Sphingosine 1-Phosphate-induced Cell Proliferation, Survival, and Related Signaling Events Mediated by G Protein-coupled Receptors Edg3 and Edg5

An, Songzhu; Zheng, Yongri; Bleu, Thieu

doi:10.1074/jbc.275.1.288

Cited by 183 publications

(133 citation statements)

References 58 publications

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“…Besides S1P, dihydro-S1P, which is also a potent agonist for EDG5 (71), inhibited IGF I-induced chemotaxis with a potency similar to that of S1P (Table 1). SPC, a weaker agonist for EDG5 (4,20,52,75), inhibited IGF I-induced chemotaxis with less potency than S1P and dihydro-S1P. Sphingosine, which does not serve as an agonist for EDG5 (8,20,71), was essentially ineffective at the doses employed.…”

Section: Resultsmentioning

confidence: 95%

“…EDG3 is coupled via Gi to Ras-MAPK activation and adenylate cyclase inhibition and also to phospholipase C activation largely via Gq/11 (4,8,34,51,75). EDG5 is coupled to Ras-MAPK activation, to phospholipase C activation, and to adenylate cyclase stimulation via Gi, Gq/11, and Gs, respectively (4,8,20,34,51,71,75). In addition, EDG3 and EDG5, but not EDG1, mediate S1P-induced stress fiber formation (20,40).…”

mentioning

confidence: 99%

“…EDG1 is coupled exclusively via the heterotrimeric Gi protein to multiple signaling pathways including phospholipase C activation, Ca 2ϩ mobilization, Ras-mitogen activated protein kinase (MAPK)-extracellular signal-regulated protein kinase (ERK) activation, and inhibition of adenylate cyclase (8,34,39,51,52,70,75). EDG3 is coupled via Gi to Ras-MAPK activation and adenylate cyclase inhibition and also to phospholipase C activation largely via Gq/11 (4,8,34,51,75). EDG5 is coupled to Ras-MAPK activation, to phospholipase C activation, and to adenylate cyclase stimulation via Gi, Gq/11, and Gs, respectively (4,8,20,34,51,71,75).…”

mentioning

confidence: 99%

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Inhibitory Regulation of Rac Activation, Membrane Ruffling, and Cell Migration by the G Protein-Coupled Sphingosine-1-Phosphate Receptor EDG5 but Not EDG1 or EDG3

Okamoto

Takuwa

Yokomizo

et al. 2000

Molecular and Cellular Biology

306

302

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Sphingosine-1-phosphate (S1P) is a bioactive lysophospholipid that induces a variety of biological responses in diverse cell types. Many, if not all, of these responses are mediated by members of the EDG (endothelial differentiation gene) family G protein-coupled receptors EDG1, EDG3, and EDG5 (AGR16). Among prominent activities of S1P is the regulation of cell motility; S1P stimulates or inhibits cell motility depending on cell types. In the present study, we provide evidence for EDG subtype-specific, contrasting regulation of cell motility and cellular Rac activity. In CHO cells expressing EDG1 or EDG3 (EDG1 cells or EDG3 cells, respectively) S1P as well as insulin-like growth factor I (IGF I) induced chemotaxis and membrane ruffling in phosphoinositide (PI) 3-kinase-and Rac-dependent manners. Both S1P and IGF I induced a biphasic increase in the amount of the GTP-bound active form of Rac. In CHO cells expressing EDG5 (EDG5 cells), IGF I similarly stimulated cell migration; however, in contrast to what was found for EDG1 and EDG3 cells, S1P did not stimulate migration but totally abolished IGF I-directed chemotaxis and membrane ruffling, in a manner dependent on a concentration gradient of S1P. In EDG5 cells, S1P stimulated PI 3-kinase activity as it did in EDG1 cells but inhibited the basal Rac activity and totally abolished IGF I-induced Rac activation, which involved stimulation of Rac-GTPase-activating protein activity rather than inhibition of Rac-guanine nucleotide exchange activity. S1P induced comparable increases in the amounts of GTP-RhoA in EDG3 and EDG5 cells. Neither S1P nor IGF I increased the amount of GTP-bound Cdc42. However, expression of N 17 -Cdc42, but not N 19 -RhoA, suppressed S1P-and IGF I-directed chemotaxis, suggesting a requirement for basal Cdc42 activity for chemotaxis. Taken together, the present results demonstrate that EDG5 is the first example of a hitherto-unrecognized type of receptors that negatively regulate Rac activity, thereby inhibiting cell migration and membrane ruffling.

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Section: Resultsmentioning

confidence: 95%

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confidence: 99%

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confidence: 99%

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Inhibitory Regulation of Rac Activation, Membrane Ruffling, and Cell Migration by the G Protein-Coupled Sphingosine-1-Phosphate Receptor EDG5 but Not EDG1 or EDG3

Okamoto

Takuwa

Yokomizo

et al. 2000

Molecular and Cellular Biology

306

302

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“…S1P has been shown to act both intracellularly as a second messenger and extracellularly through binding to GPCR (8,(42)(43)(44)(45). Indeed, in human fibroblasts, it has been shown that endogenous sphingolipid metabolites are involved as coregulators of the TGF-␤-induced signaling cascade (46).…”

Section: Figmentioning

confidence: 99%

Involvement of Smad Signaling in Sphingosine 1-Phosphate-mediated Biological Responses of Keratinocytes

Sauer

Vogler

Wenckstern

et al. 2004

Journal of Biological Chemistry

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The lysophospholipid sphingosine 1-phosphate and the cytokine-transforming growth factor ␤ are both released from degranulating platelets at wound sites, suggesting a broad spectrum of effects involved in wound healing. Interestingly, both of these molecules have been previously shown to induce chemotaxis but to strongly inhibit the growth of keratinocytes, while stimulating the proliferation of fibroblasts. In contrast to sphingosine 1-phosphate, the signaling cascade of the growth factor has been extensively examined. Specifically, Smad3 has been shown to be an essential mediator of transforming growth factor ␤-dependent chemotaxis of keratinocytes and mediates, in part, its growth-inhibitory effect. Here we show that sphingosine 1-phosphate, independently of transforming growth factor ␤ secretion, induces a rapid phosphorylation of Smad3 on its C-terminal serine motif and induces its partnering with Smad4 and the translocation of the complex into the nucleus. Moreover, sphingosine 1-phosphate fails to induce chemotaxis or inhibit the growth of Smad3-deficient keratinocytes, suggesting that Smad3 plays an unexpected functional role as a new target in sphingosine 1-phosphate signaling. Both sphingosine 1-phosphate receptors and the transforming growth factor ␤-type I receptor serine/threonine kinase are essential for activation of Smad3 by this lysophospholipid and the dependent biological responses, indicating a novel crosstalk between serine/threonine kinase receptors and G-protein coupled receptors.

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“…S1P 1 , which is highly expressed in EC, couples almost exclusively to G i and stimulates cell growth through activation of Ras/mitogen-activated protein kinase, cell survival through AKT, and cell migration through activation of Rac1 (21,22,24,30,31). In contrast, S1P 2 , which is expressed highly in adult medial SMC, couples only weakly to G i but strongly activates the small GTPase, RhoA, by coupling to G12 ⁄13 (18,32,33). Activation of RhoA in SMC leads to increased actin polymerization and cellular contractility and can promote or inhibit SMC migration depending upon the model system studied (34,35).…”

mentioning

confidence: 99%

Sphingosine 1-Phosphate Stimulates Smooth Muscle Cell Differentiation and Proliferation by Activating Separate Serum Response Factor Co-factors

Lockman

Hinson

Medlin

et al. 2004

Journal of Biological Chemistry

145

162

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Sphingosine 1-phosphate (S1P) is a lipid agonist that regulates smooth muscle cell (SMC) and endothelial cell functions by activating several members of the S1P subfamily of G-protein-coupled Edg receptors. We have shown previously that SMC differentiation is regulated by RhoA-dependent activation of serum response factor (SRF). Because S1P is a strong activator of RhoA, we hypothesized that S1P would stimulate SMC differentiation. Treatment of primary rat aortic SMC cells with S1P activated RhoA as measured by precipitation with a glutathione S-transferase-rhotekin fusion protein. In SMC and 10T1 ⁄2 cells, S1P treatment up-regulated the activities of several transiently transfected SMC-specific promoters, and these effects were inhibited by the Rho-kinase inhibitor, Y-27632. S1P also increased smooth muscle ␣-actin protein levels in SMC but had no effect on SRF binding to the smooth muscle ␣-actin CArG B element. Quantitative reverse transcriptase-PCR showed that S1P treatment of SMC or 10T1 ⁄2 cells did not increase the mRNA level of either of the recently identified SRF co-factors, myocardin or myocardin-related transcription factor-A (MRTF-A). MRTF-A protein was expressed highly in SMC and 10T1 ⁄2 cultures, and importantly the effects of S1P were inhibited by a dominant negative form of MRTF-A indicating that S1P may regulate the transcriptional activity of MRTF-A. Indeed, S1P treatment increased the nuclear localization of FLAG-MRTF-A, and the effect of MRTF-A overexpression on smooth muscle ␣-actin promoter activity was inhibited by dominant negative RhoA. S1P also stimulated SMC growth by activating the early growth response gene, c-fos. This effect was not attenuated by Y-27632 but could be inhibited by the MEK inhibitor, UO126. S1P enhanced SMC growth through ERK-mediated phosphorylation of the SRF cofactor, Elk-1, as measured by gel shift and Elk-1 activation assays. Taken together these results demonstrate that S1P activates multiple signaling pathways in SMC and regulates proliferation by ERK-dependent activation of Elk-1 and differentiation by RhoA-dependent activation of MRTF-A.

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Sphingosine 1-Phosphate-induced Cell Proliferation, Survival, and Related Signaling Events Mediated by G Protein-coupled Receptors Edg3 and Edg5

Cited by 183 publications

References 58 publications

Inhibitory Regulation of Rac Activation, Membrane Ruffling, and Cell Migration by the G Protein-Coupled Sphingosine-1-Phosphate Receptor EDG5 but Not EDG1 or EDG3

Inhibitory Regulation of Rac Activation, Membrane Ruffling, and Cell Migration by the G Protein-Coupled Sphingosine-1-Phosphate Receptor EDG5 but Not EDG1 or EDG3

Involvement of Smad Signaling in Sphingosine 1-Phosphate-mediated Biological Responses of Keratinocytes

Sphingosine 1-Phosphate Stimulates Smooth Muscle Cell Differentiation and Proliferation by Activating Separate Serum Response Factor Co-factors

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