, Carroll S. Constitutive activation of the neuregulin-1/erbB signaling pathway promotes the proliferation of a human peripheral neuroepithelioma cell line. J Neurooncol. 2004;66:273-84 pubmed
- Schoneberg T, Schulz A, Grosse R, Schade R, Henklein P, Schultz G, et al. A novel subgroup of class I G-protein-coupled receptors. Biochim Biophys Acta. 1999;1446:57-70 pubmed..Since none of the applied substances led to significant changes in second messenger levels (cAMP and inositol phosphates), the natural ligand and coupling profile of this novel GPCR subgroup remains unknown. ..
- Yamazaki Y, Kon J, Sato K, Tomura H, Sato M, Yoneya T, et al. Edg-6 as a putative sphingosine 1-phosphate receptor coupling to Ca(2+) signaling pathway. Biochem Biophys Res Commun. 2000;268:583-9 pubmed..We conclude that Edg-6 is one of S1P or lysosphingolipid receptors that couple to phospholipase C-Ca(2+) system through pertussis toxin-sensitive G-proteins. ..
- Sato K, Ui M, Okajima F. Differential roles of Edg-1 and Edg-5, sphingosine 1-phosphate receptors, in the signaling pathways in C6 glioma cells. Brain Res Mol Brain Res. 2000;85:151-60 pubmed..Taken together, these results suggest that Edg-1 may be the main receptor mediating the stimulation of ERK/Egr-1/FGF-2 system but that Edg-5 may be responsible for the stimulation of PLC-Ca(2+) system and PLD in native C6 glioma cells. ..
- Villullas I, Smith A, Heavens R, Simpson P. Characterisation of a sphingosine 1-phosphate-activated Ca2+ signalling pathway in human neuroblastoma cells. J Neurosci Res. 2003;73:215-26 pubmed..Despite its slow time course of response, S1P appears to activate the same single Ca(2+) store in SH-SY5Y cells as is activated by methacholine and other G protein coupled receptors. ..
- Gunn M, Kelsoe G. Should we B-leavin' now?. Nat Immunol. 2004;5:703-4 pubmed
- Duong C, Bared S, Abu Khader A, Buechler C, Schmitz A, Schmitz G. Expression of the lysophospholipid receptor family and investigation of lysophospholipid-mediated responses in human macrophages. Biochim Biophys Acta. 2004;1682:112-9 pubmed..Altogether, these data give insights into the expression and regulation of lysophospholipid receptors in primary human monocytes, macrophages and foam cells.
- Katsuma S, Hada Y, Ueda T, Shiojima S, Hirasawa A, Tanoue A, et al. Signalling mechanisms in sphingosine 1-phosphate-promoted mesangial cell proliferation. Genes Cells. 2002;7:1217-30 pubmed..S1P may cooperate with PDGF to increase the proliferation of mesangial cells during pathophysiological processes. ..
- Fueller M, Wang D, Tigyi G, Siess W. Activation of human monocytic cells by lysophosphatidic acid and sphingosine-1-phosphate. Cell Signal. 2003;15:367-75 pubmed..Our study is the first report showing the receptor-mediated activation of human monocytic cells by low nanomolar concentrations of LPA and S1P, and suggests a role of these lipid mediators in inflammation and atherogenesis. ..
- Makide K, Kitamura H, Sato Y, Okutani M, Aoki J. Emerging lysophospholipid mediators, lysophosphatidylserine, lysophosphatidylthreonine, lysophosphatidylethanolamine and lysophosphatidylglycerol. Prostaglandins Other Lipid Mediat. 2009;89:135-9 pubmed publisher..In this review, we summarize the actions of these LPLs as lipid mediators including LPS, LPT, LPE and LPG. ..
- Ikeda H, Yatomi Y, Yanase M, Satoh H, Maekawa H, Ogata I, et al. Biological activities of novel lipid mediator sphingosine 1-phosphate in rat hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2000;279:G304-10 pubmed..Considering that HSCs are capable of production of extracellular matrices and modulation of blood flow in sinusoids, our results suggest that S-1-P may play a role in wound healing process in the liver...
- Kohno T, Igarashi Y. [N-glycosylation of sphingosine 1-phosphate receptor, Edg-1, and its role on receptor internalization through membrane microdomain]. Tanpakushitsu Kakusan Koso. 2002;47:503-8 pubmed
- Igarashi Y. [Current studies on a novel lipid mediator, sphingosine 1-phosphate, and its receptors]. Tanpakushitsu Kakusan Koso. 2002;47:476-9 pubmed
- Brinkmann V, Davis M, Heise C, Albert R, Cottens S, Hof R, et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem. 2002;277:21453-7 pubmed..Our results suggest that FTY720, after phosphorylation, acts through sphingosine 1-phosphate signaling pathways to modulate chemotactic responses and lymphocyte trafficking. ..
- Kimura T, Sato K, Malchinkhuu E, Tomura H, Tamama K, Kuwabara A, et al. High-density lipoprotein stimulates endothelial cell migration and survival through sphingosine 1-phosphate and its receptors. Arterioscler Thromb Vasc Biol. 2003;23:1283-8 pubmed..HDL-induced endothelial cell migration and survival may be mediated by the lipoprotein component S1P and the lipid receptors S1P1 and S1P3. ..
- Muraki K, Itoh T, Imaizumi Y. [Effects of sphingosine-1-phosphate, a lipid mediator, in cardiovascular tissues]. Nihon Yakurigaku Zasshi. 2002;120:101P-103P pubmed..These results suggest that responses of vascular tissues to S1P vary from cell to cell. To clarify physiological and pharmacological significance of S1P in cardiovascular system, comprehensive analyses are required. ..
- Clemens J, Davis M, Lynch K, Macdonald T. Synthesis of para-alkyl aryl amide analogues of sphingosine-1-phosphate: discovery of potent S1P receptor agonists. Bioorg Med Chem Lett. 2003;13:3401-4 pubmed..We also report the effects associated with introduction of a phenyl ring between the 'linker' and 'lipophilic tail' regions of the analogues, for example total loss of activity at S1P(2) and increased agonism at S1P(5). ..
- Sugimoto N, Takuwa N, Takuwa Y. [Molecular mechanisms of sphingosine-1-phosphate receptor S1P2/Edg5-mediated inhibition of Rac and cell migration]. Seikagaku. 2003;75:597-600 pubmed
- An S, Goetzl E, Lee H. Signaling mechanisms and molecular characteristics of G protein-coupled receptors for lysophosphatidic acid and sphingosine 1-phosphate. J Cell Biochem Suppl. 1998;30-31:147-57 pubmed..This review summarizes our current understanding of signaling pathways critical for cellular responses to LPA and S1P and of recent progress in the molecular biological analyses of the Edg receptors. ..
- Graeler M, Goetzl E. Activation-regulated expression and chemotactic function of sphingosine 1-phosphate receptors in mouse splenic T cells. FASEB J. 2002;16:1874-8 pubmed..S1P may be a distinctive contributor to compartmental immunity by attracting naïve and memory T cells preferentially over activated effector T cells. ..
- Parrill A. Lysophospholipid interactions with protein targets. Biochim Biophys Acta. 2008;1781:540-6 pubmed publisher..The direct structural characterization studies are the focus of this review, and provide the insight necessary to stimulate structure-based therapeutic lead discovery efforts in the future. ..
- Im D, Ungar A, Lynch K. Characterization of a zebrafish (Danio rerio) sphingosine 1-phosphate receptor expressed in the embryonic brain. Biochem Biophys Res Commun. 2000;279:139-43 pubmed..Our findings suggest that nonmammalian vertebrates use S1P to signal during embryogenesis and that the properties of Edg1 receptor have been conserved for 400 million years. ..
- Hla T, Lee M, Ancellin N, Thangada S, Liu C, Kluk M, et al. Sphingosine-1-phosphate signaling via the EDG-1 family of G-protein-coupled receptors. Ann N Y Acad Sci. 2000;905:16-24 pubmed..Thus SPP signaling as an extracellular mediator via the EDG-1 family of GPCRs may be a heretofore unrecognized mechanism for the regulation of angiogenesis and vascular endothelial cell function. ..
- Koh E, Bandle R, Clair T, Roberts D, Stracke M. Trichostatin A and 5-aza-2'-deoxycytidine switch S1P from an inhibitor to a stimulator of motility through epigenetic regulation of S1P receptors. Cancer Lett. 2007;250:53-62 pubmed..S1P receptors, therefore, appear to be susceptible to epigenetic regulation, accompanied by altered cellular functionality. ..
- Niedernberg A, Scherer C, Busch A, Kostenis E. Comparative analysis of human and rat S1P(5) (edg8): differential expression profiles and sensitivities to antagonists. Biochem Pharmacol. 2002;64:1243-50 pubmed..Taken together, our data imply that differences between hS1P(5) and rS1P(5) will be an important point to be considered in the development of selective receptor antagonists. ..
- MacLennan A, Carney P, Zhu W, Chaves A, Garcia J, Grimes J, et al. An essential role for the H218/AGR16/Edg-5/LP(B2) sphingosine 1-phosphate receptor in neuronal excitability. Eur J Neurosci. 2001;14:203-9 pubmed..Therefore, H218 plays an essential, unanticipated and functionally important role in the proper development and/or mediation of neuronal excitability. ..
- Igarashi J, Erwin P, Dantas A, Chen H, Michel T. VEGF induces S1P1 receptors in endothelial cells: Implications for cross-talk between sphingolipid and growth factor receptors. Proc Natl Acad Sci U S A. 2003;100:10664-9 pubmed
- Sawicka E, Zuany Amorim C, Manlius C, Trifilieff A, Brinkmann V, Kemeny D, et al. Inhibition of Th1- and Th2-mediated airway inflammation by the sphingosine 1-phosphate receptor agonist FTY720. J Immunol. 2003;171:6206-14 pubmed
- Kimura T, Watanabe T, Sato K, Kon J, Tomura H, Tamama K, et al. Sphingosine 1-phosphate stimulates proliferation and migration of human endothelial cells possibly through the lipid receptors, Edg-1 and Edg-3. Biochem J. 2000;348 Pt 1:71-6 pubmed
- Watterson K, Sankala H, Milstien S, Spiegel S. Pleiotropic actions of sphingosine-1-phosphate. Prog Lipid Res. 2003;42:344-57 pubmed..Recent studies demonstrate that intracellular generated SIP can act in a paracrine or autocrine manner to activate its cell surface receptors. ..
- Forrest M, Sun S, Hajdu R, Bergstrom J, Card D, Doherty G, et al. Immune cell regulation and cardiovascular effects of sphingosine 1-phosphate receptor agonists in rodents are mediated via distinct receptor subtypes. J Pharmacol Exp Ther. 2004;309:758-68 pubmed
- Igarashi J, Michel T. Agonist-modulated targeting of the EDG-1 receptor to plasmalemmal caveolae. eNOS activation by sphingosine 1-phosphate and the role of caveolin-1 in sphingolipid signal transduction. J Biol Chem. 2000;275:32363-70 pubmed..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. ..